Vutrisiran Reduces Neurologic Damage, Improves Physical Function, Trial Data Show

Vutrisiran, a second-generation RNA interference (RNAi) therapy candidate, safely and effectively reduces neurologic impairment and improves physical function and quality of life in adults with familial amyloid polyneuropathy (FAP).

That’s according to top-line, nine-month data from the global HELIOS-A Phase 3 trial.

Alnylam Pharmaceuticals, Vutrisiran’s developer, plans to present the trial’s full results at a medical meeting in the upcoming months and to announce additional 18-month data by late 2021.

“The HELIOS-A results reinforce our commitment to building an industry-leading franchise of medicines for the treatment of ATTR amyloidosis which began with the development and approval of Onpattro as a treatment for patients with [FAP],” John Maraganore, PhD, Alnylam’s CEO, said in a press release.

“Indeed, the vutrisiran results from HELIOS-A now serve as a second example of the potential for RNAi therapeutics to have a meaningful impact for patients, showing the ability to halt and potentially even reverse polyneuropathy manifestations of the disease,” Maraganore added.

Based on the positive findings, Alnylam plans to file an application with the U.S. Food and Drug Administration in the upcoming months seeking vutrisiran’s approval as a treatment for FAP. Submissions to regulatory agencies in additional countries, such as Brazil and Japan, are expected to quickly follow. Meanwhile, an application to the European Medicines Agency will only be made once the 18-month results are out, as previously agreed by the two sides.

“We look forward to initiating our regulatory filings in early 2021 as we work to bring this investigational treatment one step closer to patients with this rare disease,” said Akshay Vaishnaw, MD, PhD, president of Alnylam’s research and development.

RNAi is a natural process of gene silencing in which small interfering RNA molecules bind to a specific messenger RNA (mRNA) — the molecule generated from DNA that serves as a template for protein production — targeting it for destruction and ultimately preventing the production of that protein.

Formerly known as ALN-TTRsc02, vutrisiran is a second-generation RNAi therapy designed to specifically block the production of the abnormal, misfolded transthyretin (TTR) protein in FAP patients. Those misfolded proteins form toxic aggregates, or clumps, in different tissues and organs. Vutrisiran works by binding to and silencing TTR’s mRNA.

Compared with Onpattro (patisiran), Alnylam’s first-generation RNAi therapy for FAP, vutrisiran has greater stability, allowing significantly higher potency and durability. Of note, Onpattro was the first RNAi therapy to be approved in the U.S. for treating FAP, also known as hereditary transthyretin amyloidosis (hATTR) with polyneuropathy.

Vutrisiran received orphan drug status in both the U.S. and Europe, as well as fast track designation in the U.S., for the treatment of FAP and related hereditary ATTR diseases. All of these designations are meant to expedite the therapy’s development and review.

The ongoing HELIOS-A study (NCT03759379), expected to run until May 2024, is evaluating the safety and effectiveness of vutrisiran in 164 adults with FAP, recruited at 57 sites across 22 countries.

Participants were randomly assigned to receive either 25 mg of vutrisiran, given via an under-the-skin (subcutaneous) injection once every 12 weeks, or about every three months (122 patients), or 0.3 mg/kg of Onpattro, given directly into the bloodstream, once every three weeks (42 patients), for 18 months, or about 1.5 years.

HELIOS-A’s main goal was to assess changes in neurologic impairment, as measured with the modified Neurologic Impairment Score, at nine months of treatment. Secondary goals include changes in quality of life — evaluated through the Norfolk Quality of Life-Diabetic Neuropathy — and in physical function, measured with a timed 10-meter walk test, after nine months.

The trial also comprises several exploratory goals, such as measuring the levels of NT-proBNP, a heart failure biomarker.

These and other measures also will be assessed at the end of treatment, after which all participants will be eligible to receive vutrisiran for an additional 18 months (1.5 years) as part of an open-label extension study.

For most study goals, data from vutrisiran-treated participants will be compared with those of an external, historical group of patients given a placebo during the now-completed APOLLO Phase 3 study (NCT01960348), which tested Onpattro against a placebo in 200 FAP patients.

Top-line, nine-month data from HELIOS-A showed that the trial met both its main and secondary goals, with vutrisiran-treated patients exhibiting significant reductions in neurologic problems and significant improvements in physical function and quality of life, compared with the historical placebo group.

The therapy also led to a significant drop in NT-proBNP levels, suggesting a beneficial effect on patients’ cardiac health.

In addition, vutrisiran showed a favorable safety and tolerability profile, with similar or lower rates of most common adverse events (side effects) — including diarrhea, pain in the extremities, falls, and urinary tract infections — to those reported for the historical placebo group.

Two serious side effects, specifically, high levels of fat molecules in the blood and urinary tract infections, were deemed related to vutrisiran. Two patients died during the study, but neither death was considered related to treatment.

“We believe that vutrisiran, as a low-dose, once-quarterly, [under-the-skin] administered therapy, has the potential to be a highly attractive therapeutic option for patients living with this progressive, life-threatening, multi-system disease,” Vaishnaw said.

“We would like to recognize and extend our profound gratitude to the patients, caregivers, investigators, and study staff who are participating in HELIOS-A and who, through their commitment during an especially difficult year, have helped make possible another potential advancement in the treatment of hATTR amyloidosis with polyneuropathy,” he added.

Alnylam also is testing vutrisiran against a placebo in a separate Phase 3 trial, called HELIOS-B (NCT04153149), which is enrolling ATTR patients with heart disease. The study is still recruiting patients at several sites around the world; more information can be found here.

Together, the trials are intended to demonstrate vutrisiran’s benefits across the full spectrum of ATTR symptoms.