Vutrisiran’s Benefits Sustained Over 18 Months in HELIOS-A Trial

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by Marta Figueiredo PhD |

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HELIOS-A | FAP News Today | Clinical trials | Illustration of charts and pill bottle

The benefits of Vutrisiran in reducing neurologic impairment and overall disability, and improving the quality of life in adults with familial amyloid polyneuropathy (FAP) were sustained over 18 months, according to new data from the ongoing Phase 3 HELIOS-A trial.

“These results build on the positive vutrisiran data shared earlier this year and suggest that the reduction of neurologic impairment and improvement in quality of life in patients with [FAP] observed as early as nine months are maintained at 18 months,” Rena Denoncourt, vice president, TTR Franchise lead at Alnylam Pharmaceuticals, which is developing the treatment, said in a press release.

“We are also encouraged by the hypothesis-supporting, exploratory endpoints and cardiac amyloid imaging results” that showed reduced signs of heart involvement and stress with vutrisiran, Denoncourt added. This provided preliminary evidence of the therapy’s potential to lessen heart-related disease burden.

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These findings are expected to further support vutrisiran’s approval for FAP — an indication for which the therapy is currently being reviewed by health authorities in the U.S., Europe, and Brazil. A decision in the U.S. is expected no later than April 14, 2022.

These regulatory reviews bring “this low-dose, once-quarterly, [under-the-skin] administered investigational therapy with a highly-attractive profile one step closer to being a potentially available therapeutic option for patients living with this progressive, life-threatening, multi-system disease,” Denoncourt said.

The data were recently discussed by Alnylam as part of its 2021 third-quarter financial results conference call. Full 1.5-year results are expected to be presented at a medical conference in early 2022.

In HELIOS-A (NCT03759379), 164 adults with FAP were randomly assigned to receive vutrisiran (122 patients) or Onpattro (patisiran) (42 patients) for 18 months (1.5 years).

Onpattro, also developed by Alnylam, is approved for FAP and uses the same mechanism as vutrisiran to lower the levels of transthyretin (TTR) — the faulty protein that causes FAP. However, vutrisiran was designed to have greater stability, potentially allowing for a stronger and longer-lasting effect than Onpattro. This, in turn, may allow vutrisiran to be administered less frequently, lowering the burden and healthcare costs for patients.

In the trial, vutrisiran (25 mg) was given through an under-the-skin injection once every three months, while Onpattro (0.3 mg/kg) was administered directly into the bloodstream once every three weeks.

Patients who received a placebo in the previous Phase 3 APOLLO trial (NCT01960348), whose findings supported Onpattro’s approval, were used as an external control group for the HELIOS-A trial and most of its goals.

Top-line, nine-month results showed that vutrisiran was generally safe and significantly superior to placebo at lessening neurologic impairments, improving quality of life, and preserving walking abilities in participants — meeting the trial’s main and secondary goals.

The therapy also lessened overall disability, improved nutritional status, and lowered the levels of NT-proBNP, a marker of heart stress and damage, compared with the external placebo group.

These significant improvements were observed across all pre-specified patient subgroups, including those grouped by age, sex, ethnic origin, geographical location, degree of neurologic impairment before treatment, and other factors.

Newly-announced data showed that all of vutrisiran-related benefits were sustained after 1.5 years of treatment, meeting all of the trial’s secondary 18-month goals. Also, the second-generation therapy was found to be non-inferior to Onpattro at lowering blood TTR levels, similar to what was reported at nine months.

Vutrisiran-treated patients showed improvements in several exploratory measures of heart health. These included greater reductions in NT-proBNP levels and better echocardiographic parameters relative to the placebo group. Other improvements included a reduction in technetium uptake in the heart since the study’s start in most of the 48 patients pre-selected to be part of this analysis. Technetium is a radioactive molecule that strongly binds to TTR and is used as an imaging marker of disease burden in FAP patients.

These heart-related findings provide “potential evidence for reduced cardiac amyloid burden,” according to Alnylam.

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Moreover, vutrisiran continued to show an encouraging safety and tolerability profile, with no new safety concerns identified and an additional case of treatment discontinuation since month 9 that was deemed unrelated to the therapy.

Commonly reported adverse events included falls, pain in the extremities, diarrhea, leg/hand swelling, urinary tract infections, joint pain, and dizziness. All, except for pain in the extremities and the joints, occurred at a similar or lower rate in the vutrisiran group compared with the external placebo group.

Injection-site reactions were reported in five (4.1%) vutrisiran-treated patients and were all mild and temporary. No liver-related safety concerns were reported.

After completing the 18-month treatment in HELIOS-A, participants will choose whether to enter its extension phase, in which all will receive 25 mg of vutrisiran once quarterly, or 50 mg once every six months for 1.5 years. The study is expected to conclude in May 2024.