Alnylam Hopes To Resume Fitusiran Dosing Quickly, Despite Unclear Cause Of Trial Death

The RNAi pioneer voluntarily suspended dosing of the hemophilia candidate to consider trial protocol alterations after a patient receiving fitusiran in an open-label, Phase II trial died following a thrombosis event.

Less than a year after shuttering its amyloidosis candidate revusiran due to patient deaths in a Phase III trial, Alnylam Pharmaceuticals Inc. announced another setback Sept. 7, saying it was temporarily suspending dosing in ongoing studies of its hemophilia candidate fitusiran because of a patient death in a Phase II trial.

Alnylam said it hopes to restart dosing of fitusiran within three to six months by amending safety protocols in ongoing studies, including the just initiated Phase III trial ATLAS. Nonetheless, investors were dismayed, sending the company's stock down 15.7% to close at $72.53.

After the termination of revusiran last year, several analysts said it suggested little read-through to the rest of Alnylam's pipeline because the drug stemmed from an earlier technology than used in other Alnylam assets. (Also see "Alnylam's 'Day After' Revusiran Failure Bad, Maybe Not Catastrophic" - Scrip, 6 Oct, 2016.) There appear to be mitigating factors around the fitusiran patient death, as well.

During a Sept. 7 investor call, Alnylam executives explained that the patient who died presented symptoms, including severe headache and hip pain due to exercise. Physicians responded with the appropriate treatment for their diagnosis, subarachnoid hemorrhage, including administration of hemophilia A replacement Factor VIII two to three times a day, but the patient worsened over a 14-day hospital stay before dying. An investigator determined the death was not related to fitusiran.

The patient was enrolled in an open-label, Phase II study including patients with hemophilia A or B, with or without inhibitors to treatment with replacement factors. Prior to the fitusiran trials, the patient received Factor VIII on demand and had an annualized bleeding rate of 32 episodes. He first was dosed with fitusiran in a Phase I study in August 2015 and then joined the open-label extension after a treatment gap in March 2016, receiving 80 mg of study drug monthly, the higher of two doses being investigated. Alnylam said the patient demonstrated good hemostatic response and was bleed-free since August 2016.

Following the death, Alnylam asked three independent neuro-radiologists to review the patient's CT scans. On Sept. 1 those investigators determined that the adverse event had been a cerebral venous sinus thrombosis, not a subarachnoid hemorrhage. This conclusion re-opens the question of whether treatment with fitusiran played a role in the patient's death, Alnylam conceded.

The cerebral venous sinus thrombosis "may be related to the effects of fitusiran that the patient was receiving and positively may have been related to the antecedent administration of [replacement] factor for hip pain," Alnylam Executive VP-R&D Akshay Vaishnaw told the call. He added that recommended treatment for subarachnoid hemorrhage and cerebral venous sinus thrombosis are "quite different."

CEO John Maraganore said Alnylam still hopes to develop fitusiran, partnered with Sanofi, as a novel, monthly therapeutic alternative for both hemophilia A and B. He noted that treatment experience with the candidate so far includes 42 patients in Phase I or Phase II studies with a total of 31 patient years. The Phase III ATLAS trial has been initiated with active clinical sites, but dosing has not begun. The biotech's stated goal had been to file fitusiran for FDA approval in 2018. (Also see "Alnylam's Fitusiran Could Provide Comprehensive Hemophilia Therapy Option" - Scrip, 29 Aug, 2016.)

"The risk of thrombosis is a known and reported side effect of approved drugs and other investigational drugs in development, and safety monitoring is an important part of risk management in hemophilia," the CEO told the call. "We remain very committed to continuing the development of fitusiran as an investigational medicine that we believe has the potential to make a significant difference for patients with hemophilia and other rare bleeding disorders and we look forward to working with regulators to allow the resumption of dosing in the coming months."

Targeting Anti-Thrombin Always Presented Risks

Analysts said fitusiran's mechanism of targeting anti-thrombin always presented risks by affecting the balance between clotting and bleeding, but overall predicted that Alnylam would get the okay to resume dosing of the drug.

Do Kim of BMO Capital Markets wrote Sept. 7 that "high levels of Factor VIII" used to treat the patient who died likely were a contributing factor to the outcome, "which suggests appropriate protocol changes could mitigate the risk of thrombosis." Kim predicted the Phase III study would be delayed between three and six months, the timeframe in which Maraganore said Alnylam hoped to resume dosing.

Paul Matteis of Leerink Partners noted the risk of blood clots has often been cited as a theoretical concern for fitusiran. He predicted Sept. 7 that even if the fitusiran trials restart with revised safety protocols, the drug's commercial opportunity may be limited "given the risk-averse nature of the hemophilia patient population (especially patients without inhibitors)."

He conceded, however, that it remains uncertain if fitusiran will be implicated in the patient's death. "It seems that care for this patient was uniquely poor, and it's unclear if the event would have been fatal had it been caught earlier," Matteis said.

Credit Suisse analyst Alethia Young agreed, stating "in this case, it sounds like there were some other factors that may have led to the outcome." But targeting anti-thrombin to increase patients' thrombin levels always presented "a challenging target due to achieving the right dose to balance the cascade," she wrote in a Sept. 7 note.

Acknowledging last year's failure of revusiran, Young pointed out that it and fitusiran both derive from Alnylam's GalNAc technology, but that the latter candidate also employs next-generation enhanced stabilization chemistry to make it a more potent technology. BMO's Kim also contended that the thrombosis event seen with fitusiran seems unlikely to have any connection to problems related to revusiran treatment, because the two drugs address different targets as well as different indications.

Fitusiran is thought to offer a valuable therapeutic alternative in hemophilia, because it could apply to both hemophilia A and B in patients with or without inhibitors to existing therapies, and because its monthly administration would be much less frequent than the dosing of current therapies. (Also see "Momentum Builds For Tomorrow's More Convenient Hemophilia Drugs" - Scrip, 13 Jul, 2017.)