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ORGANIC SPECTROSCOPY

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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

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Mirvetuximab soravtansine-gynx


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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
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//////////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.

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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

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Ozoralizumab



Ozoralizumab

FormulaC1682H2608N472O538S12
CAS 1167985-17-2
Mol weight38434.3245 

PMDA JAPAN  APPROVED 2022 2022/9/26 Nanozora

anti-TNFα Nanobody®; ATN-103; Nanozora; PF-5230896; TS-152

Ozoralizumab is a humanized monoclonal antibody designed for the treatment of inflammatory diseases.[1]

Ozoralizumab was developed by Pfizer Inc, and now belongs to Ablynx NV. Ablynx has licensed the rights to the antibody in China to Eddingpharm.

Ozoralizumab has been used in trials studying the treatment of Rheumatoid Arthritis and Active Rheumatoid Arthritis.

Ozoralizumab is a 38 kDa humanized trivalent bispecific construct consisting of two anti-TNFα NANOBODIES® and anti-HSA NANOBODY® that was generated at Ablynx by a previously described method (23). Llamas were immunized with human TNFα and human muscle extract, which is rich in HSA, to induce the formation of anti-TNFα VHH and anti-HSA VHH. Both the anti-TNFα VHH and anti-HSA VHH were humanized by a complementary determining regions (CDR) grafting approach in which the CDR of the gene encoding llama VHH was grafted onto the most homologous human VHH framework sequence. Since binding to serum albumin prolongs the half-life of VHH (23, 26, 27), an anti-HSA VHH which efficiently binds murine serum albumin as well was incorporated into the two anti-TNFα VHHs. The three components were fused using a flexible Gly-Ser linker.

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Monoclonal antibody
TypeWhole antibody
SourceHumanized
Clinical data
ATC codenone
Identifiers
CAS Number1167985-17-2 
ChemSpidernone
UNII05ZCK72TXZ
KEGGD09944
Chemical and physical data
FormulaC1682H2608N472O538S12
Molar mass38434.85 g·mol−1
  • OriginatorAblynx
  • DeveloperAblynx; Eddingpharm; Pfizer; Taisho Pharmaceutical
  • ClassAnti-inflammatories; Antirheumatics; Monoclonal antibodies; Proteins
  • Mechanism of ActionTumour necrosis factor alpha inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes
  • RegisteredRheumatoid arthritis
  • DiscontinuedAnkylosing spondylitis; Crohn’s disease; Psoriatic arthritis
  • 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent pending for Nanobodies® (Sanofi website, October 2022)
  • 05 Oct 2022Sanofi’s affiliate Ablynx has worldwide patent protection for Nanobodies® (Sanofi website, October 2022)
  • 26 Sep 2022First global approval – Registered for Rheumatoid arthritis in Japan (SC)

References

  1. ^ Kratz F, Elsadek B (July 2012). “Clinical impact of serum proteins on drug delivery”. J Control Release161 (2): 429–45. doi:10.1016/j.jconrel.2011.11.028PMID 22155554.

////////Ozoralizumab, Nanozora, Monoclonal antibody, nanobody, Treatment inflammation, ATN 103, APPROVALS 2022, JAPAN 2022

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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

////////

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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

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Lutetium (177Lu) chloride


Lutetium (177Lu) chloride.png
LuCl3structure.jpg

Lutetium (177Lu) chloride

塩化ルテチウム (177Lu)

FormulaLu. 3Cl
CAS16434-14-3
Mol weight281.326

2022/9/15 EMA 2022, Illuzyce

EndolucinBeta

(177Lu)lutetium(3+) trichloride

Diagnostic aid, Radioactive agent

Lutetium 177 is an isotope of a rare-earth lanthanide metal lutetium. Radioactive decay of Lu 177 produces electrons with low energies making the isotope suitable for treatment of metastatic disease. A complex of Lu177 and somatostatin analog DOTA-TATE was approved by the FDA for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors in adults. It is marketed under a tradename Lutathera. Lutetium in the complex with other carriers – phosphonates and monoclonal antibodies – was investigated in clinical trials as radiotherapy to prostate, ovarian, renal and other types of cancer.Lutetium (177Lu) chloride is a radioactive compound used for the radiolabeling of pharmaceutical molecules, aimed either as an anti-cancer therapy or for scintigraphy (medical imaging).[5][6] It is an isotopomer of lutetium(III) chloride containing the radioactive isotope 177Lu, which undergoes beta decay with a half-life of 6.65 days.

Medical uses

Lutetium (177Lu) chloride is a radiopharmaceutical precursor and is not intended for direct use in patients.[5] It is used for the radiolabeling of carrier molecules specifically developed for reaching certain target tissues or organs in the body. The molecules labeled in this way are used as cancer therapeutics or for scintigraphy, a form of medical imaging.[5] 177Lu has been used with both small molecule therapeutic agents (such as 177Lu-DOTATATE) and antibodies for targeted cancer therapy[8][9]

