New Drug Approvals

Home » 0rphan drug status

Category Archives: 0rphan drug status

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

Blog Stats

  • 3,268,404 hits

Flag and hits

Flag Counter

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

Join 2,590 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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

Join 2,590 other followers

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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Devimistat


Devimistat Chemical Structure
DEVIMISTAT
6,8-Bis(benzylthio)octanoic acid.png

Devimistat

CPI-613

Molecular Weight388.59
FormulaC₂₂H₂₈O₂S₂
CAS No.95809-78-2
SMILESO=C(O)CCCCC(SCC1=CC=CC=C1)CCSCC2=CC=CC=C2

phase III, hematological cancer

6,8-Bis(benzylsulfanyl)octanoic acid

Octanoic acid, 6,8-bis[(phenylMethyl)thio]-

Octanoic acid, 6,8-bis((phenylmethyl)thio)-

Rafael Pharmaceuticals (formerly Cornerstone Pharmaceuticals), a subsidiary of Rafael Holdings, is developing devimistat, the lead candidate from a program of thioctans and their derivatives that act as pyruvate dehydrogenase and alpha-ketoglutarate inhibitors and stimulators of pyruvate dehydrogenase kinase (PDK), using the company’s proprietary Altered Energy Metabolism Directed (AEMD) platform, for the iv treatment of hematological cancer [phase III, January 2021].

Devimistat (INN; development code CPI-613) is an experimental anti-mitochondrial drug being developed by Rafael Pharmaceuticals.[1] It is being studied for the treatment of patients with metastatic pancreatic cancer and relapsed or refractory acute myeloid leukemia (AML).

Devimistat’s mechanism of action differs from other drugs, operating on the tricarboxylic acid cycle and inhibiting enzymes involved with cancer cell energy metabolism. A lipoic acid derivative different from standard cytotoxic chemotherapy, devimistat is currently being studied in combination with modified FOLFIRINOX to treat various solid tumors and heme malignancies.

Regulation

The U.S. Food and Drug Administration (FDA) has designated devimistat as an orphan drug for the treatment of pancreatic cancer, AML, myelodysplastic syndromes (MDS), peripheral T-cell lymphoma, and Burkitt’s lymphoma, and given approval to initiate clinical trials in pancreatic cancer and AML.

Clinical trials

Clinical trials of the drug are underway including a Phase III open-label clinical trial[2] to evaluate efficacy and safety of devimistat plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas.

Developed as part of Rafael’s proprietary Altered Metabolism Directed (AMD) drug platform, CPI-613® was discovered at Stony Brook University. CPI-613® is designed to target the mitochondrial tricarboxylic acid (TCA) cycle, an indispensable process essential to tumor cell multiplication and survival, selectively in cancer cells.

The attacks of CPI-613® on the TCA cycle also substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents. This synergy allows for combinations of CPI-613® with lower doses of these generally toxic drugs to be highly effective with lower patient side effects. Combinations with CPI-613® represent a diverse range of potential opportunities to substantially improve patient benefit in many different cancers.

The U.S. Food and Drug Administration (FDA) has given Rafael approval to initiate pivotal clinical trials in pancreatic cancer and acute myeloid leukemia (AML), and has designated CPI-613® as an orphan drug for the treatment of pancreatic cancer, AML, Myelodysplastic syndromes (MDS), peripheral T-cell lymphoma and Burkitt’s lymphoma. The EMA has granted orphan drug designation to CPI-613® for pancreatic cancer and AML.


Learn more about recent developments involving CPI-613®CPI-613® (devimistat) Fact Sheet

he FDA granted a Fast Track designation to devimistat for the treatment of patients with acute myeloid leukemia.

The FDA has granted a Fast Track designation to devimistat (CPI-613) for the treatment of patients with acute myeloid leukemia (AML), Rafael Pharmaceuticals, announced in a press release.1

“This designation underscores the pressing need to find new ways to combat this aggressive disease,” said Jorge Cortes, MD, director of the Georgia Cancer Center at Augusta University, and principal investigator on the phase 3 clinical trial, in a statement. “It brings hope not only to clinicians, but to patients who hear that they have been diagnosed.”

The first-in-class agent devimistat targets enzymes that are involved in cancer cell energy metabolism. This therapy substantially increases the sensitivity of cancer cells to a diverse range of chemotherapies, and this synergy allows for potential combinations that could be more effective with devimistat and lower doses of drugs that are generally toxic.

“Receiving Fast Track designation, especially during a pandemic that has created significant challenges for many trials across the globe, is a testament to the dedicated work of the Rafael team,” stated Sanjeev Luther, president and CEO of Rafael Pharmaceuticals, Inc.

Devimistat combinations appear promising with a diverse range of potential opportunities to improve benefit in patients with various cancer types. Two pivotal phase 3 clinical trials, including the AVENGER 500 study in pancreatic cancer (NCT03504423) and ARMADA 2000 for AML (NCT03504410), have been approved for initiation by the FDA.

The primary end point of the multicenter, open-label, randomized ARMADA 2000 study is complete response (CR), and secondary end points include overall survival and CR plus CR with partial hematologic recovery rate. To be eligible to enroll to the study, patients must be aged ≥50 years with a documented AML diagnosis that has relapsed from or became refractory to previous standard therapy. Patients must have an ECOG performance status of 0 to 2 and an expected survival longer than 3 months.

Five hundred patients are expected to be enrolled and randomized in the study. To enroll, patients could not have received prior radiotherapy or cytotoxic chemotherapy for their current AML. Those with active central nervous system involvement, active uncontrolled bleeding, history of other malignancy, or known hypersensitivity to study drugs are ineligible to enroll to the trial as well.

This study aims to determine the safety and efficacy of devimistat in combination with high-dose cytarabine and mitoxantrone in older patients with relapsed/refractory AML compared with high-dose cytarabine and mitoxantrone therapy alone. Other control groups include patients treated with mitoxantrone, etoposide, and cytarabine and the combination of fludarabine, cytarabine, and filgrastim. The addition of devimistat is expected to improve the CR rate in patients who are aged 50 years or older with relapsed/refractory AML.

In a prior phase 1 study of devimistat plus high-dose cytarabine and mitoxantrone in patients with relapsed/refractory AML, the addition of devimistat sensitized AML cells to chemotherapy treatment.2

The objective response rate was 50% including CRs in 26 of 62 evaluable patients. Median overall survival was 6.7 months. In patients above age 60, the CR or CR with incomplete hematologic recovery rate was 47% and the median survival was 6.9 months.

This designation for this experimental anti-mitochondrial agent follows news of another Fast Track designation granted to devimistat for the treatment of patients with metastatic pancreatic cancer in November 2020, as well as an Orphan Drug designation granted in October 2020 for the treatment of patients with soft tissue sarcoma.

References

1. Rafael Pharmaceuticals Receives FDA Fast Track Designation for CPI-613® (devimistat) for the treatment of acute myeloid leukemia (AML). News Release. Rafael Pharmaceuticals, Inc. December 15, 2020. Accessed December 15, 2020. https://bit.ly/34g6YsR

2. Pardee TS, Anderson RG, Pladna KM, et al. A Phase I Study of CPI-613 in Combination with High-Dose Cytarabine and Mitoxantrone for Relapsed or Refractory Acute Myeloid Leukemia. Clin Cancer Res. 2018;24(9):2060-2073. doi:10.1158/1078-0432.CCR-17-2282 P[APERJournal of the American Chemical Society (1954), 76, 4109-12.https://pubs.acs.org/doi/abs/10.1021/ja01645a016
PAPERJournal of the American Chemical Society (1955), 77, 416-19.https://pubs.acs.org/doi/abs/10.1021/ja01607a057PAPERJustus Liebigs Annalen der Chemie (1958), 614, 66-83.https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/jlac.19586140108PATENTWO 2009123597WO 2009110859WO 2010110771PATENTCN 111362848

PATENT

WO-2021011334

Deuterated derivatives of 6,8-bis(benzylsulfanyl)octanoic acid (CPI-613 or devimistat ) or its salts for treating cancer.

CPI-613 (6,8-bis(benzylsulfanyl)octanoic acid) is a first-in-class investigational small-molecule (lipoate analog), which targets the altered energy metabolism unique to many cancer cells. CPI-613 is currently being evaluated in two phase III clinical trials, and has been granted orphan drug designation for the treatment of pancreatic cancer, acute myeloid leukemia (AML), peripheral T-cell lymphoma (PTCL), Burkitt lymphoma and myelodysplastic syndromes (MDS).

[0004] One limitation to the clinical utility of CPI-613 is its very rapid metabolism. After IV dosing the half-life of 6,8-bis(benzylsulfanyl)octanoic acid is only about 1-2 hours (Pardee,

T.S. et al, Clin Cancer Res. 2014, 20, 5255-64). The short half-life limits the patient’s overall exposure to the drug and necessitates administration of relatively high doses. For safety reasons, CPI-613 is administered via a central venous catheter as an IV infusion over 30-120 minutes, with higher doses requiring longer infusion times.

The terms“6,8-bis(benzylsulfanyl)octanoic acid” and“ 6,8-bis-benzylthio-octanoic acid” refer to the compound known as CPI-613 or devimistat, having the chemical structure

PATENT

WO2020132397

claiming the use of CPI-613 in combination with an autophagy inhibitor eg chloroquine for treating eg cancers.

CPI-613 (6,8-bis-benzylthio-octanoic acid) is a first-in-class investigational small-molecule (lipoate analog), which targets the altered energy metabolism that is common to many cancer cells. CPI-613 has been evaluated in multiple phase I, I/II, and II clinical studies, and has been granted orphan drug designation for the treatment of pancreatic cancer, acute myeloid leukemia (AML), peripheral T-cell lymphoma (PTCL), Burkitt lymphoma and myelodysplastic syndromes (MDS).

PAPER

https://pubs.acs.org/doi/10.1021/op200091t

An Efficient, Economical Synthesis of the Novel Anti-tumor Agent CPI-613

Cite this: Org. Process Res. Dev. 2011, 15, 4, 855–857

Publication Date:May 2, 2011
https://doi.org/10.1021/op200091t

An efficient and practical synthesis of the novel anti-tumor compound 6,8-dithiobenzyl octanoic acid, CPI-613 (2), was developed and executed on a practical scale. CPI-613 can be made in a single vessel from (±)-lipoic acid (1) via reductive opening of the disulfide ring followed by benzylation of the sulfhydryls with benzyl bromide. CPI-613 was isolated by simple crystallization in high yield and purity. The process is scaleable and has been demonstrated at up to 100 kg.CPI-613 (2) was isolated [4.7 kg (90%)] with an HPLC purity of 99.8 area %. Mp 66–67 °C. IR: 3050, 1710, 1400, 668 cm–11H NMR (400 MHz, CDCl3) δ 7.40–7.20 (m, 10 H), 3.80–3.60 (m, 4 H), 2.60–2.50 (m, 2 H), 2.44 (t, J = 8.7, 2 H), 2.23 (t, J = 8.1, 2 H) 2.03–1.30 (m, 8 H). Anal. Calc for C22H28O2S2: C, 68.00; H, 7.26; S, 16.50. Found: C, 67.99; H, 7.31; S, 16.37. 

References

  1. ^ “CPI-613”. Rafael Pharmaceuticals.
  2. ^ Philip PA, Buyse ME, Alistar AT, Rocha Lima CM, Luther S, Pardee TS, Van Cutsem E (October 2019). “A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas”Future Oncology15 (28): 3189–3196. doi:10.2217/fon-2019-0209PMC 6854438PMID 31512497.
Clinical data
Other namesCPI-613
Legal status
Legal statusInvestigational
Identifiers
IUPAC name[show]
CAS Number95809-78-2
PubChem CID24770514
DrugBank12109
ChemSpider28189062
UNIIE76113IR49
ChEMBLChEMBL3186849
CompTox Dashboard(EPA)DTXSID70914807
ECHA InfoCard100.231.125 
Chemical and physical data
FormulaC22H28O2S2
Molar mass388.58 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]C1=CC=C(C=C1)CSCCC(CCCCC(=O)O)SCC2=CC=CC=C2

//////////devimistat, CPI-613, CPI 613, phase 3, hematological cancer , Fast Track designation, ORPHAN DRUG, 

Lurbinectedin


Lurbinectedin.png

Lurbinectedin

(1’R,6R,6aR,7R,13S,14S,16R)-5-(Acetyloxy)-2′,3′,4′,6,6a,7,9′-decahydro-8,14-dihydroxy-6′,9-dimethoxy-4,10,23-trimethyl-spiro(6,16-(epithiopropaneoxymethano)-7.13-imino-12H-1,3-dioxolo[7,8]soquino[3,2-b][3]benzazocine-20,1′-[1H]pyrido[3,4-b]indol]-19-one

Molecular Weight784.87
FormulaC41H44N4O10S
CAS No.497871-47-3 (Lurbinectedin);
Chemical NameSpiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′-[1H]pyrido[3,4-b]indol]-19-one, 5-(acetyloxy)-2′,3′,4′,6,6a,7,9′,13,14,16-decahydro-8,14-dihydroxy-6′,9-dimethoxy-4,10,23-trimethyl-, (1’R,6R,6aR,7R,13S,14S,16R)- (9CI)

fda approved , 6/15/2020 , ZEPZELCA, Pharma Mar S.A.

To treat metastatic small cell lung cancer
Drug Trials Snapshot

Research Code:PM-01183; PM-1183

MOA:RNA polymerase inhibitor

Indication:Ovarian cancer; Breast cancer; Non small cell lung cancer (NSCLC)лурбинектединلوربينيكتيدين芦比替定(1R,1’R,2’R,3’R,11’S,12’S,14’R)-5′,12′-Dihydroxy-6,6′-dimethoxy-7′,21′,30′-trimethyl-27′-oxo-2,3,4,9-tetrahydrospiro[β-carboline-1,26′-[17,19,28]trioxa[24]thia[13,30]diazaheptacyclo[12.9.6.13,11. 02,13.04,9.015,23.016,20]triaconta[4,6,8,15,20,22]hexaen]-22′-yl acetate [ACD/IUPAC Name]2CN60TN6ZS497871-47-3[RN]9397

Lurbinectedin is in phase III clinical development for the treatment of platinum refractory/resistant ovarian cancer.

Phase II clinical trials are also ongoing for several oncology indications: non-small cell lung cancer, breast cancer, small cell lung cancer, head and neck carcinoma, neuroendocrine tumors, biliary tract carcinoma, endometrial carcinoma, germ cell tumors and Ewing’s family of tumors.

Lurbinectedin, sold under the brand name Zepzelca, is a medication for the treatment of adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.[1][2][3]

The most common side effects include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.[1][2][3]

Lurbinectedin is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity.[4] Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.[4]

Lurbinectedin was approved for medical use in the United States in June 2020.[5][1][2][3][6]

Structure

Lurbinectedin is structurally similar to trabectedin, although the tetrahydroisoquinoline present in trabectedin is replaced with a tetrahydro β-carboline which enables lurbinectedin to exhibit increased antitumor activity compared with trabectedin.[7]

Biosynthesis

Lurbinectedin a marine agent isolated from the sea squirt species Ecteinascidia turbinata. Synthetic production is necessary because very small amounts can be obtained from sea organisms. For example, one ton (1000 kg) of sea squirts are required to produce one gram of trabectedin, which is analogue of lurbinectedin. Complex synthesis of lurbinectedin starts from small, common starting materials that require twenty-six individual steps to produce the drug with overall yield of 1.6%.[8][9]

Mechanism of action

According to PharmaMar,[10] lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences. On one hand, it promotes tumor cell death, and on the other it normalizes tumor microenvironment. Active transcription is the process by which there are specific signal where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slides down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has important role in tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system. Literally, macrophages work in any tumor’s favor. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.[11][12] Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. So, not only that macrophages inhibit immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death and secondly, inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

History

Lurbinectedin was approved for medical use in the United States in June 2020.[5][1][2][3][6]

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 participants with metastatic SCLC who had disease progression on or after platinum-based chemotherapy.[3][6] Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.[3] The trial was conducted at 26 sites in the United States, Great Britain, Belgium, France, Italy, Spain and Czech Republic.[6]

The U.S. Food and Drug Administration (FDA) granted the application for lurbinectedin priority review and orphan drug designations and granted the approval of Zepzelca to Pharma Mar S.A.[3][13]

Research

Clinical Trials

Lurbinectedin can be used as monotherapy in the treatment of SCLC.  Lurbinectedin monotherapy demonstrated the following clinical results in relapsed extensive stage SCLC:

  • For sensitive disease (chemotherapy-free interval of ≥ 90 days) overall response rate (ORR) was 46.6% with 79.3% disease control rate and median overall survival (OS) being increased to 15.2 months.[14]
  • For resistant disease (chemotherapy-free interval of < 90 days) overall response rate (ORR) was 21.3% with 46.8% disease control rate and 5.1 months median overall survival (OS).[14]

Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized Phase III trial.[medical citation needed] While overall survival in this trial is not yet known, response rates at second line were

  • 91.7% in sensitive disease with median progression-free survival of 5.8 months, and
  • 33.3% in resistant disease with median progression-free of 3.5 months.[15]

Lurbinectedin is available in the U.S. under Expanded Access Program (EAP).[15][16]

SYN

SYN

WO2011/147828

Ecteinascidins is a group of naturally occurring marine compounds and analogs thereof, which are well identified and structurally characterized, and are disclosed to have antibacterial and cytotoxic properties. See for example, European Patent 309.477; WO 03/66638; WO 03/08423; WO 01 /771 15; WO 03/014127; R. Sakai et al., 1992, Proc. Natl. Acad. Sci. USA 89, pages 1 1456- 1 1460; R. Menchaca et al., 2003, J. Org. Chem. 68(23), pages 8859-8866; and I. Manzanares et al., 2001 , Curr. Med. Chem. Anti-Cancer Agents, 1 , pages 257-276; and references therein. Examples of ecteinascidins are provided by ET-743, ET-729, ET-745, ET-759A, ET-759B, ET-759C, ET-770, ET-815, ET-731 , ET-745B, ET-722, ET-736, ET-738, ET-808, ET-752, ET-594, ET-552, ET-637, ET-652, ET-583, ET-597, ET-596, ET-639, ET-641 , and derivatives thereof, such as acetylated forms, formylated forms, methylated forms, and oxide forms.

