Duvelisib

Duvelisib
Clinical data
Synonyms IPI-145
Routes of
administration		 PO
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C22H17ClN6O
Molar mass 416.86 g/mol
3D model (JSmol)

Duvelisib (INN,[1] previously known as IPI-145) is a dual inhibitor of PI3Kδ and PI3Kγ,[2] in development as a treatment for hematologic malignancies as well as a broad range of inflammatory conditions.[3] The phosphoinositide 3-kinases are involved in cell proliferation and differentiation and have significant potential in hematology fields and inflammatory disease treatments.[2] Ibrutinib and acalabrutinib are other inhibitors that are being used or researched for similar treatments.

Mechanism of action

It is a Phosphoinositide 3-kinase inhibitor, specifically of the delta and gamma isoforms of PI3K.[4] This class of compounds works by preventing PI3K from playing its role in tranducing signals from outside of cells into various intracellular pathways involved in cell cycle regulation, apoptosis, DNA repair, senescence, angiogenesis and cell metabolism, including the PI3K/AKT/mTOR pathway.[4]

History

Duvelisib, also known as IPI-145, was discovered by Intellikine,[5] a company that had been founded in September 2007 based on biochemistry research from the lab of Kevan Shokat at the University of California San Francisco.[6]

In 2010, Intellikine licensed its portfolio of PI3K inhibitors to Infinity Pharmaceuticals (INFI) for $13.5 million upfront, $475 million in milestones, two years of research funding, and royalties; the deal included a right for Intellikine to give up its royalties in exchange for sharing profits and costs.[7]

In 2011, Infinity started two phase I clinical trials.[3]

At the end of 2011, Takeda Pharmaceuticals, through its Millennium Pharmaceuticals subsidiary, acquired Intellikine, making it the licensor for Infinity.[6]

During 2012 and 2013, Infinity experienced financial difficulties after clinical data for their drug Saridegib showed results demonstrating little effectiveness in treating bone marrow malignancies. As a result, the company reduced their portfolio to two drugs candidates, one of which was duvelisib.[8]

Two months later, Infinity and Takeda amended their license agreement, and Infinity paid $5M for the right to buy out its royalty payment obligations to Takeda for a one-time payment of $52.5 million.[9] A few days later, Infinity entered into a collaboration with AbbVie to develop and commercialize duvelisib in which Infinity received a $275 million upfront payment from AbbVie, with more promised at later stages of development.[10]

In late July 2014, Gilead's competing drug idelalisib became the first PI3K inhibitor to be approved by the FDA.[11] In March 2016, clinical trials of idelalisib were halted due to deaths in the trials, raising questions about the safety of the PI3K inhibitor drug class, and by that time ibrutinib had won approval in the indications being sought for duvelisib and had gained strong market share.[12]

In mid-June 2016, Infinity announced results of Phase II clinical trial of duvelisib.[4][13]

At the end of June, Abbvie terminated the collaboration, leading Infinity to cut 58% of its staff.[14]

In November 2016, Infinity exclusively licensed the worldwide rights to duvelisib to Verastem for little money compared to earlier deals; the deal included no upfront payment, a $6 million milestone for success in a Phase 3 trial in chronic lymphocytic leukemia, a $22 million payment for an FDA approval, and royalties.[12]

See also

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 72" (PDF). World Health Organization. p. 393. Retrieved 16 April 2016.
  2. 1 2 "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". finanznachrichten.de. 31 October 2011.
  3. 1 2 "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
  4. 1 2 3 Anastasia, A; Rossi, G (1 November 2016). "Novel Drugs in Follicular Lymphoma". Mediterranean journal of hematology and infectious diseases. 8 (1): e2016061. doi:10.4084/MJHID.2016.061. PMC 5111511. PMID 27872741.
  5. ↑ "Duvelisib". AdisInsight. Retrieved 11 January 2017.
  6. 1 2 Timmerman, Luke (20 December 2011). "Millennium: Takeda Acquires San Diego's Intellikine for $190M Upfront". Xconomy.
  7. ↑ Carroll, John (Jul 8, 2010). "Infinity inks $488M pact on Intellikine's PI3K portfolio". FierceBiotech.
  8. ↑ Jones, Kristin (2012-06-18). "Market Watch". Retrieved 2016-11-19.
  9. ↑ Carroll, John (September 3, 2014). "AbbVie ties the knot with Infinity in $805M blood cancer collaboration". FierceBiotech.
  10. ↑ Levin, Jennifer (September 3, 2014). "Infinity and AbbVie Announce Global Strategic Collaboration to Develop and Commercialize Duvelisib (IPI-145) In Oncology". FierceBiotech.
  11. ↑ Morrison, C (October 2014). "First PI3k inhibitor launches into crowded hematology markets". Nature Biotechnology. 32 (10): 963–4. doi:10.1038/nbt1014-963. PMID 25299893.
  12. 1 2 Fidler, Ben (2 November 2016). "Verastem Takes a Low-Cost Flier on Infinity's Blood Cancer Drug". Xconomy.
  13. ↑ Carroll, John (June 14, 2016). "Infinity Pharma back under a cloud after duvelisib disappoints in PhII". FierceBiotech.
  14. ↑ Adams, Ben (June 28, 2016). "AbbVie scraps Infinity collab in wake of weak data; biotech slashes jobs". FierceBiotech.
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