////////

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

Clinical data
Trade namesLumark, EndolucinBeta, Illuzyce
AHFS/Drugs.comLumark UK Drug Information
EndolucinBeta UK Drug Information
License dataEU EMAby INN
Pregnancy
category
AU: X (High risk)[1][2]
ATC codeNone
Legal status
Legal statusAU: Unscheduled [3][4]EU: Rx-only [5][6][7]In general: ℞ (Prescription only)
Identifiers
showIUPAC name
CAS Number16434-14-3
PubChem CID71587001
DrugBankDBSALT002634
ChemSpider32700269
UNII1U477369SN
KEGGD10828
CompTox Dashboard (EPA)DTXSID20167745 
Chemical and physical data
FormulaCl3Lu
Molar mass281.32 g·mol−1
3D model (JSmol)Interactive image
hideSMILES[Cl-].[Cl-].[Cl-].[177Lu+3]

Contraindications

Medicines radiolabeled with lutetium (177Lu) chloride must not be used in women unless pregnancy has been ruled out.[5]

Adverse effects

The most common side effects are anaemia (low red blood cell counts), thrombocytopenia (low blood platelet counts), leucopenia (low white blood cell counts), lymphopenia (low levels of lymphocytes, a particular type of white blood cell), nausea (feeling sick), vomiting and mild and temporary hair loss.[5]

Society and culture

Legal status

Lutetium (177Lu) chloride (Lumark) was approved for use in the European Union in June 2015.[5] Lutetium (177Lu) chloride (EndolucinBeta) was approved for use in the European Union in July 2016.[6]

On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Illuzyce, a radiopharmaceutical precursor.[10] Illuzyce is not intended for direct use in patients and must be used only for the radiolabelling of carrier medicines that have been specifically developed and authorized for radiolabelling with lutetium (177Lu) chloride.[10] The applicant for this medicinal product is Billev Pharma ApS.[10] Illuzyce was approved for medical use in the European Union in September 2022.[7]

References

  1. ^ “Lutetium (177Lu) Chloride”Therapeutic Goods Administration (TGA). 21 January 2022. Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  2. ^ “Updates to the Prescribing Medicines in Pregnancy database”Therapeutic Goods Administration (TGA). 12 May 2022. Archived from the original on 3 April 2022. Retrieved 13 May 2022.
  3. ^ “TGA eBS – Product and Consumer Medicine Information Licence”Archived from the original on 5 February 2022. Retrieved 5 February 2022.
  4. ^ http://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=1C7A40803A3A3F94CA2587D4003CE48A&agid=(PrintDetailsPublic)&actionid=1 Archived 30 July 2022 at the Wayback Machine[bare URL PDF]
  5. Jump up to:a b c d e f g “Lumark EPAR”European Medicines Agency (EMA)Archived from the original on 25 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. Jump up to:a b c “EndolucinBeta EPAR”European Medicines Agency (EMA)Archived from the original on 28 October 2020. Retrieved 7 May 2020. Text was copied from this source under the copyright of the European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. Jump up to:a b “Illuzyce EPAR”European Medicines Agency (EMA). 18 July 2022. Archived from the original on 22 September 2022. Retrieved 21 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ Lundsten S, Spiegelberg D, Stenerlöw B, Nestor M (December 2019). “The HSP90 inhibitor onalespib potentiates 177Lu‑DOTATATE therapy in neuroendocrine tumor cells”International Journal of Oncology55 (6): 1287–1295. doi:10.3892/ijo.2019.4888PMC 6831206PMID 31638190.
  9. ^ Michel RB, Andrews PM, Rosario AV, Goldenberg DM, Mattes MJ (April 2005). “177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo”. Nuclear Medicine and Biology32 (3): 269–78. doi:10.1016/j.nucmedbio.2005.01.003PMID 15820762.
  10. Jump up to:a b c “Illuzyce: Pending EC decision”European Medicines Agency. 21 July 2022. Archived from the original on 30 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

External links

.///////////Lutetium (177Lu) chloride, EMA 2022, EU 2022, APPROVALS 2022,  Illuzyce, EndolucinBeta, 塩化ルテチウム (177Lu), 

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Valemetostat tosilate


Valemetostat tosilate (JAN).png
2D chemical structure of 1809336-93-3

Valemetostat tosilate

バレメトスタットトシル酸塩

FormulaC26H34ClN3O4. C7H8O3S
CAS1809336-93-3
Mol weight660.2205

PMDA JAPAN approved 2022/9/26, Ezharmia

  • 1,3-Benzodioxole-5-carboxamide, 7-chloro-N-((1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl)-2-(trans-4-(dimethylamino)cyclohexyl)-2,4-dimethyl-, (2R)-, compd. with 4-methylbenzenesulfonate (1:1)

Antineoplastic, histone methyltransferase inhibitor

1809336-39-7 (free base). 1809336-93-3 (tosylate)   1809336-92-2 (mesylate)   1809336-94-4 (fumarate)   1809336-95-5 (tarate)

Synonym: Valemetostat; DS-3201; DS 3201; DS3201; DS-3201b

日本医薬品一般的名称(JAN)データベース

(2R)-7-Chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide mono(4-methylbenzenesulfonate)

C26H34ClN3O4▪C7H8O3S : 660.22
[1809336-93-3]

STR1
img

1809336-39-7 (free base)
Chemical Formula: C26H34ClN3O4
Exact Mass: 487.2238
Molecular Weight: 488.02

(2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide

 Valemetostat, also known as DS-3201 is a potent, selective and orally active EZH1/2 inhibitor. DS-3201 selectively inhibits the activity of both wild-type and mutated forms of EZH1 and EZH2. Inhibition of EZH1/2 specifically prevents the methylation of lysine 27 on histone H3 (H3K27). This decrease in histone methylation alters gene expression patterns associated with cancer pathways, enhances transcription of certain target genes, and results in decreased proliferation of EZH1/2-expressing cancer cells.

