New Drug Approvals

Home » Posts tagged 'FDA 2022'

Tag Archives: FDA 2022

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 4,123,848 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,772 other subscribers
Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,772 other subscribers
DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Mirvetuximab soravtansine-gynx


STR1

Mirvetuximab soravtansine-gynx

FDA 11/14/2022,To treat patients with recurrent ovarian cancer that is resistant to platinum therapy

Elahere

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

https://www.biochempeg.com/article/315.html

4846-85a8-48171ab38275

FDA Approves Mirvetuximab Soravtansine-gynx for FRα+ Platinum-resistant Ovarian Cancer

November 15, 2022

Kristi Rosa

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of select patients with folate receptor α–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The FDA has granted accelerated approval to mirvetuximab soravtansine-gynx (Elahere) for the treatment of adult patients with folate receptor α (Frα)–positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received 1 to 3 prior systemic treatment regimens.1-3

The regulatory agency also gave the green light to the VENTANA FOLR1 (FOLR-2.1) RxDx Assay for use as a companion diagnostic device to identify patients who are eligible to receive the agent. Testing can be done on fresh or archived tissue. Newly diagnosed patients can be tested at diagnosis to determine whether this agent will be an option for them at the time of progression to platinum resistance.

The decision was supported by findings from the phase 3 SORAYA trial (NCT04296890), in which mirvetuximab soravtansine elicited a confirmed investigator-assessed objective response rate (ORR) of 31.7% (95% CI, 22.9%-41.6%); this included a complete response rate of 4.8% and a partial response rate of 26.9%. Moreover, the median duration of response (DOR) was 6.9 months (95% CI, 5.6-9.7) per investigator assessment.

“The approval of Elahere is significant for patients with FRα-positive platinum-resistant ovarian cancer, which is characterized by limited treatment options and poor outcomes,” Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute, professor of medicine at the Harvard Medical School, and SORAYA co-principal investigator, stated in a press release. “Elahere impressive anti-tumor activity, durability of response, and overall tolerability observed in SORAYA demonstrate the benefit of this new therapeutic option, and I look forward to treating patients with Elahere.”

The global, single-arm SORAYA trial enrolled a total of 106 patients with platinum-resistant ovarian cancer whose tumors expressed high levels of FRα. Patients were allowed to have received up to 3 prior lines of systemic treatment, and all were required to have received bevacizumab (Avastin).

If patients had corneal disorders, ocular conditions in need of ongoing treatment, peripheral neuropathy that was greater than grade 1 in severity, or noninfectious interstitial lung disease, they were excluded.

Study participants received intravenous mirvetuximab soravtansine at 6 mg/kg once every 3 weeks until progressive disease or unacceptable toxicity. Investigators conducted tumor response assessments every 6 weeks for the first 36 weeks, and every 12 weeks thereafter.

Confirmed investigator-assessed ORR served as the primary end point for the research, and the key secondary end point was DOR by RECIST v1.1 criteria.

In the efficacy-evaluable population (n = 104), the median age was 62 years (range, 35-85). Ninety-six percent of patients were White, 2% were Asian, and 2% did not have their race information reported; 2% of patients were Hispanic or Latino. Regarding ECOG performance status, 57% of patients had a status of 0 and the remaining 43% had a status of 1.

Ten percent of patients received 1 prior line of systemic treatment, 39% received 2 prior lines, and 50% received 3 or more prior lines. All patients previously received bevacizumab, as required, and 47% previously received a PARP inhibitor.

The safety of mirvetuximab soravtansine was evaluated in all 106 patients. The median duration of treatment with the agent was 4.2 months (range, 0.7-13.3).

The all-grade toxicities most commonly experienced with mirvetuximab soravtansine included vision impairment (50%), fatigue (49%), increased aspartate aminotransferase (50%), nausea (40%), increased alanine aminotransferase (39%), keratopathy (37%), abdominal pain (36%), decreased lymphocytes (35%), peripheral neuropathy (33%), diarrhea (31%), decreased albumin (31%), constipation (30%), increased alkaline phosphatase (30%), dry eye (27%), decreased magnesium (27%), decreased leukocytes (26%), decreased neutrophils (26%), and decreased hemoglobin (25%).

Thirty-one percent of patients experienced serious adverse reactions with the agent, which included intestinal obstruction (8%), ascites (4%), infection (3%), and pleural effusion (3%). Toxicities proved to be fatalfor 2% of patients, and these included small intestinal obstruction (1%) and pneumonitis (1%).

Twenty percent of patients required dose reductions due to toxicities. Eleven percent of patients discontinued treatment with mirvetuximab soravtansine because of adverse reactions. Toxicities that resulted in more than 2% of patients discontinuing treatment included intestinal obstruction (2%) and thrombocytopenia (2%). One patient discontinued because of visual impairment.

References

  1. ImmunoGen announces FDA accelered approval of Elahere (mirvetuximab soravtansine-gynx) for the treatment of platinum-resistant ovarian cancer. News release. ImmunoGen Inc. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3GgrCwL
  2. FDA grants accelerated approval to mirvetuximab soravtansine-gynx for FRα positive, platinum-resistant epithelial ovarian, fallopian tube, or peritoneal cancer. News release. FDA. November 14, 2022. Accessed November 14, 2022. http://bit.ly/3UP742w
  3. Elahere (mirvetuximab soravtansine-gynx). Prescribing information; ImmunoGen Inc; 2022. Accessed November 14, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761310s000lbl.pdf
wdt-2

NEW DRUG APPROVALS

ONE TIME

$10.00

////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

//////////Mirvetuximab soravtansine-gynx, FDA 2022, APPROVALS 2022,  recurrent ovarian cancer, 

Elahere

Tremelimumab


(Light chain)
DIQMTQSPSS LSASVGDRVT ITCRASQSIN SYLDWYQQKP GKAPKLLIYA ASSLQSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YYSTPFTFGP GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Heavy chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV IWYDGSNKYY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDP RGATLYYYYY GMDVWGQGTT
VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSN FGTQTYTCNV DHKPSNTKVD KTVERKCCVE CPPCPAPPVA
GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVQFN WYVDGVEVHN AKTKPREEQF
NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTI SKTKGQPREP QVYTLPPSRE
EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP MLDSDGSFFL YSKLTVDKSR
WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K
(Disulfide bridge: L23-L88, L134-L194, L214-H139, H22-H96, H152-H208, H265-H325, H371-H429, H227-H’227, H228-H’228, H231-H’231, H234-H’234)

Tremelimumab 5GGV.png

Fab fragment of tremelimumab (blue) binding CTLA-4 (green). From PDB entry 5GGV.

Tremelimumab

FormulaC6500H9974N1726O2026S52
CAS745013-59-6
Mol weight146380.4722

FDA APPROVED2022/10/21, Imjudo

PEPTIDE, CP 675206

Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody
  DiseaseHepatocellular carcinoma

Tremelimumab (formerly ticilimumabCP-675,206) is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer,[1] it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca.[2] It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Imjudo (tremelimumab) in combination with Imfinzi approved in the US for patients with unresectable liver cancer

PUBLISHED24 October 2022

https://www.astrazeneca.com/media-centre/press-releases/2022/imfinzi-and-imjudo-approved-in-advanced-liver-cancer.html

24 October 2022 07:00 BST
 

Approval based on HIMALAYA Phase III trial results which showed single priming dose of Imjudo added to Imfinzi reduced risk of death by 22% vs. sorafenib
 

AstraZeneca’s Imjudo (tremelimumab) in combination with Imfinzi (durvalumab) has been approved in the US for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. The novel dose and schedule of the combination, which includes a single dose of the anti-CTLA-4 antibody Imjudo 300mg added to the anti-PD-L1 antibody Imfinzi 1500mg followed by Imfinzi every four weeks, is called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab).

The approval by the US Food and Drug Administration (FDA) was based on positive results from the HIMALAYA Phase III trial. In this trial, patients treated with the combination of Imjudo and Imfinzi experienced a 22% reduction in the risk of death versus sorafenib (based on a hazard ratio [HR] of 0.78, 95% confidence interval [CI] 0.66-0.92 p=0.0035).1 Results were also published in the New England Journal of Medicine Evidence showing that an estimated 31% of patients treated with the combination were still alive after three years, with 20% of patients treated with sorafenib still alive at the same duration of follow-up.2

Liver cancer is the third-leading cause of cancer death and the sixth most commonly diagnosed cancer worldwide.3,4 It is the fastest rising cause of cancer-related deaths in the US, with approximately 36,000 new diagnoses each year.5,6

Ghassan Abou-Alfa, MD, MBA, Attending Physician at Memorial Sloan Kettering Cancer Center (MSK), and principal investigator in the HIMALAYA Phase III trial, said: “Patients with unresectable liver cancer are in need of well-tolerated treatments that can meaningfully extend overall survival. In addition to this regimen demonstrating a favourable three-year survival rate in the HIMALAYA trial, safety data showed no increase in severe liver toxicity or bleeding risk for the combination, important factors for patients with liver cancer who also have advanced liver disease.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “With this first regulatory approval for Imjudo, patients with unresectable liver cancer in the US now have an approved dual immunotherapy treatment regimen that harnesses the potential of CTLA-4 inhibition in a unique combination with a PD-L1 inhibitor to enhance the immune response against their cancer.”

Andrea Wilson Woods, President & Founder, Blue Faery: The Adrienne Wilson Liver Cancer Foundation, said: “In the past, patients living with liver cancer had few treatment options and faced poor prognoses. With today’s approval, we are grateful and optimistic for new, innovative, therapeutic options. These new treatments can improve long-term survival for those living with unresectable hepatocellular carcinoma, the most common form of liver cancer. We appreciate the patients, their families, and the broader liver cancer community who continue to fight for new treatments and advocate for others.”

The safety profiles of the combination of Imjudo added to Imfinzi and for Imfinzi alone were consistent with the known profiles of each medicine, and no new safety signals were identified.

Regulatory applications for Imjudo in combination with Imfinzi are currently under review in Europe, Japan and several other countries for the treatment of patients with advanced liver cancer based on the HIMALAYA results.

Notes

Liver cancer
About 75% of all primary liver cancers in adults are HCC.3 Between 80-90% of all patients with HCC also have cirrhosis.Chronic liver diseases are associated with inflammation that over time can lead to the development of HCC.7

More than half of patients are diagnosed at advanced stages of the disease, often when symptoms first appear.8 A critical unmet need exists for patients with HCC who face limited treatment options.8 The unique immune environment of liver cancer provides clear rationale for investigating medications that harness the power of the immune system to treat HCC.8

HIMALAYA
HIMALAYA was a randomised, open-label, multicentre, global Phase III trial of Imfinzi monotherapy and a regimen comprising a single priming dose of Imjudo 300mg added to Imfinzi 1500mg followed by Imfinzi every four weeks versus sorafenib, a standard-of-care multi-kinase inhibitor.

The trial included a total of 1,324 patients with unresectable, advanced HCC who had not been treated with prior systemic therapy and were not eligible for locoregional therapy (treatment localised to the liver and surrounding tissue).

The trial was conducted in 181 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. The primary endpoint was overall survival (OS) for the combination versus sorafenib and key secondary endpoints included OS for Imfinzi versus sorafenib, objective response rate and progression-free survival (PFS) for the combination and for Imfinzi alone.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi was recently approved to treat patients with advanced biliary tract cancer in the US based on results from the TOPAZ-1 Phase III trial. It is the only approved immunotherapy in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiotherapy and is the global standard of care in this setting based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial. In 2021, updated results from the CASPIAN trial showed Imfinzi plus chemotherapy tripled patient survival at three years versus chemotherapy alone.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.

Since the first approval in May 2017, more than 100,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal (GI) cancers, ovarian cancer, endometrial cancer, and other solid tumours.

Imfinzi combinations have also demonstrated clinical benefit in metastatic NSCLC in the POSEIDON Phase III trial.

Imjudo
Imjudo (tremelimumab) is a human monoclonal antibody that targets the activity of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Imjudo blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death.

Beyond HIMALAYA, Imjudo is being tested in combination with Imfinzi across multiple tumour types including locoregional HCC (EMERALD-3), SCLC (ADRIATIC) and bladder cancer (VOLGA and NILE).

Imjudo is also under review by global regulatory authorities in combination with Imfinzi and chemotherapy in 1st-line metastatic NSCLC based on the results of the POSEIDON Phase III trial, which showed the addition of a short course of Imjudo to Imfinzi plus chemotherapy improved both overall and progression-free survival compared to chemotherapy alone.

AstraZeneca in GI cancers
AstraZeneca has a broad development programme for the treatment of GI cancers across several medicines spanning a variety of tumour types and stages of disease. In 2020, GI cancers collectively represented approximately 5.1 million new diagnoses leading to approximately 3.6 million deaths.9

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic, and colorectal cancers.

Imfinzi (durvalumab) is being assessed in combinations in oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

The Company aims to understand the potential of Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, in the two most common GI cancers, colorectal and gastric cancers. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

Lynparza (olaparib) is a first-in-class PARP inhibitor with a broad and advanced clinical trial programme across multiple GI tumour types including pancreatic and colorectal cancers. Lynparza is developed and commercialised in collaboration with MSD (Merck & Co., Inc. inside the US and Canada).

AstraZeneca in immuno-oncology (IO)
Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. The Company’s immuno-oncology (IO) portfolio is anchored in immunotherapies that have been designed to overcome evasion of the anti-tumour immune response. AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.

The Company is pursuing a comprehensive clinical trial programme that includes Imfinzi as a single treatment and in combination with Imjudo (tremelimumab) and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.

In addition, the ability to combine the IO portfolio with radiation, chemotherapy, and targeted small molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Mechanism of action

Tremelimumab aims to stimulate an immune system attack on tumors. Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism (immune checkpoint) that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.[3] This is immune checkpoint blockade.

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.

Unlike Ipilimumab (another fully human anti-CTLA-4 monoclonal antibody), which is an IgG1 isotype, tremelimumab is an IgG2 isotype.[4][5]

Clinical trials

Melanoma

Phase 1 and 2 clinical studies in metastatic melanoma showed some responses.[6] However, based on early interim analysis of phase III data, Pfizer designated tremelimumab as a failure and terminated the trial in April 2008.[1][7]

However, within a year, the survival curves showed separation of the treatment and control groups.[8] The conventional Response Evaluation Criteria in Solid Tumors (RECIST) may underrepresent the merits of immunotherapies. Subsequent immunotherapy trials (e.g. ipilimumab) have used the Immune-Related Response Criteria (irRC) instead.

Mesothelioma

Although it was designated in April 2015 as orphan drug status in mesothelioma,[9] tremelimumab failed to improve lifespan in the phase IIb DETERMINE trial, which assessed the drug as a second or third-line treatment for unresectable malignant mesothelioma.[10][11]

Non-small cell lung cancer

In a phase III trial, AstraZeneca paired tremelimumab with a PD-L1 inhibitor, durvalumab, for the first-line treatment of non-small cell lung cancer.[12] The trial was conducted across 17 countries, and in July 2017, AstraZeneca announced that it had failed to meet its primary endpoint of progression-free survival.[13]

References

  1. Jump up to:a b “Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma”. Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
  2. ^ Mechanism of Pathway: CTLA-4 Inhibition[permanent dead link]
  3. ^ Antoni Ribas (28 June 2012). “Tumor immunotherapy directed at PD-1”. New England Journal of Medicine366 (26): 2517–9. doi:10.1056/nejme1205943PMID 22658126.
  4. ^ Tomillero A, Moral MA (October 2008). “Gateways to clinical trials”. Methods Find Exp Clin Pharmacol30 (8): 643–72. doi:10.1358/mf.2008.30.5.1236622PMID 19088949.
  5. ^ Poust J (December 2008). “Targeting metastatic melanoma”. Am J Health Syst Pharm65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461PMID 19052265.
  6. ^ Reuben, JM; et al. (1 Jun 2006). “Biologic and immunomodulatory events after CTLA-4 blockade with tremelimumab in patients with advanced malignant melanoma”Cancer106 (11): 2437–44. doi:10.1002/cncr.21854PMID 16615096S2CID 751366.
  7. ^ A. Ribas, A. Hauschild, R. Kefford, C. J. Punt, J. B. Haanen, M. Marmol, C. Garbe, J. Gomez-Navarro, D. Pavlov and M. Marsha (May 20, 2008). “Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma”Journal of Clinical Oncology26 (15S): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011.[permanent dead link]
  8. ^ M.A. Marshall, A. Ribas, B. Huang (May 2010). “Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma”Journal of Clinical Oncology28 (15S): 2609. doi:10.1200/jco.2010.28.15_suppl.2609.[permanent dead link]
  9. ^ FDA Grants AstraZeneca’s Tremelimumab Orphan Drug Status for Mesothelioma [1]
  10. ^ “Tremelimumab Fails Mesothelioma Drug Trial”. Archived from the original on 2016-03-06. Retrieved 2016-03-06.
  11. ^ AZ’ tremelimumab fails in mesothelioma trial
  12. ^ “AstraZeneca’s immuno-oncology combo fails crucial Mystic trial in lung cancer | FierceBiotech”.
  13. ^ “AstraZeneca reports initial results from the ongoing MYSTIC trial in Stage IV lung cancer”.

///////////Tremelimumab, Imjudo, APPROVALS 2022, FDA 2022, PEPTIDE, CP 675206, Antineoplastic, Immune checkpoint inhibitor, Anti-CTLA4 antibody

wdt-4

NEW DRUG APPROVALS

ONE TIME

$10.00

Futibatinib


Futibatinib (JAN/USAN/INN).png
img

Futibatinib

フチバチニブ

FormulaC22H22N6O3
CAS1448169-71-8
Mol weight418.4485

2022/9/30 FDA APPROVED, Lytgobi

Antineoplastic, Receptor tyrosine kinase inhibitor
  DiseaseCholangiocarcinoma (FGFR2 gene fusion)

1-[(3S)-3-[4-amino-3-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinyl]-2-propen-1-one

TAS-120, TAS 120, TAS120; Futibatinib

Futibatinib, also known as TAS-120 is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. FGFR inhibitor TAS-120 selectively and irreversibly binds to and inhibits FGFR, which may result in the inhibition of both the FGFR-mediated signal transduction pathway and tumor cell proliferation, and increased cell death in FGFR-overexpressing tumor cells. FGFR is a receptor tyrosine kinase essential to tumor cell proliferation, differentiation and survival and its expression is upregulated in many tumor cell types.

