ASH: Sanofi uncorks late-stage data for RNAi drug fitusiran in hemophilia, with all eyes on safety profile
Sanofi’s fitusiran has had a rough road in hemophilia, weathering clinical holds and program halts tied to its lingering safety woes. Now, the drug is nearing the finish line with late-stage data in hand, but will those same safety concerns slam the brakes on the program despite its deliriously effective results?
Fitusiran, an RNAi drug designed to silence the gene that overproduces a protein responsible for clotting suppression, significantly reduced the annualized rate of bleeding over on-demand factor therapy in hemophilia A/B patients without preexisting factor inhibitors in the blood, according to late-breaking data presented Tuesday at #ASH21.
Fitusiran cut patients’ ARB rate by 89% over control, proving a powerful prophylactic for bleeding episodes as a once-monthly injection. In this Phase III study, dubbed ATLAS-A/B, 50.6% of patients treated with fitusiran had zero treated bleeds during the study compared with just 5% of patients in the on-demand arm.
These data are a longtime coming for fitusiran, originally an Alnylam candidate that has previously run into brick walls at the FDA due to its safety profile, particularly a troubling rate of thromboembolism and increased levels of a protein tied to liver damage.
In November of last year, Sanofi hit the brakes on its late-stage studies of fitusiran, which includes ATLAS-A/B and a late-stage test in patients with preexisting factor inhibitors dubbed ATLAS-INH, after a new case of thrombosis cropped up. The program faced a clinical hold four years ago on earlier safety worries.
On Tuesday, Sanofi revealed safety data from ATLAS-A/B with 19% of patients in the fitusiran arm reporting abnormally high levels of the ALT and AST proteins. Meanwhile, there were no reported cases of thrombosis.
However, in a separate plenary session this weekend, Sanofi reported updated results from ATLAS-INH showing 24.4% of patients in the study had abnormally high levels of ALT/AST and two patients presented suspected or confirmed thrombosis. In that study, fitusiran also cut ARB by 89% compared with on-demand bypass therapy control.
Sanofi has gone out of its way to portray those thrombosis events as an expected if undesired side effect of fitusiran’s use, with head of clinical development Dietmar Berger describing the drugmaker’s goal of hitting a sweet spot with dosing on an Endpoints News webinar Monday.
Indeed, Sanofi is flirting with the possibility of amending its trial protocol to include lower doses than the 80mg administered in these studies as well as potentially trying out a once-every-two-month prophylactic schedule.
Fitusiran is one of a group of next-gen therapies looking for breakthroughs in hemophilia, alongside investigational gene therapies from companies like BioMarin, uniQure and bluebird bio, as well as emerging bispecific antibodies among other attempts.
Several days ago, uniQure and partner CSL announced they would file gene therapy etranacogene dezaparvovec with the FDA after a late-stage test compared favorably with Factor IX prophylaxis in hemophilia B.