  • OriginatorDaiichi Sankyo Inc
  • DeveloperCALYM Carnot Institute; Daiichi Sankyo Inc; Lymphoma Academic Research Organisation; Lymphoma Study Association; University of Texas M. D. Anderson Cancer Center
  • ClassAmides; Amines; Antineoplastics; Benzodioxoles; Chlorinated hydrocarbons; Cyclohexanes; Pyridones; Small molecules
  • Mechanism of ActionEnhancer of zeste homolog 1 protein inhibitors; Enhancer of zeste homolog 2 protein inhibitors
  • Orphan Drug StatusYes – Adult T-cell leukaemia-lymphoma; Peripheral T-cell lymphoma
  • New Molecular EntityYes
  • RegisteredAdult T-cell leukaemia-lymphoma
  • Phase IIB-cell lymphoma; Peripheral T-cell lymphoma
  • Phase I/IISmall cell lung cancer
  • Phase INon-Hodgkin’s lymphoma; Prostate cancer; Renal cell carcinoma; Urogenital cancer
  • PreclinicalDiffuse large B cell lymphoma
  • No development reportedAcute myeloid leukaemia; Precursor cell lymphoblastic leukaemia-lymphoma
  • 26 Sep 2022First global approval – Registered for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO)
  • 26 Sep 2022Updated efficacy and adverse events data from a phase II trial in Adult T-cell leukaemia-lymphoma released by Daiichi Sankyo
  • 28 Dec 2021Preregistration for Adult T-cell leukaemia-lymphoma (Monotherapy, Second-line therapy or greater) in Japan (PO
Targeting Enhancer of Zeste Homolog 2 for the Treatment of Hematological Malignancies and Solid Tumors: Candidate Structure–Activity Relationships Insights and Evolution Prospects | Journal of Medicinal Chemistry

PATENT

WO 2015141616

 Watson, W. D. J. Org. Chem. 1985, 50, 2145.
 Lengyel, I. ; Cesare, V. ; Stephani, R. Synth. Common. 1998, 28, 1891.

PATENT

WO2022009911

The equipment and measurement conditions for the powder X-ray diffraction measurement in the examples are as follows.
Model: Rigaku Rint TTR-III
Specimen: Appropriate
X-ray generation conditions: 50 kV, 300 mA
Wavelength: 1.54 Å (Copper Kα ray)
Measurement temperature: Room temperature
Scanning speed: 20°/min
Scanning range: 2 to 40°
Sampling width: 0.02°

[0043]

(Reference Example 1) Production of ethyl trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate

[0044]

[hua 6]

[0045]

 Under a nitrogen atmosphere, ethanol (624 L) and ethyl trans-4-aminocyclohexanecarboxylate monohydrochloride (138.7 kg, 667.8 mol) were added to a reaction vessel and cooled. Triethylamine (151.2 kg, 1495 .5 mol) and di-tert-butyl dicarbonate (160.9 kg, 737.2 mol) were added dropwise while maintaining the temperature below 20°C. After stirring at 20-25°C for 4 hours, water (1526 kg) was added dropwise at 25°C or lower, and the mixture was further stirred for 2 hours. The precipitated solid was collected by filtration, washed with a mixture of ethanol:water 1:4 (500 L), and dried under reduced pressure at 40°C to obtain 169.2 kg of the title compound (yield 93.4%). .
1 H NMR (500 MHz, CDCl 3 ): δ 4.37 (br, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.41 (br, 1H), 2.20 (tt, J = 4.8, 1.4 Hz, 1H),2.07(m,2H),2.00(m,2H),1.52(dq,J=4.6,1.4Hz,2H),1.44(s,9H),1.24(t,J=2.8Hz,3H), 1.11(dq,J=4.6,1.4Hz,2H)

[0046]

(Reference Example 2) Production of tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate

[0047]

[hua 7]

[0048]

 Under a nitrogen atmosphere, tetrahydrofuran (968 kg), ethyl = trans-4-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylate (110 kg, 405.4 mol), lithium chloride (27.5 kg, 648 kg) were placed in a reaction vessel. .6 mol), potassium borohydride (32.8 kg, 608.1 mol), and water (2.9 L, 162.2 mol) were added, the temperature was slowly raised to 50°C, and the mixture was further stirred for 6 hours. Cooled to 0-5°C. Acetone (66 L) and 9 wt % ammonium chloride aqueous solution (1210 kg) were added dropwise while maintaining the temperature at 20° C. or lower, and the mixture was stirred at 20-25° C. for 1 hour. Additional ethyl acetate (550 L) was added, the aqueous layer was discarded and the organic layer was concentrated to 550 L. Ethyl acetate (1650 L) and 9 wt% aqueous ammonium chloride solution (605 kg) were added to the residue, and the aqueous layer was discarded after stirring. Washed sequentially with water (550 L). The organic layer was concentrated to 880 L, ethyl acetate (660 L) was added to the residue, and the mixture was concentrated to 880 L while maintaining the internal temperature at 40-50°C. The residue was cooled to 0-5° C. and stirred for 1 hour, petroleum ether (1760 L) was added dropwise over 30 minutes, and the mixture was stirred at the same temperature for 2 hours. The precipitated solid was collected by filtration, washed with a petroleum ether:ethyl acetate 3:1 mixture (220 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to give 86.0 kg of the title compound (yield: obtained at a rate of 92.3%).
1 H NMR (500 MHz, CDCl 3 ): δ 4.37 (br, 1H), 3.45 (d, J = 2.2 Hz, 2H), 3.38 (br, 1H), 2.04 (m, 2H),
1.84(m,2H),1.44(m,10H),1.28-1.31(m,1H),1.00-1.13(m,4H)

