Ridaforolimus

Short description: Chemical compound

Ridaforolimus

Clinical data
ATC code|

* L01EG03 (WHO)

Identifiers

IUPAC name

* (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate

CAS Number|

* 572924-54-0 Y

PubChem CID|

* 11520894

IUPHAR/BPS|

* 7884

ChemSpider|

* 24597928 Y

UNII|

* 48Z35KB15K

ChEBI|

* CHEBI:82677 N

ChEMBL|

* ChEMBL2103804 N

Chemical and physical data
Formula| C53H84NO14P
Molar mass| 990.222 g·mol−1
3D model (JSmol)|

* Interactive image

SMILES

* CC1CCC2CC(/C(=C/C=C/C=C/C(CC(C(=O)C(C(/C(=C/C(C(=O)CC(OC(=O)C3CCCCN3C(=O)C(=O)C1(O2)O)C(C)CC4CCC(C(C4)OC)OP(=O)(C)C)C)/C)O)OC)C)C)/C)OC

InChI

* InChI=1S/C53H84NO14P/c1-32-18-14-13-15-19-33(2)44(63-8)30-40-23-21-38(7)53(61,67-40)50(58)51(59)54-25-17-16-20-41(54)52(60)66-45(35(4)28-39-22-24-43(46(29-39)64-9)68-69(11,12)62)31-42(55)34(3)27-37(6)48(57)49(65-10)47(56)36(5)26-32/h13-15,18-19,27,32,34-36,38-41,43-46,48-49,57,61H,16-17,20-26,28-31H2,1-12H3/b15-13+,18-14+,33-19+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 Y

* Key:BUROJSBIWGDYCN-GAUTUEMISA-N Y

NY (what is this?) (verify)

Ridaforolimus (also known as AP23573 and MK-8669; formerly known as deforolimus[1]) is an investigational targeted and small-molecule inhibitor of the protein mTOR, a protein that acts as a central regulator of protein synthesis, cell proliferation, cell cycle progression and cell survival, integrating signals from proteins, such as PI3K, AKT and PTEN known to be important to malignancy. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis.[2]

It has had promising results in a clinical trial for advanced soft tissue and bone sarcoma.

## Contents

* 1 Commercial arrangements
* 2 Clinical trials
* 2.1 Phase III SUCCEED
* 3 See also
* 4 References
* 5 External links

## Commercial arrangements

Ridaforolimus is being co-developed by Merck and ARIAD Pharmaceuticals. On May 5, 2010, Ariad Pharmaceuticals and Merck & Company announced a clinical development and marketing agreement. With this agreement, Ariad received $125 million in upfront payments from Merck and $53 million in milestone payments. Future payments are triggered upon acceptance of the NDA by the FDA with another payment when the drug receives marketing approval. There are similar milestones for acceptance and approval in both Europe and Japan . Other milestone payments are tied to revenue goals for the drug.[3] ARIAD has opted to co-promote ridaforolimus in the U.S. Merck plans to submit a New Drug Application (NDA) for ridaforolimus to the U.S. Food and Drug Administration (FDA) and a marketing application in the European Union in 2011.[4] After formal rejection by the FDA in June 2012 ARIAD/MSD decided to withdraw their EMA application for Ridaforolimus in November 2012. [5]

## Clinical trials

### Phase III SUCCEED

On June 6, 2011, Ariad and Merck announced detailed results from the largest randomized study ever in the soft tissue and bone sarcoma population, the Phase III SUCCEED clinical trial. SUCCEED evaluated oral ridaforolimus, in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy. In this patient population, ridaforolimus improved progression-free survival (PFS) compared to placebo, the primary endpoint of the study. The complete study results were presented by Sant P. Chawla, M.D., director, Sarcoma Oncology Center, Santa Monica, CA, during the 2011 American Society of Clinical Oncology (ASCO) annual meeting.
The SUCCEED (Sarcoma Multi-Center Clinical Evaluation of the Efficacy of Ridaforolimus) trial was a randomized (1:1), placebo-controlled, double-blind study of oral ridaforolimus administered at 40 mg/day (five of seven days per week) in patients with metastatic soft-tissue or bone sarcomas who previously had a favorable response to chemotherapy. Oral ridaforolimus was granted a Special Protocol Assessment (SPA) by the FDA for the SUCCEED trial.
Based on 552 progression-free survival (PFS) events in 711 patients, (ridaforolimus (N=347), placebo (N=364) determined by an independent radiological review committee, the study achieved its primary endpoint of improvement in PFS, with a statistically significant (p=0.0001) 28 percent reduction in the risk of progression or death observed in those treated with ridaforolimus compared to placebo (hazard ratio=0.72). Median PFS was 17.7 weeks for those treated with ridaforolimus compared to 14.6 weeks in the placebo group. Furthermore, based on the full analysis of PFS determined by investigator assessment, there was a statistically significant (p<0.0001) 31 percent reduction by ridaforolimus in the risk of progression or death compared to placebo (hazard ratio=0.69). In the investigator assessment analysis, median PFS was 22.4 weeks for those treated with ridaforolimus compared to 14.7 weeks in the placebo group [6]

