Long-term Amvuttra benefits hATTR-PN patients, trial data show
Treatment safely demonstrated sustained improvement in nerve function
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Long-term treatment with Amvuttra (vutrisiran) was found to be safe and to sustain disease stability in people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).
That’s according to up to five years of data from the Phase 3 HELIOS-A clinical trial (NCT03759379), in which patients showed a sustained improvement in nerve function, mobility, and quality of life.
These results “demonstrate relative stability with only modest changes in disease activity, sustained [reductions in the faulty transthyretin, or TTR, protein], and an acceptable safety profile with long-term [Amvuttra] treatment in patients with [hATTR-PN],” the researchers wrote.
The results were published in the study “Long-term efficacy and safety of vutrisiran in hereditary transthyretin amyloidosis with polyneuropathy: final analysis of the HELIOS-A randomized treatment extension,” which was published in Amyloid.
Amvuttra targets RNA molecule derived from key gene
A progressive disease, hATTR-PN is caused by mutations in the TTR gene that result in the production of a faulty TTR protein that is prone to form toxic clumps. These aggregates accumulate mainly in the peripheral nerves, or those found outside the brain and spinal cord, causing neurological symptoms.
Amvuttra, marketed by Alnylam Pharmaceuticals, is an RNA interference (RNAi) therapy that works by targeting an RNA molecule derived from the TTR gene that is used as a template to produce TTR protein. The therapy is specifically designed to target liver cells, where most TTR is produced.
This is expected to prevent accumulation of toxic TTR clumps, easing symptoms and slowing disease progression.
Amvuttra’s approvals for hATTR-PN were based on data from the first part of the HELIOS-A study, in which 164 patients were randomly assigned to receive either Amvuttra or Onpattro (patisiran), an older hATTR-PN-approved therapy, for up to 18 months (1.5 years).
Results showed that Amvuttra led to a reduction in neurological symptoms and disability compared with an external group of patients given a placebo in the Phase 3 APOLLO trial (NCT01960348), data from which supported Onpattro’s approval.
Participants’ blood TTR levels were reduced by a mean of 84.5%
In this study, researchers assessed Amvuttra’s long-term safety and efficacy in 149 patients who completed HELIOS-A’s first part and entered its randomized treatment extension (RTE), in which all received Amvuttra for up to 3.5 years.
RTE participants had a median age of 62 years and were mostly men (62.4%). Most (75.2%) had been originally assigned Amvuttra, while about one-quarter transitioned from Onpattro. A total of 45 patients were treated continuously with the therapy for about five years during HELIOS-A.
After up to five years in the study, participants’ blood TTR levels were reduced by a mean of 84.5%. This drop was seen early on and maintained across the study duration. Similar reductions were observed in patients who received Amvuttra for the entire study and those who transitioned from Onpattro to Amvuttra.
In addition, Amvuttra’s efficacy in terms of reducing or slowing the progression of disability and nutritional defects, as well as improving quality of life, was sustained from the start of the RTE to 1.5 years later.
Specifically, nerve damage-related disability (as assessed with the validated modified Neurologic Impairment Score plus 7 and the polyneuropathy disability score) and walking ability, measured with the 10-meter walking distance, showed only small changes during the extension portion.
These data are in alignment with the findings from the initial [1.5-year] treatment period, supporting the long-term efficacy and safety of [Amvuttra] in patients with [hATTR-PN].
Patients’ quality of life, as assessed with the Norfolk Quality of Life-Diabetic Neuropathy, disability assessments (evaluated with the Rasch-built Overall Disability Scale), and nutritional status also remained largely unchanged.
“Importantly, consistent results were observed for both TTR reduction and clinical efficacy [measures] in patients who received [Onpattro] for 18 months [in the first part of the trial] and transitioned to [Amvuttra] in the RTE,” the researchers wrote. “These findings are notable in a disease with a well-recognized natural history of rapid and inexorable decline in untreated patients,” the researchers wrote.
Patients showed a generally acceptable safety profile, with most adverse events being of mild to moderate severity. The most common events were COVID-19 (31.5%), urinary tract infection (17.4%) and falls (14.8%). No new safety concerns were identified with longer treatment.
Overall, 19 patients (12.8%) discontinued Amvuttra during the extension portion, but none was related to adverse events.
“These data are in alignment with the findings from the initial [1.5-year] treatment period, supporting the long-term efficacy and safety of [Amvuttra] in patients with [hATTR-PN],” and “reinforce the established clinical benefits of TTR knockdown with RNAi therapeutics,” the researchers wrote.
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