Vutrisiran Easing FAP Disability and Aiding Life Quality: HELIOS-A Update

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by Steve Bryson PhD |

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Vutrisiran, an experimental therapy for familial amyloid polyneuropathy (FAP), continued to safely alleviate neurologic impairments and overall disability over 18 months of treatment, according to new data from the ongoing Phase 3 HELIOS-A trial.

Those being given the therapy, administered as an under-the-skin injection once every three months, showed improvements in walking speed, nutritional status, and quality of life, Alnylam Pharmaceuticals, the therapy’s developer, reported.

These findings aim to support vutrisiran’s approval for FAP. Approval requests are currently being reviewed by regulatory agencies in the U.S., Europe, Japan, and Brazil. A decision in the U.S. is expected by April 14.

“Vutrisiran is currently under review by multiple regulatory authorities around the world, bringing us a step closer to potentially making this low-dose, once-quarterly, subcutaneously administered treatment option available for patients living with the [FAP],” Rena Denoncourt, a vice president at Alnylam, said in a press release.

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Presented at the Société Francophone du Nerf Périphérique (SFNP) Annual Meeting, these 18-month data are consistent with the primary and secondary goals achieved in the HELIOS-A (NCT03759379) trial after nine months of treatment.

“These HELIOS-A results show that the improvement in neuropathy impairment and quality of life observed with vutrisiran at 9 months is maintained through Month 18, with the treatment effect increasing over time and an encouraging safety profile,” Denoncourt said.

HELIOS-A enrolled 164 FAP patients, randomly assigned to either vutrisiran (122 people) or Onpattro (patisiran; 42 people), an approved FAP treatment also developed by Alnylam.

Vutrisiran and Onpattro work by lowering the production of transthyretin (TTR), the faulty protein that builds in peripheral nerves — those outside the brain and spinal cord — leading to nerve damage, or polyneuropathy. Compared to Onpattro, vutrisiran is designed to be more stable, potentially allowing for longer-lasting effects, less frequent dosing, and lower healthcare costs.

HELIOS-A patients were given vutrisiran (25 mg) as an under-the-skin injection every three months, while Onpattro (0.3 mg/kg) was infused directly into the bloodstream once every three weeks.

The 77 people assigned to a placebo in the Phase 3 APOLLO trial (NCT01960348), which supported Onpattro’s approval, were used as a comparison (control group) to vutrisiran in HELIOS-A.

18-month findings with vutrisiran

After 18 months of treatment, vutrisiran met all HELIOS-A secondary goals, with statistically significant gains in clinical outcomes compared to placebo.

Its use resulted in a 0.46-point mean decrease (improvement) in the modified Neuropathy Impairment Score (mNIS+7) in contrast to a 28.09-point mean increase (worsening) for the external placebo group — a 28.55-point mean difference.

Nearly half (48%) of vutrisiran-treated patients had better mNIS+7 scores, compared with 4% of those in the placebo group.

In quality of life (QoL) assessments, vutrisiran resulted in a 1.2-point mean decrease (improvement) in Norfolk QoL-DN scores compared with a 19.8-point mean increase (worsening) with placebo — a 21-point mean difference. A better life quality was reported by 57% of vutrisiran-treated patients and 10% of those given a placebo.

In the 10-meter walking test assessing speed over a short distance, vutrisiran increased walking speed by a mean of 0.24 meters/second (m/s) relative to placebo.

Nutritional status was assessed using the modified body mass index (mBMI), which multiplies the body mass index (BMI), a measure of body fat, by blood albumin protein levels to correct for weight gains associated with TTR amyloidosis. Vutrisiran led to a 25-point mean increase (improvement) in mBMI relative to a 115.7-point mean decrease with placebo — a 140.7-point mean increase.

Vutrisiran’s use also led to a mean decrease of 8.4 points in the Rasch-built Overall Disability scale (R-ODS),  which evaluates limitations on activity and social participation, compared with placebo.

Consistent with nine-month results, vutrisiran led to rapid and sustained drops in TTR protein levels in the bloodstream for 18 months, with a mean reduction of 88% compared with pre-treatment, similar to Onpattro.

Exploratory heart measures and safety

HELIOS-A participants also showed improvements in measures of heart muscle damage, which can occur due to the buildup of amyloid deposits in the heart.

Alnylam is also evaluating the potential of vutrisiran and Onpattro to treat heart manifestations of ATTR amyloidosis, a group of disorders that also includes FAP, in HELIOS-B (NCT04153149) and APOLLO-B (NCT03997383).

Compared with placebo, vutrisiran-treated patients showed improvements in NT-proBNP, a marker of heart strain, and several other heart function measures. Its use also reduced the uptake of the radioactive compound technetium, suggesting a lesser amyloid burden in the heart, according to Alnylam.

“We are encouraged by the exploratory cardiac endpoint results, particularly new data indicating that 18 months of vutrisiran treatment resulted in reduced technetium uptake in the heart compared to baseline in the majority of patients who were in a planned cohort, suggesting the potential for amyloid regression,” Denoncourt said.

“We look forward to seeing data from the APOLLO-B and HELIOS-B studies, which are investigating the potential of patisiran and vutrisiran, respectively, to treat the cardiac manifestations of disease in patients with ATTR amyloidosis with cardiomyopathy [heart disease],” Denoncourt added.

At 18 months, vutrisiran continued to show a promising safety and tolerability profile. Adverse events occurring in 10% or more participants included falls, pain in extremities, diarrhea, swelling, urinary tract infection, joint stiffness, and dizziness. All of these, except pain in extremities and joint stiffness, occurred at similar or lower rates as placebo.

As reported after nine months of treatment, two serious adverse events were deemed related to vutrisiran: urinary tract infection and dyslipidemia (unhealthy blood levels of one or more types of fatty molecules). One person left the study due to non-fatal heart failure, and two others died; none of these events were considered related to vutrisiran.

Mild, short-lived injection site reactions were reported in five patients. There were no significant changes in liver function tests.

“The 18-month results of the HELIOS-A Phase 3 study build on the results observed at 9 months and continue to underscore the potential of vutrisiran as an attractive new treatment option that can be administered subcutaneously four times a year,” said David Adams, MD, PhD, principal investigator for HELIOS-A.

Patients who complete HELIOS-A have the option to enter its open-label study, in which all will receive 25 mg of vutrisiran once every three months, or 50 mg once every six months for 1.5 years. This study is expected to wrap up in May 2024.