The structural characterizations of such ecteinascidins are not given again explicitly herein because from the detailed description provided in such references and citations any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources.

At least one of the ecteinascidin compounds, ecteinascidin 743 (ET-743), has been extensively studied, and it will be referred to

specifically herein to illustrate features of this invention. ET-743 is being employed as an anticancer medicament, under the international nonproprietary name (INN) trabectedin, for the treatment of patients with advanced and metastatic soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide, or who are unsuited to receive such agents, and for the treatment of relapsed platinum- sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.

ET-743 has a complex tris(tetrahydroisoquinoline) structure of formula

It was originally prepared by isolation from extracts of the marine tunicate Ecteinascidia turbinata. The yield was low, and alternative preparative processes had been sought.

The first synthetic process for producing ecteinascidin compounds was described in US Patent 5,721 ,362. This process employed sesamol as starting material and yielded ET-743 after a long and complicated sequence of 38 examples each describing one or more steps in the synthetic sequence.

An improvement in the preparation of one intermediate used in such process was disclosed in US Patent 6,815,544. Even with this improvement, the total synthesis was not suitable for manufacturing ET-743 at an industrial scale.

A hemisynthetic process for producing ecteinascidin compounds was described in EP 1.185.536. This process employs cyanosafracin B as starting material to provide ET-743. Cyanosafracin B is a pentacyclic antibiotic obtained by fermentation from the bacteria Pseudomonas fluorescens.

Cyanosafracin B

An improvement in such hemisynthetic process was disclosed in

EP 1.287.004.

To date four additional synthetic process (2 total and 2 formal synthesis) have been disclosed in patent applications JP 2003221395, WO 2007/045686, and WO 2007/087220 and in J. Org. Chem. 2008, 73, pages 9594-9600.

WO 2007/045686 also relates to the synthesis of Ecteinascidins-583 and 597 using intermediate compounds of formula:

Total synthesis strategies for the synthesis of the pentacyclic core -743 are overviewed in Figure I.

X = OH or CI

R = Protecting Group

WO2007087220 JOC 2008, 73, 9594-9600

EXAMPLE 3: SYNTHESIS OF COMPOUND 17.

Scheme X above provides an example of the synthesis of compound 17 from intermediate 10.

Compounds 16 and 17 are obtainable from intermediate 15 using the same procedures than those previously described in WO03/014127.

SYN

Reference:

1. WO2003014127A1.

https://patents.google.com/patent/WO2003014127A1/en

The ecteinascidins are exceedingly potent antitumour agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example:

U.S. Patent No 5.256.663, which describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins, and the use of such compositions as antibacterial, antiviral, and/ or antitumour agents in mammals.

U.S. Patent No 5.089.273, which describes novel compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumour agents in mammals.

U.S. Patent No 5.149.804 which describes Ecteinascidins 722 and 736 (Et’s 722 and 736) isolated from the Caribbean tunicate Ecteinascidia turbinata and their structures. Et’s 722 and 736 protect mice in vivo at very low concentrations against P388 lymphoma, B 16 melanoma, and Lewis lung carcinoma.

U.S. Patent No 5.478.932, which describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B 16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- 1 human lung and MX- 1 human mammary carcinoma xenografts.

U.S. Patent No 5.654.426, which describes several ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B 16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX- 1 human mammary carcinoma xenografts.

U.S. Patent No 5.721.362 which describes a synthetic process for the formation of ecteinascidin compounds and related structures.

U.S. Patent No 6.124.292 which describes a series of new ecteinascidin- like compounds.

WO 0177115, WO 0187894 and WO 0187895, which describe new synthetic compounds of the ecteinascidin series, their synthesis and biological properties.

See also: Corey, E.J., J. Am. Chem. Soc, 1996, 118 pp. 9202-9203; Rinehart, et al., Journal of Natural Products, 1990, “Bioactive Compounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771- 792; Rinehart et al., Pure and Appl. Chem., 1990, “Biologically active natural products”, vol 62, pp. 1277- 1280; Rinehart, et al., J. Org. Chem., 1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent Antitumour Agents from the Caribbean Tunicate Ecteinascidia tuminata”, vol. 55, pp. 4512-4515; Wright et al., J. Org. Chem., 1990, “Antitumour Tetrahydroisoquinoline Alkaloids from the Colonial ascidian Ecteinascidia turbinata”, vol. 55, pp. 4508-4512; Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional anitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 1 1456- 1 1460; Science 1994, “Chemical Prospectors Scour the Seas for Promising Drugs”, vol. 266, pp.1324; Koenig, K.E., “Asymmetric Synthesis”, ed. Morrison, Academic Press, Inc., Orlando, FL, vol. 5, 1985, p. 71; Barton, et al., J. Chem Soc. Perkin Trans., 1 , 1982, “Synthesis and Properties of a Series of Sterically Hindered Guanidine bases”, pp. 2085; Fukuyama et al., J. Am. Chem. Soc, 1982, “Stereocontrolled Total Synthesis of (+)-Saframycin B”, vol. 104, pp. 4957; Fukuyama et al., J. Am. Chem. Soc, 1990, “Total Synthesis of (+) – Saframycin A”, vol. 112, p. 3712; Saito, et al., J. Org. Chem., 1989, “Synthesis of Saframycins. Preparation of a Key tricyclic Lactam Intermediate to Saframycin A”, vol. 54, 5391; Still, et al., J Org. Chem., 1978, “Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W.G.; Baclawski, L.M., J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J. Biomolec Struc & Dynam., vol. 10, pp. 793-817 (1993); Shamma et al., “Carbon- 13 NMR Shift Assignments of Amines and Alkaloids”, p. 206 (1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361-375 (1985); Ito, CRC Crit. Rev. Anal. Chem., 17, 65- 143 (1986); Rinehart et al., “Topics in Pharmaceutical Sciences 1989”, pp. 613-626, D. D. Breimer, D. J. A. Cromwelin, K. K. Midha, Eds., Amsterdam Medical Press B. V., Noordwijk, The Netherlands (1989); Rinehart et al., “Biological Mass Spectrometry”, 233-258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec. Struct. & Dynam., vol. 10 pp. 793-817 (1993); Nakagawa et al., J. Amer. Chem. Soc, 11 1 : 2721-2722 (1989);; Lichter et al., “Food and Drugs from the Sea Proceedings” (1972), Marine Technology Society, Washington, D.C. 1973, 117- 127; Sakai et al., J. Amer. Chem. Soc, 1996, 1 18, 9017; Garcϊa-Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; and pommier et al., Biochemistry, 1996, 35: 13303- 13309;

In 2000, a hemisynthetic process for the formation of ecteinascidin compounds and related structures such as phthalascidin starting from natural bis(tetrahydroisoquinoline) alkaloids such as the saframycin and safracin antibiotics available from different culture broths was reported; See Manzanares et al., Org. Lett., 2000, “Synthesis of Ecteinascidin ET-743 and Phthalascidin Pt-650 from Cyanosafracin B”, Vol. 2, No 16, pp. 2545-2548; and International Patent Application WO 00 69862.

Ecteinascidin 736 was first discovered by Rinehart and features a tetrahydro-β-carboline unit in place of the tetrahydroisoquinoline unit more usually found in the ecteinascidin compounds isolated from natural sources; See for example Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 11456-11460.

Figure imgf000005_0001

Et-736

WO 9209607 claims ecteinascidin 736, as well as ecteinascidin 722 with hydrogen in place of methyl on the nitrogen common to rings C and D of ecteinascidin 736 and O-methylecteinascidin 736 with methoxy in place of hydroxy on ring C of ecteinascidin 736.

Despite the positive results obtained in clinical applications in chemotherapy, the search in the field of ecteinascidin compounds is still open to the identification of new compounds with optimal features of cytotoxicity and selectivity toward the tumour and with a reduced systemic toxicity and improved pharmacokinetic properties.

PATENT

WO2001087894A1.

PATENT

 US 20130066067

https://patents.google.com/patent/US20130066067A1/en

  • Ecteinascidins is a group of naturally occurring marine compounds and analogs thereof, which are well identified and structurally characterized, and are disclosed to have antibacterial and cytotoxic properties. See for example, European Patent 309.477; WO 03/66638; WO 03/08423; WO 01/77115; WO 03/014127; R. Sakai et al., 1992, Proc. Natl. Acad. Sci. USA 89, pages 11456-11460; R. Menchaca et al., 2003, J. Org. Chem. 68(23), pages 8859-8866; and I. Manzanares et al., 2001, Curr. Med. Chem. AntiCancer Agents, 1, pages 257-276; and references therein. Examples of ecteinascidins are provided by ET-743, ET-729, ET-745, ET-759A, ET-759B, ET-759C, ET-770, ET-815, ET-731, ET-745B, ET-722, ET-736, ET-738, ET-808, ET-752, ET-594, ET-552, ET-637, ET-652, ET-583, ET-597, ET-596, ET-639, ET-641, and derivatives thereof, such as acetylated forms, formylated forms, methylated forms, and oxide forms.
  • [0003]
    The structural characterizations of such ecteinascidins are not given again explicitly herein because from the detailed description provided in such references and citations any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources.
  • [0004]
    At least one of the ecteinascidin compounds, ecteinascidin 743 (ET-743), has been extensively studied, and it will be referred to specifically herein to illustrate features of this invention. ET-743 is being employed as an anticancer medicament, under the international nonproprietary name (INN) trabectedin, for the treatment of patients with advanced and metastatic soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide, or who are unsuited to receive such agents, and for the treatment of relapsed platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.
  • [0005]
    ET-743 has a complex tris(tetrahydroisoquinoline) structure of formula
  • [0006]
    It was originally prepared by isolation from extracts of the marine tunicate Ecteinascidia turbinata. The yield was low, and alternative preparative processes had been sought.
  • [0007]
    The first synthetic process for producing ecteinascidin compounds was described in U.S. Pat. No. 5,721,362. This process employed sesamol as starting material and yielded ET-743 after a long and complicated sequence of 38 examples each describing one or more steps in the synthetic sequence.
  • [0008]
    An improvement in the preparation of one intermediate used in such process was disclosed in U.S. Pat. No. 6,815,544. Even with this improvement, the total synthesis was not suitable for manufacturing ET-743 at an industrial scale.
  • [0009]
    A hemisynthetic process for producing ecteinascidin compounds was described in EP 1.185.536. This process employs cyanosafracin B as starting material to provide ET-743. Cyanosafracin B is a pentacyclic antibiotic obtained by fermentation from the bacteria Pseudomonas fluorescens.
  • [0010]
    An improvement in such hemisynthetic process was disclosed in EP 1.287.004.
  • [0011]
    To date four additional synthetic process (2 total and 2 formal synthesis) have been disclosed in patent applications JP 2003221395, WO 2007/045686, and WO 2007/087220 and in J. Org. Chem. 2008, 73, pages 9594-9600.
  • [0012]
    WO 2007/045686 also relates to the synthesis of Ecteinascidins-583 and 597 using intermediate compounds of formula:
  • [0013]
    Total synthesis strategies for the synthesis of the pentacyclic core of ET-743 are overviewed in FIG. 1.

PAPER

Angewandte Chemie, International Edition (2019), 58(12), 3972-3975.

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201900035

An efficient and scalable approach is described for the total synthesis of the marine natural product Et‐743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz‐protected (S)‐tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light‐mediated remote C−H bond activation to assemble a benzo[1,3]dioxole‐containing intermediate.

Synthesis of lactone SI-5. A mixture of 19 (98.0 mg, 0.16 mmol, 1.0 equiv), 2-(5-methoxy-1H-indol-3-yl) ethanamine hydrochloride salt (357.8 mg, 1.58 mmol, 10.0 equiv) and NaOAc (144 mg, 1.74 mmol, 11.0 equiv) in anhydrous EtOH (5.0 mL) was stirred at 60 oC for 5 h. The cooled mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with DCM/MeOH = 20:1) to afford compound SI-5 (109 mg, 87%). [α]𝐷 20 = -27.7 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.66 (s, 1H), 6.22 (d, J = 1.0 Hz, 1H), 6.02 (d, J = 1.0 Hz, 1H), 5.78 (s, 1H), 5.08 (d, J = 11.7 Hz, 1H), 4.55 (s, 1H), 4.32 (s, 1H), 4.27 (d, J = 3.8 Hz, 1H), 4.23–4.15 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.47–3.39 (m, 2H), 3.20–3.10 (m, 1H), 3.06 (d, J = 18.1 Hz, 1H), 2.93 (dd, J = 18.2, 9.1 Hz, 1H), 2.86–2.76 (m, 1H), 2.62 (dt, J = 14.9, 4.8 Hz, 1H), 2.56–2.47 (m, 2H), 2.37 (s, 3H), 2.30–2.27 (m, 1H), 2.26 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.6, 168.8, 154.0, 148.2, 145.8, 143.1, 141.3, 140.5, 131.4, 130.8, 130.7, 129.4, 127.3, 120.9, 120.8, 118.4, 118.4, 113.9, 113.8, 112.2, 111.8, 110.2, 102.2, 100.5, 62.6, 61.4, 60.7, 60.5, 59.6, 59.6, 55.9, 54.9, 54.8, 42.1, 41.6, 39.9, 39.5, 29.5, 24.0, 20.8, 16.0, 9.9; HRMS (ESI) m/z calcd. for C42H43N5O9S [M + H]+ 794.2860, found 794.2858

Lurbinectedin: To a solution of SI-5 (80 mg, 0.1 mmol, 1.0 equiv) in acetonitrile and water (3:2, v/v, 10 mL) was added silver nitrate (514 mg, 3 mmol, 30.0 equiv). The suspension was stirred at 25 oC for 24 h before a mixture of saturated brine (5.0 mL) and saturated sodium hydrogen carbonate (5 mL) were added. The resultant mixture was stirred at 25 oC for 15 min before it was filtered through celite and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (eluting with DCM/MeOH = 20:1) to afford Lurbinectedin (71 mg, 89%). [α]𝐷 20 = -45.0 (c = 1.0, CHCl3) 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.74 (dd, J = 8.8, 2.4 Hz, 1H), 6.67 (s, 1H), 6.19 (d, J = 1.1 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 5.77 (br s, 1H), 5.20 (d, J = 11.3 Hz, 1H), 4.82 (s, 1H), 4.53–4.40 (m, 2H), 4.18–4.08 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.49 (d, J = 4.2 Hz, 1H), 3.24–3.13 (m, 2H), 3.01 (d, J = 17.9 Hz, 1H), 2.88–2.79 (m, 2H), 2.63 (dt, J = 15.0, 4.9 Hz, 1H), 2.56–2.47 (m, 2H), 2.37 (s, 3H), 2.32–2.27 (m, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 168.8, 153.8, 147.9, 145.5, 142.9, 141.1, 140.7, 131.8, 131.3, 130.7, 129.1, 127.3, 121.4, 121.0, 118.2, 115.6, 112.9, 111.9, 111.7, 110.0, 101.8, 100.4, 82.0, 62.4, 61.9, 60.4, 57.8, 57.5, 56.0, 55.8, 55.0, 42.2, 41.3, 39.8, 39.3, 29.3, 23.6, 20.6, 15.9, 9.7; HRMS (ESI) m/z calcd. for C41H44N4O10S [M – OH]+ 767.2745, found 767.2742.

References

  1. Jump up to:a b c d e “Zepzelca- lurbinectedin injection, powder, lyophilized, for solution”DailyMed. 15 June 2020. Retrieved 24 September 2020.
  2. Jump up to:a b c d “Jazz Pharmaceuticals Announces U.S. FDA Accelerated Approval of Zepzelca (lurbinectedin) for the Treatment of Metastatic Small Cell Lung Cancer” (Press release). Jazz Pharmaceuticals. 15 June 2020. Retrieved 15 June 2020 – via PR Newswire.
  3. Jump up to:a b c d e f g “FDA grants accelerated approval to lurbinectedin for metastatic small”U.S. Food and Drug Administration (FDA). 15 June 2020. Retrieved 16 June 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Lurbinectedin”National Cancer Institute. Retrieved 15 June 2020.  This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b “Zepzelca: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 15 June 2020.
  6. Jump up to:a b c d “Drug Trials Snapshots: Zepzelca”U.S. Food and Drug Administration (FDA). 15 June 2020. Retrieved 28 June 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi (17 March 2016). “Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary”PLOS ONE11 (3): e0151050. Bibcode:2016PLoSO..1151050Tdoi:10.1371/journal.pone.0151050PMC 4795692PMID 26986199.
  8. ^ Total synthesis of marine antitumor agents trabectedin and lurbinectedin | https://www.sciencedaily.com/releases/2019/02/190219111659.htm
  9. ^ A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin | https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201900035
  10. ^ PharmaMar presentation of Lurbinectedin’s Mechanism of Action Lurbinectedin Mechanisim of Action | https://www.youtube.com/watch?v=8daELhxAXcQ
  11. ^ Qian BZ, Pollard JW (April 2010). “Macrophage diversity enhances tumor progression and metastasis”Cell141 (1): 39–51. doi:10.1016/j.cell.2010.03.014PMC 4994190PMID 20371344.
  12. ^ Engblom C, Pfirschke C, Pittet MJ (July 2016). “The role of myeloid cells in cancer therapies”. Nature Reviews. Cancer16 (7): 447–62. doi:10.1038/nrc.2016.54PMID 27339708S2CID 21924175.
  13. ^ “Lurbinectedin Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 1 August 2018. Retrieved 16 June 2020.
  14. Jump up to:a b Paz-Ares, Luis G.; Trigo Perez, Jose Manuel; Besse, Benjamin; Moreno, Victor; Lopez, Rafael; Sala, Maria Angeles; Ponce Aix, Santiago; Fernandez, Cristian Marcelo; Siguero, Mariano; Kahatt, Carmen Maria; Zeaiter, Ali Hassan; Zaman, Khalil; Boni, Valentina; Arrondeau, Jennifer; Martinez Aguillo, Maite; Delord, Jean-Pierre; Awada, Ahmad; Kristeleit, Rebecca Sophie; Olmedo Garcia, Maria Eugenia; Subbiah, Vivek (20 May 2019). “Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial”. Journal of Clinical Oncology37 (15_suppl): 8506. doi:10.1200/JCO.2019.37.15_suppl.8506.
  15. Jump up to:a b Calvo, E.; Moreno, V.; Flynn, M.; Holgado, E.; Olmedo, M.E.; Lopez Criado, M.P.; Kahatt, C.; Lopez-Vilariño, J.A.; Siguero, M.; Fernandez-Teruel, C.; Cullell-Young, M.; Soto Matos-Pita, A.; Forster, M. (October 2017). “Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study”Annals of Oncology28 (10): 2559–2566. doi:10.1093/annonc/mdx357PMC 5834091PMID 28961837Lay summary.
  16. ^ Farago, Anna F; Drapkin, Benjamin J; Lopez-Vilarino de Ramos, Jose Antonio; Galmarini, Carlos M; Núñez, Rafael; Kahatt, Carmen; Paz-Ares, Luis (January 2019). “ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line”Future Oncology15 (3): 231–239. doi:10.2217/fon-2018-0597PMC 6331752PMID 30362375.

