Springworks sees the way to a small market niche

Nirogacestat, a gamma secretase inhibitor Pfizer discarded five years ago, today gave Springworks a pivotal clinical trial win. In the phase 3 DeFi study in desmoid tumours nirogacestat beat placebo on the primary endpoint of progression-free survival, Springworks said, as well as meeting “all key” secondaries, setting the asset up for US filing later this year. Still, desmoid tumours are rare, slow growing and benign, and while Springworks argues that they cause pain and morbidity they likely do not translate into a major market opportunity. Moreover, nirogacestat has just three years’ patent life, and at least in desmoid tumours, which have no approved therapy, doctors might choose to give patients Nexavar off label; the Bayer kidney cancer drug has shown a strong PFS benefit in a small academic-run trial in desmoid tumours. Despite nirogacestat’s big opportunity in multiple myeloma, where six different combo studies with BCMA-targeting agents are under way, investors remained wary of the significant risks here, and sent Springworks down 7% this morning. And Ayala Pharmaceuticals, a micro cap biotech that boasts two gamma secretase inhibitors but lacks cash, slumped 20%.

After this story was published Springworks pointed out that it is clinically studying nirogacestat's polymorphc form, which has composition patent coverage until 2039.

Selected gamma secretase inhibitors in oncology
Project Company Clinical trial Detail
(ex Pfizer)
DeFi (ph3) Desmoid tumours, vs placebo
NCT05090566 (ph2) Multiple myeloma combo with Pfizer's elranatamab
Dreamm-5 (ph1/2) Multiple myeloma combo with GSK's Blenrep
NCT04171843 (ph1/2) Multiple myeloma combo with Precision's PBCAR269A
NCT04722146 (ph1) Multiple myeloma combo with J&J's teclistamab 
Universal (ph1) Multiple myeloma combo with Allogene's ALLO-715 
NCT05259839 (ph1) Multiple myeloma combo with Abbvie's ABBV-383
None yet started Multiple myeloma combo with Regeneron's REGN5458
None yet started Multiple myeloma combo with Seagen's SEA-BCMA
AL102 (BMS-986115) Ayala (ex Bristol Myers Squibb) Ringside (ph2/3) Desmoid tumours, vs placebo
NCT04123418 (ph1) Multiple myeloma combo with Novartis's WVT078
AL101 (BMS-906024) Ayala (ex Bristol Myers Squibb) Accuracy (ph2) Adenoid cystic carcinoma with Notch mutations
Crenigacestat (BMS-986405/ LY3039478) Bristol Myers Squibb (ex Celgene/ Juno/ Lilly) Karmma-7 (ph1/2) Multiple myeloma combo with Abecma
NCT04036461 (ph1) Multiple myeloma combo with CC-99712
Source: clinicaltrials.gov & company statements.

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