Alnylam plans to submit a NDA for the orphan drug used to treat hATTR with amyloidosis in adults.
New topline results have stakeholders hopeful Vutrisiran could be an effective treatment option for patients with transthyretin-mediated (ATTR) amyloidosis with polyneuropathy.
Following the topline results from the HELIOS-A phase 3 trial testing the investigational RNAi therapeutic, Alnylam Pharmaceuticals plans to submit a New Drug Application (NDA) with the FDA in 2021. They also plan on following with regulatory filings in additional countries, including Brazil, Japan, and the European Union.
The HELIOS-A Study
The investigators sough primary endpoints of the change from baseline in the modified Neuropathy Impairment Score (mNIS+7) at 9 months as compared to historical placebo data from the APOLLO phase 3 study of vutrisiran.
The HELIOS-A trial is a phase 3 global, randomized, open-label study evaluating the efficacy and safety of vutrisiran in 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries.
Each patient was randomized in a 3:1 ratio to receive either 25 mg of the study drug (n = 122) via subcutaneous injection once ever 3 months or 0.3 mg/kg of vutrisiran (n = 42) via intravenous infusions once every 3 week for 18 months.
The research team also sought secondary endpoints of the changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and gait speed, which was assessed by the timed 10-meter walk test (10-MWT) compared to historical placebo.
Positive Initial Results
Overall, the treatment met the primary endpoints (P<0.001), as well as both secondary endpoints at 9 months, showing statistically significant results (P <0.001) for each of the Norfolk QoL-DN and 10-MWT secondary endpoints.
The investigators also found the treatment improved on the exploratory cardiac biomarker endpoint NT-proBNP (P <0.05) when compared to placebo.
Vutrisiran also presented an encouraging safety and tolerability profile with only 2 discontinuations (1.6%) because of adverse events, both due to deaths unrelated to the study drug.
There were also 2 serious adverse events consisting of dyslipidemia and urinary tract infections related to vutrisiran.
Treatment emergent adverse events occurred in 10% or more of the patients, including diarrhea, pain in extremities, fall and urinary tract infections. However, these events occurred at a similar or lower rate as compared with historical placebo.
“We are excited to report positive topline results from the HELIOS-A study, which show that vutrisiran reduces neurologic impairment and improves quality of life in patients with hATTR amyloidosis with polyneuropathy as soon as 9 months, with an encouraging safety and tolerability profile,” Akshay Vaishnaw, MD, PhD, President of R&D at Alnylam, said in a statement. In addition, we’re very pleased to see evidence for reversal of polyneuropathy manifestations of disease and also favorable effects on the exploratory cardiac endpoint, NT-proBNP. We believe that vutrisiran, as a low-dose, once-quarterly, subcutaneously administered therapy, has the potential to be a highly attractive therapeutic option for patients living with this progressive, life-threatening, multi-system disease.”
The investigators plan to examine secondary endpoints at 18 months, including the change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels.
They will also evaluate additional exploratory cardiac endpoint data at 18 months including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging.
After the 18-month study period concludes, the patients will be eligible to receive vutrisiran for an additional 18 months as part of an open-label extension.
Stakeholders will also present the full 9-month results at a conference early in 2021, as well as the topline 18-month results.
Vutrisiran has been granted an Orphan Drug Designation by the FDA and has been granted a Fast Track designation for the treatment of the polyneuropathy of hATTR amyloidosis in adults.