SYN

Patent Document 1: International Publication WO 2007/087395 pamphlet
Patent Document 2: International Publication WO 2008/121742 pamphlet
Patent Document 3: International Publication WO 2010/043865 pamphlet
Patent Document 4: International Publication WO 2011/115937 pamphlet

 

Unlicensed Document 1 : J. Clin. Oncol. 24, 3664-3671 (2006)
Non-licensed Document 2: Mol. Cancer Res. 3, 655-667 (2005)
Non-licensed Document 3: Cancer Res. 70, 2085-2094 (2010)
Non-licensed Document 4: Clin. Cancer Res. 17, 6130-6139 (2011)
Non-licensed Document 5: Nat. Med. 1, 27-31 (1995)

WO2020095452

WO2020096042

WO2020096050

WO2019034075

WO2015008844

WO2015008839

WO2013108809

SYN

US9108973

SYN

Reference Example 1: WXR1

Compound WXR1 was synthesized according to the route reported in patent WO2015008844. 1 H NMR(400MHz, DMSO-d 6 )δ8.40(d,J=3.0Hz,1H),6.93(d,J=2.5Hz,2H),6.74-6.52(m,2H),6.20-6.16( m,1H), 5.74-5.69(m,1H), 5.45-5.61(m,1H), 4.12-3.90(m,2H), 3.90-3.79(m,8H), 2.47-2.30(m,2H). MS m/z: 419.1[M+H] +

PAPER

Bioorg Med Chem, March 2013, Vol.21, No.5, pp.1180-1189

SYN

WO2015008844

PATENT

////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Clinical data
Trade namesLytgobi
Other namesTAS-120
License dataUS DailyMedFutibatinib
Routes of
administration
By mouth
Drug classAntineoplastic
ATC codeL01EN04 (WHO)
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1448169-71-8
PubChem CID71621331
IUPHAR/BPS9786
DrugBankDB15149
ChemSpider58877816
UNII4B93MGE4AL
KEGGD11725
ChEMBLChEMBL3701238
PDB ligandTZ0 (PDBeRCSB PDB)
Chemical and physical data
FormulaC22H22N6O3
Molar mass418.457 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

Futibatinib, sold under the brand name Lytgobi, is a medication used for the treatment of cholangiocarcinoma (bile duct cancer).[1][2] It is a kinase inhibitor.[1][3] It is taken by mouth.[1]

Futibatinib was approved for medical use in the United States in September 2022.[1][2][4]

Medical uses

Futibatinib is indicated for the treatment of adults with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring fibroblast growth factor receptor 2 (FGFR2) gene fusions or other rearrangements.[1][2]

Names

Futibatinib is the international nonproprietary name (INN).[5]

References

  1. Jump up to:a b c d e f “Lytgobi (futibatinib) tablets, for oral use” (PDF). Archived (PDF) from the original on 4 October 2022. Retrieved 4 October 2022.
  2. Jump up to:a b c https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2022/214801Orig1s000ltr.pdf Archived 4 October 2022 at the Wayback Machine Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Lytgobi (Futibatinib) FDA Approval History”Archived from the original on 4 October 2022. Retrieved 4 October 2022.
  4. ^ “FDA Approves Taiho’s Lytgobi (futibatinib) Tablets for Previously Treated, Unresectable, Locally Advanced or Metastatic Intrahepatic Cholangiocarcinoma” (Press release). Taiho Oncology. 30 September 2022. Archived from the original on 4 October 2022. Retrieved 4 October 2022 – via PR Newswire.
  5. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

External links

//////////Futibatinib, Lytgobi, FDA 2022, APPROVALS 2022, フチバチニブ , ANTINEOPLASTIC, TAS 120

C=CC(N1C[C@@H](N2N=C(C#CC3=CC(OC)=CC(OC)=C3)C4=C(N)N=CN=C42)CC1)=O

wdt-1

NEW DRUG APPROVALS

ONE TIME

$10.00

Gadopiclenol


STR1
Chemical structure of gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid)]. The PCTA parent structure is shown in red. Two water molecules are included to show the coordination in solution.
Molecules 27 00058 g003 550

Gadopiclenol

ガドピクレノール;

FormulaC35H54N7O15. Gd
CAS933983-75-6
Mol weight970.0912

FDA APPROVED 2022/9/21, Elucirem

Diagnostic agent (MR imaging), WHO 10744, P 03277, UNII: S276568KOY

EluciremTM; G03277; P03277; VUEWAY

(alpha3,alpha6,alpha9-Tris(3-((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-kappaN3,kappaN6,kappaN9,kappaN15,kappaO3,kappaO6,kappaO9)gadolinium

Molecules 27 00058 g002 550
  • OriginatorGuerbet
  • ClassDiagnostic agents; Gadolinium-containing contrast agents; Macrocyclic compounds; Propylamines; Pyridines
  • Mechanism of ActionMagnetic resonance imaging enhancers
  • RegisteredCNS disorders
  • Phase IIIUnspecified
  • Phase IILiver cancer
  • 21 Sep 2022Registered for CNS disorders (Diagnosis) in USA (IV)
  • 13 Jun 2022Guerbet plans to launch Gadopiclenol in Europe
  • 13 Jun 2022The European Medicines Agency (EMA) accepts brand name EluciremTM for Gadopiclenol

PATENT

https://patents.google.com/patent/WO2020030618A1/en

MRI contrast agents used in daily diagnostic practice typically include gadolinium complex compounds characterized by high stability constants that guarantee against the in vivo release of the free metal ion (that is known to be extremely toxic for living organisms).

Another key parameter in the definition of the tolerability of a gadolinium-based contrast agent is the kinetic inertness (or kinetic stability) of Gd(III)-complex, that is estimated through the half-life (ti/2) of the dissociation (i.e. decomplexation) of the complex.

A high inertness becomes crucial in particular for those complex compounds having lower thermodynamic stability and/or longer retention time before excretion, in order to avoid or minimize possible decomplexation or transmetallation reactions.

EP1931673 (Guerbet) discloses PCTA derivatives of formula

Figure imgf000002_0001

and a synthetic route for their preparation.

EP 2988756 (same Applicant) discloses a pharmaceutical composition comprising the above derivatives together with a calcium complex of 1,4,7, 10-tetraazacyclododecane- 1,4,7, 10-tetraacetic acid. According to the EP 2988756, the calcium complex compensates the weak thermodynamic stability observed for PCTA-based gadolinium complexes, by forming, through transmetallation, a strong complex with free lanthanide ion, thereby increasing the tolerability of the contrast agent.

Both EP1931673 and EP 2988756 further refer to enantiomers or diastereoisomers of the claimed compounds, or mixture thereof, preferentially chosen from the RRS, RSR, and RSS diastereoisomers. Both the above patents disclose, among the specific derivatives, (a3, a6, a9)-tris(3- ((2,3-dihydroxypropyl)amino)-3-oxopropyl)-3,6,9,15-tetraazabicyclo(9.3.1)pentadeca- l(15),l l,13-triene-3,6,9-triacetato(3-)-(KN3,KN6,KN9,KN15,K03,K06,K09)gadolinium, more recently identified as gadolinium chelate of 2,2′,2″-(3,6,9-triaza-l(2,6)- pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid), (CAS registry number: 933983-75-6), having the following formula

Figure imgf000003_0001

otherwise identified as P03277 or Gadopiclenol.

For Gadopiclenol, EP1931673 reports a relaxivity of 11 mM _1_1Gd 1 (in water, at 0.5 T, 37°C) while EP 2988756 reports a thermodynamic equilibrium constant of 10 14 9 (log Kterm

= 14.9).

Furthermore, for this same compound a relaxivity value of 12.8 mM _11 in human serum (37°C, 1.41 T), stability (log Kterm) of 18.7, and dissociation half-life of about 20 days (at pH 1.2; 37°C) have been reported by the proprietor (Investigative Radiology 2019, Vol 54, (8), 475-484).

The precursor for the preparation of the PCTA derivatives disclosed by EP1931673 (including Gadopiclenol) is the Gd complex of the 3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),l l,13-triene-tri(a-glutaric acid) having the following formula

Figure imgf000003_0002

Gd(PCTA-tris-glutaric acid)

herein identified as “Gd(PCTA-tris-glutaric acid)”. In particular, Gadopiclenol is obtained by amidation of the above compound with isoserinol.

As observed by the Applicant, Gd(PCTA-tris-qlutaric acid) has three stereocenters on the glutaric moieties (identified with an asterisk (*) in the above structure) that lead to a 23 = 8 possible stereoisomers. More particularly, the above structure can generate four pairs of enantiomers, schematized in the following Table 1

Table 1

Figure imgf000004_0002

Isomer RRR is the mirror image of isomer SSS and that is the reason why they are called enantiomers (or enantiomer pairs). As known, enantiomers display the same physicochemical properties and are distinguishable only using chiral methodologies, such as chiral chromatography or polarized light.

On the other hand, isomer RRR is neither equal to nor is it the mirror image of any of the other above six isomers; these other isomers are thus identified as diastereoisomers of the RRR (or SSS) isomer. Diastereoisomers may display different physicochemical properties, (e.g., melting point, water solubility, relaxivity, etc.).

Concerning Gadopiclenol, its chemical structure contains a total of six stereocenters, three on the glutaric moieties of the precursor as above discussed and one in each of the three isoserinol moieties attached thereto, identified in the following structure with an asterisk (*) and with an empty circle (°), respectively:

Figure imgf000004_0001

This leads to a total theoretical number of 26 = 64 stereoisomers for this compound. However, neither EP1931673 nor EP 2988756 describe the exact composition of the isomeric mixture obtained by following the reported synthetic route, nor does any of them provide any teaching for the separation and characterization of any of these isomers, or disclose any stereospecific synthesis of Gadopiclenol. Summary of the invention

The applicant has now found that specific isomers of the above precursor Gd(PCTA- tris-glutaric acid) and of its derivatives (in particular Gadopiclenol) possess improved physico-chemical properties, among other in terms of relaxivity and kinetic inertness.

An embodiment of the invention relates to a compound selected from the group consisting of:

the enantiomer [(aR,a’R,a”R)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium (RRR enantiomer) having the formula (la):

Figure imgf000005_0001

the enantiomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo- [9.3.1]pentadeca-l(15),ll,13-triene-3,6,9-triacetato(3-)KN3,KN6,KN9,KN15,K03,K06,K09]- gadolinium (SSS enantiomer) having the formula (lb):

Figure imgf000005_0002

the mixtures of such RRR and SSS enantiomers, and a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to an isomeric mixture of Gd(PCTA-tris- glutaric acid) comprising at least 50% of the RRR isomer [(aR,a’R,a”R)-a,a’,a”-tris(2- carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9- triacetato(3-)-KN3,KN6,KN9,KN15,K03,K06,K09]-gadolinium, of formula (la), or of the SSS isomer [(aS,a’S,a”S)-a,a’,a”-tris(2-carboxyethyl)-3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,6,9-triacetato(3-)- Kl\l3,Kl\l6,Kl\l9,Kl\ll5,K03,K06,K09]-gadolinium of formula (lb), or of a mixture thereof, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to the amides obtained by conjugation of one of the above compounds or isomeric mixture with an amino group, e.g. preferably, serinol or isoserinol.

An embodiment of the invention relates to an amide derivative of formula (II A)

F( N RI R2)3 (II A)

in which :

F is:

a RRR enantiomer residue of formula Ilia

Figure imgf000006_0001

a SSS enantiomer residue of formula Illb

Figure imgf000006_0002

or a mixture of such RRR and SSS enantiomer residues;

and each of the three -NRIR2 group is bound to an open bond of a respective carboxyl moiety of F, identified with a full circle (·) in the above structures;

Ri is H or a Ci-Ce alkyl, optionally substituted by 1-4 hydroxyl groups;

R2 is a Ci-Ce alkyl optionally substituted by 1-4 hydroxyl groups, and preferably a C1-C3 alkyl substituted by one or two hydroxyl groups.

Another embodiment of the invention relates to an isomeric mixture of an amide derivative of Gd(PCTA-tris-glutaric acid) having the formula (II B)

F'( N RI R2)3 (II B)

in which :

F’ is an isomeric mixture of Gd(PCTA-tris-glutaric acid) residue of formula (III)

Figure imgf000007_0001

said isomeric mixture of the Gd(PCTA-tris-glutaric acid) residue comprising at least 50 % of an enantiomer residue of the above formula (Ilia), of the enantiomer residue of the above formula (Illb), or of a mixture thereof; and each of the -NR1R2 groups is bound to an open bond of a respective carboxyl moiety of F’, identified with a full circle (·) in the above structure, and is as above defined for the compounds of formula (II A).

EXPERIMENTAL PART

HPLC characterization of the obtained compounds.

General procedures

Procedure 1: HPLC Characterization of Gd(PCTA-tris-glutaric acid) (isomeric mixture and individual/enriched isomers).

The HPLC characterization of the Gd(PCTA-tris-glutaric acid) obtained as isomeric mixture from Example 1 was performed with Agilent 1260 Infinity II system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector ( Agilent 1260 Infinity II system)

Stationary phase: Phenomenex Gemini® 5pm C18 lloA

Mobile phase: H2O/HCOOH 0.1% : Methanol

Elution : Gradient Time (min) H2O/HCOOH 0.1% Methanol

0 95 5

5 95 5

30 50 50

35 50 50

40 95 5

Flow 0.6 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

Injection volume 50 pL

Sample Cone. 0.2 mM Gd(PCTA-tris-glutaric acid) complex

Stop time 40 min

Retention time GdL = 18-21 min.

Obtained HPLC chromatogram is shown in Figure 1

The HPLC chromatogram of the enriched enantiomers pair C is shown in Figure 2.

Procedure 2: HPLC Characterization of Gadopiclenol (isomeric mixture) and compounds obtained by coupling of enantiomers pair C with R, S, or racemic isoserinol.

The HPLC characterization of Gadopiclenol either as isomeric mixture obtained from Example 2, or as the compound obtained by conjugation of enantiomers pair C of the Gd(PCTA-tris-glutaric acid) with R, S, or racemic isoserinol was performed with Thermo Finnigan LCQ DECA XPPIus system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC system HPLC equipped with quaternary pump, degasser, autosampler,

PDA and MS detector (LCQ Deca XP-Plus – Thermo Finnigan )

Stationary phase: Phenomenex Gemini 5u C18 110A

Mobile phase: H2O/TFA 0.1% : Acetonitrile/0.1%TFA

Elution : Gradient Time (min) H2O/TFA 0.1% Acetonitrile/0.1%TFA

0 100 0

5 100 0

22 90 10

26 90 10

Flow 0.5 mL/min

Temperature 25 °C

Detection PDA scan wavelenght 190-800nm

MS positive mode – Mass range 100-2000

Injection volume 50 pL

Sample cone. 0.2 mM Gd complex

Stop time 26 min

Retention time GdL = 20-22min.

Obtained HPLC chromatograms are shown in Figure 6.

Procedure 3: Chiral HPLC method for the separation of enantiomers of the compound C

A specific chiral HPLC method was set up in order to separate the RRR and SSS enantiomers of the enantiomers pair C (compound VI), prepared as described in Example 3. The separation and characterization of the enantiomers were performed with Agilent 1200 system or Waters Alliance 2695 system. The experimental setup of the HPLC measurements are summarized below.

Analytical conditions

HPLC System HPLC equipped with quaternary pump, degasser, autosampler,

PDA detector

Stationary phase SUPELCO Astec CHIROBIOTIC 5 pm 4.6x250mm

Mobile phase H2O/HCOOH 0.025% : Acetonitrile

Elution : isocratic 2% Acetonitrile for 30 minutes

Flow 1 mL/min

Column Temperature 40°C

Detection 210-270 nm. Obtained HPLC chromatogram is shown in Figure 5a) compared to the chromatograms of the pure RRR enantiomer (compound XII of Example 5, Tr. 7.5 min.) and the pure SSS enantiomer (Compound XVII of Example 6, Tr. 8.0 min), shown in figure 5b) and 5c), respectively.

Example 1: Synthesis of Gd(PCTA-tris-glutaric acid) (isomeric mixture)

Gd(PCTA-tris-glutaric acid) as an indiscriminate mixture of stereoisomers has been prepared by using the procedure reported in above mentioned prior-art, according to the following synthetic Scheme 1 :

Scheme 1

Figure imgf000030_0001

a) Preparation of Compound II

Racemic glutamic acid (33.0 g, 0.224 mol) and sodium bromide (79.7 g, 0.782 mol) were suspended in 2M HBr (225 ml_). The suspension was cooled to -5°C and NaN02 (28.0 g, 0.403 mol) was slowly added in small portions over 2.5 hours, maintaining the inner temperature lower than 0 °C. The yellow mixture was stirred for additional 20 minutes at a temperature of -5°C; then concentrated sulfuric acid (29 ml.) was dropped in the mixture. The obtained dark brown mixture was warmed to RT and then extracted with diethyl ether (4×150 ml_). The combined organic phases were washed with brine, dried over Na2S04 and concentrated to a brown oil (21.2 g), used in the following step without further purification. The oil was dissolved in ethanol (240 ml_), the resulting solution was cooled in ice and thionyl chloride (14.5 ml_, 0.199 mol) was slowly added. The slightly yellow solution was stirred at RT for 2 days. Then the solvent was removed in vacuum and the crude oil was dissolved in dichloromethane (200 ml.) and washed with 5% aq. NaHCC>3 (4×50 ml_), water (1×50 ml.) and brine (1×50 ml_). The organic phase was concentrated and purified on silica eluting with petroleum ether-ethyl acetate 3: 1, obtaining 19.5 g of pure product. (Yield 33%).

b) Preparation of Compound IV

A solution of Compound II (17.2 g, 0.0645 mol) in acetonitrile (40 ml.) was added to a suspension of 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene (pyclen) Compound (III) (3.80 g, 0.018 mol) and K2CO3 (11.2 g, 0.0808 mol) in acetonitrile (150 ml_). The yellow suspension was heated at 65 °C for 24 h, then the salts were filtered out and the organic solution was concentrated. The orange oil was dissolved in dichloromethane and the product was extracted with 1M HCI (4 x 50 ml_). The aqueous phases were combined, cooled in ice and brought to pH 7-8 with 30% aq. NaOH. The product was then extracted with dichloromethane (4 x 50 ml.) and concentrated to give a brown oil (10.1 g, yield 73%). The compound was used in the following step without further purification.

c) Preparation of compound V

Compound IV (9.99 g, 0.013 mol) was dissolved in Ethanol (40 ml.) and 5M NaOH (40 ml_). The brown solution was heated at 80 °C for 23 h. Ethanol was concentrated; the solution was cooled in ice and brought to pH 2 with cone HCI. The ligand was purified on resin Amberlite XAD 1600, eluting with water-acetonitrile mixture, obtaining after freeze- drying 5.7 g as white solid (yield 73%). The product was characterized in HPLC by several peaks.

d) Preparation of compound VI

Compound V (5.25 g, 0.0088 mol) was dissolved in deionized water (100 ml.) and the solution was brought to pH 7 with 2M NaOH (20 ml_). A GdCh solution (0.0087 mol) was slowly added at RT, adjusting the pH at 7 with 2M NaOH and checking the complexation with xylenol orange. Once the complexation was completed, the solution was concentrated and purified on resin Amberlite XAD 1600 eluting with water-acetonitrile gradient, in order to remove salts and impurities. After freeze-drying the pure compound was obtained as white solid (6.79 g, yield 94%). The product was characterized in HPLC; the obtained HPLC chromatogram, characterized by several peaks, is shown in Figure 1 A compound totally equivalent to compound VI, consisting of an isomeric mixture with a HPLC chromatogram substantially superimposable to that of Figure 1 is obtained even by using (S)-methyl a-bromoglutarate obtained starting from L-glutamic acid.

Example 2: Synthesis of Gadopiclenol (isomeric mixture)

Gadopiclenol as an indiscriminate mixture of stereoisomers has been prepared as disclosed in EP11931673 B1 by coupling the isomeric mixture of Gd(PCTA-tris-glutaric acid) obtained from Example 1 with racemic isoserinol according to the following synthetic Scheme 2:

Scheme 2

Figure imgf000032_0001

Preparation of compound VII

Compound VI (0.90 g, 0.0011 mol) obtained from Example 1 was added to a solution of racemic isoserinol (0.40 g, 0.0044 mol) in water adjusted to pH 6 with cone. HCI. Then N- ethyl-N’-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI-HCI) (1.0 g, 0.0055 mol) and hydroxybenzotriazole (HOBT) (0.12 g, 0.00088 mol) were added and the resulting solution was stirred at pH 6 and RT for 24 h. The product was then purified on preparative HPLC on silica C18, eluting with water/acetonitrile gradient. Fractions containing the pure compound were concentrated and freeze-dried, obtaining a white solid (0.83 g, yield 78%). The product was characterized in HPLC; the obtained HPLC chromatogram is shown in Figure 4a.

Example 3: Isolation of the enantiomers pair related to the peak C.

Compound VI obtained as described in Example 1 (step d) (1.0 g, 0.0013 mol) was dissolved in water (4 ml.) and the solution was acidified to pH 2-3 with cone. HCI. The obtained solution was loaded into a pre-packed column of silica C18 (Biotage® SNAP ULTRA C18 120 g, HP-sphere C18 25 pm) and purified with an automated flash chromatography system eluting with deionized water (4 CV) and then a very slow gradient of acetonitrile. Fractions enriched of the enantiomers pair related to the peak C were combined, concentrated and freeze-dried obtaining a white solid (200 mg).

