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hATTR amyloidosis with polyneuropathy: Vutrisiran has improved progression of neuropathy, quality of life, and gait speed

HELIOS-A phase 3 study of Vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated ( ATTR ) amyloidosis, met its primary and both secondary endpoints at 9 months in patients with hATTR amyloidosis with polyneuropathy.

The primary endpoint was the change from baseline in the mNIS+7 ( modified Neuropathy Impairment Score ) at 9 months as compared to historical placebo data from the APOLLO phase 3 study of Patisiran.
The two secondary endpoints were changes in quality of life assessed by Norfolk QoL-DN ( Norfolk Quality of Life Questionnaire-Diabetic Neuropathy ) and gait speed assessed by the timed 10-meter walk test ( 10-MWT ) compared to historical placebo.

Vutrisiran met the primary endpoint ( p less than 0.001 ) and achieved statistically significant results ( p less than 0.001 ) for each of the Norfolk QoL-DN and 10-MWT secondary endpoints.
In addition, Vutrisiran treatment showed improvement compared to placebo on the exploratory cardiac biomarker endpoint, NT-proBNP ( nominal p less than 0.05 ).
Vutrisiran has also demonstrated an encouraging safety and tolerability profile.

HELIOS-A is a phase 3 global, randomized, open-label study to evaluate the efficacy and safety of Vutrisiran.
The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries.
Patients were randomized 3:1 to receive either 25mg of Vutrisiran ( n=122 ) via subcutaneous injection once every three months or 0.3 mg/kg of Patisiran ( n=42 ) via intravenous infusion once every three weeks ( as a reference comparator ) for 18 months.
The primary endpoint is the change from baseline in mNIS+7 score at 9 months, relative to historical placebo. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to historical placebo. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months.
The efficacy results of Vutrisiran in HELIOS-A are compared to historical placebo control data from the landmark APOLLO phase 3 study, which evaluated the efficacy and safety of Patisiran in a patient population similar to that studied in HELIOS-A.
Following the 18-month study period, all patients are eligible to receive Vutrisiran for an additional 18 months as part of an open-label extension study.

Vutrisiran has demonstrated an encouraging safety profile. There were two study discontinuations ( 1.6% ) due to adverse events in the Vutrisiran arm by month 9, both due to deaths, neither of which was considered related to study drug.
There were two serious adverse events deemed related to Vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection.
Treatment emergent adverse events occurring in 10% or more patients included diarrhea, pain in extremity, fall and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with historical placebo.
Injection site reactions ( ISRs ) were reported in 5 patients ( 4.1% ) and were all mild and transient. There were no clinically significant changes in liver function tests ( LFTs ).

Vutrisiran is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin ( TTR ) protein before it is made.
Quarterly administration of Vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues.

Hereditary transthyretin-mediated amyloidosis is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations.
hATTR affects approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival ( 3.4 years ) for patients presenting with cardiomyopathy. ( Xagena )

Source: Alnylam Pharmaceuticals, 2021