Further Benefits With Vutrisiran Seen in FAP Patients in Phase 3 Trial

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by Steve Bryson PhD |

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Vutrisiran, an investigational therapy for familial amyloid polyneuropathy (FAP), eased neurological impairments, lessened heart stress, and ameliorated quality of life, nutritional status, and social engagement in adult patients, according to new nine-month data from HELIOS-A trial.

“These additional data from the HELIOS-A study show the potential of vutrisiran in treating a broad group of patients with hATTR amyloidosis with polyneuropathy, with encouraging improvements seen across a range of important health and functional measures,” Pushkal Garg, MD, chief medical officer of Alnylam Pharmaceuticals, the therapy’s developer, said in a press release.

Presented at the 3rd European ATTR Amyloidosis Meeting, held Sept. 6–8, these data support previously reported results on primary and secondary goals achieved in HELIOS-A (NCT03759379), a Phase 3 trial sponsored by Alnylam, at nine months of treatment.

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The U.S. Food and Drug Administration (FDA) is reviewing an application from the company seeking the approval of vutrisiran in treating FAP, which was largely supported by previous HELIOS-A data. A decision is expected on or before April 14, 2022.

Alnylam is also planning to file a similar approval request to regulatory authorities in Europe. Top-line study data evaluating 18 months of treatment is expected to be announced later this year.

“We look forward to sharing additional results at the 18-month readout,” Garg said. “With the recent NDA [new drug application] submission accepted for review by the U.S. FDA and planned regulatory submission in Europe ahead of schedule, we are continuing our progress to bring vutrisiran forward as a potential new treatment option for [FAP], with subcutaneous administration and quarterly dosing.”

HELIOS-A enrolled 164 FAP patients, assigned to receive either vutrisiran or Onpattro (patisiran) — an FDA-approved treatment for FAP also developed by Alnylam.

Both vutrisiran and Onpattro are RNA interference therapies designed to lower the production of transthyretin (TTR), the faulty protein that is FAP’s underlying cause. However, vutrisiran intends to be more stable, potentially allowing for longer-lasting effects compared with Onpattro.

After nine months of vutrisiran, which was given by a subcutaneous (under-the-skin) injection every three months, patients experienced significant improvements in quality of life and walking speed, and fewer neurological impairments compared with those given a placebo in an earlier trial of Onpattro, an intravenous infusion therapy.

Additional subgroup analyses and exploratory efficacy data from HELIOS-A now confirmed that vutrisiran was associated with consistent improvements in the modified Neuropathy Impairment Score (mNIS+7) — a measure of neurological problems — and in the Norfolk Quality of Life-Diabetic Neuropathy Score (Norfolk QOL-DN), compared with the external placebo. In both measures, higher scores indicate worse neurological impairment and poorer quality of life.

These results were similar across all pre-specified patient subgroups, including those grouped by age, sex, ethnic origin, geographical location, degree of nerve impairment (neuropathy) before treatment, genetics, and prior TTR stabilizer use.

Vutrisiran also enhanced patients’ social participation, as well as their ability to perform daily life activities, as measured by the Rasch-built Overall Disability Scale (R-ODS), a patient-ranked scale.

Modified body mass index (mBMI) scores, which reflect the amount of body fat, increased in patients given vutrisiran, indicating improvements in their overall nutritional status throughout the nine months. Assessments of patients’ muscle strength, sensation, and reflexes also improved significantly with treatment.

Analyses also showed vutrisiran lowered the levels of NT-proBNP, a marker of cardiac stress, compared with the external placebo group.

Another analysis from HELIOS-A focused on assessing the effects of vutrisiran in patients previously treated with TTR stabilizers. Although TTR stabilizers were not permitted at study entry, two-thirds of enrolled patients had previously used a TTR stabilizer, but stopped due to study participation or disease progression.

Here, data revealed that all vutrisiran-treated patients, including those previously treated with TTR stabilizers and those who never received these therapies, experienced improvements in quality of life and fewer neurological impairments compared with the Onpattro trial’s placebo group.

“Patients experienced improvements in neuropathy impairment and quality of life scores regardless of prior TTR stabilizer use,” Garg said.

Over the course of nine months of treatment, vutrisiran demonstrated an acceptable safety and tolerability profile regardless of prior TTR stabilizer use. Most adverse events were mild to moderate in severity, and there were no reported study discontinuations or deaths related to treatment.