The HPLC chromatogram of the obtained enriched enantiomers pair C is shown in Figure 2.

Corresponding MS spectrum (Gd(H4L)+:752.14 m/z) is provided in Figure 3

Example 4: Coupling of the enantiomers pair C with isoserinol.

a) Coupling of the enantiomers pair C with R-isoserinol.

Enriched enantiomers pair C collected e.g. as in Example 3 (34 mg, titer 90%, 0.040 mmol) was dissolved in deionized water (5 ml_), and R-isoserinol (16 mg, 0.17 mmol) was added adjusting the pH at 6 with HCI 1M. Then, EDCI-HCI (39 mg, 0.20 mmol) and HOBT (3 mg, 0.02 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (21 mg, yield 54%).

The HPLC chromatogram of the obtained product is shown in Figure 6b.

b) Coupling of the enantiomers pair C with S-isoserinol

Enriched enantiomers pair C collected e.g. as in Example 3 (55 mg, titer 90%, 0.066 mmol) was dissolved in deionized water (5 mL), and S-isoserinol (34 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (64 mg, 0.33 mmol) and HOBT (4.5 mg, 0.033 mmol) were added and the solution was stirred at RT at pH 6 for 48 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (52 mg, yield 81%).

HPLC chromatogram of the obtained product is shown in Figure 6c.

c) Coupling of the enantiomers pair C with racemic isoserinol.

The enriched enantiomers pair C collected e.g. as in Example 3 (54 mg, titer 90%, 0.065 mmol) was dissolved in deionized water (5 mL), and racemic isoserinol (27 mg, 0.29 mmol) was added adjusting the pH at 6 with 1M HCI. Then, EDCI-HCI (62 mg, 0.32 mmol) and HOBT (4.3 mg, 0.032 mmol) were added and the solution was stirred at RT at pH 6 for 24 h. The solution was concentrated and loaded to pre-packed silica C18 column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with water/acetonitrile gradient using an automated flash chromatography system. Fractions containing the pure product, or showing a major peak at the HPLC with area greater than 90%, were combined, concentrated and freeze-dried giving a white solid (60 mg, yield 95%).

HPLC chromatogram of the obtained product is shown in Figure 6d. Example 5: Stereoselective synthesis of the RRR Gd(PCTA-tris-glutaric acid) (compound XII).

RRR enriched Gd(PCTA-tris-glutaric acid) acid has been prepared by following the synthetic Scheme 3 below

Scheme 3

Figure imgf000034_0001

comprising :

a) Preparation of Compound VIII

The preparation was carried out as reported in Tetrahedron 2009, 65, 4671-4680.

In particular: 37% aq. HCI (50 pL) was added to a solution of (S)-(+)-5- oxotetrahydrofuran-2-carboxylic acid (2.48 g, 0.019 mol) (commercially available) in anhydrous methanol (20 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHCC>3 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (2.97 g, yield 89%).

b) Preparation of Compounds IX and X

Compound VIII (445 mg, 2.52 mmol) obtained at step a) was dissolved in anhydrous dichloromethane (6 ml.) and triethylamine (0.87 ml_, 6.31 mmol) was added. The solution was cooled at -40°C and then (triflic) trifluoromethansulfonic anhydride (0.49 ml_,2.91 mmol) was slowly added. The dark solution was stirred at -40°C for 1 h, then a solution of Compound III (104 mg, 0.506 mmol) in anhydrous dichloromethane (3 ml.) and triethylamine (1 ml_, 7.56 mmol) were added and the solution was slowly brought to RT and stirred at RT overnight. The organic solution was then washed with 2M HCI (4x 10 ml_), the aqueous phase was extracted again with dichloromethane (3 x 10 ml_). The organic phases were combined and concentrated in vacuum, obtaining 400 mg of a brown oil that was used in the following step with no further purification.

c) Preparation of Compound XI

Compound X (400 mg, 0.59 mmol) was dissolved in methanol (2.5 ml.) and 5M NaOH (2.5 ml_). The brown solution was heated at 80°C for 22 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 1 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (64 mg, yield 18 %). The HPLC showed a major peak.

d) Compound XII

Compound XI (32 mg, 0.054 mmol) was dissolved in deionized water (4 mL) and the pH was adjusted to 7 with 1M NaOH. GdCl3-6H20 (20 mg, 0.054 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The clear solution was stirred at RT overnight and the end of the complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired RRR isomer as major peak: about 80% in area %. The mixture was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-sphere C18 25 pm), eluting with deionized water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (36 mg, yield 90%).

By reaction of the collected compound with isoserinol e.g. by using the procedure of the Example 2, the corresponding RRR amide derivative can then be obtained.

Example 6: stereoselective synthesis of the SSS Gd(PCTA-tris-glutaric acid) (compound XVII).

SSS enriched Gd(PCTA-tris-glutaric acid) acid has been similarly prepared by following the synthetic Scheme 4 below Scheme 4

Figure imgf000036_0001

comprising :

a) Preparation of Compound XIII

37% aq. HCI (100 pl_) was added to a solution of (R)-(-)-5-oxotetrahydrofuran-2- carboxylic acid (5.0 g, 0.038 mol) (commercially available) in anhydrous methanol (45 ml_). The solution was refluxed under N2 atmosphere for 24 h. After cooling in ice, NaHC03 was added, the suspension was filtered, concentrated and purified on silica gel with hexanes/ethyl acetate 1 : 1. Fractions containing the pure product were combined and concentrated, giving a colorless oil (6.7 g, yield 99%).

b) Preparation of Compounds XIV and XV

Compound XIII (470 mg, 2.67 mmol) was dissolved in anhydrous dichloromethane (6 ml.) and trimethylamine (0.93 ml_, 6.67 mmol) was added. The solution was cooled down at -40°C and then trifluoromethanesulfonic anhydride (0.50 ml_, 3.07 mmol) was slowly dropped. The dark solution was stirred at -40°C for 1 h, then Compound III (140 mg, 0.679 mmol) and trimethylamine (0.93 ml_, 6.67 mmol) were added and the solution was slowly brought to RT overnight. The organic solution was then washed with water (3 x 5 ml.) and 2M HCI (4 x 5 ml_). The aqueous phase was extracted again with dichloromethane (3 x 10 ml_). the organic phases were combined and concentrated in vacuum, obtaining 350 mg of a brown oil that was used in the following step with no further purification. c) Preparation of Compound XVI

Compound XV (350 mg, 0.514 mmol) was dissolved in methanol (4.5 ml.) and 5M NaOH (4.5 ml_). The obtained brown solution was heated at 80°C for 16 h to ensure complete hydrolysis. Methanol was concentrated, the solution was brought to pH 2 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product were combined, concentrated and freeze-dried (52 mg, yield 17%). The HPLC showed a major peak.

d) Preparation of Compound XVII

Compound XVI (34 mg, 0.057 mmol) was dissolved in deionized water (5 mL) and the pH was adjusted to 7 with 1 M HCI. GdCl3-6H20 (20 mg, 0.0538 mmol) was added and the pH was adjusted to 7 with 0.1 M NaOH. The solution was stirred at RT overnight and the end of complexation was checked by xylenol orange and HPLC. The HPLC of the crude showed the desired SSS isomer as major peak: about 85% in area %. The solution was brought to pH 2.5 with concentrated HCI and purified through an automated flash chromatography system with a silica C18 pre-packed column (Biotage® SNAP ULTRA C18 12 g, HP-SPHERE C18 25 pm), eluting with a water/acetonitrile gradient. Fractions containing the pure product SSS were combined, concentrated and freeze-dried (39 mg, yield 87%).

Example 7: Kinetic studies of the dissociation reactions of Gd(PCTA-tris- glutaric acid) (isomeric mixture) in 1.0 M HCI solution (25°C)

The kinetic inertness of a Gd(III)-complex is characterized either by the rate of dissociation measured in 0.1-1.0 M HCI or by the rate of the transmetallation reaction, occurring in solutions with Zn(II) and Cu(II) or Eu(III) ions. However, the dissociation of lanthanide(III)-complexes formed with macrocyclic ligands is very slow and generally proceeds through a proton-assisted pathway without the involvement of endogenous metal ions like Zn2+ and Cu2+.

We characterized the kinetic inertness of the complex Gd(PCTA-tris-glutaric acid) by the rates of the dissociation reactions taking place in 1.0 M HCI solution. The complex (isomeric mixture from Example 1) (0.3 mg) was dissolved in 2.0 mL of 1.0 M HCI solution and the evolution of the solution kept at 25 °C was followed over time by HPLC. The HPLC measurements were performed with an Agilent 1260 Infinity II system by use of the analytical Procedure 1.

The presence of a large excess of H+ ([HCI] = 1.0 M), guarantees the pseudo-first order kinetic conditions.

GdL + yH÷ ^ Gd3+ + HyL y=7 and 8 (Eg. 1) where L is the protonated PCTA-tri-glutaric acid, free ligand, and y is the number of protons attached to the ligand.

The HPLC chromatogram of Gd(PCTA-tris-glutaric acid) is characterized by the presence of four signals (A, B, C and D) having the same m/z ratio (Gd(H4L)+ :752.14 m/z) in the MS spectrum. Each of these peaks is reasonably ascribable to one of the 4 pairs of enantiomers generated by the three stereocenters on the three glutaric arms of the molecule, formerly identified in Table 1. The HPLC chromatogram of this complex in the presence of 1.0 M HCI changes over time: in particular, the areas of peaks A, B, C, and D decrease, although not in the same way for the different peaks, while new signals corresponding to non-complexed diastereoisomers are formed and grow over time. Differences in the decrease of the integral areas of the peaks can be interpreted by a different dissociation rate of the enantiomer pairs associated to the different peaks.

In the presence of [H + ] excess the dissociation reaction of enantiomer pairs of Gd(PCTA-tris-glutaric acid) can be treated as a pseudo-first-order process, and the rate of the reactions can be expressed with the following Eq. 2, where kA, kB, kc and kD are the pseudo-first-order rate constants that are calculated by fitting the area-time data pair, and [A]t, [B]t, [C]t and [D]t are the total concentration of A, B, C and D compounds at time t.

Figure imgf000038_0001

The decrease of the area values of signals of A, B, C, and D has been assessed and plotted over time. Area values of A, B, C and D signals as a function of time are shown in Figure 7.

Area value at time t can be expressed by the following equation:

A. = A + (A0 – A )e kxt

(Eg. 3)

where At, A0 and Ae are the area values at time t, at the beginning and at the end of the reactions, respectively, kx pseudo-first-order rate constants (/fX=/fA, kB, kc and kD) characterizing the dissociation rate of the different enantiomer pairs of Gd(PCTA-tris-glutaric acid) complex were calculated by fitting the area – time data pairs of Figure 7 to the above equation 3. kx rate constants and half-lives (ti/2= In2/ x) are thus obtained, as well as the average the half-life value for the isomeric mixture of Gd(PCTA-tris-glutaric acid), calculated by considering the percentage composition of the mixture. Obtained values are summarized in the following Table 2, and compared with corresponding values referred in the literature for some reference contrast agents. (Gd-DOTA or DOTAREM™). Table 2. Rate constants ( kx ) and half-lives (ti/2= In2/ x) characterizing the acid catalyzed dissociation of the different stereoisomers of Gd(PCTA-tris-glutaric acid), Dotarem® and Eu(PCTA) in 1.0 M HCI (pH 0) ( 25°C)

A B C D

Ms 1) (4.5±0.1) x105 (1.1±0.1)x104 (1.6±0.1)x10-6 (1.2±0.1)x10-5 fi/2 (hour) 4.28 ± 0.03 1.76 ± 0.02 120 ± 3 15.8 ± 0.5

fi/2 (hour)

Figure imgf000039_0001

average

Dotarem a

k, (S‘1) 8.0×10-6

fi/2 (hour) 23 hour

Eu(PCTA) b

*1 (s·1) 5.08X10·4

fi/2 (hour) 0.38 hour

a) Inorg. Chem. 1992, 31 ,1095-1099.

b) Tircso, G. et al. Inorg Chem 2006, 45 (23), 9269-80.

/////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

A gadolinium-based paramagnetic contrast agent, with potential imaging enhancing activity upon magnetic resonance imaging (MRI). Upon administration of gadopiclenol and placement in a magnetic field, this agent produces a large magnetic moment and creates a large local magnetic field, which can enhance the relaxation rate of nearby protons. This change in proton relaxation dynamics, increases the MRI signal intensity of tissues in which this agent has accumulated; therefore, contrast and visualization of those tissues is enhanced compared to unenhanced MRI.

FDA Approves New MRI Contrast Agent Gadopiclenol

September 22, 2022

https://www.diagnosticimaging.com/view/fda-approves-new-mri-contrast-agent-gadopiclenol

Requiring only half of the gadolinium dose of current non-specific gadolinium-based contrast agents (GBCAs), gadopiclenol can be utilized with magnetic resonance imaging (MRI) to help detect lesions with abnormal vascularity in the central nervous system and other areas of the body.

Gadopiclenol, a new magnetic resonance imaging (MRI) contrast agent that offers high relaxivity and reduced dosing of gadolinium, has been approved by the Food and Drug Administration (FDA).1

Approved for use with MRI in adults and pediatric patients two years of age or older, gadopiclenol is a macrocyclic gadolinium-based contrast agent that aids in the diagnosis of lesions with abnormal vascularity in the brain, spine, abdomen, and other areas of the body.

Recently published research demonstrated that gadopiclenol provides contrast enhancement and diagnostic efficacy at half of the gadolinium dosing of other gadolinium-based contrast agents (GBCAs) such as gadobutrol and gadobenate dimeglumine.2

Co-developed by Bracco Diagnostics and Guerbet, gadopiclenol will be manufactured and marketed as Vueway™ (Bracco Diagnostics) and Elucirem™ (Guerbet).1,3

Alberto Spinazzi, M.D., the chief medical and regulatory officer at Bracco Diagnostics, said gadopiclenol is “a first of its kind MRI agent that delivers the highest relaxivity and highest kinetic stability of all GBCAs on the market today.”

Reference

1. Bracco Diagnostics. Bracco announces FDA approval of gadopiclenol injection, a new macrocyclic high-relaxivity gadolinium-based contrast agent which will be commercialized as VUEWAY™ (gadopiclenol) injection and VUEWAY™ (gadopiclenol) phamarcy bulk package by Bracco. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/bracco-announces-fda-approval-of-gadopiclenol-injection-a-new-macrocyclic-high-relaxivity-gadolinium-based-contrast-agent-which-will-be-commercialized-as-vueway-gadopiclenol-injection-and-vueway-gadopiclenol-pharmacy-bulk-p-301630124.html . Published September 21, 2022. Accessed September 21, 2022.

2. Bendszus M, Roberts D, Kolumban B, et al. Dose finding study of gadopiclenol, a new macrocyclic contrast agent, in MRI of central nervous system. Invest Radiol. 2020;55(3):129-137.

3. Guerbet. Guerbet announces U.S. Food and Drug Administration (FDA) approval of Elucirem™ (gadopiclenol) injection for use in contrast-enhanced MRI. Cision PR Newswire. Available at: https://www.prnewswire.com/news-releases/guerbet-announces-us-food-and-drug-administration-fda-approval-of-elucirem-gadopiclenol-injection-for-use-in-contrast-enhanced-mri-301630085.html . Published September 21, 2022. Accessed September 21, 2022.

////Gadopiclenol, FDA 2022, APPROVALS 2022, ガドピクレノール, WHO 10744, P 03277,  EluciremTM, G03277; P03277, VUEWAY, Guerbet

wdt-5

NEW DRUG APPROVALS

ONE TIME

$10.00

Eflapegrastim


2D chemical structure of 1384099-30-2
STR1

Eflapegrastim

エフラペグラスチム;

Molecular Formula

  • C15-H28-N2-O6(C2-H4-O)n

Molecular Weight

  • 376.4468
FormulaC3070H4764N806O927S23.(C2H4O)n

UNII: UT99UG9QJX

HM10460A
SPI-2012

  • HNK460

Reducing neutropenia and the incidence of infecton in patients with cancer

(2S)-1-{3-[2-(3-{[(1S,2R)-1-carboxy-2-hydroxypropyl]amino}propoxy)ethoxy]propyl}pyrrolidine-2-carboxylic acid

APPROVED FDA 2022/9/9, Rolvedon

CAS: 1384099-30-2

LAPS-GCSF, ROLONTIS

Antineutropenic, Leukocyte growth factor

Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 1-ether with immunoglobulin G4 [1-[1-(3-hydroxypropyl)proline]] (human Fc fragment), (3→3′)-disulfide with immunoglobulin G4 (human Fc fragment), 1′′-ether with granulocyte colony-stimulating factor [N-(3-hydroxypropyl),17-serine,65-serine] (human) (ACI)

A long-acting, recombinant analog of the endogenous human granulocyte colony-stimulating factor (G-CSF) with hematopoietic activity. Similar to G-CSF, eflapegrastim binds to and activates specific cell surface receptors and stimulates neutrophil progenitor proliferation and differentiation, as well as selected neutrophil functions. Therefore, this agent may decrease the duration and incidence of chemotherapy-induced neutropenia. Eflapegrastim extends the half-life of G-CSF, allowing for administration once every 3 weeks.

  • A long-acting GCSF that consists of 17th serine-G-CSF conjugated to the G4 fragment HMC001 via a PEG linker.

PATENT

 WO2021113597

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021113597

Neutropenia is a relatively common disorder most often due to chemotherapy treatments, adverse drug reactions, or autoimmune disorders. Chemotherapy-induced neutropenia is a common toxicity caused by the administration of anticancer drugs. It is associated with life-threatening infections and may alter the chemotherapy schedule, thus impacting on early and long term outcome. Febrile Neutropenia (FN) is a major dose-limiting toxicity of myelosuppressive chemotherapy regimens such as docetaxel, doxorubicin, cyclophosphamide (TAC); dose-dense doxorubicin plus cyclophosphamide (AC), with or without subsequent weekly or semiweekly paclitaxel; and docetaxel plus cyclophosphamide (TC). It usually leads to prolonged hospitalization, intravenous administration of broad-spectrum antibiotics, and is often associated with significant morbidity and mortality.

Current therapeutic modalities employ granulocyte colony-stimulating factor (G-CSF) and/or antibiotic agents to combat this condition. G-CSF or its other polypeptide derivatives are easy to denature or easily de-composed by proteolytic enzymes in blood to be readily removed through the kidney or liver. Therefore, to maintain the blood concentration and titer of the G-CSF containing drugs, it is necessary to frequently administer the protein drug to patients, which causes excessive suffering in patients. To solve such problems, G-CSF was chemically attached to polymers having a high solubility such as polyethylene glycol (“PEG”), thereby increasing its blood stability and maintaining suitable blood concentration for a longer time.

Filgrastim, tbo-filgrastim, and pegfilgrastim are G-CSFs currently approved by the US Food and Drug Administration (FDA) for the prevention of chemotherapy-induced neutropenia, While the European guidelines also include lenograstim as a recommended G-CSF in solid tumors and non-myeloid malignancies, it is not approved for use in the US. Binding of PEG to G-CSF, even though may increase blood stability, does dramatically reduce the titer needed for optimal physiologic effect. Thus there is a need to address this shortcoming in the art.

PATENT

WO2021112654

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021112654

Eflapegrastim

[54]

Eflapegrastim, as known as Rolontis ®, SPI-2012, HM10460A, and 17,65S-G-CSF, is a long-acting granulocyte-colony stimulating factor (G-CSF) that has been developed to reduce the severity and duration of severe neutropenia, as well as complications of neutropenia, associated with the use of myelosuppressive anti-cancer drugs or radiotherapy. Eflapegrastim consists of a recombinant human G-CSF analog (ef-G-CSF) and a recombinant fragment of the Fc region of human immunoglobulin G4 (IgG4), linked by a Bifunctional polyethylene glycol linker. In certain embodiments, the recombinant human G-CSF analog (ef-G-CSF) varies from human G-CSF (SED ID NO: 1) at positions 17 and 65 which are substituted with serine (SED ID NO: 2). Without wishing to be bound by theory, it is believed that the Fc region of human IgG4 increases the serum half-life of ef-G-CSF.