External links

FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer

On June 15, 2020, the Food and Drug Administration granted accelerated approval to lurbinectedin(ZEPZELCA, Pharma Mar S.A.) for adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed overall response rate (ORR) determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was 35% (95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30% (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4).

The most common adverse reactions (≥20%), including laboratory abnormalities, were myelosuppression, fatigue, increased creatinine, increased alanine aminotransferase, increased glucose, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.

The recommended lurbinectedin dose is 3.2 mg/m2 every 21 days.

View full prescribing information for ZEPZELCA.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this application, a modified Project Orbis was undertaken because of the timing of submission to other regulatory agencies. FDA is collaborating with the Australian Therapeutic Goods Administration (TGA). FDA approved this application 2 months ahead of the goal date. The review is ongoing for the Australian TGA.

FDA granted lurbinectedin orphan drug  designation for the treatment of SCLC and priority review to this application. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

REFERENCES

1: Calvo E, Moreno V, Flynn M, Holgado E, Olmedo ME, Lopez Criado MP, Kahatt C, Lopez-Vilariño JA, Siguero M, Fernandez-Teruel C, Cullell-Young M, Soto Matos-Pita A, Forster M. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Ann Oncol. 2017 Oct 1;28(10):2559-2566. doi: 10.1093/annonc/mdx357. PubMed PMID: 28961837.

2: Erba E, Romano M, Gobbi M, Zucchetti M, Ferrari M, Matteo C, Panini N, Colmegna B, Caratti G, Porcu L, Fruscio R, Perlangeli MV, Mezzanzanica D, Lorusso D, Raspagliesi F, D’Incalci M. Ascites interferes with the activity of lurbinectedin and trabectedin: Potential role of their binding to alpha 1-acid glycoprotein. Biochem Pharmacol. 2017 Nov 15;144:52-62. doi: 10.1016/j.bcp.2017.08.001. Epub 2017 Aug 4. PubMed PMID: 28782526.

3: Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L, Beltrame L, Marchini S, Galmarini CM, Mantovani A, Frapolli R, Allavena P, D’Incalci M. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017 Aug 22;117(5):628-638. doi: 10.1038/bjc.2017.205. Epub 2017 Jul 6. PubMed PMID: 28683469; PubMed Central PMCID: PMC5572168.

4: Jimeno A, Sharma MR, Szyldergemajn S, Gore L, Geary D, Diamond JR, Fernandez Teruel C, Soto Matos-Pita A, Iglesias JL, Cullell-Young M, Ratain MJ. Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule. Invest New Drugs. 2017 Aug;35(4):471-477. doi: 10.1007/s10637-017-0427-2. Epub 2017 Jan 20. PubMed PMID: 28105566.

5: Paz-Ares L, Forster M, Boni V, Szyldergemajn S, Corral J, Turnbull S, Cubillo A, Teruel CF, Calderero IL, Siguero M, Bohan P, Calvo E. Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors. Invest New Drugs. 2017 Apr;35(2):198-206. doi: 10.1007/s10637-016-0410-3. Epub 2016 Nov 21. PubMed PMID: 27873130.

6: Harlow ML, Maloney N, Roland J, Guillen Navarro MJ, Easton MK, Kitchen-Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D’Incalci M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM, Grohar PJ. Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus. Cancer Res. 2016 Nov 15;76(22):6657-6668. doi: 10.1158/0008-5472.CAN-16-0568. Epub 2016 Oct 3. PubMed PMID: 27697767; PubMed Central PMCID: PMC5567825.

7: Céspedes MV, Guillén MJ, López-Casas PP, Sarno F, Gallardo A, Álamo P, Cuevas C, Hidalgo M, Galmarini CM, Allavena P, Avilés P, Mangues R. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech. 2016 Dec 1;9(12):1461-1471. Epub 2016 Oct 20. PubMed PMID: 27780828; PubMed Central PMCID: PMC5200894.

8: Santamaría Nuñez G, Robles CM, Giraudon C, Martínez-Leal JF, Compe E, Coin F, Aviles P, Galmarini CM, Egly JM. Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells. Mol Cancer Ther. 2016 Oct;15(10):2399-2412. Epub 2016 Sep 14. PubMed PMID: 27630271.

9: Metaxas Y, Cathomas R, Mark M, von Moos R. Combination of cisplatin and lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma: Report of two cases. Lung Cancer. 2016 Dec;102:136-138. doi: 10.1016/j.lungcan.2016.07.012. Epub 2016 Jul 14. PubMed PMID: 27440191.

10: Lima M, Bouzid H, Soares DG, Selle F, Morel C, Galmarini CM, Henriques JA, Larsen AK, Escargueil AE. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair. Oncotarget. 2016 May 3;7(18):25885-901. doi: 10.18632/oncotarget.8292. PubMed PMID: 27029031; PubMed Central PMCID: PMC5041952.

11: Takahashi R, Mabuchi S, Kawano M, Sasano T, Matsumoto Y, Kuroda H, Kozasa K, Hashimoto K, Sawada K, Kimura T. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary. PLoS One. 2016 Mar 17;11(3):e0151050. doi: 10.1371/journal.pone.0151050. eCollection 2016. PubMed PMID: 26986199; PubMed Central PMCID: PMC4795692.

12: Pernice T, Bishop AG, Guillen MJ, Cuevas C, Aviles P. Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM01183 (lurbinectedin), a novel antineoplastic agent, in mouse, rat, dog, Cynomolgus monkey and mini-pig plasma. J Pharm Biomed Anal. 2016 May 10;123:37-41. doi: 10.1016/j.jpba.2016.01.043. Epub 2016 Jan 21. PubMed PMID: 26871278.

13: Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ. First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Clin Cancer Res. 2014 Apr 15;20(8):2205-14. doi: 10.1158/1078-0432.CCR-13-1880. Epub 2014 Feb 21. PubMed PMID: 24563480.

14: Romano M, Frapolli R, Zangarini M, Bello E, Porcu L, Galmarini CM, García-Fernández LF, Cuevas C, Allavena P, Erba E, D’Incalci M. Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104). Int J Cancer. 2013 Nov;133(9):2024-33. doi: 10.1002/ijc.28213. Epub 2013 May 25. PubMed PMID: 23588839.

15: Vidal A, Muñoz C, Guillén MJ, Moretó J, Puertas S, Martínez-Iniesta M, Figueras A, Padullés L, García-Rodriguez FJ, Berdiel-Acer M, Pujana MA, Salazar R, Gil-Martin M, Martí L, Ponce J, Molleví DG, Capella G, Condom E, Viñals F, Huertas D, Cuevas C, Esteller M, Avilés P, Villanueva A. Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res. 2012 Oct 1;18(19):5399-411. doi: 10.1158/1078-0432.CCR-12-1513. Epub 2012 Aug 15. PubMed PMID: 22896654.

Clinical data
PronunciationLOOR-bih-NEK-teh-din
Trade namesZepzelca
Other namesPM-01183
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620049
License dataUS DailyMedLurbinectedin
Pregnancy
category
US: N (Not classified yet)
Routes of
administration
Intravenous
Drug classAntineoplastic agent
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
IUPAC name[show]
CAS Number497871-47-3
PubChem CID57327016
DrugBank12674
ChemSpider32701856
UNII2CN60TN6ZS
KEGGD11644
ChEMBLChEMBL4297516
CompTox Dashboard (EPA)DTXSID30198065 
Chemical and physical data
FormulaC41H44N4O10S
Molar mass784.88 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CC1=CC2=C([C@@H]3[C@@H]4[C@H]5C6=C(C(=C7C(=C6[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)C9=C(CCN8)C2=C(N9)C=CC(=C2)OC)OCO7)C)OC(=O)C)C(=C1OC)O
InChI[hide]InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1Key:YDDMIZRDDREKEP-HWTBNCOESA-N

//////////lurbinectedin,  FDA 2020, 2020 APPROVALS, ORPHAN, priority review , ZEPZELCA, Pharma Mar, PM-1183, PM 1183, PM 01183, лурбинектедин , لوربينيكتيدين  , 芦比替定

Cc1cc2c(c(c1OC)O)[C@@H]3[C@@H]4[C@H]5c6c(c7c(c(c6OC(=O)C)C)OCO7)[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)c9c(c1cc(ccc1[nH]9)OC)CCN8

Naxitamab


Danyelza (naxitamab) Cancer Medication - Cancer Health

(Heavy chain)
QVQLVESGPG VVQPGRSLRI SCAVSGFSVT NYGVHWVRQP PGKGLEWLGV IWAGGITNYN
SAFMSRLTIS KDNSKNTVYL QMNSLRAEDT AMYYCASRGG HYGYALDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(Light chain)
EIVMTQTPAT LSVSAGERVT ITCKASQSVS NDVTWYQQKP GQAPRLLIYS ASNRYSGVPA
RFSGSGYGTE FTFTISSVQS EDFAVYFCQQ DYSSFGQGTK LEIKRTVAAP SVFIFPPSDE
QLKSGTASVV CLLNNFYPRE AKVQWKVDNA LQSGNSQESV TEQDSKDSTY SLSSTLTLSK
ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE C
(Disulfide bridge: H22-H95, H146-H202, H222-L211, H228-H’228, H231-H’231, H263-H323, H369-H427, H’22-H’95, H’146-H’202, H’222-L’211, H’263-H’323, H’369-H’427, L23-L88, L131-L191, L’23-L’88, L’131-L’191)

Naxitamab

ナキシタマブ;

Antineoplastic, Anti-GD2 antibody

FormulaC6414H9910N1718O1996S44
CAS1879925-92-4
Mol weight144434.4882

FDA APPROVED 2020/11/25, Danyelza

FDA grants accelerated approval to naxitamab for high-risk neuroblastoma in bone or bone marrow

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-naxitamab-high-risk-neuroblastoma-bone-or-bone-marrow

On November 25, 2020, the Food and Drug Administration granted accelerated approval to naxitamab (DANYELZA, Y-mAbs Therapeutics, Inc.) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for pediatric patients one year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.

Efficacy was evaluated in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm, open-label trials: Study 201 (NCT 03363373) and Study 12-230 (NCT 01757626). Patients with progressive disease following their most recent therapy were excluded. Patients received 3 mg/kg naxitamab administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. At the investigator’s discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to non-target bony lesions or soft tissue disease in Study 12-230.

The main efficacy outcome measures were confirmed overall response rate (ORR) per the revised International Neuroblastoma Response Criteria (INRC) and duration of response (DOR). Among 22 patients treated in the multicenter Study 201, the ORR was 45% (95% CI: 24%, 68%) and 30% of responders had a DOR greater or equal to 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR greater or equal to 6 months. For both trials, responses were observed in either the bone, bone marrow or both.

The prescribing information contains a Boxed Warning stating that naxitamab can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). To mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least two hours following completion of each infusion.

The most common adverse reactions (incidence ≥25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.

The recommended naxitamab dose is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle, administered after dilution as an intravenous infusion in combination with GM-CSF, subcutaneously at 250 µg/m2/day on days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles are repeated every 4 to 8 weeks.

View full prescribing information for DANYELZA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761171lbl.pdf

This review used the Real-Time Oncology Review (RTOR) pilot program and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted accelerated approval based on overall response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

This application was granted priority review, breakthrough therapy, and orphan drug designation. A priority review voucher was issued for this rare pediatric disease product application. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

////////////Naxitamab, priority review, breakthrough therapy, orphan drug, FDA 2020, 2020 APPROVALS, Danyelza, MONOCLONAL ANTIBODY, PEPTIDE, ナキシタマブ, 

Ansuvimab-zykl


Ebola Virus Treatment Ebanga Gets FDA Approval - MPR

Ansuvimab-zykl

FDA APPROVED, 12/21/2020, EBANGA

To treat ebola

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-treatment-ebola-virus

The U.S. Food and Drug Administration approved Ebanga (Ansuvimab-zykl), a human monoclonal antibody, for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga blocks binding of the virus to the cell receptor, preventing its entry into the cell.

Zaire ebolavirus is one of four Ebolavirus species that can cause a potentially fatal human disease. It is transmitted through blood, body fluids, and tissues of infected people or wild animals, and through surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who care for people with the disease, including health care workers who do not use correct infection control precautions, are at the highest risk for infection.

During an Ebola outbreak in the Democratic Republic of the Congo (DRC) in 2018-2019, Ebanga was evaluated in a clinical trial (the PALM trial). The PALM trial was led by the U.S. National Institutes of Health and the DRC’s Institut National de Recherche Biomédicale with contributions from several other international organizations and agencies.

In the PALM trial, the safety and efficacy of Ebanga was evaluated in a multi-center, open-label, randomized controlled trial. 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. The primary analysis population was all patients who were randomized and concurrently eligible to receive either Ebanga or the investigational control during the same time period of the trial. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

The most common symptoms experienced while receiving Ebanga include: fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection. Hypersensitivity, including infusion-related events, can occur in patients taking Ebanga, and treatment should be discontinued in the event of a hypersensitivity reaction.

Patients who receive Ebanga should avoid the concurrent administration of a live virus vaccine against Ebolavirus. There is the potential for Ebanga to inhibit replication of a live vaccine virus and possibly reduce the efficacy of this vaccine.

Ebanga was granted an Orphan Drug designation, which provides incentives to assist and encourage drug development for rare diseases. Additionally, the agency granted Ebanga a Breakthrough Therapy designation.

FDA granted the approval to Ridgeback Biotherapeutics, LP.

Ansuvimab, sold under the brand name Ebanga, is a monoclonal antibody medication for the treatment of Zaire ebolavirus (Ebolavirus) infection.[1][2]

The most common symptoms include fever, tachycardia (fast heart rate), diarrhea, vomiting, hypotension (low blood pressure), tachypnea (fast breathing) and chills; however, these are also common symptoms of Ebolavirus infection.[1]

Ansuvimab was approved for medical use in the United States in December 2020.[1][2]

Chemistry

The drug is composed of a single monoclonal antibody (mAb) and was initially isolated from immortalized B-cells that were obtained from a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo.[3] In work supported by the United States National Institutes of Health and the Defense Advanced Projects Agency, the heavy and light chain sequences of ansuvimab mAb was cloned into CHO cell lines and initial production runs were produced by Cook Phamica d.b.a. Catalent under contract of Medimmune.[4][5]

Mechanism of action

Neutralization

Ansuvimab is a monoclonal antibody therapy that is infused intravenously into patients with Ebola virus disease. Ansuvimab is a neutralizing antibody,[3] meaning it binds to a protein on the surface of Ebola virus that is required to infect cells. Specifically, ansuvimab neutralizes infection by binding to a region of the Ebola virus envelope glycoprotein that, in the absence of ansuvimab, would interact with virus’s cell receptor protein, Niemann-Pick C1 (NPC1).[6][7][8] This “competition” by ansuvimab prevents Ebola virus from binding to NPC1 and “neutralizes” the virus’s ability to infect the targeted cell.[6]

Effector function

Antibodies have antigen-binding fragment (Fab) regions and constant fragment (Fc) regions. The Neutralization of virus infection occurs when the Fab regions of antibodies binds to virus antigen(s) in a manner that blocks infection. Antibodies are also able to “kill” virus particles directly and/or kill infected cells using antibody-mediated “effector functions” such as opsonization, complement-dependent cytotoxicityantibody-dependent cell-mediated cytotoxicity and antibody-dependent phagocytosis. These effector functions are contained in the Fc region of antibodies, but is also dependent on binding of the Fab region to antigen. Effector functions also require the use of complement proteins in serum or Fc-receptor on cell membranes. Ansuvimab has been found to be capable of killing cells by antibody-dependent cell-mediated cytotoxicity.[3] Other functional killing tests have not been performed.

