Incyte follows Gilead in retreating from PI3K delta

Incyte’s discontinuation of the PI3K delta inhibitor parsaclisib in indolent lymphoma mirrors last week’s move by Gilead to pull from the market some uses of the similarly acting Zydelig. Many will say this had long been coming, and that PI3K delta inhibition in blood cancers is too fraught with toxicity concerns, especially given the rise of BTK inhibition and other novel mechanisms, to make it worthwhile. Still, MEI Pharma and TG Therapeutics will disagree, having placed significant bets on zandelisib and Ukoniq respectively, two PI3K inhibitors with very different target engagement and safety profiles. Zydelig had been plagued with toxicity problems from the start, and remains on the market for chronic lymphocytic leukaemia; Gilead said accelerated approval for indolent lymphomas including follicular lymphoma (FL) had been contingent on confirmatory trials into which it had proved impossible to recruit patients given changes in the competitive landscape. Incyte, meanwhile, had flirted with an intermittent dosing schedule for parsaclisib, but yesterday said it no longer made sense to invest in FL and similar uses; the project remains in development for myelofibrosis. TG’s Ukoniq was recently approved for FL, an indication in which MEI expects to file zandelisib this year.

Clinical-stage PI3K inhibitors with delta subtype specificity in oncology
Project Company Indication focus Note
Zydelig Gilead Approved for CLL Withdrawn for FL & SLL
Ukoniq (umbralisib) TG Therapeutics Approved for FL & MZL Ublituximab combo filed
Phase 3  
Zandelisib/ME-401 MEI Pharma/Kyowa Kirin Indolent lymphoma (Rituxan combo)  Accelerated filing (on ph2 data) due 2022
Parsaclisib Incyte/Innovent Myelofibrosis (Jakafi combo) Discontinued for FL, MZL & MCL
Phase 2  
Amdizalisib (HMPL-689) Hutchmed FL & MZL
Linperlisib/YY-20394 Jiangsu Hengrui/Shanghai Yingli Lymphoma Ex-US (China)
Phase 1  
BGB-10188 Beigene Lymphomas, CLL & solid tumours MonoRx & combos with BTK/PD-1 blockade
ACP-319 Acerta Pharma CLL (Calquence combo) Ph1/2 completed 2020
IOA-244 Ionctura Lymphoma, melanoma & mesothelioma
Source: Evaluate Pharma. CLL=chronic lymphocytic leukaemia; FL=follicular lymphoma; SLL=small lymphocytic leukaemia; MZL=marginal zone lymphoma; MCL=mantle cell lymphoma.

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