[0049]

(Reference Example 3) Production of tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate

[0050]

[hua 8]

[0051]

(Step 1)
 Under a nitrogen atmosphere, ethyl acetate (50 L), tert-butyl = [trans-4-(hydroxymethyl)cyclohexyl]carbamate (2.5 kg, 10.90 mol), potassium bromide ( 39.3 g, 0.33 mol), 2,2,6,6-tetramethylpiperidine 1-oxyl (51.1 g, 0.33 mol), 4.8% aqueous sodium hydrogen carbonate solution (26.25 kg ) was added and cooled to 0-5°C, 9.9% sodium hypochlorite (8.62 kg, 11.45 mol) was added at 5°C or lower, and the mixture was further stirred at 0°C for 4 hours. Sodium sulfite (250 g) was added to the mixture and stirred at 0-5°C for 30 minutes before warming to 20-25°C. Thereafter, the aqueous layer was discarded and washed with a 20% aqueous sodium chloride solution (12.5 kg), then the organic layer was dried over sodium sulfate and concentrated to 7.5 L. Ethyl acetate (12.5 L) was added to the residue, the mixture was concentrated again to 7.5 L, and used in the next reaction as a tert-butyl=(trans-4-formylcyclohexyl)carbamate solution.

[0052]

(Step 2)
Under a nitrogen atmosphere, tetrahydrofuran (30 L) and triphenylphosphine (5.72 kg, 21.8 mol) were added to a reaction vessel, heated to 40°C, and stirred for 5 minutes. Carbon tetrabromide (3.61 kg, 10.9 mol) was added over 30 minutes and stirred at 40-45° C. for another 30 minutes. A mixture of tert-butyl (trans-4-formylcyclohexyl)carbamate solution and triethylamine (2.54 kg, 25.1 mol) was added below 45°C over 20 minutes and stirred at 40°C for an additional 15 hours. After cooling the reaction solution to 0° C., water (0.2 L) was added at 10° C. or lower, and water (25 L) was added. After heating to 20-25° C., the aqueous layer was discarded, ethyl acetate (4.5 kg) and 10% aqueous sodium chloride solution (25 kg) were added, and after stirring, the aqueous layer was discarded again. After the obtained organic layer was concentrated to 15 L, 2-propanol (19.65 kg) was added and concentrated to 17.5 L. 2-Propanol (11.78 kg) and 5 mol/L hydrochloric acid (151.6 g) were added to the residue, and the mixture was stirred at 25-35°C for 2.5 hours. Water (16.8 L) was added dropwise to the resulting solution, and the mixture was stirred at 20-25°C for 30 minutes and then stirred at 0°C for 2 hours. The precipitated solid was collected by filtration, washed with a mixture (11 kg) of acetonitrile:water 60:40 cooled to 0-5°C, and dried at 40°C under reduced pressure to give 3.05 kg of the title compound (yield 73%). .0%).
1 H NMR (500 MHz, CDCl3):δ6.20(d,J=3.6Hz,1H),4.37(br,1H),3.38(br,1H),2.21(dtt,J=3.6,4.6,1.4Hz,1H),2.05-2.00(m,2H),1.80-1.83(m,2H),1.44(s,9H),1.23(ddd,J=9.9,5.3,1.2 Hz,2H), 1.13(ddt,J=4.6,1.4,5.2 Hz,2H)

[0053]

(Reference Example 4) Production of tert-butyl = (trans-4-ethynylcyclohexyl) carbamate

[0054]

[Chemical 9]

[0055]

Under a nitrogen atmosphere, toluene (1436 kg), tert-butyl = [trans-4-(2,2-dibromoethenyl)cyclohexyl]carbamate (110 kg, 287.1 mol), and N,N,N ‘,N’-Tetramethylethane-1,2-diamine (106.7 kg, 918.8 mol) was added and cooled to -10°C. An isopropylmagnesium chloride-tetrahydrofuran solution (2.0 mol/L, 418 kg, 863 mol) was added dropwise at -5°C or lower, and stirred at -10°C for 30 minutes. After the reaction, 5 mol/L hydrochloric acid (465 kg) was added at 5°C or lower, heated to 20-25°C, and further 5 mol/L hydrochloric acid (41.8 kg) was used to adjust the pH to 5.0-. adjusted to 6.0. After discarding the aqueous layer, the organic layer was washed twice with water (550 L) and concentrated to 550 L. 2-Propanol (1296 kg) was added to the concentrate and concentrated to 550 L again. Further, 2-propanol (1296 kg) was added to the residue, and after concentrating to 550 L, water (770 L) was added dropwise in 4 portions. At that time, it was stirred for 30 minutes after each addition. After the addition, the mixture was stirred for 1 hour and further stirred at 0° C. for 1 hour. The precipitated solid was collected by filtration, washed with a 5:7 mixture of 2-propanol:water (550 L) cooled to 0-5°C, and dried at 40°C under reduced pressure to yield 57.8 kg of the title compound. obtained at a rate of 90.2%).
1 H NMR (500 MHz, CDCl 3 ): δ 4.36 (br, 1H), 3.43 (br, 1H), 2.18-2.23 (m, 1H), 1.97-2.04 (m, 5H), 1.44-1.56 (m, 11H ),1.06-1.14(m,2H)