History

Ansuvimab is a monoclonal antibody that is being evaluated as a treatment for Ebola virus disease.[9] Its discovery was led by the laboratory of Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and J. J. Muyembe-Tamfum from the Institut National pour la Recherche Biomedicale (INRB) in the Democratic Republic of Congo, working in collaboration with the Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] Ansuvimab was isolated from the blood of a survivor of the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo roughly ten years later.[3]

In 2018, a Phase 1 clinical trial of ansuvimab was conducted by Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Julie E. Ledgerwood.[5][4][11] Ansuvimab is also being evaluated during the 2018 North Kivu Ebola outbreak.[12]

Ansuvimab has also shown success with lowering the mortality rate from ~70% to about 34%. In August 2019, Congolese health authorities, the World Health Organization, and the U.S. National Institutes of Health promoted the use of ansuvimab, alongside REGN-EB3, a similar Regeneron-produced monoclonal antibody treatment, over other treatments yielding higher mortality rates, after ending clinical trials during the outbreak.[13][14]

Discovery

A 2016 paper describes the efforts of how ansuvimab was originally developed as part of research efforts lead by Dr. Nancy Sullivan at the United States National Institute of Health Vaccine Research Center and Dr. J. J. Muyembe-Tamfum from the Institut National de Recherche Biomedicale (INRB) in the Democratic Republic of Congo.[3][10] This collaborative effort also involved researchers from Institute of Biomedical Research and the United States Army Medical Research Institute of Infectious Diseases.[3][10] A survivor from the 1995 outbreak of Ebola virus disease in KikwitDemocratic Republic of Congo donated blood to the project that began roughly ten years after they had recovered.[3] Memory B cells isolated from the survivor’s blood were immortalized, cultured and screened for their ability to produce monoclonal antibodies that reacted with the glycoprotein of Ebola virus. Ansuvimab was identified from one of these cultures and the antibody heavy and light chain gene sequences were sequenced from the cells.[3] These sequences were then cloned into recombinant DNA plasmids and purified antibody protein for initial studies was produced in cells derived from HEK 293 cells.[3]

Ansuvimab and mAb100 combination

In an experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and treated with a combination of ansuvimab and another antibody isolated from the same subject, mAb100. Three doses of the combination were given once a day starting 1 day after the animals were infected. The control animal died and the treated animals all survived.[3]

Ansuvimab monotherapy

In a second experiment described in the 2016 paper, rhesus macaques were infected with Ebola virus and only treated with ansuvimab. Three doses of ansuvimab were given once a day starting 1 day or 5 days after the animals were infected. The control animals died and the treated animals all survived.[3] Unpublished data referred to in a publication of the 2018 Phase I clinical trial results of ansuvimab, reported that a single infusion of ansuvimab provided full protection of rhesus macaques and was the basis of the dosing used for human studies.[5][4]

Development

Ansuvimab was developed by the Vaccine Research Center with support of the United States National Institutes of Health and the Defense Advanced Projects Agency. The heavy and light chain sequences of ansuvimab mAb were cloned into CHO cell lines to enable large-scale production of antibody product for use in humans.[4][5]

Human safety testing

In early 2018,[9] a Phase 1 clinical trial of ansuvimab’s safety, tolerability and pharmacokinetics was conducted by Dr. Martin Gaudinski within the Vaccine Research Center Clinical Trials Program that is led by Dr. Julie E. Ledgerwood.[5][4][11] The study was performed in the United States at the NIH Clinical Center and tested single dose infusions of ansuvimab infused over 30 minutes. The study showed that ansuvimab was safe, had minimal side effects and had a half-life of 24 days.[5][4]

Ridgeback Biotherapeutics

A license for ansuvimab was obtained by Ridgeback Biotherapeutics in 2018, from the National Institutes of HealthNational Institute of Allergy and Infectious Diseases.[15] Ansuvimab was given orphan drug status in May 2019 and March 2020.[16][17][18]

Experimental use in the Democratic Republic of Congo

During the 2018 Équateur province Ebola outbreak, ansuvimab was requested by the Democratic Republic of Congo (DRC) Ministry of Public Health. Ansuvimab was approved for compassionate use by the World Health Organization MEURI ethical protocol and at DRC ethics board. Ansuvimab was sent along with other therapeutic agents to the outbreak sites.[19][20][11] However, the outbreak came to a conclusion before any therapeutic agents were given to patients.[11]

Approximately one month following the conclusion of the Équateur province outbreak, a distinct outbreak was noted in Kivu in the DRC (2018–20 Kivu Ebola outbreak). Once again, ansuvimab received approval for compassionate use by WHO MEURI and DRC ethic boards and has been given to many patients under these protocols.[11] In November 2018, the Pamoja Tulinde Maisha (PALM [together save lives]) open-label randomized clinical control trial was begun at multiple treatment units testing ansuvimab, REGN-EB3 and remdesivir to ZMapp. Despite the difficulty of running a clinical trial in a conflict zone, investigators have enrolled 681 patients towards their goal of 725. An interim analysis by the Data Safety and Monitoring Board (DSMB) of the first 499 patient found that ansuvimab and REGN-EB3 were superior to the comparator ZMapp. Overall mortality of patients in the ZMapp and remdesivir groups were 49% and 53% compared to 34% and 29% for ansuvimab and REGN-EB3. When looking at patients who arrived early after disease symptoms appeared, survival was 89% for ansuvimab and 94% for REGN-EB3. While the study was not powered to determine whether there is any difference between REGN-EB3 and ansuvimab, the survival difference between those two therapies and ZMapp was significant. This led to the DSMB halting the study and PALM investigators dropping the remdesivir and ZMapp arms from the clinical trial. All patients in the outbreak who elect to participate in the trial will now be given either ansuvimab or REGN-EB3.[21][22][13][12]

In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab (Inmazeb, formerly REGN-EB3) with an indication for the treatment of infection caused by Zaire ebolavirus.[23]

FDA approves ansuvimab-zykl for Ebola virus infection

DECEMBER 21, 2020 BY JANICE REICHERThttps://www.antibodysociety.org/antibody-therapeutic/fda-approves-ansuvimab-zykl-for-ebola-virus-infection/embed/#?secret=zWW0Sr0BdW

On December 21, 2020, the US Food and Drug Administration approved Ebanga (ansuvimab-zykl) for the treatment for Zaire ebolavirus (Ebolavirus) infection in adults and children. Ebanga had been granted US Orphan Drug designation and Breakthrough Therapy designations. Ansuvimab is a human IgG1 monoclonal antibody that binds and neutralizes the virus.

The safety and efficacy of Ebanga were evaluated in the multi-center, open-label, randomized controlled PALM trial. In this study, 174 participants (120 adults and 54 pediatric patients) with confirmed Ebolavirus infection received Ebanga intravenously as a single 50 mg/kg infusion and 168 participants (135 adults and 33 pediatric patients) received an investigational control. The primary efficacy endpoint was 28-day mortality. Of the 174 patients who received Ebanga, 35.1% died after 28 days, compared to 49.4% of the 168 patients who received a control.

Ebanga is the 12th antibody therapeutic to be granted a first approval in the US or EU during 2020.

The Antibody Society maintains a comprehensive table of approved monoclonal antibody therapeutics and those in regulatory review in the EU or US. The table, which is located in the Web Resources section of the Society’s website, can be downloaded in Excel format.

References

  1. Jump up to:a b c d “FDA Approves Treatment for Ebola Virus”U.S. Food and Drug Administration. 21 December 2020. Retrieved 23 December 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “Ridgeback Biotherapeutics LP Announces the Approval of Ebanga for Ebola” (Press release). Ridgeback Biotherapeutics LP. 22 December 2020. Retrieved 23 December 2020– via Business Wire.
  3. Jump up to:a b c d e f g h i j k l Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. (March 2016). “Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody”Science351 (6279): 1339–42. Bibcode:2016Sci…351.1339Cdoi:10.1126/science.aad5224PMID 26917593.
  4. Jump up to:a b c d e f Clinical trial number NCT03478891 for “Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults” at ClinicalTrials.gov
  5. Jump up to:a b c d e f Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, et al. (March 2019). “Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody ansuvimab targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study”Lancet393 (10174): 889–898. doi:10.1016/S0140-6736(19)30036-4PMC 6436835PMID 30686586.
  6. Jump up to:a b Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, et al. (March 2016). “Structural and molecular basis for Ebola virus neutralization by protective human antibodies”Science351 (6279): 1343–6. Bibcode:2016Sci…351.1343Mdoi:10.1126/science.aad6117PMC 5241105PMID 26917592.
  7. ^ Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. (August 2011). “Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection”Nature477 (7364): 344–8. Bibcode:2011Natur.477..344Cdoi:10.1038/nature10380PMC 3230319PMID 21866101.
  8. ^ Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. (August 2011). “Ebola virus entry requires the cholesterol transporter Niemann-Pick C1”Nature477 (7364): 340–3. Bibcode:2011Natur.477..340Cdoi:10.1038/nature10348PMC 3175325PMID 21866103.
  9. Jump up to:a b “NIH begins testing Ebola treatment in early-stage trial”National Institutes of Health (NIH). 2018-05-23. Retrieved 2018-10-15.
  10. Jump up to:a b c Hayden EC (2016-02-26). “Ebola survivor’s blood holds promise of new treatment”Naturedoi:10.1038/nature.2016.19440ISSN 1476-4687.
  11. Jump up to:a b c d e “NIH VideoCast – CC Grand Rounds: Response to an Outbreak: Ebola Virus Monoclonal Antibody (mAb114) Rapid Clinical Development”videocast.nih.gov. Retrieved 2019-08-09.
  12. Jump up to:a b Kingsley-Hall A. “Congo’s experimental mAb114 Ebola treatment appears successful: authorities | Central Africa”http://www.theafricareport.com. Retrieved 2018-10-15.
  13. Jump up to:a b McNeil DG (12 August 2019). “A Cure for Ebola? Two New Treatments Prove Highly Effective in Congo”The New York Times. Retrieved 13 August 2019.
  14. ^ Molteni M (12 August 2019). “Ebola is Now Curable. Here’s How The New Treatments Work”Wired. Retrieved 13 August 2019.
  15. ^ “Ridgeback Biotherapeutics LP announces licensing of mAb114, an experimental Ebola treatment, from the National Institute of Allergy and Infectious Diseases” (Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  16. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 8 May 2019. Retrieved 24 December 2020.
  17. ^ “Ansuvimab Orphan Drug Designations and Approvals”accessdata.fda.gov. 30 March 2020. Retrieved 24 December 2020.
  18. ^ “Ridgeback Biotherapeutics LP Announces Orphan Drug Designation for mAb114”(Press release). Ridgeback Biotherapeutics LP. Retrieved 2019-08-17 – via PR Newswire.
  19. ^ Check Hayden, Erika (May 2018). “Experimental drugs poised for use in Ebola outbreak”Nature557 (7706): 475–476. Bibcode:2018Natur.557..475Cdoi:10.1038/d41586-018-05205-xISSN 0028-0836PMID 29789732.
  20. ^ WHO: Consultation on Monitored Emergency Use of Unregistered and Investigational Interventions for Ebola virus Disease. https://www.who.int/emergencies/ebola/MEURI-Ebola.pdf
  21. ^ Mole B (2019-08-13). “Two Ebola drugs boost survival rates, according to early trial data”Ars Technica. Retrieved 2019-08-17.
  22. ^ “Independent monitoring board recommends early termination of Ebola therapeutics trial in DRC because of favorable results with two of four candidates”National Institutes of Health (NIH). 2019-08-12. Retrieved 2019-08-17.
  23. ^ “FDA Approves First Treatment for Ebola Virus”U.S. Food and Drug Administration(FDA) (Press release). 14 October 2020. Retrieved 14 October 2020.  This article incorporates text from this source, which is in the public domain.

External links

  • “Ansuvimab”Drug Information Portal. U.S. National Library of Medicine.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetZaire ebolavirus
Clinical data
Trade namesEbanga
Other namesAnsuvimab-zykl, mAb114
License dataUS DailyMedAnsuvimab
Routes of
administration
Intravenous
Drug classMonoclonal antibody
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
CAS Number2375952-29-5
DrugBankDB16385
UNIITG8IQ19NG2
KEGGD11875
Chemical and physical data
FormulaC6368H9924N1724O1994S44
Molar mass143950.15 g·mol−1

//////////Ansuvimab-zykl , EBANGA, FDA 2020, 2020 APPROVALS, MONOCLONAL ANTIBODY, Orphan Drug designation, , Breakthrough Therapy designation , Ridgeback Biotherapeutics, 

Lumasiran


OXLUMO (lumasiran) Structural Formula - Illustration

The molecular formula of lumasiran sodium is C530H669F10N173O320P43S6Na43 and the molecular weight is 17,286 Da.

lumasiran

CAS 1834610-13-7

FDA APPROVED, 11/23/2020, Oxlumo

To treat hyperoxaluria type 1
Press Release
Drug Trials Snapshot

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

Nucleic Acid Sequence

Sequence Length: 44, 23, 2115 a 8 c 7 g 14 umultistranded (2); modified

OXLUMO is supplied as a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous administration containing the equivalent of 94.5 mg of lumasiran (provided as lumasiran sodium) in 0.5 Ml of water for injection and sodium hydroxide and/or phosphoric acid to adjust the pH to ~7.0.

Lumasiran An investigational RNAi Therapeutic for Primary Hyperoxaluria Type 1 (PH1)

Overview • Lumasiran (ALN-GO1) is an investigational, subcutaneously administered (under the skin) RNA interference (RNAi) therapeutic targeting glycolate oxidase (GO) in development for the treatment of primary hyperoxaluria type 1 (PH1).

• PH1 is a rare, life-threatening disease that can cause serious damage to kidneys and progressively to other organs.1

• PH1 is characterized by the pathologic overproduction of oxalate by the liver. Oxalate is an end product of metabolism that, when in excess, is toxic and accumulates in the kidneys forming calcium oxalate crystals.1,2

• Symptoms of PH1 are often associated with recurrent kidney stones and include flank pain, urinary tract infections, painful urination, and blood in the urine.2,3

• Currently, the only curative treatment is a liver transplant, to correct the metabolic defect, combined with a kidney transplant, to replace the terminally damaged kidneys.1,3 Clinical Development

• The safety and efficacy of lumasiran are being evaluated in a randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study of approximately 30 PH1 patients, called ILLUMINATE-A (NCT03681184).

• The primary endpoint is percent change in 24-hour urinary oxalate excretion from baseline to Month 6.

• Key secondary and exploratory endpoints in ILLUMINATE-A will evaluate additional measures of urinary oxalate, estimated glomerular filtration rate (eGFR), safety, and tolerability. 

Regulatory Designations • Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) • Priority Medicines (PRIME) Designation from the European Medicines Agency (EMA) • Orphan Drug Designations in both the U.S. and the European Union

Alnylam Announces U.S. Food and Drug Administration Has Granted Priority  Review of the Lumasiran New Drug Application for the Treatment of Primary  Hyperoxaluria Type 1 | Business Wire

/////////lumasiran, fda 2020, 2020 approvals, Oxlumo, Breakthrough Therapy Designation, Orphan Drug, Priority Medicines (PRIME) Designation

Setmelanotide


Setmelanotide.svg
ChemSpider 2D Image | Setmelanotide | C49H68N18O9S2
Setmelanotide.png
SVG Image

Setmelanotide

Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2

  • Molecular FormulaC49H68N18O9S2
  • Average mass1117.309 Da
  • N-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide (2->8)-disulfide

1,2-Dithia-5,8,11,14,17,20-hexaazacyclotricosane-4-carboxamide, 22-[[(2S)-2-(acetylamino)-5-[(diaminomethylene)amino]-1-oxopentyl]amino]-10-[3-[(diaminomethylene)amino]propyl]-16-(1H-imidazol-5-ylmeth yl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-13-(phenylmethyl)-, (4R,7S,10S,13R,16S,19R,22R)- [ACD/Index Name]10011920014-72-8[RN]Imcivree [Trade name]N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-Ltryptophyl- L-cysteinamide, cyclic (2-8)-disulfideN7T15V1FUYRM-493, BIM-22493UNII-N7T15V1FUYсетмеланотид [Russian] [INN]سيتميلانوتيد [Arabic] [INN]司美诺肽 [Chinese] [INN](4R,7S,10S,13R,16S,19R,22R)-22-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-13-benzyl-10-[3-(diaminomethylideneamino)propyl]-16-(1H-imidazol-5-ylmethyl)-7-(1H-indol-3-ylmethyl)-19-methyl-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carboxamide

FDA 11/25/2020, Imcivree, To treat obesity and the control of hunger associated with pro-opiomelanocortin deficiency, a rare disorder that causes severe obesity that begins at an early age
Drug Trials Snapshot, 10MG/ML, SOLUTION;SUBCUTANEOUS, Orphan

Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE™ (setmelanotide) as First-ever Therapy for Chronic Weight Management in Patients with Obesity Due to POMC, PCSK1 or LEPR Deficiency Nasdaq:RYTM
Setmelanotide

DESCRIPTION

IMCIVREE contains setmelanotide acetate, a melanocortin 4 (MC4) receptor agonist. Setmelanotide is an 8 amino acid cyclic peptide analog of endogenous melanocortin peptide α-MSH (alpha-melanocyte stimulating hormone).

The chemical name for setmelanotide acetate is acetyl-L-arginyl-L-cysteinyl-D-alanyl-Lhistidinyl-D-phenylalanyl-L-arginyl-L-tryptophanyl-L-cysteinamide cyclic (2→8)-disulfide acetate. Its molecular formula is C49H68N18O9S2 (anhydrous, free-base), and molecular mass is 1117.3 Daltons (anhydrous, free-base).

The chemical structure of setmelanotide is:

IMCIVREE (setmelanotide) Structrual Formula Illustration

IMCIVREE injection is a sterile clear to slightly opalescent, colorless to slightly yellow solution. Each 1 mL of IMCIVREE contains 10 mg of setmelanotide provided as setmelanotide acetate, which is a salt with 2 to 4 molar equivalents of acetate, and the following inactive ingredients: 100 mg N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3phosphoethanolamine sodium salt, 8 mg carboxymethylcellulose sodium (average MWt 90,500), 11 mg mannitol, 5 mg phenol, 10 mg benzyl alcohol, 1 mg edetate disodium dihydrate, and Water for Injection. The pH of IMCIVREE is 5 to 6.

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor. Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects. Setmelanotide increases resting energy expenditure in both obese animals and humans. Setmelanotide has been reported to possess the following activity profile (cAMP, EC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).

Setmelanotide, sold under the brand name Imcivree, is a medication for the treatment of obesity.[1]

The most common side effects include injection site reactions, skin hyperpigmentation (skin patches that are darker than surrounding skin), headache and gastrointestinal side effects (such as nausea, diarrhea, and abdominal pain), among others.[1] Spontaneous penile erections in males and adverse sexual reactions in females have occurred with treatment.[1] Depression and suicidal ideation have also occurred with setmelanotide.[1]

SYN

WO 2011060355

Medical uses

Setmelanotide is indicated for chronic weight management (weight loss and weight maintenance for at least one year) in people six years and older with obesity due to three rare genetic conditions: pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, and leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes considered pathogenic (causing disease), likely pathogenic, or of uncertain significance.[1] Setmelanotide is the first FDA-approved treatment for these genetic conditions.[1]

Setmelanotide is not approved for obesity due to suspected POMC, PCSK1, or LEPR deficiency with variants classified as benign (not causing disease) or likely benign or other types of obesity, including obesity associated with other genetic syndromes and general (polygenic) obesity.[1]

Setmelanotide binds to and activates MC4 receptors in the paraventricular nucleus (PVN) of the hypothalamus and in the lateral hypothalamic area (LHA), areas involved in the regulation of appetite, and this action is thought to underlie its appetite suppressant effects.[2] In addition to reducing appetite, setmelanotide increases resting energy expenditure in both obese animals and humans.[3] Importantly, unlike certain other MC4 receptor agonists, such as LY-2112688, setmelanotide has not been found to produce increases in heart rate or blood pressure.[4]

Setmelanotide has been reported to possess the following activity profile (cAMPEC50): MC4 (0.27 nM) > MC3 (5.3 nM) ≈ MC1 (5.8 nM) > MC5 (1600 nM) ≟ MC2 (>1000 nM).[5] (19.6-fold selectivity for MC4 over MC3, the second target of highest activity.)

