Duvelisib

Mechanism of action

It is a Phosphoinositide 3-kinase inhibitor, specifically of the delta and gamma isoforms of PI3K. 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.

History

Duvelisib, also known as IPI-145, was discovered by Intellikine, 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. 33 patents have been granted that are related to the drug duvelisib belonging to various pharmaceutical companies including Infinity, Novartis, and Intellikine.

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.

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

During 2012 and 2013, INFI 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 stated they would be focusing efforts on two drugs, one of which being Duvelisib.

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

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 for an FDA approval, and royalties.

Hematological malignancies

In 2011, INFI announced that two phase I clinical trials would be started to explore duvelisib's effect on hematologic cancers. In July 2012, the phase I clinical trial was expanded and two phase II trials were planned.

In late July 2014, Gilead's competing drug idelalisib became the first PI3K inhibitor to be approved by the FDA. 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.

In mid-June 2016, INFI announced results of Phase II clinical trial of duvelisib that hit its endpoints but was no better than competing drugs. At the end of the month, Abbvie terminated the collaboration, leading INFI to cut 58% of its staff.

As of January 2017 two phase III clinical trials were active but not recruiting, one was recruiting, and one had been withdrawn and a phase II trial for refractory indolent non-Hodgkin lymphoma was ongoing.

Inflammatory conditions

Phase II clinical trials have evaluated duvelisib for efficacy in treatment of diseases such as rheumatoid arthritis and asthma.