[0056]

(Reference Example 5) Production of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

[0057]

[Chemical 10]

[0058]

Under a nitrogen atmosphere, water (300 L), 2-cyanoacetamide (20 kg, 238 mol), 1-pentane-2-4-dione (26.2 kg, 262 mol), potassium carbonate (3.29 mol) were added to a reaction vessel. kg, 23.8 mol) was added and stirred at room temperature for 6 hours or longer. After the reaction, the precipitated solid was collected by filtration, washed with water (60 L), further washed with a mixture of methanol (40 L) and water (40 L), and dried under reduced pressure at 40°C to give the title compound as 34 Obtained in .3 kg (97.3% yield).
1 H NMR (500 MHz, DMSO-d 6 ): δ 2.22 (s, 3H), 2.30 (s, 3H), 6.16 (s, 1H), 12.3 (brs, 1H)

[0059]

(Reference Example 6) Production of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one monohydrochloride

[0060]

[Chemical 11]

[0061]

 Under a nitrogen atmosphere, water (171 L), methanol (171 L), 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (17.1 kg, 116 mol), concentrated After adding hydrochloric acid (15.8 kg, 152 mol) and 5% palladium carbon (55% wet) (3.82 kg), the inside of the reaction vessel was replaced with hydrogen. Then, the mixture was pressurized with hydrogen and stirred overnight at 30°C. After the reaction, the reaction vessel was purged with nitrogen, the palladium on carbon was removed by filtration, and the palladium on carbon was washed with a 70% aqueous solution of 2-propanol (51 L). Activated carbon (0.86 kg) was added to the filtrate and stirred for 30 minutes. Activated carbon was removed by filtration and washed with 70% aqueous 2-propanol solution (51 L). The filtrate was concentrated under reduced pressure until the liquid volume became 103 L, and 2-propanol (171 L) was added. The mixture was again concentrated under reduced pressure until the liquid volume reached 103 L, then 2-propanol (171 L) was added, and the mixture was stirred for 1 hour or longer. Precipitation of a solid was confirmed, and the solution was concentrated to a volume of 103 L. Further, 2-propanol (51 L) was added, and after concentration under reduced pressure until the liquid volume reached 103 L, the mixture was stirred at 50° C. for 30 minutes. After adding acetone (171 L) over 1 hour while keeping the internal temperature at 40° C. or higher, the mixture was stirred at 40 to 45° C. for 30 minutes. The solution was cooled to 25°C and stirred for 2 hours or longer, and the precipitated solid was collected by filtration, washed with acetone (86 L) and dried under reduced pressure at 40°C to give 19.7 kg of the title compound (yield 90.4%). ).
1 H NMR (500 MHz, methanol-d 4 ): δ 2.27 (s, 3H), 2.30 (s, 3H), 4.02 (s, 2H), 6.16 (s, 1H)

[0062]

(Example 1-1) Production of methyl 5-chloro-3,4-dihydroxy-2-methylbenzoate

[0063]

[Chemical 12]

[0064]

 Under a nitrogen atmosphere, water (420 L), toluene (420 L), acetonitrile (420 L), and methyl 3,4-dihydroxy-2-methylbenzoate (1) (60 kg, 329 mol) were added to the reactor and cooled. After that, sulfuryl chloride (133.4 kg, 988 mol) was added dropwise while maintaining the temperature at 20°C or lower. After the reaction, the mixture was separated into an organic layer 1 and an aqueous layer, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. Water (420 L) and acetonitrile (210 L) were added to the organic layer 1, and after cooling, sulfuryl chloride (88.9 kg, 659 mol) was added dropwise at 20°C or lower, and sulfuryl chloride (53.2 kg, 394 mol) was added. ) was added in portions. After the reaction, the mixture was separated into an organic layer 3 and an aqueous layer, and the organic layer 2 was added to the aqueous layer and stirred. Water (420 L), acetonitrile (210 L) were added to the combined organic layer, sulfuryl chloride (44.5 kg, 329 mol) was added dropwise below 20°C, and sulfuryl chloride (106.4 kg, 788 mol) was added. ) was added in portions. After the reaction, the organic layer 4 and the aqueous layer were separated, acetonitrile (60 L) and toluene (120 L) were added to the aqueous layer, and the mixture was stirred. The combined organic layers were washed three times with 20 wt % aqueous sodium chloride solution (300 L) and then concentrated under reduced pressure to 600 L. After repeating the operation of adding toluene (300 L) and concentrating under reduced pressure to 600 L again twice, the mixture was heated and stirred at 60° C. for 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with toluene (120 L), and dried under reduced pressure at 40°C to give 52.1 kg of the crude title compound (2) (yield: 73.0%). ).