History

Setmelanotide was evaluated in two one-year studies.[1] The first study enrolled participants with obesity and confirmed or suspected POMC or PCSK1 deficiency while the second study enrolled participants with obesity and confirmed or suspected LEPR deficiency; all participants were six years or older.[1] The effectiveness of setmelanotide was determined by the number of participants who lost more than ten percent of their body weight after a year of treatment.[1]

The effectiveness of setmelanotide was assessed in 21 participants, ten in the first study and eleven in the second.[1] In the first study, 80 percent of participants with POMC or PCSK1 deficiency lost ten percent or more of their body weight.[1] In the second study, 46 percent of participants with LEPR deficiency lost ten percent or more of their body weight.[1]

The study also assessed the maximal (greatest) hunger in sixteen participants over the previous 24 hours using an eleven-point scale in participants twelve years and older.[1] In both studies, some, but not all, of participants’ weekly average maximal hunger scores decreased substantially from their scores at the beginning of the study.[1] The degree of change was highly variable among participants.[1]

The U.S. Food and Drug Administration (FDA) granted the application for setmelanotide orphan disease designation, breakthrough therapy designation, and priority review.[1] The FDA granted the approval of Imcivree to Rhythm Pharmaceutical, Inc.[1]

Research

Setmelanotide is a peptide drug and investigational anti-obesity medication which acts as a selective agonist of the MC4 receptor.[6][4] Its peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It was first discovered at Ipsen and is being developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes.[6] In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity.[7] As of December 2014, the drug is in phase II clinical trials for obesity and PWS.[6][8][9][needs update] So far, preliminary data has shown no benefit of Setmelanotide in Prader-Willi syndrome.[10]

PATENT

WO 2007008704

WO 2011060355

WO 2011060352

US 20120225816

PAPER

Journal of Medicinal Chemistry, 61(8), 3674-3684; 2018

PATENT

https://patents.google.com/patent/US9314509

Synthesis of Example 1i.e., Ac-Arg-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2

Figure US09314509-20160419-C00004

The title peptide having the above structure was assembled using Fmoc chemistry on an Apex peptide synthesizer (Aapptec; Louisville, Ky., USA). 220 mg of 0.91 mmol/g (0.20 mmoles) Rink Amide MBHA resin (Polymer Laboratories; Amherst, Mass., USA) was placed in a reaction well and pre-swollen in 3.0 mL of DMF prior to synthesis. For cycle 1, the resin was treated with two 3-mL portions of 25% piperidine in DMF for 5 and 10 minutes respectively, followed by 4 washes of 3-mL DMF—each wash consisting of adding 3 mL of solvent, mixing for 1 minute, and emptying for 1 minute. Amino acids stocks were prepared in NMP as 0.45M solutions containing 0.45M HOBT. HBTU was prepared as a 0.45M solution in NMP and DIPEA was prepared as a 2.73M solution in NMP. To the resin, 2 mL of the first amino acid (0 9 mmoles, Fmoc-Cys(Trt)-OH) (Novabiochem; San Diego, Calif., USA) was added along with 2 mL (0.9 mmoles) of HBTU and 1.5 mL (4.1 mmoles) of DIPEA. After one hour of constant mixing, the coupling reagents were drained from the resin and the coupling step was repeated. Following amino acid acylation, the resin was washed with two 3-mL aliquots of DMF for 1 minute. The process of assembling the peptide (deblock/wash/acylate/wash) was repeated for cycles 2-9 identical to that as described for cycle 1. The following amino acids were used: cycle 2) Fmoc-Trp(Boc)-OH (Genzyme; Cambridge, Mass., USA); cycle 3) Fmoc-Arg(Pbf)-OH (Novabiochem); cycle 4) Fmoc-DPhe-OH (Genzyme); cycle 5) Fmoc-His(Trt)-OH (Novabiochem); cycle 6) Fmoc-D-Ala-OH (Genzyme); cycle 7) Fmoc-Cys(Trt)-OH, (Novabiochem); and cycle 8) Fmoc-Arg(Pbf)-OH (Genzyme). The N-terminal Fmoc was removed with 25% piperidine in DMF as described above, followed by four 3-mL DMF washes for 1 minute. Acetylation of the N-terminus was performed by adding 0.5 mL of 3M DIPEA in NMP to the resin along with 1.45 mL of 0.45M acetic anhydride in NMP. The resin was mixed for 30 minutes and acetylation was repeated. The resin was washed with 3 mL of DMF for a total of 5 times followed with 5 washes with 5 mL of DCM each.

To cleave and deprotect the peptide, 5mL of the following reagent was added to the resin: 2% TIS/5% water/5% (w/v) DTT/88% TFA. The solution was allowed to mix for 3.5 hours. The filtrate was collected into 40 mL of cold anhydrous ethyl ether. The precipitate was pelleted for 10 minutes at 3500 rpm in a refrigerated centrifuge. The ether was decanted and the peptide was re-suspended in fresh ether. The ether workup was performed three times. Following the last ether wash, the peptide was allowed to air dry to remove residual ether.

The peptide was dissolved in 10% acetonitrile and analyzed by mass spectrometry and reverse-phase HPLC employing a 30×4.6 cm C18 column (Vydac; Hesperia, Calif., USA) with a gradient of 2-60% acetonitrile (0.1% TFA) over 30 minutes. This analysis identified a product with ˜53% purity. Mass analysis employing electrospray ionization identified a main product containing a mass of 1118.4 corresponding to the desired linear product. The crude product (˜100 mg) was diluted to a concentration of 2 mg/mL in 5% acetic acid. To this solution, 0.5M iodine/methanol was added dropwise with vigorous stirring until a pale yellow color was achieved. The solution was vigorously stirred for another 10 minutes. Excess iodine was then quenched by adding 1.0M sodium thiosulfate under continuous mixing until the mixture was rendered colorless. The peptide was re-examined by mass spectrometry analysis and HPLC. Mass spectrometry analysis identified a main species with a mass of 1116.4 which indicated successful oxidation to form the cyclic peptide. The peptide solution was purified on a preparative HPLC equipped with a C18 column using a similar elution gradient. The purified product was re-analyzed by HPLC for purity (>95%) and mass spectrometry (1116.9 which is in agreement with the expected mass of 1117.3) and subsequently lyophilized. Following lyophilization, 28 mg of purified product was obtained representing a 24% yield.

The other exemplified peptides were synthesized substantially according to the procedure described for the above-described synthetic process. Physical data for select exemplified peptides are given in Table 1.

TABLE 1 Example Mol. Wt. Mol. Wt. Purity Number (calculated) (ES-MS) (HPLC) 1 1117.3 1116.9 95.1% 2 1117.3 1116.8 99.2% 3 1280.5 1280.6 98.0% 5 1216.37 1216.20 99.9%

Preparation of Pamoate Salt of Example 1

The acetate salt of Example 1 (200 mg, 0.18 mmole) was dissolved in 10 mL of water. Sodium pamoate (155 mg, 0.36 mmole) was dissolved in 10 mL of water. The two solutions were combined and mixed well. The precipitates were collected by centrifugation at 3000 rpm for 20 minutes, washed for three times with water, and dried by lyophilization.

References

  1. Jump up to:a b c d e f g h i j k l m n o p q r “FDA approves first treatment for weight management for people with certain rare genetic conditions”U.S. Food and Drug Administration (FDA) (Press release). 27 November 2020. Retrieved 27 November 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ Kim GW, Lin JE, Blomain ES, Waldman SA (January 2014). “Antiobesity pharmacotherapy: new drugs and emerging targets”Clinical Pharmacology and Therapeutics95 (1): 53–66. doi:10.1038/clpt.2013.204PMC 4054704PMID 24105257.
  3. ^ Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, et al. (April 2015). “RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals”The Journal of Clinical Endocrinology and Metabolism100 (4): 1639–45. doi:10.1210/jc.2014-4024PMC 4399297PMID 25675384.
  4. Jump up to:a b Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, et al. (February 2013). “Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques”Diabetes62 (2): 490–7. doi:10.2337/db12-0598PMC 3554387PMID 23048186.
  5. ^ Muniyappa R, Chen K, Brychta R, Abel B, Mullins K, Staker P, et al. (June 2014). “A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of a Melanocortin Receptor 4 (MC4R) Agonist, RM-493, on Resting Energy Expenditure (REE) in Obese Subjects” (PDF). Endocrine Reviews. Rhythm Pharmaceuticals. 35 (3). Retrieved 2015-05-21.
  6. Jump up to:a b c Lee EC, Carpino PA (2015). “Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014)”. Pharmaceutical Patent Analyst4 (2): 95–107. doi:10.4155/ppa.15.1PMID 25853469.
  7. ^ “Obesity and Diabetes Caused by Genetic Deficiencies in the MC4 Pathway”. Rhythm Pharmaceuticals. Retrieved 2015-05-21.
  8. ^ Jackson VM, Price DA, Carpino PA (August 2014). “Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies”. Expert Opinion on Investigational Drugs23 (8): 1055–66. doi:10.1517/13543784.2014.918952PMID 25000213S2CID 23198484.
  9. ^ “RM-493: A First-in-Class, Phase 2-Ready MC4 Agonist: A New Drug Class for the Treatment of Obesity and Diabetes”. Rhythm Pharmaceuticals. Archived from the original on 2015-06-14. Retrieved 2015-05-21.
  10. ^ Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, et al. (March 2019). “A multidisciplinary approach to the clinical management of Prader-Willi syndrome”Molecular Genetics & Genomic Medicine7 (3): e514. doi:10.1002/mgg3.514PMC 6418440PMID 30697974.

ADDITIONAL INFORMATION

The peptide sequence is Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2. It is being researched by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. In addition, Rhythm Pharmaceuticals is conducting trials of setmelanotide for the treatment of Prader–Willi syndrome (PWS), a genetic disorder which includes MC4 receptor deficiency and associated symptoms such as excessive appetite and obesity. As of December 2014, the drug is in phase II clinical trials for obesity and PWS.

L-Cysteinamide, N2-acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-, cyclic (2->8)-disulfide
Ac-Arg-Cys(1)-D-Ala-His-D-Phe-Arg-Trp-Cys(1)-NH2

REFERENCES

1: Lee EC, Carpino PA. Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014). Pharm Pat Anal. 2015;4(2):95-107. doi: 10.4155/ppa.15.1. PubMed PMID: 25853469.

2: Chen KY, Muniyappa R, Abel BS, Mullins KP, Staker P, Brychta RJ, Zhao X, Ring M, Psota TL, Cone RD, Panaro BL, Gottesdiener KM, Van der Ploeg LH, Reitman ML, Skarulis MC. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015 Apr;100(4):1639-45. doi: 10.1210/jc.2014-4024. Epub 2015 Feb 12. PubMed PMID: 25675384; PubMed Central PMCID: PMC4399297.

3: Clemmensen C, Finan B, Fischer K, Tom RZ, Legutko B, Sehrer L, Heine D, Grassl N, Meyer CW, Henderson B, Hofmann SM, Tschöp MH, Van der Ploeg LH, Müller TD. Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice. EMBO Mol Med. 2015 Feb 4;7(3):288-98. doi: 10.15252/emmm.201404508. PubMed PMID: 25652173; PubMed Central PMCID: PMC4364946.

4: Jackson VM, Price DA, Carpino PA. Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies. Expert Opin Investig Drugs. 2014 Aug;23(8):1055-66. doi: 10.1517/13543784.2014.918952. Epub 2014 Jul 7. Review. PubMed PMID: 25000213.

5: Kievit P, Halem H, Marks DL, Dong JZ, Glavas MM, Sinnayah P, Pranger L, Cowley MA, Grove KL, Culler MD. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013 Feb;62(2):490-7. doi: 10.2337/db12-0598. Epub 2012 Oct 9. PubMed PMID: 23048186; PubMed Central PMCID: PMC3554387.

6: Kumar KG, Sutton GM, Dong JZ, Roubert P, Plas P, Halem HA, Culler MD, Yang H, Dixit VD, Butler AA. Analysis of the therapeutic functions of novel melanocortin receptor agonists in MC3R- and MC4R-deficient C57BL/6J mice. Peptides. 2009 Oct;30(10):1892-900. doi: 10.1016/j.peptides.2009.07.012. Epub 2009 Jul 29. PubMed PMID: 19646498; PubMed Central PMCID: PMC2755620.

External links

Clinical data
Trade namesImcivree
Other namesRM-493; BIM-22493; IRC-022493; N2-Acetyl-L-arginyl-L-cysteinyl-D-alanyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-L-cysteinamide, cyclic (2-8)-disulfide
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
IUPAC name[show]
CAS Number920014-72-8
PubChem CID11993702
ChemSpider10166169
UNIIN7T15V1FUY
KEGGD11927
Chemical and physical data
FormulaC49H68N18O9S2
Molar mass1117.32 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]C[C@@H]1C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N)Cc2c[nH]c3c2cccc3)CCCN=C(N)N)Cc4ccccc4)Cc5cnc[nH]5
InChI[hide]InChI=1S/C49H68N18O9S2/c1-26-41(70)63-37(20-30-22-55-25-59-30)46(75)64-35(18-28-10-4-3-5-11-28)44(73)62-34(15-9-17-57-49(53)54)43(72)65-36(19-29-21-58-32-13-7-6-12-31(29)32)45(74)66-38(40(50)69)23-77-78-24-39(47(76)60-26)67-42(71)33(61-27(2)68)14-8-16-56-48(51)52/h3-7,10-13,21-22,25-26,33-39,58H,8-9,14-20,23-24H2,1-2H3,(H2,50,69)(H,55,59)(H,60,76)(H,61,68)(H,62,73)(H,63,70)(H,64,75)(H,65,72)(H,66,74)(H,67,71)(H4,51,52,56)(H4,53,54,57)/t26-,33+,34+,35-,36+,37+,38+,39+/m1/s1Key:HDHDTKMUACZDAA-PHNIDTBTSA-N

///////////Setmelanotide, FDA 2020, 2020 APPROVALS, Imcivree, Orphan, PEPTIDE, ANTIOBESITY, UNII-N7T15V1FUY, сетмеланотид , سيتميلانوتيد , 司美诺肽 , BIM 22493, RM 493

CC1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(CSSCC(C(=O)N1)NC(=O)C(CCCN=C(N)N)NC(=O)C)C(=O)N)CC2=CNC3=CC=CC=C32)CCCN=C(N)N)CC4=CC=CC=C4)CC5=CN=CN5

Berotralstat


ChemIDplus - 1809010-50-1 - UXNXMBYCBRBRFD-MUUNZHRXSA-N - Berotralstat [USAN:INN] - Similar structures search, synonyms, formulas, resource links, and other chemical information.
1809010-50-1

Berotralstat

CAS  1809010-50-1

DIHCl 1809010-52-3

Molecular Formula, C30-H26-F4-N6-O, Molecular Weight, 562.5684

1-(3-(Aminomethyl)phenyl)-N-(5-((R)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

1H-Pyrazole-5-carboxamide, 1-(3-(aminomethyl)phenyl)-N-(5-((R)-(3-cyanophenyl)((cyclopropylmethyl)amino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-

To treat patients with hereditary angioedema

FDA APPROVED 12/4/2020, Orladeyo, 110MG CAPSULE 0RAL

New Drug Application (NDA): 214094
Company: BIOCRYST PHARMACEUTICALS INC

New Drug Application (NDA): 214094
Company: BIOCRYST PHARMACEUTICALS INC

BioCryst Announces FDA Approval of ORLADEYO™ (berotralstat), First Oral, Once-daily Therapy to Prevent Attacks in Hereditary Angioedema Patients Nasdaq:BCRX

Berotralstat Hydrochloride

1-[3-(Aminomethyl)phenyl]-N-(5-{(1R)-(3-cyanophenyl)[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide dihydrochloride

C30H26F4N6O▪2HCl : 635.48
[1809010-52-3]

Berotralstat, also known as BCX-7353, is a kallikrein inhibitor. BCX7353 is a synthetic, once-daily, small molecule drug that can be taken as an oral capsule to treat HAE attacks and for prophylaxis.

Hereditary angioedema (HAE) is rare disorder caused by a SERPING1 gene mutation that triggers severe swelling of the skin and upper airway. Treatment options for HAE with deficient and dysfunctional C1-inhibitor are expanding to include small-molecule drugs that inhibit protein interactions in the kallikrein-kinin system

Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.

Kallikreins are a subgroup of serine proteases. In humans, plasma kallikrein (KLKB1) has no known homologue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. Plasma kallikrein participates in a number of pathways relating to the intrinsic pathway of coagulation, inflammation, and the complement system.

Coagulation is the process by which blood forms clots, for example to stop bleeding. The physiology of coagulation is somewhat complex insofar as it includes two separate initial pathways, which converge into a final common pathway leading to clot formation. In the final common pathway, prothrombin is converted into thrombin, which in turn converts fibrinogen into fibrin, the latter being the principal building block of cross- linked fibrin polymers which form a hemostatic plug. Of the two initial pathways upstream of the final common pathway, one is known as the contact activation or intrinsic pathway, and the other is known as the tissue factor or extrinsic pathway.

The intrinsic pathway begins with formation of a primary complex on collagen by high-molecular- weight kininogen (HMWK), prekallikrein, and FXII (Factor XII; Hageman factor). Prekallikrein is converted to kallikrein, and FXII is activated to become FXIIa. FXIIa then converts Factor XI (FXI) into FXIa, and FXIa in turn activates Factor IX (FIX), which with its co-factor F Villa form the“tenase” complex, which activates Factor X (FX) to FXa. It is FXa which is responsible for the conversion of prothrombin into thrombin within the final common pathway.