[55]

ef-G-CSF is produced by transformed E. coli in soluble form in the periplasmic space. Separately, the Fc fragment is produced in transformed E. coli as an inclusion body. The ef-G-CSF and the Fc fragment are independently isolated and purified through successive purification steps. The purified ef-G-CSF (SEQ ID NO: 2) and Fc fragment (SEQ ID NOs: 3 and 4) are then linked via a 3.4 kDa PEG molecule that was designed with reactive groups at both ends. Eflapegrastim itself is the molecule resulting from the PEG linker binding at each of the N-termini of ef-G-CSF and the Fc fragment. The G-CSF analog is conjugated to the 3.4 kDa polyethylene glycol analogue with propyl aldehyde end groups at both ends, (OHCCH 2CH 2(OCH 2CH 2nOCH 2CH 2CHO) at the nitrogen atom of its N-terminal Thr residue via reductive amination to form a covalent bond. The resulting G-CSF-PEG complex is then linked to the N-terminal Pro at the nitrogen of the recombinant Fc fragment variant produced in E. coli via reductive amination to yield the final conjugate of Eflapegrastim.

[56]

Example 1: Preparation of Eflapegrastim ( 17,65S-G-CSF-PEG-Fc)

[120]

Step 1: Preparation of Immunoglobulin Fc Fragment Using Immunoglobulin

[121]

Preparation of an immunoglobulin Fc fragment was prepared as follows.

[122]

200 mg of 150-kDa immunoglobulin G (IgG) (Green Cross, Korea) dissolved in 10 mM phosphate buffer was treated with 2 mg of a proteolytic enzyme, papain (Sigma) at 37℃ for 2 hrs with gentle agitation.

[123]

After the enzyme reaction, the immunoglobulin Fc fragment regenerated thus was subjected to chromatography for purification using sequentially a Superdex column, a protein A column and a cation exchange column. In detail, the reaction solution was loaded onto a Superdex 200 column (Pharmacia) equilibrated with 10 mM sodium phosphate buffer (PBS, pH 7.3), and the column was eluted with the same buffer at a flow rate of 1 ml/min. Unreacted immunoglobulin molecules (IgG) and F(ab’)2, which had a relatively high molecular weight compared to the immunoglobulin Fc fragment, were removed using their property of being eluted earlier than the Ig Fc fragment. Fab fragments having a molecular weight similar to the Ig Fc fragment were eliminated by protein A column chromatography (FIGURE 1). The resulting fractions containing the Ig Fc fragment eluted from the Superdex 200 column were loaded at a flow rate of 5 ml/min onto a protein A column (Pharmacia) equilibrated with 20 mM phosphate buffer (pH 7.0), and the column was washed with the same buffer to remove proteins unbound to the column. Then, the protein A column was eluted with 100 mM sodium citrate buffer (pH 3.0) to obtain highly pure immunoglobulin Fc fragment. The Fc fractions collected from the protein A column were finally purified using a cation exchange column (polyCAT, PolyLC Company), wherein this column loaded with the Fc fractions was eluted with a linear gradient of 0.15-0.4 M NaCl in 10 mM acetate buffer (pH 4.5), thus providing highly pure Fc fractions. The highly pure Fc fractions were analyzed by 12% SDS-PAGE (lane 2 in FIGURE 2).

[124]

Step 2: Preparation of 17,65S-G-CSF-PEG Complex

[125]

3.4-kDa polyethylene glycol having an aldehyde reactive group at both ends, ALD-PEG-ALD (Shearwater), was mixed with human granulocyte colony stimulating factor ( 17,65S-G-CSF, MW: 18.6 kDa) dissolved in 100 mM phosphate buffer in an amount of 5 mg/ml at a 17,65S-G-CSF: PEG molar ratio of 1:5. To this mixture, a reducing agent, sodium cyanoborohydride (NaCNBH 3, Sigma), was added at a final concentration of 20 mM and was allowed to react at 4℃ for 3 hrs with gentle agitation to allow PEG to link to the amino terminal end of 17,65S-G-CSF. To obtain a 1:1 complex of PEG and 17,65S-G-CSF, the reaction mixture was subjected to size exclusion chromatography using a Superdex R column (Pharmacia). The 17,65S-G-CSF-PEG complex was eluted from the column using 10 mM potassium phosphate buffer (pH 6.0) as an elution buffer, and 17,65S-G-CSF not linked to PEG, unreacted PEG and dimer byproducts where PEG was linked to 17,65S-G-CSF molecules were removed. The purified 17,65S-G-CSF-PEG complex was concentrated to 5 mg/ml. Through this experiment, the optimal reaction molar ratio for 17,65S-G-CSF to PEG, providing the highest reactivity and generating the smallest amount of byproducts such as dimers, was found to be 1:5.

[126]

Step 3: Preparation of the 17,65S-G-CSF-PEG-Fc Conjugate

[127]

To link the 17,65S-G-CSF-PEG complex purified in the above step 2 to the N-terminus of an immunoglobulin Fc fragment, the immunoglobulin Fc fragment (about 53 kDa) prepared in Step 1 was dissolved in 10 mM phosphate buffer and mixed with the 17,65S-G-CSF-PEG complex at an 17,65S-G-CSF-PEG complex:Fc molar ratio of 1:1, 1:2, 1:4 and 1:8. After the phosphate buffer concentration of the reaction solution was adjusted to 100 mM, a reducing agent, NaCNBH 3, was added to the reaction solution at a final concentration of 20 mM and was allowed to react at 4℃ for 20 hrs with gentle agitation. Through this experiment, the optimal reaction molar ratio for 17,65S-G-CSF-PEG complex to Fc, providing the highest reactivity and generating the fewest byproducts such as dimers, was found to be 1:2.

[128]

Step 4: Isolation and Purification of the G-CSF-PEG-Fc Conjugate

[129]

After the reaction of the above step 3, the reaction mixture was subjected to Superdex size exclusion chromatography so as to eliminate unreacted substances and byproducts and purify the 17,65S-G-CSF-PEG-Fc protein conjugate produced. After the reaction mixture was concentrated and loaded onto a Superdex column, 10 mM phosphate buffer (pH 7.3) was passed through the column at a flow rate of 2.5 ml/min to remove unbound Fc and unreacted substances, followed by column elution to collect 17,65S-G-CSF-PEG-Fc protein conjugate fractions. Since the collected 17,65S-G-CSF-PEG-Fc protein conjugate fractions contained a small amount of impurities, unreacted Fc and interferon alpha dimers, cation exchange chromatography was carried out to remove the impurities. The 17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyCAT LP column (PolyLC) equilibrated with 10 mM sodium acetate (pH 4.5), and the column was eluted with a linear gradient of 0-0.5 M NaCl in 10 mM sodium acetate buffer (pH 4.5) using 1 M NaCl. Finally, the 17,65S-G-CSF-PEG-Fc protein conjugate was purified using an anion exchange column. The 17,65S-G-CSF-PEG-Fc protein conjugate fractions were loaded onto a PolyWAX LP column (PolyLC) equilibrated with 10 mM Tris-HCl (pH 7.5), and the column was then eluted with a linear gradient of 0-0.3 M NaCl in 10 mM Tris-HCl (pH 7.5) using 1 M NaCl, thus isolating the 17,65S-G-CSF-PEG-Fc protein conjugate in a highly pure form.

[130]

[131]

Example 2: Efficacy Study of Eflapegrastim by Different Dosing Regimens in Rats with Docetaxel/Cyclophosphamide induced Neutropenia

[132]

The efficacy of Eflapegrastim (HM10460A), a long acting G-CSF analogue, was compared with Pegfilgrastim by different dosing regimens in a chemotherapy-induced neutropenic rat model.

[133]

In the following study, the Eflapegrastim was created essentially as described in Example 1.

[134]

(i) Materials for Study

[135]

[Table 1] Test Articles

NameBatch/Lot No.Storage ConditionPurity (%)Expiration DateSupplier
HM10460A9066170012~8 ℃RP-HPLC: 98.6% IE-HPLC: 97.4%
SE-HPLC: 98.6%
01/31/2019
Pegfilgrastim10703342~8 ℃Amgen

[136]

[Table 2] Vehicles

NameCompositionStorage ConditionSupplier
Dulbecco’s phosphate buffered saline (DPBS)2~8 ℃Sigma-Aldrich

[137]

[Table 3] Neutropenia-Inducing Agents

NameBatch/Lot No.Storage ConditionPurity (%)Expiration DateSupplier
Cyclo-phosphamideC32500002~8 ℃Sigma-Aldrich
Docetaxel17006RT (20 – 25 ℃)10/31/2020Hanmi Pharmaceutical Co.

[138]

Preparing HM10460A Solutions for Subcutaneous Administration

[139]

Preparation of a 61.8 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 92.7 μL was diluted with DPBS 17907.3 μL.

[140]

Preparation of a 372.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[141]

Preparation of a 496.0 ㎍/kg HM10460A solution for subcutaneous administration: a stock solution of HM10460A (6.0 mg/mL) 744.0μL was diluted with DPBS 17256.0 μL.

[142]

The test article was prepared based on G-CSF protein dosage on drug label(HM10460A.)

[143]

The HM10460A solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[144]

Preparing Pegfilgrastim Solutions for Subcutaneous Administration

[145]

Preparation of a 103.3 ㎍/kg Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 93.0 μL was diluted with DPBS 17907.0 μL.

[146]

Preparation of a 620.0 ㎍/k Pegfilgrastim solution for subcutaneous administration: a stock solution of Pegfilgrastim (10 mg/mL) 558.0 μL was diluted with DPBS 17442.0 μL.

[147]

The Pegfilgrastim solution for subcutaneous administration was then diluted with DPBS to a final dose concentration of 2 mL/kg.

[148]

Preparing Solutions of Neutropenia-Inducing Agents

[149]

To induce neutropenia in rats, Docetaxel/cyclophosphamide was administered using a 1/3 human equivalent dose (Docetaxel 4 mg/kg and CPA 32 mg/kg) (“TC”).

[150]

Preparation of a 32 mg/kg cyclophosphamide solution for subcutaneous administration: cyclophosphamide powder (CPA, Sigma, USA) 2560.0 g was diluted with distilled water (DW, Daihan, Korea) 80000.0 μL.

[151]

Preparation of a 4 mg/kg docetaxel solution for subcutaneous administration: Docel inj. (Hanmi Pharmaceutical, Korea) (42.68 mg/mL) 29070.0 μL was diluted with a commercial formulation buffer (FB, Etahnol 127.4mg/mL in DW) 30930.0 μL.

[152]

The docetaxel and cyclophosphamide solutions for subcutaneous administration were then diluted with FB to a final dose concentration of 1 mL/kg. HM10460A and Pegfilgrastim were diluted with DPBS to a final dose concentration of 2 mL/kg.

[153]

(ii) Methods

[154]

Test System

[155]

[Table 4]

Species and StrainRats
Crl: CD Sprague Dawley (SD)
Justification for SpeciesSD rats were chosen due to their extensive characterization collected from various preclinical studies, especially with the study done to test G-CSF analogue1), 2).
SupplierOrient Bio corp. Korea 143-1, Sangdaewondong, Jungwon-gu, Seongnam-si, Gyeonggi-do, Korea
Number of animalsMale 125 (at group allocation)
Age8 weeks (at group allocation)
Body weight range239.54 ~ 316.46 g (at start of dosing)
Neutropenia induction with chemotherapyNormal SD rats were administered with Docetaxel 4 mg/kg and CPA 32 mg/kg once intraperitoneally to induce neutropenia. Docetaxel and CPA were injected to induce neutropenia in a rat model according to 4 different regimens: Concomitant (G2-G7), 2 hour (G8-G13), 5 hour (G14-G19), and 24 hour (G20-G25) prior to test article administration.

[156]

Animal Care and Identification

/////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Eflapegrastim

25/10/2019by Christian Hilscher

Neutropenia in Breast Cancer: Spectrum Pharmaceuticals has submitted an updated regulatory submission to the US FDA for its biologic Rolontis

10/25/2019 Spectrum Pharmaceutical announced that it has filed an updated Biologics License Application (BLA) with the US Food and Drug Administration (FDA) for Rolontis (eflapegrastim).

The BLA for Rolontis is supported by data from two identically designed Phase 3 clinical trials – ADVANCE and RECOVER – that evaluated the safety and efficacy of eflapegrastim in 643 patients with early breast cancer for the treatment of neutropenia with myelosuppressive chemotherapy.

In both studies, eflapegrastim demonstrated the pre-specified hypothesis of non-inferiority (NI) in Duration of Severe Neutropenia (DSN) and a similar safety profile to pegfilgrastim .

Eflapegrastim also demonstrated non-inferiority to pegfilgrastim in DSN across all 4 cycles in both studies (all NI p<0.0001), the company writes.
© arznei-news.de – Source: Spectrum Pharmaceuticals

Eflapegrastim, sold under the brand names Rolvedon among others, is a long-acting G-CSF analog developed by Hanmi Pharmaceutical and licensed to Spectrum Pharmaceuticals.[2] Eflapegrastim is a leukocyte growth factor.[1] It is used to reduce the risk of febrile neutropenia in people with non-myeloid malignancies receiving myelosuppressive anti-cancer agents.[1]

Eflapegrastim was approved for medical use in the United States in September 2022.[1][3][4]

Medical uses

Eflapegrastim is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adults with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.[1]

Its efficacy has been shown to be non-inferior to pegfilgrastim.[1]

References

  1. Jump up to:a b c d e f “Archived copy” (PDF). Archived (PDF) from the original on 19 September 2022. Retrieved 19 September 2022.
  2. ^ pharmaceutical, hanmi. “Pipeline – R&D”Hanmi PharmaceuticalArchived from the original on 2 February 2017. Retrieved 23 January 2017.
  3. ^ “Rolvedon: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA)Archived from the original on 19 September 2022. Retrieved 18 September 2022.
  4. ^ “Spectrum Pharmaceuticals Receives FDA Approval for Rolvedon (eflapegrastim-xnst) Injection”Business Wire (Press release). 9 September 2022. Archived from the original on 9 September 2022. Retrieved 18 September 2022.

External links

  • “Eflapegrastim”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02643420 for “SPI-2012 vs Pegfilgrastim in the Management of Neutropenia in Participants With Breast Cancer With Docetaxel and Cyclophosphamide (ADVANCE) (ADVANCE)” at ClinicalTrials.gov
  • Clinical trial number NCT02953340 for “SPI-2012 vs Pegfilgrastim in Management of Neutropenia in Breast Cancer Participants With Docetaxel and Cyclophosphamide” at ClinicalTrials.gov
Clinical data
Trade namesRolvedon
Other namesEflapegrastim-xnst, HM-10460A, SPI-2012
Routes of
administration
Subcutaneous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number1384099-30-2
ChemSpiderNone
UNIIUT99UG9QJX
KEGGD11188

////////////Eflapegrastim, Rolvedon, APPROVALS 2022, FDA 2022, エフラペグラスチム , HM10460A, SPI-2012, HNK460, ROLONTIS

wdt-4

NEW DRUG APPROVALS

ONE TIME

$10.00

Terlipressin acetate


Terlipressin.png
Terlipressin acetate.png
2D chemical structure of 1884420-36-3

Terlipressin acetate

テルリプレシン酢酸塩

C52H74N16O15S2. (C2H4O2)x

CAS: 914453-96-6 ACETATEFREE  FORM 14636-12-5

Terlipressin acetate (JAN);
Heamopressin (TN);
Terlivaz (TN)

Cardiovascular agent

Antidiuretic, Vasoconstrictor, Arginine vasopressin receptor agonist

USFDA APPROVED 2022/9/14

An inactive peptide prodrug that is slowly converted in the body to lypressin. It is used to control bleeding of ESOPHAGEAL VARICES and for the treatment of HEPATORENAL SYNDROME.

SVG Image
IUPAC CondensedH-Gly-Gly-Gly-Cys(1)-Tyr-Phe-Gln-Asn-Cys(1)-Pro-Lys-Gly-NH2.CH3CO2H
SequenceGGGCYFQNCPKG
IUPACglycyl-glycyl-glycyl-L-cysteinyl-L-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparagyl-L-cysteinyl-L-prolyl-L-lysyl-glycinamide (4->9)-disulfide acetic acid
  • EINECS 238-680-8
  • Terlipressin
  • Terlipressina
  • Terlipressina [INN-Spanish]
  • Terlipressine
  • Terlipressine [INN-French]
  • Terlipressinum
  • Terlipressinum [INN-Latin]
  • UNII-7Z5X49W53P

acetic acid;(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]pyrrolidine-2-carboxamide

FREE FORM

Molecular Structure of 14636-12-5 (Terlipressin)
Formula:C52H74N16O15S2
Molecular Weight:1227.39

14636-12-5

(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-13-benzyl-10-(2-carbamoylethyl)-7-(carbamoylmethyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(1S)-5-amino-1-(carbamoylmethylcarbamoyl)pentyl]pyrrolidine-2-carboxamide;N-(N-(N-Glycylglycyl)glycyl)-8-L-lysinevasopressin;Glypressin;Terlipressin Acetate;Remestyp;Thymosin α1 Acetate;Gly-Gly-Gly-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2 (disulfide bridge 4:9);Glycylpressin;

/////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Terlipressin, sold under the brand name Terlivaz among others, is an analogue of vasopressin used as a vasoactive drug in the management of low blood pressure. It has been found to be effective when norepinephrine does not help. Terlipressin is a vasopressin receptor agonist.[1]

Medical uses

Terlipressin is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function.[1]

Indications for use include norepinephrine-resistant septic shock[2] and hepatorenal syndrome.[3] In addition, it is used to treat bleeding esophageal varices.[4]

Contraindications

Terlipressin is contraindicated in people experiencing hypoxia or worsening respiratory symptoms and in people with ongoing coronary, peripheral or mesenteric ischemia.[1] Terlipressin may cause fetal harm when used during pregnancy.[1]

Society and culture

Terlipressin is available in New Zealand,[5] Australia, the European Union,[6] India, Pakistan & UAE. It is sold under various brand names including Glypressin.

Clinical data
Trade namesTerlivaz
AHFS/Drugs.comInternational Drug Names
Routes of
administration
Intravenous
ATC codeH01BA04 (WHO)
Legal status
Legal statusUS: ℞-only [1]
Pharmacokinetic data
Protein binding~30%
Identifiers
showIUPAC name
CAS Number14636-12-5 
PubChem CID72081
DrugBankDB02638 
ChemSpider65067 
UNII7Z5X49W53P
KEGGD06672 
CompTox Dashboard (EPA)DTXSID7048952 
ECHA InfoCard100.035.149 
Chemical and physical data
FormulaC52H74N16O15S2
Molar mass1227.38 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

References

  1. Jump up to:a b c d e “Archived copy” (PDF). Archived (PDF) from the original on 2022-09-19. Retrieved 2022-09-19.
  2. ^ O’Brien A, Clapp L, Singer M (2002). “Terlipressin for norepinephrine-resistant septic shock”. Lancet359 (9313): 1209–10. doi:10.1016/S0140-6736(02)08225-9PMID 11955542S2CID 38463837.
  3. ^ Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, Salmerón J, Bataller R, Mas A, Navasa M, Arroyo V, Rodés J (2000). “Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome”. J Hepatol33 (1): 43–8. doi:10.1016/S0168-8278(00)80158-0PMID 10905585.
  4. ^ Ioannou G, Doust J, Rockey D (2003). Ioannou GN (ed.). “Terlipressin for acute esophageal variceal hemorrhage”Cochrane Database Syst Rev (1): CD002147. doi:10.1002/14651858.CD002147PMC 7017851PMID 12535432.
  5. ^ http://www.medsafe.govt.nz/profs/datasheet/g/Glypressin01mgmlFerringinj.pdf Archived 2021-12-20 at the Wayback Machine[bare URL PDF]
  6. ^ “Terlipressin”Archived from the original on 2019-06-26. Retrieved 2018-01-23.