[0065]

 Under a nitrogen atmosphere, toluene (782 L) and crude title compound (52.1 kg, 241 mol) were added to a reactor and heated to 80°C. After confirming that the crystals were completely dissolved, they were filtered and washed with heated toluene (261 L). The mixture was cooled to 60° C. and stirred for 0.5 hours after crystallization. After cooling to 10°C, the precipitated solid was collected by filtration, washed with toluene (156 L), and dried under reduced pressure at 40°C to give 47.9 kg of the title compound (2) (yield 91.9%). Acquired.
1 H NMR (500 MHz, methanol-d 4 ): δ 2.41 (s, 3H), 3.82 (s, 3H), 7.41 (s, 1H)

[0066]

(Example 1-2) Examination of chlorination conditions 1 Since
it is difficult to remove compound (1), which is the starting material, and compound (4), which is a by-product of the reaction, even in subsequent steps, need to control. Therefore, chlorination was investigated in the same manner as in Example 1-1 using compound (1) as a starting material. Table 1 shows the results.

[0067]

[Chemical 13]

[0068]

[Table 1]

[0069]

HPLC condition
detection: 220 nm
column: ACQUITY UPLC BEH C18 (2.1 mm ID x 50 mm, 1.7 μm, Waters)
column temperature: 40 ° C
 mobile phase: A: 0.1 vol% trifluoroacetic acid aqueous solution, B: acetonitrile
Gradient conditions:

[0070]

[Table 2]

[0071]

Flow rate: 1.0 mL/min
Injection volume: 1 μL
Sample solution: acetonitrile/water (1:1)
wash solution: acetonitrile/water (1:1)
purge solution: acetonitrile/water (1:1)
seal wash solution : Acetonitrile/water (1:1)
Sample cooler temperature: None
Measurement time: 5 minutes
Area measurement time: about 0.5 minutes – 4.0 minutes
Comp. 1: 1.11 min, Comp. 2: 1.55 min,
Comp. 3: 1.44 min, Comp. 4: 1.70 min

[0072]

(Example 1-3) Examination of chlorination conditions 2
Compound (1) was used as a starting material, sulfuryl chloride was used as a chlorination reagent, and chlorination in various solvents was examined. Table 3 shows the results.

[0073]

[table 3]

[0074]

(Example 2) Methyl (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5- Manufacture of carboxylates

[0075]

[Chemical 14]

[0076]

 Toluene (9.0 L), tert-butyl = (trans-4-ethynylcyclohexyl) carbamate (2.23 kg, 9.99 mol), methyl = 5-chloro-3,4- were added to a reaction vessel under a nitrogen atmosphere. Dihydroxy-2-methylbenzoate (1.80 kg, 8.31 mol), tri(o-tolyl)phosphine (76.0 g, 250 mmol), triruthenium dodecacarbonyl (53.0 g, 82.9 mmol) ) was added, and the mixture was heated and stirred at 80 to 90° C. for 7 hours under an oxygen-containing nitrogen stream. The reaction solution was cooled to room temperature to obtain a toluene solution of the title compound.

[0077]

(Example 3) (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carvone acid production

[0078]

[Chemical 15]

[0079]

Methyl = (2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole obtained in Example 2 -5-carboxylate toluene solution (13 L, equivalent to 7.83 mol), methanol (9.0 L), 1,2-dimethoxyethane (3.6 L), 5 mol / L sodium hydroxide aqueous solution ( 2.50 L, 12.5 mol) was added and stirred at 55-65° C. for 3 hours. After adding water (5.4 L), the mixture was allowed to stand and separated into an organic layer and an aqueous layer. After cooling to room temperature, 1,2-dimethoxyethane (16.2 L) was added to the aqueous layer, and after adjusting the pH to 4.0 to 4.5 with 3 mol/L hydrochloric acid, toluene (5.4 L) was added. added. After heating to 50-60° C., the organic layer and aqueous layer were separated, and the organic layer was washed with a 20 wt % sodium chloride aqueous solution (7.2 L). Then, 1,2-dimethoxyethane (21.6 L) was added to the organic layer, and after concentration under reduced pressure to 9 L, 1,2-dimethoxyethane (21.6 L) was added and heated to 50-60°C. After that, filtration was performed to remove inorganic substances. Then, after washing with 1,2-dimethoxyethane (1.8 L), the 1,2-dimethoxyethane solution of the title compound (quantitative value 89.6% (Example 2 total yield from ), corresponding to 7.45 mol).

[0080]

(Example 4) (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1, Preparation of 3-benzodioxole-5-carboxylate

[0081]

[Chemical 16]

[0082]

(2RS)-2-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5 obtained in Example 3 – A solution of carboxylic acid in dimethoxyethane (21.6 L, corresponding to 7.45 mol) was heated to 75-80°C, and then (1S)-1-phenylethanamine (1.02 kg, 8.42 mmol). was added and stirred for 4 hours. A mixture of 1,2-dimethoxyethane (9.2 L) and water (3.4 L) heated to 50-60° C. was added, stirred, and then cooled to room temperature. The precipitated solid was collected by filtration and washed with 1,2-dimethoxyethane (9 L) to give a crude title compound (1.75 kg (converted to dry matter), yield 38.5% (Example 2 total yield from ) and an optical purity of 93.8% ee).

