#AANAM – Vutrisiran Leads to Certain Benefits for Phase 3 Trial Patients

Editor’s note: The FAP News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

Vutrisiran, an investigational therapy for familial amyloid polyneuropathy (FAP), safely and effectively eased neurologic impairments and improved quality of life and walking abilities in adults with FAP, according to nine-month data from an ongoing Phase 3 trial.

The experimental therapy, from Alnylam Pharmaceuticals, was able to rapidly and sustainably lower the levels of transthyretin (TTR) protein, which underlies the disease, in the blood of trial participants, data from the study, called HELIOS-A (NCT03759379), showed.

Based on these positive findings, Alnylam submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) requesting vutrisiran’s approval for the treatment of FAP in adults.

“With our NDA filing now completed, we look forward to potentially bringing vutrisiran to patients as a new treatment option for [FAP] with subcutaneous administration and quarterly dosing,” Akshay Vaishnaw, MD, PhD, president of research and development at Alnylam, said in a press release.

Findings from HELIOS-A were presented by David Adams, MD, PhD, head of the French National Reference Centre for Familial Amyloidotic Polyneuropathy, at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting, held online April 17–22. The presentation was titled, “HELIOS-A: 9-month Results from the Phase 3 Study of Vutrisiran in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy.”

FAP is caused by the production of a faulty TTR protein that clumps together forming abnormal deposits that have toxic effects on cells in the body.

Vutrisiran works by decreasing the production of this protein through a process called RNA interference, or RNAi, in which small RNA molecules are used to target and inactivate the messenger RNA (mRNA) that cells would normally use as a template to create a specific protein of interest. In this case, vutrisiran is designed to specifically target and inactivate TTR’s mRNA.

Another RNAi therapy, Onpattro (patisiran), also developed by Alnylam, has been approved by the FDA to treat FAP. Compared to Onpattro, vutrisiran is designed to have greater stability, allowing for a more potent and durable effect.

HELIOS-A is an open-label Phase 3 trial to assess the safety and efficacy of vutrisiran in adults, ages 18–85, with FAP. The study enrolled 164 participants, who were assigned randomly to receive vutrisiran (122 participants) or Onpattro (42 participants) for 18 months.

Vutrisiran was administered by a subcutaneous (under-the-skin) injection every three months, while Onpattro was given intravenously (infusion directly into the bloodstream) every three weeks.

About three-quarters of trial participants were male, with an average age of 60 years.

The main goal of HELIOS-A was to test the effects of treatment on neurologic impairment, which was assessed by the modified Neurologic Impairment Score+7 (mNIS+7). Higher mNIS+7 scores indicate a greater degree of impairment.

In APOLLO (NCT01960348), a previous completed Phase 3 trial that served as the basis for Onpattro’s approval, FAP patients given a placebo experienced a continuous worsening of neurologic impairment, as evidenced by a mean increase of 14.76 points in mNIS+7 score after nine months.

In contrast, participants given vutrisiran in HELIOS-A experienced fewer impairments, with mean mNIS+7 scores dropping by 2.24 points after nine months.

“The majority of vutrisiran-treated patients showed improvement in mNIS+7 compared to baseline [the start of the trial],” Adams said during the presentation.

These improvements were observed across multiple patient subpopulations, in which participants were grouped by age, sex, race, geographic location, and other factors.

Similar results were seen for quality of life, which was evaluated with a standardized questionnaire called Norfolk Quality of Life-Diabetic Neuropathy, where higher scores indicate worse quality of life. Among patients given a placebo in APOLLO, mean scores increased by 12.9 points after nine months. In contrast, for vutrisiran-treated participants in HELIOS-A, mean scores decreased by 3.3 points after nine months.

Additionally, vutrisiran-treated participants experienced virtually no change in the average time it took them to walk 10 meters (about 33 feet) over the course of nine months, whereas individuals given a placebo in APOLLO saw their walking ability and gait speed continuously deteriorate in the same period.

The levels of TTR protein in participants’ blood decreased sharply following treatment initiation in the vutrisiran and Onpattro groups in HELIOS-A. In patients receiving vutrisiran, TTR protein levels dropped by a mean of 83% from the start of the trial. These reductions were both rapid — being clearly detectable after three weeks — and sustained over nine months.

Treatment with vutrisiran was also associated with improvements in other key exploratory endpoints, including in different measures of heart health, nutritional status, and overall disability.

The safety profile of vutrisiran in HELIOS-A was generally positive. Laboratory tests for liver and kidney function did not reveal any alarming results. Common adverse events among vutrisiran-treated participants included diarrhea, pain in the extremities, falls, and urinary tract infections. The frequency of these adverse events was similar or lower compared to that seen in patients given a placebo in APOLLO.

“The majority of adverse events were mild or moderate in severity. There were no drug-related study discontinuations or deaths,” Adams said.

Two serious adverse events were deemed to be related to vutrisiran treatment by study investigators: one case of urinary tract infection and one of dyslipidemia (abnormal levels of fatty molecules in the bloodstream). There were two deaths during the study, both deemed unrelated to the medication being tested: one due to COVID-19 pneumonia, and another due to iliac artery occlusion (blood vessel obstruction in the abdomen).

“Vutrisiran has an acceptable safety profile and favorable benefit-risk profile,” Adams said.

Vaishnaw added: “The HELIOS-A study results demonstrate that vutrisiran improves neuropathy, quality of life and gait speed as soon as 9 months [in FAP patients] with an encouraging safety and tolerability profile.”

“The positive HELIOS-A study and our NDA filing are key milestones as we continue our progress towards building an industry-leading franchise of medicines for the treatment of ATTR amyloidosis and towards our goal of expanding in the future the population of patients who may benefit from treatment with an RNAi therapeutic,” Vaishnaw said.

HELIOS-A will continue to assess the efficacy and safety of vutrisiran up until 18 months of treatment. Alnylam is expected to present additional data from the study later this year.