Prekallikrein, the inactive precursor of plasma kallikrein, is synthesized in the liver and circulates in the plasma bound to FDVTWK or as a free zymogen. Prekallikrein is cleaved by activated factor XII(FXIIa) to release activated plasma kallikrein (PK). Activated plasma kallikrein displays endopeptidase activity towards peptide bonds after arginine (preferred) and lysine. PK then generates additional FXIIa in a feedback loop which in turn activates factor XI (FXI) to FXIa to connect to the common pathway. Although the initial activation of the intrinsic pathway is through a small amount of FXIIa activating a small amount of PK, it is the subsequent feedback activation of FXII by PK that controls the extent of activation of the intrinsic pathway and hence downstream coagulation. Hathaway, W. E., et al. (1965) Blood 26:521-32.

Activated plasma kallikrein also cleaves HMWK to release the potent vasodilator peptide bradykinin. It is also able to cleave a number of inactive precursor proteins to generate active products, such as plasmin (from plasminogen) and urokinase (from prourokinase). Plasmin, a regulator of coagulation, proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.

Patients who have suffered acute myocardial infarction (MI) show clinical evidence of being in a hypercoagulable (clot-promoting) state. This hypercoagulability is

paradoxically additionally aggravated in those receiving fibrinolytic therapy. Increased generation of thrombin, as measured by thrombin-antithrombin III (TAT) levels, is observed in patients undergoing such treatment compared to the already high levels observed in those receiving heparin alone. Hoffmeister, H. M. et al. (1998) Circulation 98:2527-33. The increase in thrombin has been proposed to result from plasmin-mediated activation of the intrinsic pathway by direct activation of FXII by plasmin.

Not only does the fibrinolysis-induced hypercoagulability lead to increased rates of reocclusion, but it is also probably responsible, at least in part, for failure to achieve complete fibrinolysis of the clot (thrombus), a major shortcoming of fibrinolytic therapy (Keeley, E. C. et al. (2003) Lancet 361 : 13-20). Another problem in fibrinolytic therapy is the accompanying elevated risk of intracranial hemorrhage. Menon, V. et al. (2004) (Chest l26:549S-575S; Fibrinolytic Therapy Trialists’ Collaborative Group (1994) Lancet 343 :311-22. Hence, an adjunctive anti -coagulant therapy that does not increase the risk of bleeding, but inhibits the formation of new thrombin, would be greatly beneficial. Plasma kallikrein inhibitors also have therapeutic potential for treating hereditary angioedema (HAE). HAE is is a serious and potentially life-threatening rare genetic illness, caused by mutations in the Cl -esterase inhibitor (C1INH) gene, located on chromosome 1 lq. HAE is inherited as an autosomal dominant condition, although one quarter of diagnosed cases arise from a new mutation. HAE has been classed as an orphan disease in Europe, with an estimated prevalence of 1 in 50,000. Individuals with HAE experience recurrent acute attacks of painful subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs or genitalia which, if untreated, may last up to 5 days. Attacks vary in frequency, severity and location and can be life-threatening. Laryngeal attacks, with the potential for asphyxiation, pose the greatest risk. Abdominal attacks are especially painful, and often result in exploratory procedures or unnecessary surgery. Facial and peripheral attacks are disfiguring and debilitating.

HAE has a number of subtypes. HAE type I is defined by CllNH gene mutations which produce low levels of Cl -inhibitor, whereas HAE type II is defined by mutations which produce normal levels of ineffective Cl protein. HAE type III has separate pathogenesis, being caused by mutations in the F12 gene which codes for the serine protease known as Factor XII. Diagnostic criteria for distinguishing the subtypes of HAE, and distinguishing HAE from other angioedemas, can be found in Ann Allergy Asthma Immunol 2008; l00(Suppl2): S30-S40 and J Allergy Clin Immunol 2004; 114: 629-37, incorporated herein by reference.

Current treatments for HAE fall into two main types. Older non-specific treatments including androgens and antifibrinolytics are associated with significant side effects, particularly in females. Newer treatments are based on an understanding of the molecular pathology of the disease, namely that CllNH is the most important inhibitor of kallikrein in human plasma and that CllNH deficiency leads to unopposed activation of the kallikrein- bradykinin cascade, with bradykinin the most important mediator of the locally increased vascular permeability that is the hallmark of an attack. All of the currently available targeted therapies are administered by intravenous or subcutaneous injection. There is currently no specific targeted oral chronic therapy for HAE.

Therefore, a need exists to develop inhibitors of PK that can tip the balance of fibrinolysis/thrombosis at the occluding thrombus toward dissolution, thereby promoting reperfusion and also attenuating the hypercoagulable state, thus preventing thrombus from reforming and reoccluding the vessel. In particular, the creation of plasma kallikrein inhibitors that are specific and capable of being formulated for in vivo use could lead to a new class of therapeutics. Thus, what is needed are improved compositions and methods for preparing and formulating plasma kallikrein inhibitors.

For example, in patients with angioedema conditions, small polypeptide PK inhibitor DX-88 (ecallantide) alleviates edema in patients with hereditary angioedema (HAE). Williams, A. et al. (2003) Transfus. Apher. Sci. 29:255-8; Schneider, L. et al.

(2007) J Allergy Clin Immunol. 120:416-22; and Levy, J. H. et al. (2006) Expert Opin. Invest. Drugs 15: 1077-90. A bradykinin B2 receptor antagonist, Icatibant, is also effective in treating HAE. Bork, K. et al. (2007) J. Allergy Clin. Immunol. 119:1497-1503. Because plasma kallikrein generates bradykinin, inhibition of plasma kallikrein is expected to inhibit bradykinin production.

For example, in coagulation resulting from fibrinolytic treatment (e.g., treatment with tissue plasminogen activator or streptokinase), higher levels of plasma kallikrein are found in patients undergoing fibrinolysis. Hoffmeister, H. M. et al. (1998) J. Cardiovasc. Pharmacol. 31 :764-72. Plasmin-mediated activation of the intrinsic pathway has been shown to occur in plasma and blood and was markedly attenuated in plasma from individuals deficient in any of the intrinsic pathway components. Ewald, G. A. et al. (1995) Circulation 91 :28-36. Individuals who have had an acute MI were found to have elevated levels of activated plasma kallikrein and thrombin. Hoffmeister, H. M., et al. (1998) Circulation 98:2527-33.

DX-88 reduced brain edema, infarct volume, and neurological deficits in an animal model of ischemic stroke. Storini, C. et al. (2006) J Pharm. Exp. Ther. 318:849-854. Cl- inhibitor reduced infarct size in a mouse model of middle cerebral artery occlusion

(MCAO). De Simoni, M. G. et al. (2004) Am. J. Pathol. 164: 1857-1863; and Akita, N. et al. (2003) Neurosurgery 52:395-400). B2 receptor antagonists were found to reduce the infarct volume, brain swelling, and neutrophil accumulation and were neuroprotective in an MCAO animal model. Zausinger, S. et al. (2003 ) Acta Neurochir. Suppl. 86:205-7;

Lumenta, D. B. et al. (2006) Brain Res. 1069:227-34; Ding-Zhou, L. et al. (2003) Br. J Pharmacol. 139: 1539-47.

Regarding blood loss during cardiopulmonary bypass (CPB), it has been found that the kallikrein-kinin (i.e., contact) system is activated during CABG. Wachtfogel, Y. T. (1989) Blood 73:468. Activation of the contact system during CPB results in up to a 20- fold increase in plasma bradykinin. Cugno, M. et al. (2006) Chest 120:1776-82; and Campbell, D. J. et al. (2001 ) Am. J. Physiol. Reg. Integr. Comp. Physiol. 281 : 1059-70.

Plasma kallikrein inhibitors P8720 and PKSI-527 have also been found to reduce joint swelling in rat models of arthritis. De La Cadena, R. A. et al. (1995) FASEB J. 9:446- 52; Fujimori, Y. (1993) Agents Action 39:42-8. It has also been found that inflammation in animal models of arthritis was accompanied by activation of the contact system. Blais, C. Jr. et al. (1997) Arthritis Rheum. 40: 1327-33.

Additionally, plasma kallikrein inhibitor P8720 has been found to reduce inflammation in an acute and chronic rat model of inflammatory bowel disease (IBD). Stadnicki, A. et al. (1998) FASEB J. 12:325-33; Stadnicki, A. et al. (1996) Dig. Dis. Sci.

41 :9l2-20; and De La Cadena, R. A., et al. (1995) FASEB J. 9:446-52. The contact system is activated during acute and chronic intestinal inflammation. Sartor, R. B. et al. (1996) Gastroenterology 110: 1467-81. It has been found that B2 receptor antagonist, an antibody to high molecular weight kininogen, or reduction in levels of kininogen reduced clinicopathology in animal models of IBD. Ibid !; Arai, Y. et al. (1999) Dig. Dis. Sci.

44:845-51; and Keith, J. C. et al. (2005) Arthritis Res. Therapy 7 :R769-76.

H-D-Pro-Phe-Arg-chloromethylketone (CMK), an inhibitor of PK and FXII and a physiological inhibitor (Cl -inhibitor), has been found to reduce vascular permeability in multiple organs and reduce lesions in lipopolysaccharide (LPS)- or bacterial-induced sepsis in animals. Liu, D. et al. (2005) Blood 105:2350-5; Persson, K. et al. (2000) J. Exp. Med. 192: 1415-24. Clinical improvement was observed in sepsis patients treated with Cl- inhibitor. Zeerleder, S. et al. (2003) Clin. Diagnost. Lab. Immunol. 10:529-35; Caliezi, C., et al. (2002) Crit. Care Med. 30:1722-8; and Marx, G. et al. (1999) Intensive Care Med.

25: 1017-20. Fatal cases of septicemia are found to have a higher degree of contact activation. Martinez-Brotons, F. et al. (1987) Thromb. Haemost. 58:709-713; and Kalter, E. S. et al. (1985) J. Infect. Dis. 151 : 1019-27.

It has also been found that prePK levels are higher in diabetics, especially those with proliferative retinopathy, and correlate with fructosamine levels. Gao, B.-B., et al. (2007) Nature Med. 13: 181-8; and Kedzierska, K. et al. (2005) Archives Med. Res. 36:539- 43. PrePK is also found to be highest in those with a sensorimotor neuropathy. Christie,

M. et al. (1984) Thromb. Haemostas. (Stuttgart) 52:221-3. PrePK levels are elevated in diabetics and are associated with increased blood pressure. PrePK levels independently correlate with the albumin excretion rate and are elevated in diabetics with

macroalbuminuria, suggesting prePK may be a marker for progressive nephropathy. Jaffa, A. A. et al. (2003) Diabetes 52: 1215-21. Bl receptor antagonists have been found to decrease plasma leakage in rats treated with streptozotocin. Lawson, S. R. et al. (2005)

Eur. J. Pharmacol. 514:69-78. Bl receptor antagonists can also prevent streptozotocin- treated mice from developing hyperglycemia and renal dysfunction. Zuccollo, A. et al. (1996) Can. J. Physiol. Pharmacol. 74:586-9.

PATENT

WO 2015134998

https://patents.google.com/patent/WO2015134998A1/en

PATENT

WO 2020092898

https://patents.google.com/patent/WO2020092898A1/en

Example 1 : Synthetic protocol for racemic compound 54e

Reproduced from WO 2015/134998 and U.S. Patent Application Publication No. 2017/0073314 A1 (both incorporated by reference)

Figure imgf000026_0001

Preparation of 1 -(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide

(54e)

Step-l : Preparation of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b)

To a solution of 3-formylbenzonitrile (54a) (29 g, 217 mmol) in tetrahydrofuran (200 mL) cooled to 0 °C was added freshly prepared Grignard reagent (52c) (245 mL, 221 mmol, ~ 0.9 M in THF) stirred at 0 °C for 1 h, and room temperature for 18 h. The reaction mixture was quenched with 1 N HC1 (aq. 440 mL), stirred for 3 h, neutralized with NaOH (2 N, aq.) to pH = ~ 8. The reaction mixture was extracted with ethyl acetate (600, 300 mL). The combined extracts were washed with brine (120 mL), dried over MgS04, filtered and concentrated in vacuum. The crude product was purified by flash column

chromatography [silica gel, eluting with hexanes/ethyl acetate (1 :0 to 1 : 1) to give 3-((3- amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (36.28 g) as a brown gum which was used as such for next step; MS (ES+) 265.3 (M+23).

Step-2: Preparation of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c)

To a solution of 3-((3-amino-4-fluorophenyl)(hydroxy)methyl)benzonitrile (54b) (24.682 g, 102 mmol) in DMF (480 mL) was added l-(3-((tert- butoxycarbonylamino)methyl)phenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxylic acid (lOd) (35.0 g, 91 mmol), N-ethyl-N-isopropylpropan-2-amine (132 mL, 758 mmol), bromotripyrrolidin-l-ylphosphonium hexafluorophosphate(V) (PyBrOP, 42.8 g, 91 mmol) and stirred at room temperature for 19 h. The reaction mixture was diluted with ethyl acetate (1000 mL), washed with water (500, 400 mL), brine (400 mL), dried over MgS04, filtered and concentrated in vacuum. The crude product was purified by flash column chromatography [silica gel, eluting with hexanes/ethyl acetate (1 :0 to 1 : 1)] to afford tert- butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (4.583 g, 5% for two steps) as a yellow solid; ¾ NMR (300 MHz, DMSO-i¾) d 10.57 (s, 1H), 7.81 (t, J= 1.7 Hz, 1H), 7.73 – 7.66 (m, 2H), 7.64 – 7.19 (m, 10H), 6.25 (d, J= 4.0 Hz, 1H), 5.78 (d, J= 4.0 Hz, 1H), 4.19 (d, J= 6.1 Hz, 2H), 1.37 (s, 9H); 19F NMR (282 MHz, DMSO-i¾) d -60.81 , -123.09; MS (ES+) 632.3 (M+23).

Step-3: Preparation of tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d)

To a solution of tert-butyl 3-(5-(5-((3-cyanophenyl)(hydroxy)methyl)-2- fluorophenylcarbamoyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54c) (1.333 g, 2.187 mmol) in dichloromethane (40 mL) at 0°C was added thionyl chloride (0.340 mL, 4.59 mmol) and warmed to room temperature over 2 h. The reaction mixture was quenched with triethyl amine (2.0 mL, 14.35 mmol) stirred at room temperature for 1 h. It was then treated with cyclopropylmethanamine (4.30 mL, 48.0 mmol), concentrated to remove most of dichloromethane followed by addition of acetonitrile (30 mL), stirring at 70 °C for 14 h, and concentration in vacuum to dryness. The residue was treated with chlorofrom (200 mL), washed with water (100 mL), dried over MgS04 followed by filtration and

concentration. The crude product was purified by flash column chromatography [silica gel eluting with hexanes/ethyl acetate (1 :0 to 2: 1)] to afford tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (184 mg, 13%) as colorless gum; ¾ NMR (300 MHz, DMSO-ά) d 10.56 (s, 1H), 7.89 (t, J= 1.7 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.70 – 7.30 (m, 10H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 4.19 (d, J= 6.2 Hz, 2H), 2.26 (d, J= 6.6 Hz, 2H), 1.37 (s, 9H), 1.00 – 0.80 (m, 1H), 0.45 – 0.28 (m, 2H), 0.12 – -0.01 (m, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.80 , -123.20; MS (ES+) 663.4 (M+l). Step-4: Preparation of l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e)

To a solution of tert-butyl 3-(5-(5-((3- cyanophenyl)(cyclopropylmethylamino)methyl)-2-fluorophenylcarbamoyl)-3- (trifluoromethyl)-lH-pyrazol-l-yl)benzylcarbamate (54d) (161 mg, 0.243 mmol) in 1,4- Dioxane (18 mL) was added hydrogen chloride (2.60 mL, 10.40 mmol, 4 M in l,4-dioxane) and stirred at room temperature for 16 h. the reaction mixture was treated with hexanes, decanted, washed with hexanes, and decanted again. The insoluble crude product was purified by flash column chromatography [silica gel, eluting with chloroform/CMA80 (1 :0 to 2:1)] to afford l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e). The pure product was dissolved in methanol (10 mL) and added 4 N HC1 (aq. 0.14 mL) followed by concentration in vacuum to dryness to give HC1 salt of l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (54e) (74 mg, 48%) white solid; ¾ NMR (300 MHz, DMSO- d, D20 ex NMR) d 8.13 (t, J = 1.7 Hz, 1H), 7.98 – 7.84 (m, 3H), 7.73 – 7.64 (m, 3H), 7.63 – 7.48 (m, 4H), 7.44 (dd, J = 10.2, 8.6 Hz, 1H),

5.75 (s, 1H), 4.12 (s, 2H), 2.76 (d, J = 7.2 Hz, 2H), 1.17 – 0.94 (m, 1H), 0.68 – 0.47 (m, 2H), 0.34-0.24 (m, 2H); 19F NMR (282 MHz, DMSO- d) d -60.82, -120.02; MS (ES+): 563.3 (M+l); Analysis calculated for C30H26F4N6O2.O HCT3.0 H2O: C, 52.26; H, 4.97; N, 12.19; Found: C, 52.26; H, 5.00; N, 11.72.