External links

////Terlipressin acetate, テルリプレシン酢酸塩 , FDA 2022, APPROVALS

2022, CC(=O)O.C1CC(N(C1)C(=O)C2CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N2)CC(=O)N)CCC(=O)N)CC3=CC=CC=C3)CC4=CC=C(C=C4)O)NC(=O)CNC(=O)CNC(=O)CN)C(=O)NC(CCCCN)C(=O)NCC(=O)N

NEW DRUG APPROVALS

ONE TIME

$10.00

Betibeglogene autotemcel


Betibeglogene autotemcel

ベチベグロゲンアウトテムセル

2022/8/17, FDA APPROVED Zynteglo

Cellular therapy product
Treatment of betathalassemia

BB305 LVV

bb 1111

BB305 transduced SCD CD34+ HSCs bb1111
LentiGlobin BB305 LVV-transduced autologous SCD CD34+ HSCs bb1111
LentiGlobin drug product for SCD
LentiGlobin drug product for sickle cell disease
LentiGlobin for SCD bb1111

Betibeglogene autotemcel, sold under the brand name Zynteglo, is a medication for the treatment for beta thalassemia.[1][5][2] It was developed by Bluebird Bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in February 2015.[6][7]

The most common adverse reactions include reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch).[5]

It was approved for medical use in the European Union in May 2019,[2] and in the United States in August 2022.[5]

FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions

https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-whoFor Immediate Release:August 17, 2022

Today, the U.S. Food and Drug Administration approved Zynteglo (betibeglogene autotemcel), the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.

“Today’s approval is an important advance in the treatment of beta-thalassemia, particularly in individuals who require ongoing red blood cell transfusions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Given the potential health complications associated with this serious disease, this action highlights the FDA’s continued commitment to supporting development of innovative therapies for patients who have limited treatment options.” 

Beta-thalassemia is a type of inherited blood disorder that causes a reduction of normal hemoglobin and red blood cells in the blood, through mutations in the beta-globin subunit, leading to insufficient delivery of oxygen in the body. The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications. Transfusion-dependent beta-thalassemia, the most severe form of the condition, generally requires life-long red blood cell transfusions as the standard course of treatment. These regular transfusions can be associated with multiple health complications of their own, including problems in the heart, liver and other organs due to an excessive build-up of iron in the body.

Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient’s own cells (bone marrow stem cells) that are genetically modified to produce functional beta-globin (a hemoglobin component).

The safety and effectiveness of Zynteglo were established in two multicenter clinical studies that included adult and pediatric patients with beta-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence, which is attained when the patient maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence.

The most common adverse reactions associated with Zynteglo included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch).

There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in studies of Zynteglo. Patients who receive Zynteglo should have their blood monitored for at least 15 years for any evidence of cancer. Patients should also be monitored for hypersensitivity reactions during Zynteglo administration and should be monitored for thrombocytopenia and bleeding.

This application was granted a rare pediatric disease voucher, in addition to receiving Priority ReviewFast TrackBreakthrough Therapy, and Orphan designations.

The FDA granted approval of Zynteglo to bluebird bio, Inc.

/////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Clinical data
Trade namesZynteglo
Other namesLentiGlobin BB305, autologous CD34+ cells encoding βA-T87Q-globin gene
License dataEU EMAby INNUS DailyMedBetibeglogene autotemcel
Pregnancy
category
Contraindicated[1][2]
Routes of
administration
Intravenous[3]
ATC codeB06AX02 (WHO)
Legal status
Legal statusUK: POM (Prescription only) [1]US: ℞-only [3][4][5]EU: Rx-only [2]In general: ℞ (Prescription only)
Identifiers
UNIIMEE8487RTP
KEGGD11930

Medical uses

Betibeglogene autotemcel is indicated for the treatment of people twelve years and older with transfusion-dependent beta thalassemia (TDT) who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available.[2]

Betibeglogene autotemcel is made individually for each recipient out of stem cells collected from their blood, and must only be given to the recipient for whom it is made.[2] It is given as an autologous intravenous infusion and the dose depends on the recipient’s body weight.[3][2]

Before betibeglogene autotemcel is given, the recipient receives conditioning chemotherapy to clear their bone marrow of cells (myeloablation).[2]

To make betibeglogene autotemcel, the stem cells taken from the recipient’s blood are modified by a virus that carries working copies of the beta globin gene into the cells.[2] When these modified cells are given back to the recipient, they are transported in the bloodstream to the bone marrow where they start to make healthy red blood cells that produce beta globin.[2] The effects of betibeglogene autotemcel are expected to last for the recipient’s lifetime.[2]

Mechanism of action

Beta thalassemia is caused by mutations to or deletions of the HBB gene leading to reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals.[8] LentiGlobin BB305 is a lentiviral vector which inserts a functioning version of the HBB gene into a recipient’s blood-producing hematopoietic stem cells (HSC) ex vivo. The resulting engineered HSCs are then reintroduced to the recipient.[9][10]

History

In early clinical trials several participants with beta thalassemia, who usually require frequent blood transfusions to treat their disease, were able to forgo blood transfusions for extended periods of time.[11][12][13] In 2018, results from phase 1-2 trials suggested that of 22 participants receiving Lentiglobin gene therapy, 15 were able to stop or reduce regular blood transfusions.[14][15]

In February 2021, a clinical trial[16] of betibeglogene autotemcel in sickle cell anemia was suspended following an unexpected instance of acute myeloid leukemia.[17] The HGB-206 Phase 1/2 study is expected to conclude in March 2023.[16]

It was designated an orphan drug by the European Medicines Agency (EMA) and by the U.S. Food and Drug Administration (FDA) in 2013.[2][18] The Food and Drug Administration has also declared betibeglogene autotemcel a Regenerative Medicine Advanced Therapy.[19]

The safety and effectiveness of betibeglogene autotemcel were established in two multicenter clinical studies that included adult and pediatric particpiants with beta-thalassemia requiring regular transfusions.[5] Effectiveness was established based on achievement of transfusion independence, which is attained when the particpiant maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 particpiants receiving betibeglogene autotemcel, 89% achieved transfusion independence.[5]

Society and culture

Legal status

It was approved for medical use in the European Union in May 2019,[2] and in the United States in August 2022.[5]

Names

The international nonproprietary name (INN) is betibeglogene autotemcel.[20]

References

  1. Jump up to:a b c “Zynteglo dispersion for infusion – Summary of Product Characteristics (SmPC)”(emc). 12 May 2020. Retrieved 3 January 2021.[permanent dead link]
  2. Jump up to:a b c d e f g h i j k l m “Zynteglo EPAR”European Medicines Agency (EMA). 25 March 2019. Archived from the original on 16 August 2019. Retrieved 16 August 2019. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. Jump up to:a b c “Archived copy”Archived from the original on 26 August 2022. Retrieved 26 August 2022.
  4. ^ “Zynteglo”U.S. Food and Drug Administration. 17 August 2022. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
  5. Jump up to:a b c d e f g “FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions”U.S. Food and Drug Administration (FDA) (Press release). 17 August 2022. Archived from the original on 21 August 2022. Retrieved 20 August 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ^ “Ten things you might have missed Monday from the world of business”The Boston Globe. 3 February 2015. Archived from the original on 1 August 2020. Retrieved 13 February 2015.
  7. ^ “Lentiviral vectors”. 27 June 2019. Archived from the original on 21 August 2022. Retrieved 8 July 2019.
  8. ^ Cao A, Galanello R (February 2010). “Beta-thalassemia”Genetics in Medicine12 (2): 61–76. doi:10.1097/GIM.0b013e3181cd68edPMID 20098328.
  9. ^ Negre O, Bartholomae C, Beuzard Y, Cavazzana M, Christiansen L, Courne C, et al. (2015). “Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease” (PDF). Current Gene Therapy15 (1): 64–81. doi:10.2174/1566523214666141127095336PMC 4440358PMID 25429463Archived (PDF) from the original on 19 July 2018. Retrieved 19 June 2018.
  10. ^ Thompson AA, Rasko JE, Hongeng S, Kwiatkowski JL, Schiller G, von Kalle C, et al. (2014). “Initial Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for β-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βΑ-T87Q -Globin Vector (LentiGlobin BB305 Drug Product)”Blood124 (21): 549. doi:10.1182/blood.V124.21.549.549Archived from the original on 18 October 2019. Retrieved 13 February 2015.
  11. ^ Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. (September 2010). “Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia”Nature467 (7313): 318–322. Bibcode:2010Natur.467..318Cdoi:10.1038/nature09328PMC 3355472PMID 20844535.
  12. ^ Winslow R (8 December 2015). “New Gene Therapy Shows Promise for Lethal Blood Disease”The Wall Street JournalArchived from the original on 2 March 2020. Retrieved 13 February 2015.
  13. ^ (8 December 2014) bluebird bio Announces Data Demonstrating First Four Patients with β-Thalassemia Major Treated with LentiGlobin are Transfusion-Free Archived 26 September 2015 at the Wayback Machine Yahoo News, Retrieved 17 May 2015
  14. ^ Thompson AA, Walters MC, Kwiatkowski J, Rasko JE, Ribeil JA, Hongeng S, et al. (April 2018). “Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia”The New England Journal of Medicine378 (16): 1479–1493. doi:10.1056/NEJMoa1705342PMID 29669226.
  15. ^ Stein R (18 April 2018). “Gene Therapy For Inherited Blood Disorder Reduced Transfusions”NPRArchived from the original on 21 August 2022. Retrieved 4 March 2019.
  16. Jump up to:a b Clinical trial number NCT02140554 for “A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease” at ClinicalTrials.gov
  17. ^ “Bluebird bio Halts Sickle Cell Trials After Leukemia Diagnosis”BioSpaceArchived from the original on 27 June 2021. Retrieved 27 June 2021.
  18. ^ “Autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human BA-T87Q-globin gene Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 18 March 2013. Archived from the original on 9 June 2020. Retrieved 8 June 2020.
  19. ^ “bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111)”Bluebird Bio (Press release). 16 February 2021. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
  20. ^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”WHO Drug Information34 (1): 34. Archived from the original on 15 July 2020.

////////////Betibeglogene autotemcel, FDA 2022, APPROVALS 2022, ベチベグロゲンアウトテムセル  ,  Zynteglo, bluebird bio, bb 1111

BB305 transduced SCD CD34+ HSCs bb1111
LentiGlobin BB305 LVV-transduced autologous SCD CD34+ HSCs bb1111
LentiGlobin drug product for SCD
LentiGlobin drug product for sickle cell disease
LentiGlobin for SCD bb1111

wdt-2

NEW DRUG APPROVALS

one time

$10.00

Spesolimab


(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYSFT SSWIHWVKQA PGQGLEWMGE INPGNVRTNY
NENFRNKVTM TVDTSISTAY MELSRLRSDD TAVYYCTVVF YGEPYFPYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPEAAGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(Light chain)
QIVLTQSPGT LSLSPGERAT MTCTASSSVS SSYFHWYQQK PGQAPRLWIY RTSRLASGVP
DRFSGSGSGT DFTLTISRLE PEDAATYYCH QFHRSPLTFG AGTKLEIKRT VAAPSVFIFP
PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL
TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC
(Disulfide bridge: H22-H96, H146-H202, H222-L215, H228-H’228, H231-H’231, H263-H323, H369-H427, H’22-H’96, H’146-H’202, H’222-L’215, H’263-H’323, H’369-H’427, L23-L89, L135-L195, L’23-L’89, L’135-L’195)

Spesolimab

スペソリマブ (遺伝子組換え)

FormulaC6480H9988N1736O2012S46
cas2097104-58-8
Mol weight145878.0547
Antipsoriatic, Anti-IL-36 receptor antagonist

fda approved 2022/9/1, spevigo

BI 655130; Spesolimab-sbzo

  • OriginatorBoehringer Ingelheim
  • ClassAnti-inflammatories; Antipsoriatics; Monoclonal antibodies; Skin disorder therapies
  • Mechanism of ActionInterleukin 36 receptor antagonists
  • Orphan Drug StatusYes – Generalised pustular psoriasis
  • RegisteredGeneralised pustular psoriasis
  • Phase II/IIIUlcerative colitis
  • Phase IICrohn’s disease; Hidradenitis suppurativa; Palmoplantar pustulosis
  • DiscontinuedAtopic dermatitis
  • 01 Sep 2022First global approval – Registered for Generalised pustular psoriasis in USA (IV)
  • 01 Sep 2022Adverse events data from the Effisayil 1 phase II trial in Generalised pustular psoriasis released by Boehringer Ingelheim
  • 03 Aug 2022Boehringer Ingelheim anticipates regulatory approval in Generalised pustular psoriasis by 2022

Spesolimab (BI 655130) is a humanised monoclonal antibody, being developed by Boehringer Ingelheim, for the treatment of generalised pustular psoriasis, Crohn’s disease, palmoplantar pustulosis, ulcerative colitis and hidradenitis suppurativa.

What causes Palmoplantar Pustulosis?

Researchers have found some possible causes including smoking, infections, certain medications and genetics. Smoking: Many patients who have PPP are smokers or have smoked in the past. Smoking may cause sweat glands to become inflamed, especially on the hands and feet, which causes pustules to form.

FDA approves the first treatment option for generalized pustular psoriasis flares in adults

  • More than half of patients treated with SPEVIGO® (spesolimab-sbzo) injection, for intravenous use showed no visible pustules one week after receiving treatment
  • Spesolimab is a monoclonal antibody that inhibits interleukin-36 (IL-36) signaling

https://www.boehringer-ingelheim.us/press-release/fda-approves-first-treatment-option-generalized-pustular-psoriasis-flares-adults

Ridgefield, Conn., September 1, 2022 – Boehringer Ingelheim announced today the U.S. Food and Drug Administration has approved SPEVIGO, the first approved treatment option for generalized pustular psoriasis (GPP) flares in adults. SPEVIGO is a novel, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a key part of a signaling pathway within the immune system shown to be involved in the cause of GPP.

“GPP flares can greatly impact a patient’s life and lead to serious, life-threatening complications,” said Mark Lebwohl, M.D., lead investigator and publication author, and Dean for Clinical Therapeutics, Icahn School of Medicine at Mount Sinai, Kimberly and Eric J. Waldman Department of Dermatology, New York. “The approval of SPEVIGO is a turning point for dermatologists and clinicians. We now have an FDA-approved treatment that may help make a difference for our patients who, until now, have not had any approved options to help manage GPP flares.”

Distinct from plaque psoriasis, GPP is a rare and potentially life-threatening neutrophilic skin disease, which is characterized by flares (episodes of widespread eruptions of painful, sterile pustules). In the United States, it is estimated that 1 out of every 10,000 people has GPP. Given that it is so rare, recognizing the signs and symptoms can be challenging and consequently lead to delays in diagnosis.

“This important approval reflects our successful efforts to accelerate our research with the aim to bring innovative treatments faster to the people most in need,” said Carinne Brouillon, Member of the Board of Managing Directors, responsible for Human Pharma, Boehringer Ingelheim. “We recognize how devastating this rare skin disease can be for patients, their families and caregivers. GPP can be life-threatening and until today there have been no specific approved therapies for treating the devastating GPP flares. It makes me proud that with the approval of SPEVIGO we can now offer the first U.S. approved treatment option for those in need.” 

In the 12-week pivotal Effisayil 1 clinical trial, patients experiencing a GPP flare (N=53) were treated with SPEVIGO or placebo. After one week, patients treated with SPEVIGO showed no visible pustules (54%) compared to placebo (6%). 

In Effisayil 1, the most common adverse reactions (≥5%) in patients that received SPEVIGO were asthenia and fatigue, nausea and vomiting, headache, pruritus and prurigo, infusion site hematoma and bruising, and urinary tract infection.

“GPP can have an enormous impact on patients’ physical and emotional wellbeing. With the FDA approval of this new treatment, people living with GPP now have hope in knowing that there is an option to help treat their flares,” said Thomas Seck, M.D., Senior Vice President, Medicine and Regulatory Affairs, Boehringer Ingelheim. “SPEVIGO represents Boehringer Ingelheim’s commitment to delivering meaningful change for patients living with serious diseases with limited treatment options.”

About SPEVIGO
SPEVIGO is indicated for the treatment of GPP flares in adults. SPEVIGO is contraindicated in patients with severe or life-threatening hypersensitivity to spesolimab-sbzo or to any of the excipients in SPEVIGO. Reactions have included drug reaction with eosinophilia and systemic symptoms (DRESS).

What is SPEVIGO?
SPEVIGO is a prescription medicine used to treat generalized pustular psoriasis (GPP) flares in adults. It is not known if SPEVIGO is safe and effective in children.

U.S. FDA grants Priority Review for spesolimab for the treatment of flares in patients with generalized pustular psoriasis (GPP), a rare, life-threatening skin disease

https://www.boehringer-ingelheim.us/press-release/us-fda-grants-priority-review-spesolimab-treatment-flares-patients-generalized

December 15, 2021 – Boehringer Ingelheim today announced that the U.S. Food and Drug Administration (FDA) has accepted a Biologics License Application (BLA) and granted Priority Review for spesolimab for the treatment of generalized pustular psoriasis (GPP) flares. 

FDA grants Priority Review to applications for medicines that, if approved, would offer significant improvement over available options in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions. The FDA has granted spesolimab Orphan Drug Designation for the treatment of GPP, and Breakthrough Therapy Designation for spesolimab for the treatment of GPP flares in adults.

“The FDA acceptance of our filing for spesolimab is a critical step in our efforts to bring this first-in-class treatment to people living with GPP,” said Matt Frankel, M.D., Vice President, Clinical Development and Medical Affairs, Specialty Care, Boehringer Ingelheim. “There is an urgent unmet need for an approved treatment option that can rapidly clear painful GPP flares.”

GPP is a rare, life-threatening neutrophilic skin disease, which is distinct from plaque psoriasis. It is characterized by episodes of widespread eruptions of painful, sterile pustules (blisters of non-infectious pus). There is a high unmet need for treatments that can rapidly and completely resolve the signs and symptoms of GPP flares. Flares greatly affect a person’s quality of life and can lead to hospitalization with serious complications, including heart failure, renal failure, sepsis, and death.

About spesolimab
Spesolimab is a novel, humanized, selective antibody that blocks the activation of the interleukin-36 receptor (IL-36R), a signaling pathway within the immune system shown to be involved in the pathogeneses of several autoimmune diseases, including GPP. Spesolimab is also under investigation for the prevention of GPP flares and for the treatment of other neutrophilic skin diseases, such as palmoplantar pustulosis (PPP) and hidradenitis suppurativa (HS).

About generalized pustular psoriasis (GPP)
GPP is a rare, heterogenous and potentially life-threatening neutrophilic skin disease, which is clinically distinct from plaque psoriasis. GPP is caused by neutrophils (a type of white blood cell) accumulating in the skin, resulting in painful, sterile pustules all over the body. The clinical course varies, with some patients having a relapsing disease with recurrent flares, and others having a persistent disease with intermittent flares. While the severity of GPP flares can vary, if left untreated they can be life-threatening due to complications such as sepsis and multisystem organ failure. This chronic, systemic disease has a substantial quality of life impact for patients and healthcare burden. GPP has a varied prevalence across different geographical regions and more women are affected than men.

Boehringer Ingelheim Immunology: Pioneering Science, Inspired By Patients
Living with fibrotic and inflammatory diseases greatly impacts patients’ lives emotionally and physically. These patients are our guides, partners and inspiration as we redefine treatment paradigms. As a family-owned company, we can plan long-term. Our goal is to discover and develop first-of-their-kind therapies. With a deep understanding of molecular pathways, we are pioneering scientific breakthroughs that target, repair and prevent many fibrotic and inflammatory diseases. By building on long-term external collaborations, we strive to bring treatment breakthroughs to patients in the shortest time. We won’t rest until we can give people the chance to live the lives they want.

