Alnylam wins FDA nod for $575,000 liver med Givlaari despite safety flags

FDA Building 2
Alnylam notched a second FDA nod for liver disease med Givlaari, but the drug's safety profile is giving analysts pause. (FDA)

Alnylam is facing a major challenger to its first approved drug, Onpattro, from Pfizer's Vyndaqel just over a year into its launch. But the company now has another drug approval to bolster its portfolio––although analysts have expressed some concern about its safety profile. 

The FDA approved Givlaari (givosiran) Tuesday––well ahead of its February decision deadline––as a treatment for acute hepatic porphyria (AHP), a genetic disorder resulting in the buildup of toxic porphyrin molecules. 

Givlaari is now Alnylam's second RNA interference med to market, joining Onpattro for peripheral nerve disease caused by hereditary transthyretin-mediated amyloidosis.

"We believe the approval of Givlaari represents a landmark event for the advancement of precision genetic medicines, providing new hope for patients and their caregivers living with the debilitating manifestations of AHP and unpredictable nature of AHP attacks, as well as for the doctors who diagnose and treat these patients," Alnylam said in a release.

Givlaari will have an average annual cost of $575,000 per patient based on a list price of $39,000 per vial. In a call with analysts, Alnylam said the annual patient price after mandatory discounts will come out to around $442,000.

In a Wednesday note to investors, Cantor analyst Alethia Young highlighted Alnylam's "highly innovative" reimbursement strategy, which will utilize "prevalence-based adjustments" that offer rebates if the prevalence of AHP patients on a given plan is higher than current estimates. 

"These agreements will be negotiated on a plan-by-plan basis, and we think will give payers greater comfort in allowing rapid reimbursement without requiring documentation of attack frequency," Young wrote. "If predetermined prevalence thresholds are hit in a given plan, there would be a mechanism in place to adjust the price lower over time, which aligns incentives to diagnose and treat as many patients as possible."

The FDA based its approval off results from a phase 3 trial showing Givlaari beat out placebo at reducing the annualized rate of composite porphyria attacks including those requiring hospitalization, an urgent healthcare visit, or an administration of hemin, which is used to treat porphyria attacks.

RELATED: Alnylam’s givosiran hits the mark in phase 3 porphyria test, NDA to follow midyear

Givlaari also met five of its nine secondary endpoints, including several specific to patients with acute intermittent porphyria, the most common subset of AHP. It did not meet statistical significance for the remaining secondary endpoints, including daily worst fatigue, daily worst nausea and the physical health component of a quality-of-life survey.

However, Givlaari's safety profile left much to be desired, analysts noted. 

The drug's safety profile was “materially worse than expected,” with serious side effects affecting the Givlaari group at nearly double the rate of the placebo group, at 21% versus 9%, Leerink analysts Mani Foroohar and Rick Bienkowski wrote in March.

Adverse events on the whole occurred at roughly the same rate in both groups, in 90% of Givlaari patients and 80% of placebo patients.

“While these patients have baseline liver disease, and can be attributable to some of the underlying safety events, the more than double SAEs exhibited in the treatment arm compared to placebo could be signs of a safety signal,” the analysts wrote.

RELATED: Pfizer's early Vyndaqel launch numbers are off the charts. Should Alnylam be worried?

Assuming Givlaari's launch goes well, it should give Alnylam a bit of breathing room as Pfizer's Vyndaqel poses a major challenge to Onpattro. Earlier this month, Vyndaqel trounced its third-quarter Street sales estimate, beating out the $21 million forecast in U.S. sales by $58 million. Worldwide, the drug brought in $156 million.

In the meantime, Alnylam reported worldwide Onpattro sales of $46.1 million—largely in line with consensus of $45.5 million—with $33.6 million of that coming from the U.S. Though the RNAi drug's U.S. sales marked 19% growth quarter over quarter, its quarterly haul was still well behind Vyndaqel's.

Editor's Note: This story has been updated.

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