What next for developers seeking to emulate Zydelig?

When Gilead’s Zydelig bombed commercially the writing was pretty much on the wall for PI3K inhibitors in haematological cancers, and yet the class continued to attract biotech dollars. So yesterday’s US adcom vote – 16 to none in favour of randomised data and against accelerated approvals based on uncontrolled trials – is another black mark against this approach, now widely recognised as being toxic. Some PI3K developers already saw this coming: Incyte discontinued parsaclisib, MEI Pharma’s zandelisib was hit by an FDA request for a phase 3 study, while TG Therapeutics’ Ukoniq was pulled from the market. What about the remaining PI3K assets in haematology? Zydelig remains marketed in its fully approved indication, as does Verastem’s Copiktra. Bayer’s Aliqopa clings on to an accelerated green light, its future resting on September's outcome of the confirmatory Chronos-4 trial. As for development-stage projects, Hutchmed’s amdizalisib, Shanghai Yingli's linperlisib and Rhizen’s tenalisib must surely now be considered no hopers, given that their ongoing lymphoma studies are uncontrolled. Some will also see in this class review another example of the FDA tightening its stance in general, though a recent Vantage analysis found that accelerated approvals were being converted increasingly quickly.

Selected PI3K inhibitors in haematological cancers
Company Project Pharmacology Indication Status
Gilead Sciences  Zydelig PI3K delta  2nd-line CLL (Rituxan combo) Full approval Jul 2014, PFS benefit vs Rituxan
3rd-line FL & SLL Accelerated approval Jul 2014; withdrawn Jan 2022
Bayer  Aliqopa Pan-PI3K 3rd-line FL Accelerated approval Sep 2017; confirmatory Chronos-4 trial reads out Sep 2022
2nd-line indolent NHL (Rituxan combo) Filed May 2021, withdrawn Dec 2021
Verastem (ex Infinity) Copiktra PI3K delta & gamma 3rd-line CLL & SLL Full approval Sep 2018, PFS benefit vs Arzerra
3rd-line FL Accelerated approval Sep 2018, withdrawn Dec 2021
TG Therapeutics (ex Rhizen) Ukoniq PI3K delta  2nd-line MZL & 4th-line FL  Accelerated approval Feb 2021, withdrawn Apr 2022
Incyte  Parsaclisib PI3K delta  3rd-line+ FL & others Discontinued Jan 2022
Phase 3
MEI Pharma/ Kyowa Kirin Zandelisib PI3K delta  3rd-line+ FL FDA "discouraged" accelerated approval filing in Mar 2022; randomised Coastal trial reads out 2024
Phase 2
Rhizen Pharmaceuticals Tenalisib PI3K delta & gamma PTCL (chemo combo) Uncontrolled study; NHL trials completed, cHL terminated
Hutchmed Amdizalisib PI3K delta r/r MZL & FL Uncontrolled study
Shanghai Yingli Linperlisib PI3K delta  T/NK cell lymphoma Uncontrolled study
Phase 1
Beigene BGB-10188 PI3K delta B-cell cancers Early trial of monoRx or combos
Ionctura IOA-244 PI3K delta NHL Early trial of monoRx or chemo combo
Acerta (Astrazeneca) ACP-319 PI3K delta NHL (Calquence combo) Not in Astra's pipeline
Karus Therapeutics KA2237 PI3K beta & delta B-cell cancers Under review by potential Chinese licensor; financial compensation "modest"
FL=follicular lymphoma; MZL=marginal zone lymphoma; SLL=small lymphocytic leukaemia. CLL=chronic lymphoblastic leukaemia; NHL=non-Hodgkin's lymphoma; PTCL=peripheral T-cell lymphoma. Source: Evaluate Pharma & company communications.

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