Boehringer Ingelheim
Boehringer Ingelheim is working on breakthrough therapies that improve the lives of humans and animals. As a leading research-driven biopharmaceutical company, the company creates value through innovation in areas of high unmet medical need. Founded in 1885 and family-owned ever since, Boehringer Ingelheim takes a long-term perspective. Around 52,000 employees serve more than 130 markets in the three business areas, Human Pharma, Animal Health, and Biopharmaceutical Contract Manufacturing. Learn more at www.boehringer-ingelheim.com.

MPR-US-101971

////////Spesolimab, monoclonal antibody, fda 2022, approvals 2022, Orphan Drug Status, Generalised pustular psoriasis, BI 655130, Spesolimab-sbzo, peptide, monoclonal antibody

wdt

NEW DRUG APPROVALS

ONE TIME

$10.00

Vutrisiran sodium, ALN 65492, Votrisiran


RNA, (Um-​sp-​(2′-​deoxy-​2′-​fluoro)​C-​sp-​Um-​Um-​Gm-​(2′-​deoxy-​2′-​fluoro)​G-​Um-​Um-​(2′-​deoxy-​2′-​fluoro)​A-​Cm-​Am-​Um-​Gm-​(2′-​deoxy-​2′-​fluoro)​A-​Am-​(2′-​deoxy-​2′-​fluoro)​A-​Um-​Cm-​Cm-​Cm-​Am-​sp-​Um-​sp-​Cm)​, complex with RNA (Um-​sp-​Gm-​sp-​Gm-​Gm-​Am-​Um-​(2′-​deoxy-​2′-​fluoro)​U-​Um-​(2′-​deoxy-​2′-​fluoro)​C-​(2′-​deoxy-​2′-​fluoro)​A-​(2′-​deoxy-​2′-​fluoro)​U-​Gm-​Um-​Am-​Am-​Cm-​Cm-​Am-​Am-​Gm-​Am) 3′-​[[(2S,​4R)​-​1-​[29-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​14,​14-​bis[[3-​[[3-​[[5-​[[2-​(acetylamino)​-​2-​deoxy-​β-​D-​galactopyranosyl]​oxy]​-​1-​oxopentyl]​amino]​propyl]​amino]​-​3-​oxopropoxy]​methyl]​-​1,​12,​19,​25-​tetraoxo-​16-​oxa-​13,​20,​24-​triazanonacos-​1-​yl]​-​4-​hydroxy-​2-​pyrrolidinyl]​methyl hydrogen phosphate] (1:1)

Vutrisiran Sodium

Nucleic Acid Sequence

Sequence Length: 44, 23, 2113 a 9 c 8 g 14 umultistranded (2); modified

Vutrisiran sodium

  • ALN 65492
  • Votrisiran

C530H672F9N171Na43O323P43S6 : 17289.77
[1867157-35-4 , Vutrisiran]

FormulaC530H672F9N171O323P43S6.43Na  ORC530H672F9N171Na43O323P43S6
CAS1867157-35-4 , VURISIRAN
Mol weight17289.7661

FDA APPROVED, AMVUTTRA, 2022/6/13

ブトリシランナトリウム
EfficacyGene expression regulator
  DiseasePolyneuropathy of hereditary transthyretin-mediated amyloidosis [D
CommentRNA interference (RNAi) drug
Treatment of transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis)

UNII28O0WP6Z1P UNII

Vutrisiran
Vutrisiran Sodium is a sodium salt of an siRNA derivative targeting transthyretin (TTR) covalently linked to a triantennary GalNAc3 complex at the 3’ end of the sense strand. The siRNA moiety is composed of a duplex oligonucleotide of sense strand consisting of chemically modified 21 nucleotide residues and antisense strand consisting of chemically modified 23 nucleotide residues each.

Vutrisiran is a double-stranded small interfering ribonucleic acid (siRNA) that targets wild-type and mutant transthyretin (TTR) messenger RNA (mRNA).7 This siRNA therapeutic is indicated for the treatment of neuropathies associated with hereditary transthyretin-mediated amyloidosis (ATTR), a condition caused by mutations in the TTR gene.2 More than 130 TTR mutations have been identified so far,3 but the most common one is the replacement of valine with methionine at position 30 (Val30Met).2 The Val30Met variant is the most prevalent among hereditary ATTR patients with polyneuropathy, especially in Portugal, France, Sweden, and Japan.2

TTR mutations lead to the formation of misfolded TTR proteins, which form amyloid fibrils that deposit in different types of tissues. By targeting TTR mRNA, vutrisiran reduces the serum levels of TTR.6,7 Vutrisiran is commercially available as a conjugate of N-acetylgalactosamine (GalNAc), a residue that enables the delivery of siRNA to hepatocytes.5,7 This delivery platform gives vutrisiran high potency and metabolic stability, and allows for subcutaneous injections to take place once every three months.8 Another siRNA indicated for the treatment of polyneuropathy associated with hereditary ATTR is patisiran.2 Vutrisiran was approved by the FDA in June 2022.

CLIP

https://www.nature.com/articles/s41392-020-0207-x

figure 1

Schematic illustrations of the working mechanisms of miRNA (a) and siRNA (b)

figure 2

Structures of chemical modifications and analogs used for siRNA and ASO decoration. According to the modification site in the nucleotide acid, these structures can be divided into three classes: phosphonate modification, ribose modification and base modification, which are marked in red, purple and blue, respectively. R = H or OH, for RNA or DNA, respectively. (S)-cEt-BNA (S)-constrained ethyl bicyclic nucleic acid, PMO phosphorodiamidate morpholino oligomer

figure 3

Representative designs for the chemical modification of siRNA. The sequences and modification details for ONPATTRO®, QPI-1007, GIVLAARI™ and inclisiran are included. The representative siRNA modification patterns developed by Alnylam (STC, ESC, advanced ESC and ESC+) and arrowhead (AD1-3 and AD5) are shown. Dicerna developed four GalNAc moieties that can be positioned at the unpaired G–A–A–A nucleotides of the DsiRNA structure. 2′-OMe 2′-methoxy, 2′-F 2′-fluoro, GNA glycol nucleic acid, UNA unlocked nucleic acid, SS sense strand, AS antisense strand

figure 6

siRNA delivery platforms that have been evaluated preclinically and clinically. Varieties of lipids or lipidoids, siRNA conjugates, peptides, polymers, exosomes, dendrimers, etc. have been explored and employed for siRNA therapeutic development by biotech companies or institutes. The chemical structures of the key component(s) of the discussed delivery platforms, including Dlin-DMA, Dlin-MC3-DMA, C12-200, cKK-E12, GalNAc–siRNA conjugates, MLP-based DPC2.0 (EX-1), PNP, PEI, PLGA-based LODER, PTMS, GDDC4, PAsp(DET), cyclodextrin-based RONDEL™ and dendrimer generation 3 are shown. DLin-DMA (1,2-dilinoleyloxy-3-dimethylaminopropane), DLin-MC3-DMA (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino) butanoate, DPC Dynamic PolyConjugates, MLP membrane-lytic peptide, CDM carboxylated dimethyl maleic acid, PEG polyethylene glycol, NAG N-acetylgalactosamine, PNP polypeptide nanoparticle, PEI poly(ethyleneimine), LODER LOcal Drug EluteR, PLGA poly(lactic-co-glycolic) acid, PTMS PEG-PTTMA-P(GMA-S-DMA) poly(ethylene glycol)-co-poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl))] ethane methacrylate-co-poly(dimethylamino glycidyl methacrylate), GDDC4 PG-P(DPAx-co-DMAEMAy)-PCB, where PG is guanidinated poly(aminoethyl methacrylate) PCB is poly(carboxybetaine) and P(DPAx-co-DMAEMAy) is poly(dimethylaminoethyl methacrylate-co-diisopropylethyl methacrylate), PEG-PAsp(DET) polyethylene glycol-b-poly(N′-(N-(2-aminoethyl)-2-aminoethyl) aspartamide), PBAVE polymer composed of butyl and amino vinyl ether, RONDEL™ RNAi/oligonucleotide nanoparticle delivery

Vutrisiran SodiumVutrisiran Sodium is a sodium salt of an siRNA derivative targeting transthyretin (TTR) covalently linked to a triantennary GalNAc3 complex at the 3’ end of the sense strand. The siRNA moiety is composed of a duplex oligonucleotide of sense strand consisting of chemically modified 21 nucleotide residues and antisense strand consisting of chemically modified 23 nucleotide residues each.C530H672F9N171Na43O323P43S6 : 17289.77
[1867157-35-4 , Vutrisiran]

REF

Nucleic Acids Research (2019), 47(7), 3306-3320. 

Drug Metabolism & Disposition (2019), 47(10), 1183-1201.  

PATENT

WO 2020128816

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020128816

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt or prodrug thereof and an additional therapeutic agent for the treatment of transthyretin amyloidosis. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent for the treatment of transthyretin amyloidosis.

The present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof a combination of a benzoxazole derivative transthyretin stabilizer or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent. Particularly, the present invention relates to pharmaceutical compositions and methods of treatment comprising administering to a patient in need thereof 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof and one or more additional therapeutic agent. The compositions and methods of the invention are useful in stabilizing transthyretin, inhibiting transthyretin misfolding, proteolysis, and treating amyloid diseases associated thereto.

Transthyretin (TTR) is a 55 kDa homotetrameric protein present in serum and cerebral spinal fluid and which functions as a transporter of L-thyroxine (T4) and holo-retinol binding protein (RBP). TTR has been found to be an amyloidogenic protein that, under certain conditions, can be transformed into fibrils and other aggregates which can lead to disease pathology such as polyneuropathy or cardiomyopathy in humans.

US Patent Nos. 7,214,695; 7,214,696; 7,560,488; 8, 168.683; and 8,653,119 each of which is incorporated herein by reference, discloses benzoxazole derivatives which act as transthyretin stabilizers and are of the formula

or a pharmaceutically acceptable salt thereof; wherein Ar is 3,5-difluorophenyl, 2,6-difluorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl. Particularly, 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis) of the formula

is disclosed therein. Tafamidis is an orally active transthyretin stabilizer that inhibits tetramer dissociation and proteolysis that has been approved in certain jurisdictions for the treatment of transthyretin polyneuropathy (TTR-PN) and is currently in development for the treatment of transthyretin cardiomyopathy (TTR-CM). US Patent No. 9,249, 112, also incorporated herein by reference, discloses polymorphic forms of the meglumine salt of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis meglumine). US Patent No. 9,770,441 discloses polymorphic forms of the free acid of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (tafamidis), and is also incorporated by reference herein.

Summary of the Invention

The present invention provides pharmaceutical compositions and methods comprising the compound 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent. Particular embodiments of this invention are pharmaceutical compositions and methods comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agents selected from the group consisting of agents that lower plasma levels of TTR such as an antisense therapy, TTR gene editing therapy, transcriptional modulators, translational modulators, TTR protein degraders and antibodies that bind and reduce TTR levels; amyloid reduction therapies such as anti amyloid antibodies (either TTR selective or general), stimulators of amyloid clearance, fibril disruptors and therapies that inhibit amyloid nucleation; other TTR stabilizers; and TTR modulators such as therapeutics which inhibit TTR cleavage. Particularly, the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and the present invention provides pharmaceutical compositions and methods comprising tafamidis or tafamidis meglumine salt with one or more additional therapeutic agents. More particularly, the present invention provides pharmaceutical compositions and

methods comprising a polymorphic form of tafamidis free acid or a polymorphic form of tafamidis meglumine salt with one or more additional therapeutic agents.

The present invention also provides a method of treating or preventing transthyretin amyloidosis in a patient, the method comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of 2-(3,5-dichlorophenyl)-1,3-benzoxazole- 6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agents.

A particular embodiment of the present method of treatment is the method comprising a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent are administered orally. Additional embodiments of this invention are methods of treatment as described above wherein the 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof, and one or more additional therapeutic agent are administered parenterally (intravenously or subcutaneously). Further embodiments of this invention are methods of treatment wherein the 2-(3,5-dichlorophenyl)-1, 3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally and the one or more additional therapeutic agent is administered either orally or parenterally. Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR Another embodiment of the present invention is wherein a pharmaceutical composition comprising 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agent is administered parenterally and then 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR 5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR 5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof is administered orally. A particular method of treatment is a method of treating TTR amyloidosis such as TTR polyneuropathy or TTR

cardiomyopathy, the method comprising administering to a patient in need thereof a therapeutically effective amount of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more additional therapeutic agents.

Brief Description of the Drawings

REF

Biochemical Pharmacology (Amsterdam, Netherlands) (2021), 189, 114432.

PATENT

WO 2021041884 

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021041884

Exemplary RNAi agents that reduce the expression of TTR include patisiran and vutrisiran.

The ter s “antisense polynucleotide agent”, “antisense oligonucleotide”, “antisense compound”, and “antisense agent” as used interchangeably herein, refer to an agent comprising a single-stranded oligonucleotide that specifically binds to the target nucleic acid molecules via hydrogen bonding (e.g., Watson-Crick, Hoogsteen, or reversed Hoogsteen hydrogen bonding) and inhibits the expression of the targeted nucleic acid by an antisense mechanism of action, e.g., by RNase H. In some embodiments, an antisense agent is a nucleic acid therapeutic that acts by reducing the expression of a target gene, thereby reducing the expression of the polypeptide encoded by the target gene. Exemplary antisense agents that reduce the expression of TTR include inotersen and Ionis 682884/ ION-TTR-LRx (see, e.g., WO2014179627 which is incorporated by reference in its entirety). Further antisense agents that reduce the expression of TTR are provided, for example in WO2011139917 and WO2014179627, each of which is incorporated by reference in its entirety.

REF

Clinical Pharmacology & Therapeutics (Hoboken, NJ, United States) (2021), 109(2), 372-382

Annals of Plastic Surgery (2021), 86(2S_Suppl_1), S23-S29.

Journal of Cardiovascular Pharmacology (2021), 77(5), 544-548. 

Annals of Pharmacotherapy (2021), 55(12), 1502-1514.

Kidney International (2022), 101(2), 208-211

//////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

figure 7

Tissues targeted by siRNA and miRNA therapeutics currently being investigated at the clinical stage. The corresponding therapeutic names are shown beside the tissues

CLIP

Vutrisiran An Investigational RNAi Therapeutic for ATTR Amyloidosis Vutrisiran has not been approved by the U.S. Food and Drug Administration, European Medicines Agency, or any other regulatory authority and no conclusions can or should be drawn regarding the safety or effectiveness of this investigational therapeutic. Overview • Vutrisiran is an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, which encompasses both hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis.1, 2 • Vutrisiran inhibits the production of disease-causing transthyretin (TTR) protein by the liver, leading to a reduction in the level of TTR in the blood.1, 2 • Vutrisiran is administered subcutaneously (under the skin) and utilizes one of Alnylam’s delivery platforms known as the Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform.1, 2 • Vutrisiran is administered every three months.2 • Vutrisiran is under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA). Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In the U.S. vutrisiran has received an action date under the Prescription Drug User Fee Act (PDUFA) of April 14, 2022. The Company received orphan drug designation in Japan. Alnylam has global commercial rights to vutrisiran, assuming regulatory approvals. Clinical Development • A Phase 1 clinical study of vutrisiran was conducted in 80 healthy volunteers (60 received vutrisiran and 20 received placebo). Vutrisiran demonstrated an acceptable safety profile and a single dose reduced serum TTR for a period of at least 90 days.2 • The safety and efficacy of vutrisiran are being evaluated in the HELIOS Phase 3 clinical program, currently consisting of two clinical trials: HELIOS-A and HELIOS-B. • HELIOS-A is a randomized, open-label, global multi-center Phase 3 study of 164 adult patients with hATTR amyloidosis with polyneuropathy.1 • The primary endpoint of HELIOS-A is change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months. • Secondary endpoints at 9 months include the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score and the 10-Meter Walk Test (10-MWT). • The 9-month endpoints will be analyzed at 18 months with the addition of other secondary endpoints. • HELIOS-B is a randomized, double-blind, placebo-controlled Phase 3 study of 655 adult patients with ATTR amyloidosis with cardiomyopathy (including both hATTR and wtATTR amyloidosis).3 • The primary endpoint will evaluate the efficacy of vutrisiran versus placebo for the composite outcome of all-cause mortality and recurrent cardiovascular (CV) events (CV hospitalizations and urgent heart failure (HF) visits) at 30-36 months. • Secondary endpoints include the change from baseline in the 6-minute walk test (6-MWT), health status measured using the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), echocardiographic assessments of mean left ventricular wall thickness and global longitudinal strain, the N-terminal prohormone B-type natriuretic peptide (NT-proBNP) as a cardiac biomarker, and all-cause mortality, rate of recurrent CV events, and composite of all-cause mortality and recurrent all-cause hospitalizations and urgent HF visits at month 30 or 30-36 months. Page 2 © 2021 Alnylam Pharmaceuticals, Inc. All rights reserved. TTRsc02-USA-00012 v4 About ATTR Amyloidosis • ATTR amyloidosis is a rare, underdiagnosed, rapidly progressive, debilitating, and fatal disease caused by misfolded TTR that accumulates as amyloid fibrils in multiple tissues including the nerves, heart, and GI tract. There are two types of ATTR amyloidosis: hATTR amyloidosis and wtATTR amyloidosis.4,5,6 • hATTR amyloidosis is an inherited condition that is caused by variants (i.e., mutations) in the transthyretin (TTR) gene.5,7,8 TTR protein is produced primarily in the liver and is normally a carrier of vitamin A.9 The variant results in misfolded TTR proteins that accumulate as amyloid deposits in multiple tissues, including the nerves, heart and gastrointestinal (GI) tract.5, 6, 7 It is a multisystem disease that can include sensory and motor, autonomic, and cardiac symptoms. The condition can have a debilitating impact on a patient’s life and may lead to premature death with a median survival of 4.7 years following diagnosis.8,10 It is estimated that there are approximately 50,000 patients with hATTR amyloidosis worldwide.11 • wtATTR amyloidosis is a non-hereditary condition that occurs when misfolded wild-type TTR accumulates as amyloid deposits in multiple organs. It predominantly manifests as cardiac symptoms, but other systems are also involved, and commonly leads to heart failure and mortality within 2.5 to 5.5 years.12,13,14,15,16,17,18,19 wtATTR amyloidosis affects an estimated 200,000-300,000 people worldwide.20 • Alnylam is committed to developing multiple treatment options for people who are living with ATTR amyloidosis to help manage the debilitating and progressive nature of the disease. For more information about vutrisiran, please contact media@alnylam.com. For more information on HELIOS-A (NCT03759379) and HELIOS-B (NCT04153149) please visit http://www.clinicaltrials.gov or contact media@alnylam.com. Current information as of November 2021

CLIP

Alnylam announces extension of review period for new drug vutrisiran to treat ATTR amyloidosis

https://www.medthority.com/news/2022/4/alnylam-announces-3-month-extension-of-review-period-for-new-drug-application-for-vutrisiran-to-treat-attr-amyloidosis/

Alnylam announces 3-month extension of review period for new drug application for vutrisiran to treat ATTR amyloidosis.

Alnylam Pharmaceuticals, Inc., a RNAi therapeutics company, announced that the FDA has extended the review timeline of the New Drug Application (NDA) for vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, to allow for the review of newly added information related to the new secondary packaging and labelling facility.

Alnylam recently learned that the original third-party secondary packaging and labelling facility the Company planned to use for the vutrisiran launch was recently inspected and the inspection requires classification for the FDA to take action on the vutrisiran NDA. The inspection observations were not directly related to vutrisiran. In order to minimize delays to approval, Alnylam has identified a new facility to pack and label vutrisiran and submitted an amendment to the NDA for review by the FDA. The updated Prescription Drug User Fee Act (PDUFA) goal date to allow for this review is July 14, 2022. No additional clinical data have been requested by the FDA.