[0083]

 Under a nitrogen atmosphere, a 1,2-dimethoxyethane aqueous solution (13.6 L) was placed in a reaction vessel, and (1S)-1-phenylethanaminium obtained in step 1 (2R)-2-{trans-4-[(tert -Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate crude (1.70 kg equivalent, 3.11 mol) was added. After that, 5 mol/L hydrochloric acid (0.56 L, 2.8 mol) was added dropwise. After stirring at room temperature for 10 minutes or longer, the mixture was heated to 75° C. or higher, and (1S)-1-phenylethanamine (360 g, 2.97 mmol) was dissolved in 1,2-dimethoxyethane (2.6 L). The solution was added dropwise over 1 hour. It was then washed with 1,2-dimethoxyethane (0.9 L), stirred for 2 hours and cooled to 0-5°C. The slurry was collected by filtration and washed with 1,2-dimethoxyethane (5.1 L) cooled to 0-5° C. to give the title compound (1.56 kg, yield 91.9%, obtained with an optical purity of 99.5% ee).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.15-1.23(m,2H), 1.28-1.35(m,2H), 1.42(s,9H),
1.59(s,3H), 1.60-1.61(d ,3H,J=7.0Hz,3H),1.80-1.86(dt,J=12.0,3.0Hz,1H),1.95-1.96(m,4H),2.27(s,3H),3.24-3.28(m,1H ),4.39-4.43(q,J=7.0Hz,1H),7.07(s,1H),7.37-7.45(m,5H)

[0084]

(Example 5) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing A

[0085]

[Chemical 17]

[0086]

(Step 1)
Under a nitrogen atmosphere, 1,2-dimethoxyethane (200 L) and (1S)-1-phenylethanaminium (2R)-2-{trans-4-[(tert-butoxycarbonyl) were placed in a reaction vessel. Amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (equivalent to 87.64 kg, 160 mol), 35% hydrochloric acid (16.7 kg, 160 mol) was added and heated to 45-55° C., 35% hydrochloric acid (36.7 kg, 352 mol) was added dropwise in 7 portions and stirred for 3 hours after dropping. After cooling to room temperature, the reaction solution was added to a mixture of water (982 L) and 5 mol/L sodium hydroxide (166.34 kg, 702 mol). 3 mol/L hydrochloric acid (22.4 kg) was added dropwise to the resulting solution at 30°C, crystal precipitation was confirmed, and the mixture was stirred for 30 minutes or more, cooled to 10°C, and further stirred for 2 hours. After stirring, 3 mol/L hydrochloric acid (95.1 kg) was added dropwise at 10°C to adjust the pH to 7.0. The slurry liquid was collected by filtration, washed with water (293 L) cooled to 10° C., and (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3- Benzodioxol-5-carboxylic acid trihydrate was obtained (57.63 kg (converted to dry matter), yield 94.7%).
1 H NMR (500 MHz, methanol- d4 + D2O): 1.32-1.44 ( m, 4H), 1.61 (s, 3H), 1.89-1.94 (m, 1H), 2.01-2.13 (m, 4H) ,2.27(s,3H),2.99-3.07(m,1H),7.06(s,3H)

[0087]

(Step 2)
Under nitrogen atmosphere, 1,2-dimethoxyethane (115 L), (2R)-2-(trans-4-aminocyclohexyl)-7-chloro-2,4-dimethyl-1,3 -benzodioxole-5-carboxylic acid trihydrate (57.63 kg equivalent, 152 mmol), formic acid (34.92 kg, 759 mol), 37% formaldehyde aqueous solution (93.59 kg, 1153 mol) was added and stirred at 55-65°C for 2 hours. Cool to room temperature, add 2-propanol (864 L) and concentrate to 576 L under reduced pressure. 2-Propanol (231 L) was added thereto and concentrated under reduced pressure to 576 L. Further, 2-propanol (231 L) was added and concentrated under reduced pressure to 576 L. After concentration, 35% hydrochloric acid (20.40 kg, 196 mol) was added dropwise over 2 hours and stirred at room temperature for 30 minutes. Ethyl acetate (576 L) was added to the resulting slurry over 30 minutes and concentrated to 692 L. Ethyl acetate (461 L) was added followed by further concentration to 519 L. Ethyl acetate (634 L) was added to the residue and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration, washed with ethyl acetate (491 L) and dried under reduced pressure at 40°C to give the title compound (51. 56 kg, 87.1% yield).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.38-1.47 (m, 2H), 1.53-1.61 (m, 2H), 1.67 (s, 3H), 1.99-2.05 (m, 1H), 2.13 -2.18(m,4H),2.38(s,3H),2.84(s,6H),3.19-3.25(dt,J=12.5,3.5Hz,1H),
7.53(s,1H)

[0088]

(Example 6) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride Manufacturing B

[0089]

[Chemical 18]

[0090]

 Under a nitrogen atmosphere, formic acid (20 mL), 37% formaldehyde aqueous solution (15 mL), dimethoxyethane (10 mL), (1S)-1-phenylethanaminium (2R)-2-{trans-4- [(tert-Butoxycarbonyl)amino]cyclohexyl}-7-chloro-2,4-dimethyl-1,3-benzodioxole-5-carboxylate (10 g, 18.3 mmol) was added and Stirred for 10 hours. After cooling to room temperature and filtering the insolubles, 2-propanol (100 mL) was added and the mixture was concentrated under reduced pressure until the liquid volume became 30 mL. While stirring at room temperature, ethyl acetate (120 mL) and concentrated hydrochloric acid (6.1 mL) were added to form a slurry. This was concentrated under reduced pressure to 30 mL, ethyl acetate (120 mL) was added, and then concentrated under reduced pressure to 30 mL again. After adding ethyl acetate (120 mL), the precipitated solid was collected by filtration, washed with ethyl acetate (50 mL) and dried under reduced pressure at 40°C to give 6.56 g of the title compound (yield 92.0%). Acquired.

