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Home » EU PIPELINE » Oral Anti-Cancer Therapy Pomalidomide Now Approved by European Commission as Treatment for Patients with Relapsed/Refractory Multiple Myeloma – a Rare Form of Blood Cancer

Oral Anti-Cancer Therapy Pomalidomide Now Approved by European Commission as Treatment for Patients with Relapsed/Refractory Multiple Myeloma – a Rare Form of Blood Cancer

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POMALIDOMIDE

4-amino-2-(2,6-dixopiperidin-3- yl)isoindoline-l,3-dione; 3-(4-amino-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione; 3-(4-amino-l ,3-dioxoisoindolin-2-yl)piperidine-2,6-dione; 1 ,3-dioxo-2-(2,6- dioxopiperidin-3-yl)-4-aminoisoindoline; 3-(l,3-dioxo-4-aminoisoindolin-2-yl)- piperidine-2,6-dione;

BOUDRY, Switzerland–(BUSINESS WIRE)–Aug. 9, 2013–Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG) today announced that the European Commission (EC) has granted approval for Pomalidomide Celgene®▼(pomalidomide),

in combination with dexamethasone, for the treatment of relapsed and refractory multiple myeloma (rrMM) in adult patients who have received at least two prior therapies including both lenalidomide and bortezomib and have demonstrated disease progression on the last therapy.1 Celgene intends to launch Pomalidomide Celgene in the EU under the trade name “IMNOVID®”, following submission of a regulatory notification to the European Medicines Agency (EMA) to change the trade name.

READ ALL AT

http://www.pharmalive.com/ec-approves-celgene-blood-cancer-drug

CAS 19171-19-8

Pomalidomide, an analogue of thalidomide, is an immunomodulatory antineoplastic agent. FDA approved on February 8, 2013.

Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Pomalidomide (INN, originally CC-4047 or 3-amino-thalidomide, trade name Pomalyst[1] in the US) is a derivative of thalidomidemarketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[2] It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand nameImnovid.[3]

Origin and development

The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[4] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[5] Further structure activity studies done in Dr. Robert D’Amato’s lab at Boston Children’s Hospital led to the first claim in 1995 that amino-thalidomide had antitumor activity.[6] Interestingly, the pronounced anti-tumor activity is due to its ability to directly inhibit both the tumor cell and vascular compartments of myeloma cancers.[7] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[8]

Clinical trials

Phase I trial results showed tolerable side effects.[9]

Phase II clinical trials for multiple myeloma and myelofibrosis reported ‘promising results’.[10][11]

Phase III results were reported at ASH in 2012 and showed significant extension of progression-free survival (median 3.6 months vs. 1.8 months; P < 0.001), and overall survival in patients taking pomalidomide and dexamethasone v. dexamethasone alone.[12]

Mechanism

Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual effect is central to its activity in myeloma, rather than other pathways such as TNF alpha inhibition, since potent TNF alpha inhibitors including rolipram and pentoxifylline do not inhibit myeloma cell growth nor angiogenesis.[7] Up regulation of Interferon gamma, IL-2 and IL-10 as well as down regulation of IL-6 have been reported for pomalidomide. These changes may contribute to pomalidomide’s anti-angiogenic and anti-myeloma activities.

Pregnancy and sexual contact warnings

Because Pomalyst can cause harm to unborn babies when administered during pregnancy, women taking Pomalyst must not become pregnant. Women must produce two negative pregnancy tests and use contraception methods before beginning Pomalyst. Women must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Pomalyst, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalyst therapy. Pomalyst is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing Pomalyst, even if they have undergone a successful vasectomy. Male patients taking Pomalyst must not donate sperm.

Pomalidomide simple structure, synthesis is relatively easy. The glutamine ( 1 ), the compound 2 protected amino, thionyl chloride to ring palladium on carbon hydrogenation later deprotected to give compound 3 , 3 , and 4 direct condensation Pomalidomide.

PATENTS

Thumb

US PATENT No Patent ExpirY patent use code
5635517 Jul 24, 2016 U-1359
6045501 Aug 28, 2018 U-1361
6315720 Oct 23, 2020 U-1361
6316471 Aug 10, 2016 U-1360
6476052 Jul 24, 2016 U-1360
6561976 Aug 28, 2018 U-1361
6561977 Oct 23, 2020 U-1361
6755784 Oct 23, 2020 U-1361
6908432 Aug 28, 2018 U-1361
8158653 Aug 10, 2016
8198262 Oct 19, 2024 U-1360
8204763 Aug 28, 2018 U-1361
8315886 Oct 23, 2020 U-1361
Exclusivity Code Exclusivity Date
ODE Feb 8, 2020
NCE Feb 8, 2018

Pomalidomide-2013, FDA approved anticancer drugs. Pomalidomide isthalidomide (thalidomide) derivative, for the treatment of multiple myeloma. Trade name Pomalyst, developed by Celgene.