////////////Vutrisiran sodium,  APPROVALS 2022, FDA 2022, FDA APPROVED, AMVUTTRA, 2022/6/13, ブトリシランナトリウム , ALN 65492, Votrisiran, siRNA

wdt-2

NEW DRUG APPROVALS

ONE TIME TO SUSTAIN AND MAINTAIN THIS BLOG

$10.00

Tirzepatide


YXEGTFTSDY SIXLDKIAQK AFVQWLIAGG PSSGAPPPS

Tirzepatide.svg
tirzepatide
ChemSpider 2D Image | tirzepatide | C225H347N47O69
Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing | Organic Process Research & Development

Tirzepatide

チルゼパチド

LY3298176,

FormulaC225H348N48O68
CAS2023788-19-2
Mol weight4813.4514

FDA APPROVED 2022/5/13, Mounjaro

ClassAntidiabetic agent
GLP-1 receptor agonist
EfficacyAntidiabetic, Gastric inhibitory polypeptide receptor agonist, Glucagon-like peptide 1 (GLP-1) receptor agonist
  DiseaseType 2 diabetes mellitus

Tirzepatide is an agonist of human glucose-dependent insulinotropic polypeptide (GIP) and human glucagon-like peptide-1 (GLP-1) receptors, whose amino acid residues at positions 2 and 13 are 2-methylAla, and the C-terminus is amidated Ser. A 1,20-icosanedioic acid is attached to Lys at position 20 via a linker which consists of a Glu and two 8-amino-3,6-dioxaoctanoic acids. Tirzepatide is a synthetic peptide consisting of 39 amino acid residues.

C225H348N48O68 : 4813.45
[2023788-19-2]

L-​Serinamide, L-​tyrosyl-​2-​methylalanyl-​L-​α-​glutamylglycyl-​L-​threonyl-​L-​phenylalanyl-​L-​threonyl-​L-​seryl-​L-​α-​aspartyl-​L-​tyrosyl-​L-​seryl-​L-​isoleucyl-​2-​methylalanyl-​L-​leucyl-​L-​α-​aspartyl-​L-​lysyl-​L-​isoleucyl-​L-​alanyl-​L-​glutaminyl-​N6-​[(22S)​-​22,​42-​dicarboxy-​1,​10,​19,​24-​tetraoxo-​3,​6,​12,​15-​tetraoxa-​9,​18,​23-​triazadotetracont-​1-​yl]​-​L-​lysyl-​L-​alanyl-​L-​phenylalanyl-​L-​valyl-​L-​glutaminyl-​L-​tryptophyl-​L-​leucyl-​L-​isoleucyl-​L-​alanylglycylglycyl-​L-​prolyl-​L-​seryl-​L-​serylglycyl-​L-​alanyl-​L-​prolyl-​L-​prolyl-​L-​prolyl-

Other Names

  • L-Tyrosyl-2-methylalanyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-isoleucyl-2-methylalanyl-L-leucyl-L-α-aspartyl-L-lysyl-L-isoleucyl-L-alanyl-L-glutaminyl-N6-[(22S)-22,42-dicarboxy-1,10,19,24-tetraoxo-3,6,12,15-tetraoxa-9,18,23-triazadotetracont-1-yl]-L-lysyl-L-alanyl-L-phenylalanyl-L-valyl-L-glutaminyl-L-tryptophyl-L-leucyl-L-isoleucyl-L-alanylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide

Tirzepatide, sold under the brand name Mounjaro,[1] is a medication used for the treatment type 2 diabetes.[2][3][4] Tirzepatide is given by injection under the skin.[2] Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort and abdominal pain.[2]

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones involved in blood sugar control.[2] Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control.[2] Tirzepatide was approved for medical use in the United States in May 2022.[2]

SYN

https://pubs.acs.org/doi/10.1021/acs.oprd.1c00108

Abstract Image

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

PATENT

  • WO2016111971
  • US2020023040
  • WO2019245893
  • US2020155487
  • US2020155650
  • WO2020159949CN112592387
  • WO2021066600CN112661815
  • WO2021154593
  • US2021338769

NEW DRUG APPROVALS

ONE TIME TO MAINTAIN THIS BLOG SUBSCRIPTION

$10.00

//////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Medical uses

Tirzepatide in indicated to improve blood sugar control in adults with type 2 diabetes, as an addition to diet and exercise.[2]

Contraindications

Tirzepatide should not be used in people with a personal or family history of medullary thyroid cancer or in people with multiple endocrine neoplasia syndrome type 2.[2]

Adverse effects

Preclinical, phase I, and phase II trials have indicated that tirzepatide exhibits similar adverse effects to other established GLP-1 receptor agonists, such as GLP-1 receptor agonist dulaglutide. These effects occur largely within the gastrointestinal tract.[5] The most frequently observed adverse effects are nausea, diarrhoea and vomiting, which increased in incidence with the dosage amount (i.e. higher likelihood the higher the dose). The number of patients who discontinued taking tirzepatide also increased as dosage increased, with patients taking 15 mg having a 25% discontinuation rate vs 5.1% for 5 mg patients and 11.1% for dulaglutide.[6] To a slightly lesser extent, patients also reported reduced appetite.[5] Other side effects reported were dyspepsia, constipation, abdominal pain, dizziness and hypoglycaemia.[7][8]

Pharmacology

Tirzepatide is an analogue of gastric inhibitory polypeptide (GIP), a human hormone which stimulates the release of insulin from the pancreas. Tirzepatide is a linear polypeptide of 39 amino acids which has been chemically modified by lipidation to improve its uptake into cells and its stability to metabolism.[9] The compound is administered as a weekly subcutaneous injection.[10] It completed phase III trials globally in 2021.[11][12]

Mechanism of action

Tirzepatide has a greater affinity to GIP receptors than to GLP-1 receptors, and this dual agonist behaviour has been shown to produce greater reductions of hyperglycemia compared to a selective GLP-1 receptor agonist.[3] Signaling studies have shown that this is due to tirzepatide mimicking the actions of natural GIP at the GIP receptor.[13] However, at the GLP-1 receptor, tirzepatide shows bias towards cAMP (a messenger associated with regulation of glycogen, sugar and lipid metabolism) generation, rather than β-arrestin recruitment. This combination of preference towards GIP receptor and distinct signaling properties at GLP-1 suggest this biased agonism increases insulin secretion.[13] Tirzepatide has also been shown to increase levels of adiponectin, an adipokine involved in the regulation of both glucose and lipid metabolism, with a maximum increase of 26% from baseline after 26 weeks, at the 10 mg dosage.[3]

Chemistry

Structure

Tirzepatide is an analog of the human GIP hormone with a C20 fatty-diacid portion attached, used to optimise the uptake and metabolism of the compound.[9] The fatty-diacid section (eicosanedioic acid) is linked via a glutamic acid and two (2-(2-aminoethoxy)ethoxy)acetic acid units to the side chain of the lysine residue. This arrangement allows for a much longer half life, extending the time between doses, because of its high affinity to albumin.[14]

Synthesis

The synthesis of tirzepatide was first disclosed in patents filed by Eli Lilly and Company.[15] This uses standard solid phase peptide synthesis, with an allyloxycarbonyl protecting group on the lysine at position 20 of the linear chain of amino acids, allowing a final set of chemical transformations in which the sidechain amine of that lysine is derivatized with the lipid-containing fragment.

Large-scale manufacturing processes have been reported for this compound.[16]

History

Indiana-based pharmaceutical company Eli Lilly and Company first applied for a patent for a method of glycemic control using tirzepatide in early 2016.[15] The patent was published late that year. After passing phase 3 clinical trials, Lilly applied for FDA approval in October 2021 with a priority review voucher.[17]

Following the completion of the pivotal SURPASS-2 trial no. NCT03987919, the company announced on 28 April that tirzepatide had successfully met their endpoints in obese and overweight patients without diabetes.[18] Alongside results from the SURMOUNT-1 trial no. NCT04184622, they suggest that tirzepatide may potentially be a competitor for existing diabetic medication semaglutide, manufactured by Novo Nordisk.[19][20]

In industry-funded preliminary trials comparing tirzepatide to the existing diabetes medication semaglutide (an injected analogue of the hormone GLP-1), tirzepatide showed minor improvement of reductions (2.01%–2.30% depending on dosage) in glycated hemoglobin tests relative to semaglutide (1.86%).[21] A 10 mg dose has also been shown to be effective in reducing insulin resistance, with a reduction of around 8% from baseline, measured using HOMA2-IR (computed with fasting insulin).[3] Fasting levels of IGF binding proteins like IGFBP1 and IGFBP2 increased following tirzepatide treatment, increasing insulin sensitivity.[3] A meta-analysis published by Dutta et al. showed that over 1-year clinical use, tirzepatide was observed to be superior to dulaglutide, semaglutide, degludec, and insulin glargine with regards to glycemic efficacy and obesity reduction. Tirzepatide is perhaps the most potent agent developed to date to tackle the global problem of “diabesity“.[22]

Society and culture

Names

Tirzepatide is the international nonproprietary name (INN).[23]

References

  1. Jump up to:a b “Highlights of prescribing information” (PDF). accessdata.fda.gov. FDA. May 2022. Retrieved 14 May 2022.
  2. Jump up to:a b c d e f g h i “FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes”U.S. Food and Drug Administration (FDA) (Press release). 13 May 2022. Retrieved 13 May 2022. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. (January 2021). “Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes”The Journal of Clinical Endocrinology and Metabolism106 (2): 388–396. doi:10.1210/clinem/dgaa863PMC 7823251PMID 33236115.
  4. ^ Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al. (December 2018). “LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept”Molecular Metabolism18: 3–14. doi:10.1016/j.molmet.2018.09.009PMC 6308032PMID 30473097.
  5. Jump up to:a b Min T, Bain SC (January 2021). “The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials”Diabetes Therapy12 (1): 143–157. doi:10.1007/s13300-020-00981-0PMC 7843845PMID 33325008.
  6. ^ Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. (November 2018). “Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial”The Lancet392 (10160): 2180–2193. doi:10.1016/S0140-6736(18)32260-8PMID 30293770.
  7. ^ Frias JP, Nauck MA, Van J, Benson C, Bray R, Cui X, et al. (June 2020). “Efficacy and tolerability of tirzepatide, a dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes: A 12-week, randomized, double-blind, placebo-controlled study to evaluate different dose-escalation regimens”Diabetes, Obesity & Metabolism22 (6): 938–946. doi:10.1111/dom.13979PMC 7318331PMID 31984598.
  8. ^ Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, Rodríguez Á (February 2022). “Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial”. JAMA327 (6): 534–545. doi:10.1001/jama.2022.0078PMID 35133415.
  9. Jump up to:a b Ahangarpour M, Kavianinia I, Harris PW, Brimble MA (January 2021). “Photo-induced radical thiol-ene chemistry: a versatile toolbox for peptide-based drug design”. Chemical Society Reviews. Royal Society of Chemistry. 50 (2): 898–944. doi:10.1039/d0cs00354aPMID 33404559S2CID 230783854.
  10. ^ Bastin M, Andreelli F (2019). “Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short Review On Emerging Data And Therapeutic Potential”Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy12: 1973–1985. doi:10.2147/DMSO.S191438PMC 6777434PMID 31686879.
  11. ^ “Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly’s SURPASS program” (Press release). Eli Lilly and Company. 17 February 2021. Retrieved 28 October 2021 – via PR Newswire.
  12. ^ “Lilly : Phase 3 Tirzepatide Results Show Superior A1C And Body Weight Reductions In Type 2 Diabetes”Business Insider. RTTNews. 19 October 2021. Retrieved 28 October 2021.
  13. Jump up to:a b Willard FS, Douros JD, Gabe MB, Showalter AD, Wainscott DB, Suter TM, et al. (September 2020). “Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist”JCI Insight5 (17). doi:10.1172/jci.insight.140532PMC 7526454PMID 32730231.
  14. ^ Østergaard S, Paulsson JF, Kofoed J, Zosel F, Olsen J, Jeppesen CB, et al. (October 2021). “The effect of fatty diacid acylation of human PYY3-36 on Y2 receptor potency and half-life in minipigs”Scientific Reports11 (1): 21179. Bibcode:2021NatSR..1121179Odoi:10.1038/s41598-021-00654-3PMC 8551270PMID 34707178.
  15. Jump up to:a b US patent 9474780, Bokvist BK, Coskun T, Cummins RC, Alsina-Fernandez J, “GIP and GLP-1 co-agonist compounds”, issued 2016-10-25, assigned to Eli Lilly and Co
  16. ^ Frederick MO, Boyse RA, Braden TM, Calvin JR, Campbell BM, Changi SM, et al. (2021). “Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing”. Organic Process Research & Development25 (7): 1628–1636. doi:10.1021/acs.oprd.1c00108S2CID 237690232.
  17. ^ Sagonowsky, Eric (26 October 2021). “As Lilly gears up for key 2022 launches, Trulicity, Taltz and more drive solid growth”Fierce Pharma. Retrieved 9 April 2022.
  18. ^ Kellaher, Colin (28 April 2022). “Eli Lilly’s Tirzepatide Meets Main Endpoints in Phase 3 Obesity Study >LLY”Dow Jones Newswires. Retrieved 29 April 2022 – via MarketWatch.
  19. ^ Kahan, Scott; Garvey, W. Timothy (28 April 2022). “SURMOUNT-1: Adults achieve weight loss of 16% or more at 72 weeks with tirzepatide”healio.com. Retrieved 29 April 2022.
  20. ^ Taylor, Nick Paul (28 April 2022). “SURMOUNT-able: Lilly’s tirzepatide clears high bar set by Novo’s Wegovy in obesity”FierceBiotech. Retrieved 29 April 2022.
  21. ^ Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, et al. (August 2021). “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes”. The New England Journal of Medicine385 (6): 503–515. doi:10.1056/NEJMoa2107519PMID 34170647S2CID 235635529.
  22. ^ Dutta D, Surana V, Singla R, Aggarwal S, Sharma M (November–December 2021). “Efficacy and safety of novel twincretin tirzepatide a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis”. Indian Journal of Endocrinology and Metabolism25 (6): 475–489. doi:10.4103/ijem.ijem_423_21.
  23. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 81”. WHO Drug Information33 (1). hdl:10665/330896.

Further reading

External links

  • “Tirzepatide”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03954834 for “A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1)” at ClinicalTrials.gov
  • Clinical trial number NCT03987919 for “A Study of Tirzepatide (LY3298176) Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes (SURPASS-2)” at ClinicalTrials.gov
  • Clinical trial number NCT03882970 for “A Study of Tirzepatide (LY3298176) Versus Insulin Degludec in Participants With Type 2 Diabetes (SURPASS-3)” at ClinicalTrials.gov
  • Clinical trial number NCT03730662 for “A Study of Tirzepatide (LY3298176) Once a Week Versus Insulin Glargine Once a Day in Participants With Type 2 Diabetes and Increased Cardiovascular Risk (SURPASS-4)” at ClinicalTrials.gov
  • Clinical trial number NCT04039503 for “A Study of Tirzepatide (LY3298176) Versus Placebo in Participants With Type 2 Diabetes Inadequately Controlled on Insulin Glargine With or Without Metformin (SURPASS-5)” at ClinicalTrials.gov

CLIP

https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjarotm-tirzepatide-injection-first-and

FDA approves Lilly’s Mounjaro™ (tirzepatide) injection, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes

May 13, 2022

Download PDF

Mounjaro delivered superior A1C reductions versus all comparators in phase 3 SURPASS clinical trials

While not indicated for weight loss, Mounjaro led to significantly greater weight reductions versus comparators in a key secondary endpoint

Mounjaro represents the first new class of diabetes medicines introduced in nearly a decade and is expected to be available in the U.S. in the coming weeks

INDIANAPOLIS, May 13, 2022 /PRNewswire/ — The U.S. Food and Drug Administration (FDA) approved Mounjaro™ (tirzepatide) injection, Eli Lilly and Company’s (NYSE: LLY) new once-weekly GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Mounjaro has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.

As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones.1

“Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro’s efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials,” said Juan Pablo Frías, M.D., Medical Director, National Research Institute and Investigator in the SURPASS program.

Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

The approval was based on results from the phase 3 SURPASS program, which included active comparators of injectable semaglutide 1 mg, insulin glargine and insulin degludec. Efficacy was evaluated for Mounjaro 5 mg, 10 mg and 15 mg used alone or in combination with commonly prescribed diabetes medications, including metformin, SGLT2 inhibitors, sulfonylureas and insulin glargine. Participants in the SURPASS program achieved average A1C reductions between 1.8% and 2.1% for Mounjaro 5 mg and between 1.7% and 2.4% for both Mounjaro 10 mg and Mounjaro 15 mg. While not indicated for weight loss, mean change in body weight was a key secondary endpoint in all SURPASS studies. Participants treated with Mounjaro lost between 12 lb. (5 mg) and 25 lb. (15 mg) on average.1

Side effects reported in at least 5% of patients treated with Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion (dyspepsia), and stomach (abdominal) pain. The labeling for Mounjaro contains a Boxed Warning regarding thyroid C-cell tumors. Mounjaro is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.1

“Lilly has a nearly 100-year heritage of advancing care for people living with diabetes – never settling for current outcomes. We’re not satisfied knowing that half of the more than 30 million Americans living with type 2 diabetes are not reaching their target blood glucose levels,” said Mike Mason, president, Lilly Diabetes. “We are thrilled to introduce Mounjaro, which represents the first new class of type 2 diabetes medication introduced in almost a decade and embodies our mission to bring innovative new therapies to the diabetes community.”

Mounjaro is expected to be available in the United States in the coming weeks. Lilly is committed to helping people access the medicines they are prescribed and will work with insurers, health systems and providers to help enable patient access to Mounjaro. Lilly plans to offer a Mounjaro savings card for people who qualify. Patients or healthcare professionals with questions about Mounjaro can visit www.Mounjaro.com or call The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979).

Tirzepatide is also under regulatory review for the treatment of type 2 diabetes in Europe, Japan and several additional markets. A multimedia gallery is available on Lilly.com.

About the SURPASS clinical trial program
The SURPASS phase 3 global clinical development program for tirzepatide began in late 2018 and included five global registration trials and two regional trials in Japan. These studies ranged from 40 to 52 weeks and evaluated the efficacy and safety of Mounjaro 5 mg, 10 mg and 15 mg as a monotherapy and as an add-on to various standard-of-care medications for type 2 diabetes. The active comparators in the studies were injectable semaglutide 1 mg, insulin glargine and insulin degludec. Collectively, the five global registration trials consistently demonstrated A1C reductions for participants taking Mounjaro across multiple stages of their type 2 diabetes journeys, from an average around five to 13 years of having diabetes.2-8

  • SURPASS-1 (NCT03954834) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=121), 10 mg (N=121) and 15 mg (N=120) as monotherapy to placebo (N=113) in adults with type 2 diabetes inadequately controlled with diet and exercise alone. From a baseline A1C of 7.9%, Mounjaro reduced participants’ A1C by a mean of 1.8%* (5 mg) and 1.7%* (10 mg and 15 mg) compared to 0.1% for placebo. In a key secondary endpoint, from a baseline weight of 189 lb., Mounjaro reduced participants’ weight by a mean of 14 lb.* (5 mg), 15 lb.* (10 mg) and 17 lb.* (15 mg) compared to 2 lb. for placebo.2,3
  • SURPASS-2 (NCT03987919) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=470), 10 mg (N=469) and 15 mg (N=469) to injectable semaglutide 1 mg (N=468) in adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. From a baseline A1C of 8.3%, Mounjaro reduced participants’ A1C by a mean of 2.0% (5 mg), 2.2%* (10 mg) and 2.3%* (15 mg) compared to 1.9% for semaglutide. In a key secondary endpoint, from a baseline weight of 207 lb., Mounjaro reduced participants’ weight by a mean of 17 lb. (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to 13 lb. for semaglutide.4,5
  • SURPASS-3 (NCT03882970) was a 52-week study comparing the efficacy of Mounjaro 5 mg (N=358), 10 mg (N=360) and 15 mg (N=358) to titrated insulin degludec (N=359) in adults with type 2 diabetes treated with metformin with or without an SGLT-2 inhibitor. From a baseline A1C of 8.2%, Mounjaro reduced participants’ A1C by a mean of 1.9%* (5 mg), 2.0%* (10 mg) and 2.1%* (15 mg) compared to 1.3% for insulin degludec. From a baseline weight of 208 lb., Mounjaro reduced participants’ weight by a mean of 15 lb.* (5 mg), 21 lb.* (10 mg) and 25 lb.* (15 mg) compared to an increase of 4 lb. for insulin degludec.6
  • SURPASS-4 (NCT03730662) was a 104-week study comparing the efficacy and safety of Mounjaro 5 mg (N=328), 10 mg (N=326) and 15 mg (N=337) to insulin glargine (N=998) in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The primary endpoint was measured at 52 weeks. From a baseline A1C of 8.5%, Mounjaro reduced participants’ A1C by a mean of 2.1%* (5 mg), 2.3%* (10 mg) and 2.4%* (15 mg) compared to 1.4% for insulin glargine. From a baseline weight of 199 lb., Mounjaro reduced weight by a mean of 14 lb.* (5 mg), 20 lb.* (10 mg) and 23 lb.* (15 mg) compared to an increase of 4 lb. for insulin glargine.7
  • SURPASS-5 (NCT04039503) was a 40-week study comparing the efficacy and safety of Mounjaro 5 mg (N=116), 10 mg (N=118) and 15 mg (N=118) to placebo (N=119) in adults with inadequately controlled type 2 diabetes already being treated with insulin glargine, with or without metformin. From a baseline A1C of 8.3%, Mounjaro reduced A1C by a mean of 2.1%* (5 mg), 2.4%* (10 mg) and 2.3%* (15 mg) compared to 0.9% for placebo. From a baseline weight of 210 lb., Mounjaro reduced participants’ weight by a mean of 12 lb.* (5 mg), 17 lb.* (10 mg) and 19 lb.* (15 mg) compared to an increase of 4 lb. for placebo.8

*p<0.001 for superiority vs. placebo or active comparator, adjusted for multiplicity
p<0.05 for superiority vs. semaglutide 1 mg, adjusted for multiplicity

About Mounjaro™ (tirzepatide) injection1
Mounjaro™ (tirzepatide) injection is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. As the first and only FDA-approved GIP and GLP-1 receptor agonist, Mounjaro is a single molecule that activates the body’s receptors for GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Mounjaro will be available in six doses (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg) and will come in Lilly’s well-established auto-injector pen with a pre-attached, hidden needle that patients do not need to handle or see.

PURPOSE AND SAFETY SUMMARY WITH WARNINGS
Important Facts About MounjaroTM (mown-JAHR-OH). It is also known as tirzepatide.

  • Mounjaro is an injectable prescription medicine for adults with type 2 diabetes used along with diet and exercise to improve blood sugar (glucose).
  • It is not known if Mounjaro can be used in people who have had inflammation of the pancreas (pancreatitis). Mounjaro is not for use in people with type 1 diabetes. It is not known if Mounjaro is safe and effective for use in children under 18 years of age.

Warnings
Mounjaro may cause tumors in the thyroid, including thyroid cancer. Watch for possible symptoms, such as a lump or swelling in the neck, hoarseness, trouble swallowing, or shortness of breath. If you have a symptom, tell your healthcare provider.

  • Do not use Mounjaro if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC).
  • Do not use Mounjaro if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
  • Do not use Mounjaro if you are allergic to tirzepatide or any of the ingredients in Mounjaro.

Mounjaro may cause serious side effects, including:

Inflammation of the pancreas (pancreatitis). Stop using Mounjaro and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.

Low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Mounjaro with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include dizziness or light-headedness, sweating, confusion or drowsiness, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability, or mood changes, hunger, weakness and feeling jittery.

Serious allergic reactions. Stop using Mounjaro and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue or throat, problems breathing or swallowing, severe rash or itching, fainting or feeling dizzy, and very rapid heartbeat.

Kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.

Severe stomach problems. Stomach problems, sometimes severe, have been reported in people who use Mounjaro. Tell your healthcare provider if you have stomach problems that are severe or will not go away.

Changes in vision. Tell your healthcare provider if you have changes in vision during treatment with Mounjaro.

Gallbladder problems. Gallbladder problems have happened in some people who use Mounjaro. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include pain in your upper stomach (abdomen), fever, yellowing of skin or eyes (jaundice), and clay-colored stools.

Common side effects
The most common side effects of Mounjaro include nausea, diarrhea, decreased appetite, vomiting, constipation, indigestion, and stomach (abdominal) pain. These are not all the possible side effects of Mounjaro. Talk to your healthcare provider about any side effect that bothers you or doesn’t go away.

Tell your healthcare provider if you have any side effects. You can report side effects at 1-800-FDA-1088 or www.fda.gov/medwatch.

Before using

  • Your healthcare provider should show you how to use Mounjaro before you use it for the first time.
  • Before you use Mounjaro, talk to your healthcare provider about low blood sugar and how to manage it.

 Review these questions with your healthcare provider:

  • Do you have other medical conditions, including problems with your pancreas or kidneys, or severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems digesting food?
  • Do you take other diabetes medicines, such as insulin or sulfonylureas?
  • Do you have a history of diabetic retinopathy?
  • Are you pregnant or plan to become pregnant or breastfeeding or plan to breastfeed? It is not known if Mounjaro will harm your unborn baby.
  • Do you take birth control pills by mouth? These may not work as well while using Mounjaro. Your healthcare provider may recommend another type of birth control when you start Mounjaro or when you increase your dose.
  • Do you take any other prescription medicines or over-the-counter drugs, vitamins, or herbal supplements?

How to take

  • Read the Instructions for Use that come with Mounjaro.
  • Use Mounjaro exactly as your healthcare provider says.
  • Mounjaro is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm.
  • Use Mounjaro 1 time each week, at any time of the day.
  • Do not mix insulin and Mounjaro together in the same injection.
  • If you take too much Mounjaro, call your healthcare provider or seek medical advice promptly.

Learn more
For more information, call 1-800-LillyRx (1-800-545-5979) or go to www.mounjaro.com.

This information does not take the place of talking with your healthcare provider. Be sure to talk to your healthcare provider about Mounjaro and how to take it. Your healthcare provider is the best person to help you decide if Mounjaro is right for you.

MounjaroTM and its delivery device base are trademarks owned or licensed by Eli Lilly and Company, its subsidiaries, or affiliates.

Please click to access full Prescribing Information and Medication Guide.

TR CON CBS MAY2022

About Lilly
Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedIn. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Mounjaro™ (tirzepatide 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg) injection as a treatment to improve glycemic control in adults with type 2 diabetes, the timeline for supply of Mounjaro to become available, and certain other milestones and ongoing clinical trials of Mounjaro and reflects Lilly’s current beliefs and expectations. However, as with any pharmaceutical product or medical device, there are substantial risks and uncertainties in the process of research, development and commercialization. Among other things, there can be no guarantee that Mounjaro will be commercially successful, that future study results will be consistent with results to date, or that we will meet our anticipated timelines for the commercialization of Mounjaro. For further discussion of these and other risks and uncertainties, see Lilly’s most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

References

  1. Mounjaro. Prescribing Information. Lilly USA, LLC.
  2. Rosenstock, J, et. al. Efficacy and Safety of Once Weekly Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist Versus Placebo as Monotherapy in People with Type 2 Diabetes (SURPASS-1). Abstract 100-OR. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  3. Rosenstock, J, et. al. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6.
  4. Frías JP, Davies MJ, Rosenstock J, et al; for the SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385(6)(suppl):503-515. doi: 10.1056/NEJMoa2107519
  5. Frias, J.P. Efficacy and Safety of Tirzepatide vs. Semaglutide Once Weekly as Add-On Therapy to Metformin in Patients with Type 2 Diabetes. Abstract 84-LB. Presented virtually at the American Diabetes Association’s 81st Scientific Sessions; June 25-29.
  6. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4
  7. Del Prato S, Kahn SE, Pavo I, et al; for the SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7
  8. Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. JAMA. 2022;327(6):534-545. doi:10.1001/jama.2022.0078

CLIP

https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-225-weight-loss-adults-obesity-or

Lilly’s tirzepatide delivered up to 22.5% weight loss in adults with obesity or overweight in SURMOUNT-1

April 28, 2022

Download PDF

Participants taking tirzepatide lost up to 52 lb. (24 kg) in this 72-week phase 3 study

63% of participants taking tirzepatide 15 mg achieved at least 20% body weight reductions as a key secondary endpoint

INDIANAPOLIS, April 28, 2022 /PRNewswire/ — Tirzepatide (5 mg, 10 mg, 15 mg) achieved superior weight loss compared to placebo at 72 weeks of treatment in topline results from Eli Lilly and Company’s (NYSE: LLY) SURMOUNT-1 clinical trial, with participants losing up to 22.5% (52 lb. or 24 kg) of their body weight for the efficacy estimandi. This study enrolled 2,539 participants and was the first phase 3 global registration trial evaluating the efficacy and safety of tirzepatide in adults with obesity, or overweight with at least one comorbidity, who do not have diabetes. Tirzepatide met both co-primary endpoints of superior mean percent change in body weight from baseline and greater percentage of participants achieving body weight reductions of at least 5% compared to placebo for both estimandsii. The study also achieved all key secondary endpoints at 72 weeks.

For the efficacy estimand, participants taking tirzepatide achieved average weight reductions of 16.0% (35 lb. or 16 kg on 5 mg), 21.4% (49 lb. or 22 kg on 10 mg) and 22.5% (52 lb. or 24 kg on 15 mg), compared to placebo (2.4%, 5 lb. or 2 kg). Additionally, 89% (5 mg) and 96% (10 mg and 15 mg) of people taking tirzepatide achieved at least 5% body weight reductions compared to 28% of those taking placebo.

In a key secondary endpoint, 55% (10 mg) and 63% (15 mg) of people taking tirzepatide achieved at least 20% body weight reductions compared to 1.3% of those taking placebo. In an additional secondary endpoint not controlled for type 1 error, 32% of participants taking tirzepatide 5 mg achieved at least 20% body weight reductions. The mean baseline body weight of participants was 231 lb. (105 kg).

“Obesity is a chronic disease that often does not receive the same standard of care as other conditions, despite its impact on physical, psychological and metabolic health, which can include increased risk of hypertension, heart disease, cancer and decreased survival,” said Louis J. Aronne, MD, FACP, DABOM, director of the Comprehensive Weight Control Center and the  Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, obesity expert at NewYork-Presbyterian/Weill Cornell Medical Center and Investigator of SURMOUNT-1. “Tirzepatide delivered impressive body weight reductions in SURMOUNT-1, which could represent an important step forward for helping the patient and physician partnership treat this complex disease.”

For the treatment-regimen estimandiii, results showed:

  • Average body weight reductions: 15.0% (5 mg), 19.5% (10 mg), 20.9% (15 mg), 3.1% (placebo)
  • Percentage of participants achieving body weight reductions of ≥5%: 85% (5 mg), 89% (10 mg), 91% (15 mg), 35% (placebo)
  • Percentage of participants achieving body weight reductions of ≥20%: 30% (5 mg, not controlled for type 1 error), 50% (10 mg), 57% (15 mg), 3.1% (placebo)

The overall safety and tolerability profile of tirzepatide was similar to other incretin-based therapies approved for the treatment of obesity. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity, usually occurring during the dose escalation period. For those treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (24.6%, 33.3%, 31.0%), diarrhea (18.7%, 21.2%, 23.0%), vomiting (8.3%, 10.7%, 12.2%) and constipation (16.8%, 17.1%, 11.7%) were more frequently experienced compared to placebo (9.5% [nausea], 7.3% [diarrhea], 1.7% [vomiting], 5.8% [constipation]).

Treatment discontinuation rates due to adverse events were 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) and 2.6% (placebo). The overall treatment discontinuation rates were 14.3% (5 mg), 16.4% (10 mg), 15.1% (15 mg) and 26.4% (placebo).

Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and the potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

“Tirzepatide is the first investigational medicine to deliver more than 20 percent weight loss on average in a phase 3 study, reinforcing our confidence in its potential to help people living with obesity,” said Jeff Emmick, MD, Ph.D., vice president, product development, Lilly. “Obesity is a chronic disease that requires effective treatment options, and Lilly is working relentlessly to support people with obesity and modernize how this disease is approached. We’re proud to research and develop potentially innovative treatments like tirzepatide, which helped nearly two thirds of participants on the highest dose reduce their body weight by at least 20 percent in SURMOUNT-1.”

Tirzepatide is a novel investigational once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist, representing a new class of medicines being studied for the treatment of obesity. Tirzepatide is a single peptide that activates the body’s receptors for GIP and GLP-1, two natural incretin hormones. Obesity is a chronic, progressive disease caused by disruptions in the mechanisms that control body weight, often leading to an increase in food intake and/or a decrease in energy expenditure. These disruptions are multifactorial and can be related to genetic, developmental, behavioral, environmental and social factors. To learn more, visit Lilly.com/obesity.

Lilly will continue to evaluate the SURMOUNT-1 results, which will be presented at an upcoming medical meeting and submitted to a peer-reviewed journal. Additional studies are ongoing for tirzepatide as a potential treatment for obesity or overweight.

About tirzepatide

Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with GLP-1 receptor agonism, may result in greater effects on markers of metabolic dysregulation such as body weight, glucose and lipids. Tirzepatide is in phase 3 development for adults with obesity or overweight with weight-related comorbidity and is currently under regulatory review as a treatment for adults with type 2 diabetes. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH) and heart failure with preserved ejection fraction (HFpEF). Studies of tirzepatide in obstructive sleep apnea (OSA) and in morbidity/mortality in obesity are planned as well.

About SURMOUNT-1 and the SURMOUNT clinical trial program

SURMOUNT-1 (NCT04184622) is a multi-center, randomized, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults without type 2 diabetes who have obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease. The trial randomized 2,539 participants across the U.S., Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10 mg and/or 15 mg is superior in percentage of body weight reductions from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo. Participants who had pre-diabetes at study commencement will remain enrolled in SURMOUNT-1 for an additional 104 weeks of treatment following the initial 72-week completion date to evaluate the impact on body weight and potential differences in progression to type 2 diabetes at three years of treatment with tirzepatide compared to placebo.

All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg).

The SURMOUNT phase 3 global clinical development program for tirzepatide began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six clinical trials, four of which are global studies. Results from SURMOUNT-2, -3, and -4 are anticipated in 2023.

About Lilly 

Lilly unites caring with discovery to create medicines that make life better for people around the world. We’ve been pioneering life-changing discoveries for nearly 150 years, and today our medicines help more than 47 million people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world’s most significant health challenges, redefining diabetes care, treating obesity and curtailing its most devastating long-term effects, advancing the fight against Alzheimer’s disease, providing solutions to some of the most debilitating immune system disorders, and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we’re motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/newsroom or follow us on FacebookInstagramTwitter and LinkedInP-LLY

CLIP

https://www.pu-kang.com/Tirzepatide-results-superior-A1C-and-body-weight-reductions-compared-to-insulin-glargine-in-adults-with-type-2-diabetes-id3348038.html

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Tirzepatide results superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes

Newly published data show that participants maintained A1C and weight control up to two years in SURPASS-4, the largest and longest SURPASS trial completed to dateNo increased cardiovascular risk identified with tirzepatide; hazard ratio of 0.74 observed for MACE-4 events

SURPASS-4 is the largest and longest clinical trial completed to date of the phase 3 program studying tirzepatide as a potential treatment for type 2 diabetes. The primary endpoint was measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In newly published data from the treatment period after 52 weeks, participants taking tirzepatide maintained A1C and weight control for up to two years.

The overall safety profile of tirzepatide, assessed over the full study period, was consistent with the safety results measured at 52 weeks, with no new findings up to 104 weeks. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time.

“We are encouraged by the continued A1C and weight control that participants experienced past the initial 52 week treatment period and up to two years as we continue to explore the potential impact of tirzepatide for the treatment of type 2 diabetes,” said John Doupis, M.D., Ph.D., Director, Diabetes Division and Clinical Research Center, Iatriko Paleou Falirou Medical Center, Athens, Greece and Senior Investigator for SURPASS-4.

Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.

SURPASS-4 was an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in 2,002 adults with type 2 diabetes with increased CV risk who were treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Of the total participants randomized, 1,819 (91%) completed the primary 52-week visit and 1,706 (85%) completed the study on treatment. The median study duration was 85 weeks and 202 participants (10%) completed two years.

Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43.5 units per day.

About tirzepatide
Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes, for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).

About SURPASS-4 and the SURPASS clinical trial program
SURPASS-4 (NCT03730662) is a randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide 5 mg, 10 mg and 15 mg to insulin glargine in adults with type 2 diabetes inadequately controlled with at least one and up to three oral antihyperglycemic medications (metformin, sulfonylureas or SGLT-2 inhibitors), who have increased cardiovascular (CV) risk. The trial randomized 2,002 study participants in a 1:1:1:3 ratio to receive either tirzepatide 5 mg, 10 mg or 15 mg or insulin glargine. Participants were located in the European Union, North America (Canada and the United States), Australia, Israel, Taiwan and Latin America (Brazil, Argentina and Mexico). The primary objective of the study was to demonstrate that tirzepatide (10 mg and/or 15 mg) is non-inferior to insulin glargine for change from baseline A1C at 52 weeks in people with type 2 diabetes and increased CV risk. The primary and key secondary endpoints were measured at 52 weeks, with participants continuing treatment up to 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE). Study participants enrolled had to have a mean baseline A1C between 7.5 percent and 10.5 percent and a BMI greater than or equal to 25 kg/m2 at baseline. All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5 mg once-weekly and then increased the dose in a step-wise approach at four-week intervals to their final randomized maintenance dose of 5 mg (via a 2.5 mg step), 10 mg (via steps at 2.5 mg, 5 mg and 7.5 mg) or 15 mg (via steps at 2.5 mg, 5 mg, 7.5 mg, 10 mg and 12.5 mg). All participants in the titrated insulin glargine treatment arm started with a baseline dose of 10 units per day and titrated following a treat-to-target algorithm to reach a fasting blood glucose below 100 mg/dL.

The SURPASS phase 3 global clinical development program for tirzepatide has enrolled more than 20,000 people with type 2 diabetes across 10 clinical trials, five of which are global registration studies. The program began in late 2018, and all five global registration trials have been completed.

About Diabetes

Approximately 34 million Americans2 (just over 1 in 10) and an estimated 463 million adults worldwide3 have diabetes. Type 2 diabetes is the most common type internationally, accounting for an estimated 90 to 95 percent of all diabetes cases in the United States alone2. Diabetes is a chronic disease that occurs when the body does not properly produce or use the hormone insulin.

Clinical data
Trade namesMounjaro
Other namesLY3298176, GIP/GLP-1 RA
License dataUS DailyMedTirzepatide
Routes of
administration
subcutaneous
Drug classAntidiabeticGLP-1 receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
showIUPAC name
CAS Number2023788-19-2
PubChem CID156588324
IUPHAR/BPS11429
DrugBankDB15171
ChemSpider76714503
UNIIOYN3CCI6QE
KEGGD11360
ChEMBLChEMBL4297839
Chemical and physical data
FormulaC225H348N48O68
Molar mass4813.527 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Tirzepatide, FDA 2022, APPROVALS 2022, Mounjaro, PEPTIDE, チルゼパチド ,  LY3298176,

UNIIOYN3CCI6QE

pharma1

chart 1 Structure of GLP-1 & TZP & Exenatide & Somalutide

%d bloggers like this: