Approval milestones – Hutchmed, SpringWorks, Crispr and Ionis eye firsts

With the fourth quarter of 2023 nearly here, several key first approval verdicts loom for developers of drugs in oncology and related haematology indications. Such catalysts will fall at a time when the FDA is struggling with its workload, a fact that has recently delayed several regulatory decisions. 

Among the first approvals, perhaps the most keenly awaited is that of Crispr/Vertex’s exa-cel, an ex vivo treatment for sickle cell disease that could become the first ever US-approved Crispr-edited therapy. Behind exa-cel come several projects for niche uses, plus further approvals for a range of anti-PD-(L)1 MAbs.

In targeted therapy Bristol Myers Squibb awaits first approval of repotrectinib, acquired along with Turning Point for $4.1bn, amid questions over its addressable market size. Similar questions face SpringWorks’ nirogacestat in desmoid tumours, over a filing whose action date was delayed by three months after the FDA required more time to review additional data.

Astellas’s zolbetuximab could become the first ever Claudin18.2-targeting therapy to be approved, though testing for Claudin18.2 positivity, a setting in which both the project’s registrational trials were conducted, is not yet standard.

Meanwhile, AstraZeneca’s capivasertib could become the first approved AKT inhibitor, a blow for Roche, which has effectively written off its rival, ipatasertib. And Hutchmed/Takeda want first US approval for fruquintinib, a drug already sold in China.

Possible first US approvals awaited in 2023

Other drugs already available in China and seeking US green lights include the anti-PD-(L)1 MAbs toripalimab, tislelizumab and penpulimab, and the subcutaneously delivered benegrastim for chemotherapy-induced neutropenia in breast cancer.

US approvals of the three PD-(L)1s have been long delayed by Covid-related travel restrictions in China, and the acceptability of data generated outside the US remains an open question. Today Coherus said the FDA had now completed three inspections of toripalimab clinical trial sites in China, raising one “observation”; the group expects approval by the end of the year.

Meanwhile, Astrellas/Pfizer’s Xtandi could become the first anti-androgen approved in four separate prostate cancer settings. It has an established use in castrate-resistant metastatic disease, while the Arches and Prosper studies back approvals in hormone-sensitive and non-metastatic settings respectively; an FDA verdict on the Embark study, backing non-metastatic hormone-sensitive prostate cancer, is due in the fourth quarter.

There will be a showdown for BCMA-directed Car-T therapies, as Carvykti and Abecma seek approval in multiple myeloma use earlier than their current salvage setting of fifth line or later; the Cartitude-4 study tested Carvykti in second to fourth-line multiple myeloma, while Karmma-3 was designed to back Abecma’s use in third to fifth-line disease.

Investors will also be mindful of advisory committee meetings that could inform the approvability of two key projects. One concerns Crispr/Vertex’s exa-cel – understandable given the novelty of this therapy.

The other concerns Lumakras, the Amgen KRAS G12C inhibitor already approved on an accelerated basis, whose 5 October adcom will discuss whether this can be converted into a full green light. Notably, the supporting Codebreak-200 trial showed liver toxicity and underwhelming efficacy, and it’s possible that the FDA will ask for a second confirmatory study, of a lower dose.

Selected additional and other US approvals awaited in 2023