[0091]

(Example 7) (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl ) Preparation of methyl]-2,4-dimethyl-1,3-benzodioxole-5-carboxamide p-toluenesulfonate

[0092]

[Chemical 19]

[0093]

 Under nitrogen atmosphere, acetone (6.5 L), purified water (1.3 L), (2R)-7-chloro-2-[trans-4-(dimethylamino)cyclohexyl]-2,4- Dimethyl-1,3-benzodioxole-5-carboxylic acid monohydrochloride (650.4 g, 1.67 mol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one Monohydrochloride (330.1 g, 1.75 mol) and triethylamine (337 g, 3.33 mol) were added and stirred at room temperature for 30 minutes. After that, 1-hydroxybenzotriazole monohydrate (255 g, 1.67 mol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (383 g, 2.00 mmol) were added, and the mixture was stirred overnight at room temperature. Stirred. After adjusting the pH to 11 with 5 mol/L sodium hydroxide, toluene (9.8 L) was added, and after stirring, the mixture was separated into an organic layer 1 and an aqueous layer. Toluene (3.3 L) was added to the aqueous layer, and after stirring, the aqueous layer was discarded, and the obtained organic layer was combined with the previous organic layer 1. The combined organic layers were concentrated under reduced pressure to 9.75 L, toluene (6.5 L) was added and washed twice with purified water (3.25 L). The resulting organic layer was concentrated under reduced pressure to 4.875 L and 2-propanol (1.625 L) was added. A solution of p-toluenesulfonic acid monohydrate (0.12 kg, 0.631 mol) dissolved in 4-methyl-2-pentanone (1.14 L) was added to the organic layer heated to 68°C. The mixture was added dropwise over 5 hours and stirred at 68°C for 30 minutes. Furthermore, a solution of p-toluenesulfonic acid monohydrate (0.215 kg, 1.13 mol) dissolved in 4-methyl-2-pentanone (2.11 L) was added dropwise over 3.5 hours, Stirred at 68° C. for 30 minutes. After that, 4-methyl-2-pentanone (6.5 L) was added dropwise over 1 hour. After cooling to room temperature, the precipitated solid was collected by filtration, washed with 4-methyl-2-pentanone (3.25 L) and dried under reduced pressure at 40°C to give 1.035 kg of the crude title compound (yield 94%). .2%).

[0094]

Under a nitrogen atmosphere, 2-propanol (6.65 L) and the obtained crude title compound (950 g) were added to the reactor and stirred. Purified water (0.23 L) was added to completely dissolve the solid at 68° C., filtered, and washed with warm 2-propanol (0.95 L). After confirming that the solid was completely dissolved at an internal temperature of 68°C, the solution was cooled to 50°C. After cooling, seed crystals* (9.5 g, 0.01 wt) were added and stirred at 50° C. overnight. tert-Butyl methyl ether (11.4 L) was added dropwise thereto in 4 portions over 30 minutes each. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (0.38 L) and tert-butyl methyl ether (3.42 L), and further treated with tert-butyl methyl ether (4.75 L). ) and dried under reduced pressure at 40° C. to obtain the title compound (915.6 g, yield 96.4%).
1 H NMR (500 MHz, methanol-d 4 ): δ 1.35-1.43 (m, 2H), 1.49-1.57 (m, 2H), 1.62 (s, 3H),
1.94-2.00 (dt, J = 12.5, 3.0Hz ,1H),2.09-2.13(m,4H),2.17(s,3H),2.24(s,3H),2.35(s,3H),2.36(s,3H),2.82(s,6H),3.16- 3.22(dt,J=12.0,3.5Hz,1H),4.42(s,2H),
6.10(s,1H),6.89(s,1H),7.22-7.24(d,J=8.0Hz,2H),7.69 -7.71(dt,J=8.0,1.5 Hz,2H)
*Seed crystal preparation method
Under a nitrogen atmosphere, 2-propanol (79.0 L) and the obtained crude title compound (7.90 kg) were added to a reactor and stirred. Purified water (7.9 L) was added to completely dissolve the solid, and activated carbon (0.40 kg) was added and stirred. After filtering the activated carbon, it was washed with 2-propanol (79.0 L) and concentrated to 58 L. 2-Propanol (5 L) was added to the residue, and after heating to 64° C., tert-butyl methyl ether (19.8 L) was added, and after crystal precipitation was confirmed, tert-butyl methyl ether (75. 1 L) was added in three portions. At that time, it was stirred for 30 minutes after each addition. After cooling to room temperature, the precipitated solid was collected by filtration, washed with a mixture of 2-propanol (7.9 L) and tert-butyl methyl ether (15.8 L), and dried under reduced pressure at 40°C to obtain seed crystals. The title compound was obtained (7.08 kg, 89.6% yield).

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CN(C)[C@@H]1CC[C@H](CC1)[C@]2(C)Oc3c(C)c(cc(Cl)c3O2)C(=O)NCC4=C(C)C=C(C)NC4=O

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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.

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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

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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

/////////

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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

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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;

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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

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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.

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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

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