Example 2: Separation of enantiomers of racemic compound 54e

Reproduced from WO 2015/134998 and U.S. Patent Application Publication No. 2017/0073314 A1 (both incorporated by reference)

Figure imgf000028_0001

Compound I (free base) Separation of (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lFl-pyrazole-5-carboxamide (Compound I), and (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lFl-pyrazole-5-carboxamide ((-

)-enantiomer)

Isomers of Racemic l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lF[- pyrazole-5-carboxamide (54e) (0.4 g) were separated by using preparative SFC method using the following conditions to furnish:

Preparative SFC Method used:

Column 20mm x 25.0 cm ChromegaChiral CCS from

Regis Technologies (Morton Grove, IL)

CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1 : 1) with 1%

Isopropylamine

Isocratic Method 20 % Co-solvent at 80 mL/min

System Pressure 200 bar

Column Temperature 25 °C

Sample Diluent Methanol: Isopropanol

Chiral Purity of peaks was determined by following Analytical SFC Method:

Column 4.6 x 100 mm ChiralPak AS from Chiral

Technologies (West Chester, PA)

CO2 Co-solvent (Solvent B) Methanol: Isopropanol (1 : 1) with 0.1%

Isopropylamine

Isocratic Method 5-65 % Co-solvent Gradient at 4 mL/min System Pressure 100 bar

Column Temperature 25 °C

Sample Diluent Methanol

Peak-l (Compound I) 2.1 min 144 mg >95% ee (UV 254)

98.6 % purity (UV 254)

Peak-2 ((-)-enantiomer) 2.4 min 172 mg 95.5 % ee (UV 254)

96.5 % purity (UV 254) 1. Peak-l assigned as (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (144 mg, >95%ee) free base as white solid; Optical rotation: [O]D = (+) 6.83 [CH3OH, 1.2]; ‘H NMR (300 MHz, DMSO-£¾) d 10.53 (s, 1H, D2O exchangeable), 7.88 (t, J= 1.7 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.67 (dt, 7= 7.7, 1.4 Hz, 1H), 7.63 (dd, J= 7.5, 2.1 Hz, 1H), 7.56 (s, 1H), 7.54 – 7.47 (m, 2H), 7.47 – 7.38 (m, 2H), 7.34 (ddt, J= 8.6, 5.9, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.77 (s, 2H), 2.31 – 2.21 (m, 2H), 0.97 – 0.80 (m, 1H), 0.42 – 0.33 (m, 2H), 0.10 – -0.02 (m, 2H); 19F NMR (282 MHz, DMSO-Ts) d -60.73 , -123.20; MS (ES+) 563.3 (M+l), 561.3 (M-l). To a solution of free base mixture of (+)-l-(3-(aminomethyl)phenyl)-N-(5-((3- cyanophenyl)(cyclopropyl-methylamino)methyl)-2-fluorophenyl)-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (120 mg) in methanol (15 mL) was added hydrogen chloride (0.969 mL, 1.938 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (+)-l-(3- (aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl-methylamino)methyl)-2- fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (Compound I) (100 mg) hydrochloride salt as white solid; ¾ NMR (300 MHz, DMSO-Ts) d 10.84 (s, 1H, D2O exchangeable), 10.44 (s, 2H, D2O exchangeable), 8.44 (s, 3H, D2O exchangeable), 8.30 (s, 1H, D2O exchangeable), 8.09 (d, J= 7.9 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.91 – 7.83 (m, 1H), 7.80 – 7.50 (m, 7H), 7.42 (dd, J= 10.3, 8.6 Hz, 1H), 5.78 (d, J= 6.9 Hz, 1H), 4.13 (d, J= 5.7 Hz, 2H), 2.88 – 2.62 (m, 2H), 1.42 – 0.99 (m, 1H), 0.73 – 0.46 (m, 2H), 0.32 (d, J= 4.4 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.81 , -119.99; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-) 561.3 (M-l), 597.3 (M+Cl); Analysis calculated for C30H26F4N6O 2HC1 l.75H20: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97. Peak-2 assigned as (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (172 mg, 95.5 % ee) as free base was repurified by flash column chromatography (silica gel 12 g, eluting 0-30% MeOH in chloroform for 15 min) to afford (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) free base as an off-white solid; Optical rotation: [O]D = (-) 5.44

[CH3OH, 1.25]; ¾ NMR (300 MHz, DMSO-i¾) d 7.88 (t, J= 1.6 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.70 – 7.61 (m, 2H), 7.57 (s, 1H), 7.54 – 7.47 (m, 2H), 7.45 – 7.41 (m,

2H), 7.34 (ddq, J= 8.7, 6.1, 3.5, 2.8 Hz, 2H), 7.22 (dd, J= 10.3, 8.5 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 2H), 2.25 (d, J= 6.9 Hz, 2H), 0.90 (ddd, J= 9.8, 8.0, 5.2 Hz, 1H), 0.47 – 0.29 (m, 2H), 0.04 (dd, J= 5.0, 1.5 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.73 , -123.19; MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l). To a solution of free base of (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.124 g, 0.220 mmol) in methanol (15 mL) was added hydrogen chloride (1.102 mL, 2.204 mmol), stirred at room temperature for 10 min, evaporated to dryness to afford (-)-l-(3-(aminomethyl)phenyl)-N-(5-((3-cyanophenyl)(cyclopropyl- methylamino)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-lH-pyrazole-5-carboxamide ((-)-enantiomer) (0.121 g) hydrochloride salt as an off-white solid; Ή NMEE ¾ NMR (300 MHz, DMSO-i¾) d 10.82 (s, 1H, D20 exchangeable), 10.36 (s, 2H, D2O exchangeable), 8.38 (s, 3H, D2O exchangeable), 8.27 (s, 1H), 8.06 (d, J= 7.9 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.87 (d, J= 7.7 Hz, 1H), 7.78 – 7.49 (m, 7H), 7.48 – 7.37 (m, 1H), 5.78 (s, 1H), 4.13 (d, j= 5.7 Hz, 2H), 2.72 (s, 2H), 1.14 (s, 1H), 0.56 (d, j= 7.7 Hz, 2H), 0.31 (d, J= 5.0 Hz, 2H); 19F NMR (282 MHz, DMSO-i¾) d -60.82 , -120.03; MS (ES+): MS (ES+) 563.3 (M+l), MS (ES-), 561.3 (M-l), 597.2 (M+Cl); Analysis calculated for C30H26F4N6O.2HCI. I .75H2O: C, 54.02; H, 4.76; Cl, 10.63; N, 12.60; Found: C, 54.12; H, 4.83; Cl, 10.10; N, 11.97.

Example 3 : Preparation of a Seed Crystal of Compound I*2

Figure imgf000031_0001

A solution of Compound I ( see Example 2) in methyl tert-butyl ether (MTBE) (1 equiv) is added to a solution of HC1 (aq) (2 equiv) in methanol (cold), followed by heating to about 30°C, and keeping it at about 30°C for not longer than 5 hours while stirring at about 115 rpm. Compound I bis(HCl) is collected by filtration and dried. The crystalline material obtained can be used as a seed for the crystallization protocol described in

Example 4. Example 4: Large-Scale Synthetic & Crystallization Protocol for Compound I*2(HC1 )

Figure imgf000032_0001

Compound I (free base) Compound I bis(HCI)

37% Aqueous hydrochloric acid (38.1 kg, 32.3 L, 2.14 equiv.) was charged to a clean and empty crystallization vessel, methanol (228.9 kg, 39.5 equiv.) was added, and the contents were cooled to -7 ± 3°C. A solution of Compound I free base (approx. 101.8 kg; 180.9 moles) in MTBE (approx. 1,300 L) was filtered through a polish filter into the crystallization vessel at temperature -5 ± 5°C. After rinse with MTBE, pre-weighed Compound I»2(HCl) seed crystals (1.39 kg, 0.012 equiv.; Example 3) were charged to the crystallization vessel via the manhole. The vessel content was heated to 30-33°C, and the agitation speed was set to 25-50 rpm. After confirmed crystallization, the slurry was agitated for another three to four hours. The product slurry was transferred to centrifuge and isolated by centrifugation. The product was washed with MTBE (585 L). After dry spinning the wet product, Compound I*2(HC1), it was discharged from the centrifuge, and the product was dried at < 40°C under vacuum in a cone drier. Product Compound I»2(HCl) yield: 100 kg; 157.4 mol; approx. 85%.

‘H NMR (300 MHz, DMSO-c/i,) data is shown in the following table:

Figure imgf000033_0001

19F NMR (282 MHz, DMSO- is) data is shown in the following table:

Figure imgf000033_0002

Compound I has two basic sites. The conjugate acid of the primary amine was calculated to have a pKa value of 8.89, and the conjugate acid of the secondary amine was calculated to have a pKa value of 7.86.

The XRPD pattern of Compound I»2(HCl) is shown in Fig. 1. Compound I»2(HCl) has characteristic peaks in its XRPD pattern at values of two theta (°2Q) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31. TG-IR analysis indicated two, distinct weight loss regions: the first was completed by 125 °C while the second began at approximately 208 °C. IR analysis of the off gasses from this experiment detected only trace amounts of water at the initial weight loss while HC1 gas was detected at the 208°C event. No other solvents were detected in the sample. Thus, it was determined that Compound I*2(HC1) initially loses water when heated and, when heated to above 200°C, the salt begins to break apart and HC1 gas is evolved. The IR signal for all these events is very weak indicating that they are occurring over a range and not at a specified temperature. An exemplary TG-IR spectrum is shown in Fig. 2.

REFERENCES

1: Sohtome Y, Sodeoka M. Development of Chaetocin and S-Adenosylmethionine Analogues as Tools for Studying Protein Methylation. Chem Rec. 2018 Dec;18(12):1660-1671. doi: 10.1002/tcr.201800118. Epub 2018 Oct 16. Review. PubMed PMID: 30324709.

2: Bensussen A, Torres-Sosa C, Gonzalez RA, Díaz J. Dynamics of the Gene Regulatory Network of HIV-1 and the Role of Viral Non-coding RNAs on Latency Reversion. Front Physiol. 2018 Sep 28;9:1364. doi: 10.3389/fphys.2018.01364. eCollection 2018. PubMed PMID: 30323768; PubMed Central PMCID: PMC6172855.

////////berotralstat, Orladeyo, BIOCRYST, APPROVALS 2020, FDA 2020, ORPHAN DRUG, CX-7353, CX 7353,

NCc1cccc(c1)n2nc(cc2C(=O)Nc3cc(ccc3F)[C@H](NCC4CC4)c5cccc(c5)C#N)C(F)(F)F

Pemigatinib


Pemigatinib.svg
img

Pemigatinib

INCB054828

FormulaC24H27F2N5O4
CAS1513857-77-62379919-96-5  HCL
Mol weight487.4991

2020/4/17FDA APPROVED, PEMAZYRE

佩米替尼 [Chinese] [INN]

3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,6-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

2H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-

3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one 

  • Originator Incyte Corporation
  • Developer Incyte Corporation; Innovent Biologics
  • ClassAntineoplastics; Ethers; Fluorobenzenes; Morpholines; Pyridines; Pyrimidinones; Pyrroles; Small molecules
  • Mechanism of Action Type 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type 4 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
  • Orphan Drug Status Yes – Myeloproliferative disorders; Lymphoma; Cholangiocarcinoma
  • MarketedCholangiocarcinoma
  • Phase IIBladder cancer; Lymphoma; Myeloproliferative disorders; Solid tumours; Urogenital cancer
  • Phase I/IICancer
  • 05 Nov 2020Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, First line therapy, Inoperable/Unresectable) in Japan (PO) in November 2020
  • 05 Nov 2020Incyte Corporation stops enrolment in the FIGHT-205 trial for Bladder cancer due to regulatory feedback
  • 26 Oct 2020Preregistration for Cholangiocarcinoma (Second-line therapy or greater, Inoperable/Unresectable, Late-stage disease, Metastatic disease) in Canada (PO)

Pemigatinib, also known as INCB054828, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. FGFR inhibitor INCB054828 binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells.

Pemigatinib (INN),[2] sold under the brand name Pemazyre, is a medication for the treatment of adults with previously treated, unresectable locally advanced or metastatic bile duct cancer (cholangiocarcinoma) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.[3][4] Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.[3]

Pemigatinib belongs to a group of medicines called protein kinase inhibitors.[5] It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs).[5] FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells.[5] By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.[5]

PEMAZYRE®: Prescription Medicine that is Used to Treat Adults with Bile Duct Cancer| Pemazyre.com

The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin.[3][4] Ocular (eye) toxicity is also a risk of pemigatinib.[3][4]

Medical uses

Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine.[3] Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).[3] It should be used in patients who have been previously treated with chemotherapy and whose cancer has a certain type of abnormality in the FGFR2 gene.[6]

History

Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.[3][4][7]

The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment.[3][4][6] The trial was conducted at 67 sites in the United States, Europe, and Asia.[6] During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects.[3][4][6] To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks.[3] The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate).[3] The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response.[3] Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.[3][4]

The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority reviewbreakthrough therapy and orphan drug designations.[3][4][8][9] The FDA granted approval of Pemazyre to Incyte Corporation.[3]

On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer.[5] On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.[10]

PATENT

US 20200281907

The present disclosure is directed to, inter alia, methods of treating cancer in a patient in need thereof, comprising administering pemigatinib, which is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one, having the structure shown below:

 Pemigatinib is described in U.S. Pat. No. 9,611,267, the entirety of which is incorporated herein by reference. Pemigatinib is further described in US Publication Nos.: 2019/0337948 and 2020/0002338, the entireties of which are incorporated herein by reference.

      Provided herein is a method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a CYP3A4 perpetrator.

Example 1. Synthesis of Pemigatinib

Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde


 
      A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS #958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) and ethylamine (10M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL, 200 mmol) was heated to 130° C. and stirred overnight. The mixture was cooled to room temperature then concentrated under reduced pressure. The residue was treated with 1N HCl (30 mL) and stirred at room temperature for 1 h then neutralized with saturated NaHCO aqueous solution. The precipitate was collected via filtration then washed with water and dried to provide the desired product (2.9 g, 92%). LC-MS calculated for C 10123O [M+H] + m/z: 190.1; found: 190.1.

Step 2: 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine


 
      A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol) and [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (Aldrich, cat #21360: 2 g, 7 mmol) in xylenes (250 mL) was heated to reflux with azeotropic removal of water using Dean-Stark for 2 days at which time LC-MS showed the reaction was complete. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL) and then 2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was added slowly and the resulting mixture was stirred at 50° C. for 3 h then cooled to room temperature. The reaction was quenched by addition of water, 15% aqueous NaOH and water. The mixture was filtered and washed with THF. The filtrate was concentrated and the residue was washed with CH 2Cl and then filtered to get the pure product (11 g, 82%). LC-MS calculated for C 1821242[M+H] + m/z: 363.2; found: 363.1.

Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL) was added slowly to a mixture of 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine (5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0° C. and then the mixture was stirred at room temperature for 6 h. The mixture was cooled to 0° C. and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight and the formed precipitate was collected via filtration, washed with water, and then dried to provide the first batch of the purified desired product. The organic layer in the filtrate was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was concentrated and the residue was triturated with methylene chloride then filtered and dried to provide another batch of the product (total 5.5 g, 92%). LC-MS calculated for C 1919243[M+H] + m/z: 389.1; found: 389.1.

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH 4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C 2523245S [M+H] + m/z: 529.1; found: 529.1.

Step 5: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde


 
      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C 2623246S (M+H) + m/z: 557.1; found: 556.9.

Step 6: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCO then extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C 3032256S (M+H) + m/z: 628.2; found: 628.0.

Step 7: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib)

      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H 2O). LC-MS calculated for C 242825(M+H) + m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

PATENT

WO 2019213506

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019213506

PATENT

WO 2019213544

The present disclosure is directed to, inter alia, solid forms, including crystalline forms and amorphous forms, of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)- 1 ,3,4,7 -tetrahydro-2H-pyrrolo [3 ‘,2’ : 5 ,6]pyrido [4,3 -d]pyrimidin-2-one

(Compound 1), and processes and intermediates for preparing the compound. The structure of Compound 1 is shown below.

Compound 1

Compound 1 is described in US Patent No. 9,611,267, the entirety of which is incorporated herein by reference.

Example 1

Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l^, 4,7-tetrahydro-2H-pyrrolo[3f,2f:5,6]pyrido[4r3-d]pyrimidin-2-one (Compound 1) Scheme 1.

Step 1: Synthesis of 4-((4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b ] pyridin-2-yl) methyl) morpholine

To a l-L flask was added 4-chloro-5-(l,3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo [2,3-b] pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL) under N2. To this mixture at -70 °C was added 2.0 M lithium

diisopropylamide in THF/heptane/ethyl benzene (77.4 g, 95 mL, 190 mmol, 1.4 eq.). The mixture was stirred at -70 °C for 1 h. To the mixture was added /V- formyl morpholine (29.7 g, 258 mmol, 1.9 eq.) in THF (22. 2 g, 25 mL) dropwise. The reaction was done in 30 min after addition. LC/MS showed that the desired product, 4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)- 1 //-pyrrolo [2, 3-61 pyridine-2-carbaldehyde, was formed cleanly. The reaction was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 eq.) and the dry ice cooling was removed. To the mixture was added morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 eq.) followed by acetic acid (74.0 g, 70 mL, 1231 mmol, and 9.0 eq.) at 0 °C (internal temperature rose from 0 °C to 18 °C) and stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 eq.) was added and the reaction mixture temperature rose from 20 °C to 32 °C. The mixture was stirred at room temperature for 30 min. HPLC & LC/MS indicated the reaction was complete. Water (100 g, 100 mL) was added followed by 2.0 M sodium carbonate (Na2C03) in water (236 g, 200 mL, 400 mmol, 2.9 eq.) slowly (off gas!). The mixture was stirred for about 30 min. The organic layer was separated and water (250 g, 250 mL) and heptane (308 g, 450 mL) were added. The resulting slurry was stirred for 1 h and the solid was collected by filtration. The wet cake was washed with heptane twice (75.00 mL x 2, 51.3 g x 2) before being dried in oven at 50 °C overnight to give the desired product, 4-((4-chloro-5-( 1 3-dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-2-yl)methyl)morpholine as a light brown solid (52.00 g, 81.8 % yield): LCMS calculated for C21H23CIN2O5S [M+H]+: 464.00; Found: 464.0; ftf NMR ^OO MHz, DMSO-de) d 8.48 (s, 1 H), 8.38 (m, 2H), 7.72 (m, 1H), 7.64 (m, 2H), 6.83 (s, 1H), 6.13 (s, 1H), 4.12 (m, 2H), 4.00 (m, 2H), 3.92 (s, 2H), 3.55 (m, 4H), 2.47 (m, 4H).

