CAMBRIDGE: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, inherited, rapidly progressive, and fatal disease with debilitating polyneuropathy manifestations, for which there are few treatment options.

The U.S. Food and Drug Administration (FDA) has approved AMVUTTRA™ (vutrisiran), a therapeutic administered via subcutaneous injection once every three months (quarterly) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. 

The FDA approval is based on positive 9-month results from the HELIOS-A Phase 3 study, where AMVUTTRA significantly improved the signs and symptoms of polyneuropathy, with more than 50 percent of patients experiencing halting or reversal of their disease manifestations.

“Twenty years ago, Alnylam was founded with the bold vision for RNA interference to make a meaningful impact on the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs, such as hATTR amyloidosis. Today, AMVUTTRA has the potential to change the standard of care for people living with the polyneuropathy of this devastating disease,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam Pharmaceuticals. “We are so thankful to the patients, families and investigators involved in making AMVUTTRA a reality for the hATTR amyloidosis community.

As the fifth RNAi therapeutic developed by Alnylam to receive regulatory approval in less than four years, we believe AMVUTTRA represents an important milestone that brings us one step closer to achieving our P5x25 goals aimed at Alnylam’s transition to a leading biotech company.”

The FDA approval of AMVUTTRA is based on positive 9-month results from HELIOS-A, a global, randomized, open-label, multicenter, Phase 3 study that evaluated the efficacy and safety of AMVUTTRA across a diverse group of patients with hATTR amyloidosis with polyneuropathy.

164 patients with hATTR amyloidosis were randomized 3:1 to receive either 25 mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (reference group) for 18 months. The efficacy of AMVUTTRA was assessed by comparing the AMVUTTRA group in HELIOS-A with the placebo group (n=77) from the landmark APOLLO Phase 3 study of patisiran, a randomized controlled study in a comparable patient population.

AMVUTTRA met the primary endpoint of the study, the change from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) at 9 months. Treatment with AMVUTTRA (N=114) resulted in a 2.2 point mean decrease (improvement) in mNIS+7 from baseline as compared to a 14.8 point mean increase (worsening) reported for the external placebo group (N=67), resulting in a 17.0 point mean difference relative to placebo (p<0.0001); by 9 months, 50 percent of patients treated with AMVUTTRA experienced improvement in neuropathy impairment relative to baseline.

AMVUTTRA also met all secondary endpoints in the study at 9 months, with significant improvement in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) score and timed 10-meter walk test (10-MWT), and improvements were observed in exploratory endpoints, including change from baseline in modified body mass index (mBMI), all relative to external placebo.

Efficacy results at 18 months were consistent with 9-month data, with AMVUTTRA achieving statistically significant improvements compared to external placebo for all secondary endpoints including mNIS+7, Norfolk QoL-DN, 10-MWT and mBMI, and non-inferiority in serum TTR reduction relative to the within-study patisiran reference group.

AMVUTTRA demonstrated an encouraging safety and tolerability profile with 9 months of dosing and there were no drug-related discontinuations or deaths. The most commonly reported adverse events (AEs) in AMVUTTRA-treated patients included arthralgia (11 percent), dyspnea (7 percent) and vitamin A decreased (7 percent). Injection site reactions (ISRs) were reported in 5 patients (4 percent) and were all mild and transient.

“The FDA approval of AMVUTTRA is very encouraging for the hATTR amyloidosis community, who need additional therapies to address the polyneuropathy of this progressive, life-threatening, multisystem disease,” said Michael Polydefkis, M.D., MHS, Professor, Johns Hopkins Neurology and HELIOS-A Study Investigator. “AMVUTTRA is a new therapeutic option that has demonstrated the potential to halt or reverse polyneuropathy progression in patients with an acceptable safety profile, along with an infrequent, subcutaneous dosing regimen that may also help to improve the disease management experience for patients.”

“Today we celebrate the FDA’s approval of vutrisiran, a welcomed treatment option for hATTR amyloidosis patients experiencing the challenges of the polyneuropathy of the disease,” said Isabelle Lousada, Founder and CEO, Amyloidosis Research Consortium. “With this approval, Alnylam has expanded treatment options that may support improvements in quality of life, providing hope for patients and families in the amyloidosis community.”

Alnylam offers a patient support services program, Alnylam Assist™, for people in the U.S. prescribed AMVUTTRA and their families to receive help accessing this new therapy. Alnylam Assist includes Case Managers, a team dedicated to helping assist patients with verification of insurance benefits and financial assistance for those who qualify. Patient Education Liaisons are also available to answer patients’ questions about their disease and treatment. Physicians and patients can learn more about Alnylam’s patient support services program by visiting or calling 1-833-256-2748.

Vutrisiran is under review by the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Vutrisiran was previously granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis and in Japan for transthyretin type familial amyloidosis with polyneuropathy.

A biannual 50mg dosing regimen is under evaluation within the ongoing randomized treatment extension (RTE) period in the HELIOS-A trial. Vutrisiran is also being evaluated in the HELIOS-B Phase 3 study for the treatment of patients with ATTR amyloidosis with cardiomyopathy, including both hATTR and wild-type ATTR (wtATTR) amyloidosis.

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