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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
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
| 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 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 8198262 | 2013-02-08 | 2024-10-19 |
| United States | 8204763 | 2013-02-08 | 2018-08-28 |
| United States | 8315886 | 2013-02-08 | 2020-10-23 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 5635517 | 2013-02-08 | 2016-07-24 |
| United States | 6045501 | 2013-02-08 | 2018-08-28 |
| United States | 6315720 | 2013-02-08 | 2020-10-23 |
| United States | 6316471 | 2013-02-08 | 2016-08-10 |
| United States | 6476052 | 2013-02-08 | 2016-07-24 |
| United States | 6561976 | 2013-02-08 | 2018-08-28 |
| United States | 6561977 | 2013-02-08 | 2020-10-23 |
| United States | 6755784 | 2013-02-08 | 2020-10-23 |
| United States | 6908432 | 2013-02-08 | 2018-08-28 |
| United States | 8158653 | 2013-02-08 | 2016-08-10 |
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.
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http://www.google.com/patents/WO2012177678A2?cl=en
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Figure 1: Chronological view of the history of thalidomide and its analogs
 |
|
| 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  |
| ATC code | L04AX06 |
| PubChem | CID 134780 |
| Chemical data | |
| Formula | C13H11N3O4 |
| Mol. mass | 273.24 g/mol |
Figure 2: The mechanism of TLP in multiple myeloma. TLP refers to thalidomide, lenalidomide and pomalidomide.
CLIP
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
- “Pomalyst (Pomalidomide) Official Website”. Celgene Corporation. Retrieved 2013-08-10.
- “Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- “Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- 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.
- http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/
- 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
- 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.
- 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.
- 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.
- Jump up^ “Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH” (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
- 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.
- 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:
 |
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
| Strength | Form/Route | Marketing Status | RLD | TE Code |
|---|---|---|---|---|
| 1MG | CAPSULE;ORAL | 1 | 0 | |
| 2MG | CAPSULE;ORAL | 1 | 0 | |
| 3MG | CAPSULE;ORAL | 1 | 0 | |
| 4MG | CAPSULE;ORAL | 1 | 1 |
Approval History
2013-10-03
001
Manufacturing Change or Addition
FDA Approves Pomalyst for Advanced Multiple Myeloma – February 8, 2013
Pomalyst (pomalidomide) Capsules
Company: Celgene Corporation
Date of Approval: February 8, 2013
Treatment for: Multiple Myeloma
Pomalyst (pomalidomide) is a thalidomide analogue indicated for the treatment of patients with multiple myeloma.
The U.S. Food and Drug Administration today approved Pomalyst (pomalidomide) to treat patients with multiple myeloma whose disease progressed after being treated with other cancer drugs.
Multiple myeloma is a form of blood cancer that primarily affects older adults and arises from plasma cells in the bone marrow. According to the National Cancer Institute, approximately 21,700 Americans are diagnosed with multiple myeloma and 10,710 die yearly from the disease.
Pomalyst is a pill that modulates the body’s immune system to destroy cancerous cells and inhibit their growth. It is intended for patients who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease did not respond to treatment and progressed within 60 days of the last treatment (relapsed and refractory).
“Pomalyst is the third drug in a class of immunomodulatory agents that includes lenalidomide and thalidomide, and is the second drug approved in the past year to treat multiple myeloma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “Treatment for multiple myeloma is tailored to meet individual patient’s needs, and today’s approval provides an additional treatment option for patients who have not responded to other drugs.”
- FDA Approves Pomalyst for Advanced Multiple Myeloma – February 8, 2013
- Celgene Corporation Provides Update on FDA Advisory Committee for Pomalidomide – October 3, 2012
- The International Myeloma Foundation Says Pomalidomide, an Important New Drug for Patients, Has Been Submitted for FDA Approval – April 27, 2012
pomalidomide. 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione
Pomalidomide (INN, originally CC-4047 or 3-amino-thalidomide, marketed as Pomalyst by Celgene), is a derivative of thalidomide that is anti-angiogenic and also acts as an immunomodulator. Pomalidomide was approved on February 8, 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[1] An application for approval to treat multiple myeloma also has been submitted by Celgene to the European Medicines Agency, and a decision on that application is expected by the second half of 2013.[1]
Origin and development
The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[2] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma. Further structure activity studies done in Dr. Robert D’Amato’s lab at Boston Children’s Hospital led to the first report in 2001[3] that 3-amino-thalidomide was able to directly inhibit both the tumor cell and vascular compartments of myeloma cancers. This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[4]
Clinical trials
Phase I trial results showed tolerable side effects.[5]
Phase II clinical trials for multiple myeloma and myelofibrosis reported ‘promising results’.[6][7]
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.[8]
- “Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-02-08.
- 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.
- 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.
- 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.
- 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.
- “Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH” (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
- 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.
- “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.
- This new drug is specifically indicated for patients who have received at least 2 prior therapies, including lenalidomide (Revlimid, Celgene) and bortezomib (Velcade, Millennium Pharmaceuticals), and whose disease did not respond to treatment and progressed within 60 days of the last treatment.
New Drug Approvals 