
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 |
Marketed | ||||
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3rd-line FL & SLL | Accelerated approval Jul 2014; withdrawn Jan 2022 | |||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2nd-line indolent NHL (Rituxan combo) | Filed May 2021, withdrawn Dec 2021 | |||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3rd-line FL | Accelerated approval Sep 2018, withdrawn Dec 2021 | |||
Withdrawn/discontinued | ||||
TG Therapeutics (ex Rhizen) | Ukoniq | PI3K delta | 2nd-line MZL & 4th-line FL | Accelerated approval Feb 2021, withdrawn Apr 2022 |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. |