Onpattro stabilizes FAP progression in 2 common genetic variants
Study: Patients with either mutation were underrepresented in previous trials
Onpattro (patisiran) safely and effectively helps adults with familial amyloid polyneuropathy (FAP) caused by a V122I or T60A genetic mutation keep their disease from getting worse, according to a real-world study in the U.S.
The post-marketing Phase 4 study (NCT04201418) focused on patients with one of these two mutations because, although these variants are common in the U.S., these patients have been underrepresented in FAP trials, including those that supported Onpattro’s approvals.
The Alnylam Pharmaceuticals’ therapy is approved in the U.S. for adults with FAP, also known as hereditary transthyretin amyloidosis (hATTR) with polyneuropathy. In Europe and other regions, Onpattro is cleared for use for similar indications.
The study, “Impact of patisiran on polyneuropathy of hereditary transthyretin amyloidosis in patients with a V122I or T60A variant: a phase IV multicenter study,” was published in the Annals of Medicine. It was funded by Alnylam.
FAP is a form of hATTR affecting the peripheral nerves
In hATTR, mutations in the TTR gene cause the production of a faulty transthyretin protein that builds up as toxic clumps in the body’s tissues, resulting in damage.
FAP is a form of hATTR in which these toxic clumps accumulate mainly in the peripheral nerves — those that branch out from the spinal cord — causing polyneuropathy, or damage to multiple nerves.
The V122I and T60A mutations in the TTR gene are among the most commonly reported in the U.S. among people with hATTR. While most people carrying either of these variants mainly manifest a form of hATTR that primarily affects the heart, some patients also have FAP.
Administered as an infusion into the bloodstream once every three weeks, Onpattro is a gene-silencing medication that binds to the genetic material that carries instructions for producing transthyretin. By doing so, the therapy reduces the production of both healthy and faulty transthyretin, thereby preventing the formation of toxic clumps and easing FAP symptoms.
Participants had either a V122I or a T60A mutation
The goal of this post-marketing, real-world study was to evaluate Onpattro’s safety and efficacy in adults with FAP and a confirmed disease-causing V122I or T60A mutation in the TTR gene.
A total of 67 patients were enrolled at 27 centers across the U.S.. Fifty-eight received at least one dose of Onpattro during the study and were included in the final analyses.
The mean age of Onpattro-treated patients was 65.1 years, and 63.8% were men. The V122I mutation was present in 45 patients (77.6%), mostly of Black or African American descent, while the T60A mutation was present in 13 (22.4%), all of whom were white. On average, it took 2.7 years after the first symptoms appeared for patients to be diagnosed with FAP. At the start of the study, all patients had some polyneuropathy-related disability, although more than half (56.9%) still had preserved walking despite sensory disturbances. Most (89.7%) also had heart failure.
The majority of participants (86.2%) were prescribed Onpattro after experiencing disease progression. Over half of these 50 participants (52%) experienced progression due to polyneuropathy; 20 (40%) due to a combination of polyneuropathy and heart disease; and four (8%) due to heart disease alone. Nearly half (43.1%) also received at least one other medication for hATTR.
By the end of the study, 45 patients had completed 12 months of follow-up. Most of them had stable (64.4%) or improved (28.9%) polyneuropathy disability scores, a measure of the functional impact of polyneuropathy.
Of the three participants who worsened, two also had diabetes and one had Ehlers-Danlos syndrome — “diagnoses potentially contributing to polyneuropathy,” the researchers wrote.
[Onpattro] demonstrated a consistent positive effect across multiple [measures] in patients with V122I/T60A ATTRv amyloidosis with polyneuropathy, with the potential to stabilize or improve manifestations of polyneuropathy with 12 months of treatment.
Participants also showed improvements in quality of life and health status, as well as reductions in autonomic symptoms, which are common in FAP and include problems with blood pressure control, sweating, or digestion. These benefits were first detected within the first six months of treatment.
For most patients, the severity of heart failure remained stable or lessened.
Nearly one-third of patients (31%) reported adverse events, which were mostly mild or moderate in severity and included infusion-related reactions and heart failure (4.8% of patients each).
A total of 11 participants (19%) were hospitalized, primarily due to heart failure, but these were not considered related to Onpattro. Four patients (6.9%) died during the study, but none of the deaths were linked to the medication.
Onpattro “demonstrated a consistent positive effect across multiple [measures] in patients with V122I/T60A ATTRv amyloidosis with polyneuropathy, with the potential to stabilize or improve manifestations of polyneuropathy with 12 months of treatment,” the researchers wrote. “Patients with V122I/T60A ATTRv amyloidosis may often have multisystem disease with both [heart muscle disease] and peripheral neuropathy, highlighting the importance of a treatment that demonstrates benefit across the multisystem manifestations of this disease,” they concluded.
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