## See also

* Discovery and development of mTOR inhibitors

## References

1. ↑ "ARIAD Reports First Quarter 2009 Development Progress and Financial Results- Ridaforolimus New USAN Name to Replace Deforolimus". ARIAD Pharmaceuticals. 2009. http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1285640&highlight=.
2. ↑ "Ridaforolimus in advanced or metastatic soft tissue and bone sarcomas". Expert Review of Clinical Pharmacology 6 (5): 465–82. September 2013. doi:10.1586/17512433.2013.827397. PMID 23971829.
3. ↑ "ARIAD - News release". Phx.corporate-ir.net. http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1422441&highlight=.
4. ↑ "ARIAD - News release". Phx.corporate-ir.net. 2011-03-17. http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1540185&highlight=co-promote.
5. ↑ "UKMi New Drugs Online". http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4988.
6. ↑ "ARIAD - News release". Phx.corporate-ir.net. 2011-06-06. http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1570938&highlight=.

## External links

* ARIAD Pharmaceuticals

* v
* t
* e

Immunosuppressive drugs / Immunosuppressants (L04)

Intracellular
(initiation)|

| Antimetabolites|

* purine synthesis inhibitors
* Azathioprine
* Mycophenolic acid

* pyrimidine synthesis inhibitors
* Leflunomide
* Teriflunomide

* antifolate
* Methotrexate

|

Macrolides/
other IL-2 inhibitors|

* FKBP/Cyclophilin/Calcineurin
* Tacrolimus
* Ciclosporin
* Pimecrolimus

* Abetimus
* Gusperimus

IMiDs|

* Lenalidomide
* Pomalidomide
* Thalidomide
* PDE4 inhibitor
* Apremilast

Intracellular
(reception)|

| IL-1 receptor antagonists|

* Anakinra

|

mTOR|

* Sirolimus
* Everolimus
* Ridaforolimus
* Temsirolimus
* Umirolimus
* Zotarolimus

Extracellular|

| Antibodies|

| Monoclonal|

| Serum target
(noncellular)|

* Complement component 5
* Eculizumab
* TNF
* Adalimumab
* Afelimomab
* Certolizumab pegol
* Golimumab
* Infliximab
* Nerelimomab
* Interleukin 5
* Mepolizumab
* Immunoglobulin E
* Omalizumab

* Interferon
* Faralimomab

* IL-6
* Elsilimomab

* IL-12 and IL-23
* Lebrikizumab
* Ustekinumab

* IL-17A
* Secukinumab

|

Cellular target|

* CD3
* Muromonab-CD3
* Otelixizumab
* Teplizumab
* Visilizumab
* CD4
* Clenoliximab
* Keliximab
* Zanolimumab
* CD11a
* Efalizumab
* CD18
* Erlizumab
* CD20
* Obinutuzumab
* Rituximab
* Ocrelizumab
* Pascolizumab
* CD23
* Gomiliximab
* Lumiliximab
* CD40
* Teneliximab
* Toralizumab
* CD62L/L-selectin
* Aselizumab
* CD80
* Galiximab
* CD147/Basigin
* Gavilimomab
* CD154
* Ruplizumab

* BLyS
* Belimumab
* Blisibimod
* CTLA-4
* Ipilimumab
* Tremelimumab
* CAT
* Bertilimumab
* Lerdelimumab
* Metelimumab
* Integrin
* Natalizumab
* Vedolizumab
* Interleukin-6 receptor
* Tocilizumab
* LFA-1
* Odulimomab

* IL-2 receptor/CD25
* Basiliximab
* Daclizumab
* Inolimomab

* T-lymphocyte (Zolimomab aritox)

Unsorted|

* Atorolimumab
* Cedelizumab
* Fontolizumab
* Maslimomab
* Morolimumab
* Pexelizumab
* Reslizumab
* Rovelizumab
* Siplizumab
* Talizumab
* Telimomab aritox
* Vapaliximab
* Vepalimomab

Polyclonal|

* Anti-thymocyte globulin
* Anti-lymphocyte globulin

-cept (Fusion)|

* CTLA-4
* Abatacept
* Belatacept
* TNF inhibitor
* Etanercept
* Pegsunercept
* Aflibercept
* Alefacept
* Rilonacept

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