Step 2: Synthesis of 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b] pyridine-5 -carbaldehyde

To a 2 L reactor with a thermocouple, an addition funnel, and a mechanical stirrer was charged 4-((4-chloro-5 -(1 ,3 -dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo [2,3 -6]pyridin-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature

was 19.5 °C) to achieve a solution. To the resulting solution was added an aqueous hydrochloric acid solution (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 eq.) at room temperature in 7 min. After over 23 h agitations at room temperature, the bilayer reaction mixture turned into a thick colorless suspension. When HPLC showed the reaction was complete, the slurry was cooled to 0-5 °C and aqueous sodium hydroxide solution (1 N, 104 g, 100 mL, 100 mmol, and 2.32 eq.) was added in about 10 min to adjust the pH of the reaction mixture to 10-11. «-Heptane (164 g, 240 mL) was added and the reaction mixture and the mixture were stirred at room temperature for 1 h. The solid was collected by filtration and the wet cake was washed with water (2 x 40 mL), heptane (2 x 40 ml) before being dried in oven at 50 °C under vacuum to afford the desired product, 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-/i |pyridine-5-carbaldehyde as a light brown solid (16.9 g, 93% yield): LCMS calculated for C19H19CIN3O4S [M+H]+: 420.00; Found: 420.0; ¾ NMR (400 MHz, DMSO-de) d 10.33 (s, 1H), 8.76 (s, 1 H), 8.42 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 6.98 (s, 1H), 3.96 (m, 2H), 3.564 (m, 4H), 2.51 (m, 4H).

Step 3: Synthesis ofN-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-h] pyridin-5-yl) methyl) -2, 6-difluoro-3,5-dimethoxyaniline

To a 2-L reactor equipped with a thermocouple, a nitrogen inlet and mechanical stirrer were charged AOV-dimethyl formamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridine-5-carbaldehyde (30.0 g, 71.45 mmol) and 2,6-difluoro-3,5-dimethoxyanihne (14.2 g, 75.0 mmol). To this suspension (internal temperature 20 °C) was added chlorotrimethylsilane (19.4 g, 22. 7 mL, 179 mmol) dropwise in 10 min at room temperature (internal temperature 20-23 °C). The suspension changed into a solution in 5 min after the chlorotrimethylsilane addition. The solution was stirred at room temperature for 1.5 h before cooled to 0-5 °C with ice-bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 eq.) was added dropwise via additional funnel over 30 min while maintaining temperature at 0-5 °C. After addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice-bath cooling in 20 min, followed by slow addition of ammonium hydroxide solution (28% N¾, 15.3 g, 17 ml, 252 mmol, 3.53 eq.) to pH 9-10 while maintaining the temperature below 10 °C. More water (250 mL, 250 g) was added through the additional funnel. The slurry was stirred for 30 min and the solids were collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x2, 90 ml x 2). The product w as suction dried overnight to give the desired product LG-((4-chloro-2-(morphohnomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-Z>]pyridin-5-yl)methyl)-2,6- difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): LCMS calculated for C27H28ClF2N405S[M+H]+: 593.10; Found: 593.1 ; ¾ NMR (400 MHz, DMSO-d6) 5 8.36 (m, 2H), 8.28 (s, 1H), 7.72 (m, 1H), 7.63 (m, 2H), 6.78 (s, 1H), 6.29 (m, 1H), 5.82 (m, 1H), 4.58 (m, 2H), 3.91 (s, 2H), 3.76 (s, 6H), 3.56 (m, 4H), 2.47 (m, 4H).

Step 4: Synthesis of l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-b ] pyridin-5-yl) methyl)-! -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea

To a 2-L, 3-neck round bottom flask fitted with a thermocouple, a nitrogen bubbler inlet, and a magnetic stir were charged /V-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5 °C.

To the mixture was charged ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 eq.) over 30 sec. The temperature stayed unchanged at 0.7 °C after the charge. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 eq.) was charged dropwise over 35 min while maintaining the temperature below 2 °C. The mixture was warmed to room temperature and stirred overnight. At 24 h after addition showed that the product was 93.7%, unreacted SM was 0.73% and the major impurity (bis-isocyanate adduct) was 1.3%. The mixture was cooled with an ice-bath and quenched with sodium hydroxide (NaOH) solution (1.0M, 235 mL, 244 g, 235 mmol, 2.08 eq.) over 20 min and then saturated aqueous sodium bicarbonate

(NaHCCh) solution (1.07 M, 85 mL, 91 g, 0.091 mol, 0.80 eq.) over 10 min. Water (550 mL, 550 g) was added and the liquid became one phase. The mixture was stirred for 2 h and the solids were collected by filtration, washed with water (165 mL, 165 g) to give l-((4-chloro-2-(morpholinomethyl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo| 2.3-6 |p\ ri din-5 -y l (methy l )- 1 -(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea ( 70.3 g, 93.7% yield).

The crude l-((4-chloro-2-(morpholinomethyl)-l -(phenylsulfonyl)- li/-pyrrolo [2, 3-61 pyridin-5-yl) methyl)- 1 -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea (68.5 g, 103 mmol) was added in to acetonitrile (616 mL, 485 g). The mixture was heated 60-65 °C and an amber colored thin suspension was obtained. The solid was filtered off with celite and the celite was washed with acetonitrile (68.5 mL, 53.8 g). To the pale yellow filtrate was added water (685 g, 685 ml) to form a slurry. The slurry was stirred overnight at room temperature and filtered. The solid was added to water (685 mL, 685 g) and stirred at 60 °C for 2 h. The solid was filtered and re-slurred in heptane (685 mL, 469 g) overnight. The product was dried in an oven at 50 °C under vacuum for 48 h to afford l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-difluoro-3.5-

dimethoxyphenyl)-3-ethylurea as a colorless solid (62.2 g, 90.8% yield, 99.9% purity by HPLC area%). KF was 0.028%. Acetonitrile (by ‘H NMR) was about 1.56%, DCM (by ‘H NMR) 2.0%: LCMS calculated for C30H33CIF2N5O6S [M+H]+: EM: 664.17; Found: 664.2; ¾ NMR (400 MHz, DMSO-de) d 8.33 (m, 2H), 8.31 (s, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 6.96 (m, 2H), 6.73 (s, 1H), 6.43 (m, 1H), 4.87 (s, 2H), 3.90 (s, 2H), 3.77 (s, 6H), 3.54 (m, 4H),

3.03 (m, 2H), 2.46 (m, 4H), 0.95 (m, 3H).

Step 5: Synthesis of 3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l, 3, 4, 7-tetrahydro-2H-pyrrolo[ 3 2’:5, 6 ]pyrido[ 4, 3-d]pyrimidin-2-one

To a 2000 mL flask equipped with a thermal couple, a nitrogen inlet, and a mechanical stirrer were charged dry l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-1 //-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-dinuoro-3.5-dimetho\yphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0. l l%) and tetrahydrofuran (1200 mL, 1063 g). To this suspension at room temperature was charged 1.0 M lithium hexamethyldisilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 eq). The mixture turned into a solution after the base addition. The reaction mixture was stirred for 2 h and HPLC shows the starting material was not detectable. To this mixture was added 1.0 M hydrochloric acid (18.1 mL, -18.1 g. 18.1 mmol, 0.4 eq.). The solution was concentrated to 600 mL and water (1200 mL, 1200 g) was added. Slurry was formed after water addition. The slurry was stirred for 30 min at room temperature and the solid was collected by filtration. The wet cake was washed with water twice (60 mLx2,

60 gx2) and dried at 50 °C overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidin-2-one as a light brown solid (26.58 g, as-is yield 93.7%): THF by ‘H NMR 0.32%, KF 5.26%, adjusted yield was 88.5%: LCMS calculated for C30H32F2N5O6S [M+H]+: EM: 628.20; Found: 628.2; ¾ NMR (400 MHz, DMSO-de) d 8.41 (m, 2H), 8.07 (s, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 4.76 (s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.89 (s, 6H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).

Step 6: Synthesis of 3-( 2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-1,3, 4, 7 -tetrahydro-2H-pyrrolo [ 3 ‘, 2 5, 6 ]pyrido[ 4, 3-dJpyrimidin-2-one

To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2i/-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in l,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50 °C under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5, 6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]+: 488.20; Found: 488.2.

PATENT

US 20130338134

https://patents.google.com/patent/US20130338134A1/en

  • [0831]

Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0832]
  • [0833]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (Example 49, Step 3: 900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C25H23F2N4O5S [M+H]+ m/z: 529.1; found: 529.1.

Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

  • [0834]
  • [0835]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C26H23F2N4O6S (M+H)+ m/z: 557.1; found: 556.9.

Step 3: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0836]
  • [0837]
    To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCOthen extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C30H32F2N5O6S (M+H)+ m/z: 628.2; found: 628.0.

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0838]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H2O). LC-MS calculated for C24H28F2N5O(M+H)+ m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

PATENTS

Publication Number TitlePriority Date Grant Date
US-2013338134-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-2017137424-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-2019127376-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-9611267-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132017-04-04
WO-2014007951-A2Substituted tricyclic compounds as fgfr inhibitors2012-06-13
Publication Number TitlePriority Date Grant Date
JP-6336665-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-06-06
JP-6545863-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132019-07-17
JP-6711946-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132020-06-17
TW-201402574-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
US-10131667-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-11-20
Publication Number TitlePriority Date Grant Date
JP-2015521600-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2017222709-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2018135377-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2019178156-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-6301321-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-03-28
Publication Number TitlePriority Date Grant Date
EP-3176170-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
EP-3176170-B1Substituted tricyclic compounds as fgfr inhibitors2012-06-132018-11-14
EP-3495367-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
ES-2704744-T3Substituted tricyclic compounds as FGFR inhibitors2012-06-132019-03-19
HU-E031916-T2Substituted tricyclic compounds as fgfr inhibitors2012-06-13
Publication Number TitlePriority Date Grant Date
DK-2861595-T5Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-01-15
DK-3176170-T3Substituted tricyclic relations as fgfr inhibitors2012-06-132019-01-28
EP-2861595-A2Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
EP-2861595-B1Substituted tricyclic compounds as fgfr inhibitors2012-06-132016-12-21
EP-2861595-B9Substituted tricyclic compounds as fgfr inhibitors2012-06-132017-06-21
Publication Number TitlePriority Date Grant Date
WO-2019191707-A1Heterocyclic compounds as immunomodulators2018-03-30 
AU-2013287176-A1Substituted tricyclic compounds as FGFR inhibitors2012-06-13 
CA-2876689-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
CN-107383009-BSubstituted tricyclic compounds as FGFR inhibitors2012-06-132020-06-09
DK-2861595-T3Substituted tricyclic compounds as fgfr inhibitors2012-06-132017-02-13
Publication Number TitlePriority Date Grant Date
WO-2019213544-A2Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
WO-2019213544-A3Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
TW-202003511-AHeterocyclic compounds as immunomodulators2018-03-30 
US-10669271-B2Heterocyclic compounds as immunomodulators2018-03-302020-06-02
US-2019300524-A1Heterocyclic compounds as immunomodulators2018-03-30
Publication Number TitlePriority Date Grant Date
TW-201946630-ASalts of an FGFR inhibitor2018-05-04 
TW-202003516-ASolid forms of an FGFR inhibitor and processes for preparing the same2018-05-04 
US-2019337948-A1Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
US-2020002338-A1Salts of an fgfr inhibitor2018-05-04 
WO-2019213506-A1Salts of an fgfr inhibitor2018-05-04
Publication Number TitlePriority Date Grant Date
WO-2019227007-A1Tricyclic heterocyclic compounds as sting activators2018-05-25 
TW-201946626-AHeterocyclic compounds as immunomodulators2018-05-11 
US-10618916-B2Heterocyclic compounds as immunomodulators2018-05-112020-04-14
US-2019345170-A1Heterocyclic compounds as immunomodulators2018-05-11 
WO-2019217821-A1Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators2018-05-11
Publication Number TitlePriority Date Grant Date
US-2020040009-A1Tricyclic heteraryl compounds as sting activators2018-07-31 
WO-2020028565-A1Tricyclic heteraryl compounds as sting activators2018-07-31 
WO-2020028566-A1Heteroaryl amide compounds as sting activators2018-07-31 
WO-2019238873-A1A method of precision cancer therapy2018-06-13 
US-2019359608-A1Tricyclic heterocyclic compounds as sting activators2018-05-25
TitlePriority Date Grant Date
WO-2020131627-A1Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases2018-12-19 
WO-2020131674-A17-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer2018-12-19 
WO-2020081898-A1Non-invasive urinary biomarkers for the detection of urothelial carcinoma of the bladder2018-10-20 
US-2020115378-A1Dihydropyrido[2,3-d]pyrimidinone compounds as cdk2 inhibitors2018-10-11 
US-2020039994-A1Heteroaryl amide compounds as sting activators2018-07-31

References

  1. ^ “Pemigatinib (Pemazyre) Use During Pregnancy”Drugs.com. 11 August 2020. Retrieved 24 September 2020.
  2. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information32 (3): 479. hdl:10665/330907.
  3. Jump up to:a b c d e f g h i j k l m n o “FDA Approves First Targeted Treatment for Patients with Cholangiocarcinoma, a Cancer of Bile Ducts”U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b c d e f g h “FDA grants accelerated approval to pemigatinib for cholangiocarcinoma”U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b c d e “EU/3/18/2066”European Medicines Agency (EMA). 19 December 2018. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
  6. Jump up to:a b c d “Drug Trials Snapshot: Pemazyre”U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 5 May 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ “Pemazyre: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 21 April 2020.
  8. ^ “Pemigatinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
  9. ^ “Pemigatinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
  10. ^ “EU/3/19/2216”European Medicines Agency (EMA). 23 January 2020. Retrieved 19 April 2020.  This article incorporates text from this source, which is in the public domain.

Further reading

External links

  • “Pemigatinib”Drug Information Portal. U.S. National Library of Medicine.
  • “Pemigatinib”National Cancer Institute.
  • Clinical trial number NCT02924376 for “Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy – (FIGHT-202)” at ClinicalTrials.gov
Clinical data
Trade namesPemazyre
Other namesINCB054828
AHFS/Drugs.comMonograph
MedlinePlusa620028
License dataUS DailyMedPemigatinib
Pregnancy
category
US: N (Not classified yet)[1]
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
IUPAC name[show]
CAS Number1513857-77-6
PubChem CID86705695
DrugBankDB15102
ChemSpider68007304
UNIIY6BX7BL23K
KEGGD11417
ChEMBLChEMBL4297522
Chemical and physical data
FormulaC24H27F2N5O4
Molar mass487.508 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CCN1C2=C3C=C(NC3=NC=C2CN(C1=O)C4=C(C(=CC(=C4F)OC)OC)F)CN5CCOCC5
InChI[hide]InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)Key:HCDMJFOHIXMBOV-UHFFFAOYSA-N

/////////Pemigatinib, 佩米替尼 , PEMAZYRE, FDA 2020, 2020 APPROVALS, INCB054828, INCB 054828, Orphan Drug Status, Myeloproliferative disorders, Lymphoma,  Cholangiocarcinoma, INCYTE

O=C1N(CC)C2=C3C(NC(CN4CCOCC4)=C3)=NC=C2CN1C5=C(F)C(OC)=CC(OC)=C5F.[H]Cl

Bulevirtide acetate


Bulevirtide acetate

(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.

molecular formula C248H355N65O72,

molecular mass is 5398.9 g/mol

ブレビルチド酢酸塩;

APROVED 2020/7/31, EU, Hepcludex

MYR GmbH

Antiviral, Entry inhibitor
  Disease
Hepatitis delta virus infection

Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol

Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.

Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.

The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.

https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdf

Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.

HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.

HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.

Hepcludex contains the active substance bulevirtide.

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).[2]

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[2]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[2]

Bulevirtide was approved for medical use in the European Union in July 2020.[2]

Medical uses

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[2][3]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.[4]

The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[5][6] that can also dock to NTCP, blocking the virus’s entry mechanism.[7]

The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[7]

References

  1. ^ Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews21 (3): 126–134. doi:10.24875/AIDSRev.19000080PMID 31532397.
  2. Jump up to:a b c d e f g “Hepcludex EPAR”European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ “Summary of opinion: Hepcludex” (PDF)European Medicines Agency. 28 May 2020.
  4. ^ Francisco, Estela Miranda (29 May 2020). “Hepcludex”European Medicines Agency. Retrieved 6 August 2020.
  5. ^ Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008PMID 23246506.
  6. ^ Abbas Z, Abbas M (August 2015). “Management of hepatitis delta: Need for novel therapeutic options”World Journal of Gastroenterology21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461PMC 4548107PMID 26327754.
  7. Jump up to:a b Spreitzer H (14 September 2015). “Neue Wirkstoffe – Myrcludex B”. Österreichische Apothekerzeitung (in German) (19/2015): 12.

External links

Bulevirtide
Clinical data
Trade names Hepcludex
Other names MyrB, Myrcludex-B[1]
License data
Routes of
administration
Subcutaneous injection
ATC code
  • None
Legal status
Legal status
  • EU: Rx-only [2]
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS

Teprotumumab-trbw


Image result for teprotumumab-trbw

Tepezza (teprotumumab-trbw)

Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease

UNIIY64GQ0KC0A

CAS number1036734-93-6

R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001

Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).

FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020

Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.

“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”

Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.

Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.

The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.

The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.

Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]

The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]

It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.

Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomanon-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.

Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough TherapyOrphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]

In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]

History[edit]

Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]

Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]

The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]

References

  1. Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ https://clinicaltrials.gov/ct2/show/NCT01868997
  3. ^ http://adisinsight.springer.com/drugs/800015801
  4. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  5. ^ http://adisinsight.springer.com/drugs/800015801
  6. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  7. ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”The New England Journal of Medicine376 (18): 1748–1761. doi:10.1056/NEJMoa1614949PMC 5718164PMID 28467880.
  8. ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”Horizon Pharma plc. Retrieved 22 March 2019.
  9. ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”Horizon Therapeutics plc. Retrieved 27 August 2019.

External links

Teprotumumab
Monoclonal antibody
Type Whole antibody
Source Human
Target IGF-1R
Clinical data
Other names teprotumumab-trbw, RG-1507
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard 100.081.384 Edit this at Wikidata
Chemical and physical data
Formula C6476H10012N1748O2000S40
Molar mass 145.6 kg/mol g·mol−1

/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza,  Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS,  active thyroid eye disease, Teprotumumab

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease

%d bloggers like this: