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.
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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 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. It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand nameImnovid.
Origin and development
The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994. 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 claim in 1995 that amino-thalidomide had antitumor activity. Interestingly, the pronounced anti-tumor activity is due to its ability 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.
Phase I trial results showed tolerable side effects.
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.
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. 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.
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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.
|Systematic (IUPAC) name|
|Trade names||Imnovid, Pomalyst|
|Licence data||EMA: , US FDA:|
|Metabolism||Hepatic (mostly CYP1A2 andCYP3A4 mediated; some minor contributions by CYP2C19 andCYP2D6)|
|Excretion||Urine (73%), faeces (15%)|
|Mol. mass||273.24 g/mol|
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.
- “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.
- 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.
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.
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