    Pomalidomide simple structure, synthesis is relatively easy. (From glutamine 1 ), the compound 2 is protected amino, thionyl chloride off ring after deprotection to obtain a compound with palladium on carbon hydrogenation of 3 , 3 and 4 the direct condensation Pomalidomide.

……………………..

http://www.google.com/patents/WO2012177678A2?cl=en

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Figure 1: Chronological view of the history of thalidomide and its analogs

Pomalidomide
Pomalidomide2DACS.svg
Systematic (IUPAC) name
4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Clinical data
Trade names Imnovid, Pomalyst
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Protein binding 12–44%
Metabolism Hepatic (mostly CYP1A2 andCYP3A4 mediated; some minor contributions by CYP2C19 andCYP2D6)
Half-life 7.5 hours
Excretion Urine (73%), faeces (15%)
Identifiers
CAS number 19171-19-8 Yes
ATC code L04AX06
PubChem CID 134780
Chemical data
Formula C13H11N3O4 
Mol. mass 273.24 g/mol

Mechanism of action

Figure 2: The mechanism of TLP in multiple myeloma. TLP refers to thalidomide, lenalidomide and pomalidomide.

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09338-acsnews1-celgenecxd
HONORED
Celgene’s George Muller (left) and Roger Shen-Chu Chen celebrate at the Heroes of Chemistry banquet.
Credit: Linda Wang/C&EN

The satisfaction of helping patients is what drives George Muller as an industrial scientist. Muller is coinventor of Celgene’s Polamyst for multiple myeloma.

“It’s wonderful to be able to think that the work one did in the lab ended up helping patients,” he says. “Over my career, I’ve met patients who were taking drugs on which I had worked. It’s always amazing to see the positive effects on the lives of these patients. Some of them get their lives back.”

Muller says that during the course of developing Pomalyst, they made hundreds of compounds. “We worked on the project for probably 15-plus years,” he says. The drug was approved in 2014.

References

  1. “Pomalyst (Pomalidomide) Official Website”. Celgene Corporation. Retrieved 2013-08-10.
  2. “Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
  3. “Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
  4.  D’Amato, Robert J.; Loughnan, Michael S.; Flynn, Evelyn; Folkman, Judah (1994). “Thalidomide is an inhibitor of angiogenesis”. Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–5. Bibcode:1994PNAS…91.4082D. doi:10.1073/pnas.91.9.4082. JSTOR 2364596. PMC 43727. PMID 7513432.
  5.  http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/
  6.  http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=5,712,291.PN.&OS=PN/5,712,291&RS=PN/5,712,291
  7.  D’Amato, R; Lentzsch, S; Anderson, KC; Rogers, MS (2001). “Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma”. Seminars in Oncology 28 (6): 597–601. doi:10.1016/S0093-7754(01)90031-4. PMID 11740816.
  8.  Lentzsch, S; Rogers, MS; Leblanc, R; Birsner, AE; Shah, JH; Treston, AM; Anderson, KC; D’Amato, RJ (2002). “S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice”. Cancer Research 62 (8): 2300–5. PMID 11956087.
  9.  Streetly, Matthew J.; Gyertson, Kylie; Daniel, Yvonne; Zeldis, Jerome B.; Kazmi, Majid; Schey, Stephen A. (2008). “Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation”. British Journal of Haematology 141 (1): 41–51. doi:10.1111/j.1365-2141.2008.07013.x. PMID 18324965.
  10. Jump up^ “Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH” (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
  11. Jump up^ Tefferi, Ayalew (December 8, 2008). “Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study”. 50th ASH Annual Meeting and Exposition. San Francisco. Retrieved October 28, 2012.
  12. Jump up^ “Phase III Study (MM-003) of Pomalidomide Plus Low-Dose Dexamethasone Demonstrates Significant Progression-Free and Overall Survival Improvement for Patients with Relapsed or Refractory Multiple Myeloma.”. 11 Dec 2012.

External links

POMALYST is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3dione and it has the following chemical structure:

POMALYST® (pomalidomide) Structural Formula Illustration

The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.

Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.

POMALYST is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch and sodium stearyl fumarate. The 1 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink. The 2 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3 and white ink. The 3 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide and white ink. The 4 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2 and white ink.

NDA 204026

APPR..2013-02-08

Dosages/Routes/Forms

Celgene

Dosages/Routes/Forms
Strength Form/Route Marketing Status
1MG CAPSULE;ORAL 1
2MG CAPSULE;ORAL 1
3MG CAPSULE;ORAL 1
4MG CAPSULE;ORAL 1

Approval History

2014-09-12
Labeling Revision
2014-03-13
Labeling Revision
2013-11-15
Efficacy Supplement with Clinical Data to Support
2013-10-03
Manufacturing Change or Addition

5 Comments

  1. medchemnintabelle says:

    Reblogged this on MedCheminAustralia.

  2. arifmohammad says:

    What are the Adverse Reactions that may be chances with this drug

    Can you send to me

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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