Long-term Amvuttra treatment safe, pooled trial analysis shows
Study analyzes 5-year data from 700-plus patients in Phase 3 trials
Amvuttra (vutrisiran) appears to be safe for long-term use in adults with familial amyloid polyneuropathy (FAP) and those with another form of transthyretin amyloidosis (ATTR) that causes heart damage.
That’s according to an analysis of more than 700 patients who received Amvuttra in one of two Phase 3 clinical trials — HELIOS-A (NCT03759379) and HELIOS-B (NCT04153149) — for as long as five years. Side effects were similar to those observed with a placebo, with no concerns for the heart, eyes, liver, or kidneys.
“This pooled analysis, in a large and [variable] population of patients with ATTR who had up to [nearly five years] of treatment demonstrates that [Amvuttra] is well tolerated and has an acceptable safety profile,” the researchers wrote.
The results of the analysis were detailed in the study “Vutrisiran in Transthyretin Amyloidosis: A Pooled Safety Analysis of HELIOS-A and HELIOS-B,” published in the journal JACC: Advances by an international team of researchers. The study was funded by Alnylam Pharmaceuticals, which markets Amvuttra.
ATTR occurs when misfolded transthyretin proteins build up as toxic clumps, called amyloid deposits, in tissues. It can be hereditary or develop with aging, in which case it is called wild-type ATTR. In FAP, a hereditary form of ATTR, amyloid deposits build up in peripheral nerves, or those outside the brain and spinal cord, resulting in FAP symptoms such as loss of sensation and weakness in the body’s extremities. When these toxic transthyretin clumps accumulate mainly in the heart, the disease is called ATTR with cardiomyopathy (ATTR-CM).
Medication cuts transthyretin production to prevent amyloid deposit building
Amvuttra, administered via under-the-skin injections, is approved to treat FAP and hereditary or wild-type ATTR with cardiomyopathy. It works by reducing the production of both healthy and misfolded transthyretin, which is expected to prevent amyloid deposits from building up, easing symptoms or slowing how fast they progress.
Its approval was based on data from HELIOS-A (for FAP) and HELIOS-B (for ATTR-CM). Data from the first part of each trial, covering up to three years of treatment, showed that Amvuttra was generally safe and well tolerated. Participants completing this part of the study could enter a second part where all would receive the therapy for a longer period.
The researchers looked at how safe and well tolerated the medication is over a longer period. To do this, they combined data from 707 patients, with a mean age of 68.5, who received Amvuttra for up to 58 months (nearly five years) as part of HELIOS-A or HELIOS-B.
For comparison, data from the external placebo group used for HELIOS-A and the group of participants in HELIOS-B who were assigned a placebo were also considered.
In HELIOS-A, 160 adults with FAP were treated for a median of 44.3 months (about 3.5 years). In HELIOS-B, 547 adults with hereditary or wild-type ATTR-CM received Amvuttra for a median of 19.3 months (about 1.5 years). Among all participants, the medication was given for a median of 33.4 months, or nearly three years (range, zero months to nearly five years).
Results showed that the rates of adverse events in Amvuttra-treated patients were similar to or lower than those observed with a placebo. They were also similar to what had been reported during the initial parts of the HELIOS-A and HELIOS-B trials, suggesting that long-term treatment does not introduce new safety concerns.
“For the majority of [adverse events], severity was classified as mild or moderate,” the researchers wrote.
Severe adverse events rates with Amvuttra were also comparable to or lower than those of the placebo.
The most commonly reported adverse event was COVID-19, followed by heart failure, abnormal heart rhythm, and falls. These occurred less often in patients treated with Amvuttra compared with those on the placebo.
Heart-related adverse events “reflected the underlying … disease [at study’s start] as shown by the event rates in the combined [Amvuttra] group, separate HELIOS-A and HELIOS-B [Amvuttra] groups, and the respective placebo comparator groups,” the team wrote.
Injection-site reactions were uncommon. When they did occur, they were mild or moderate and did not lead to serious problems.
No safety concerns were seen in the eyes, liver, or kidneys. These organs are routinely monitored in clinical studies because damage to them can be serious and lead to complications.
“In a broad population of patients with ATTR who were treated for up to 58 months, [Amvuttra] was well tolerated and had an acceptable safety profile, consistent with that previously reported for the HELIOS-A and HELIOS-B studies,” the researchers wrote. “Continued monitoring of safety events will provide further long-term data on the safety of [Amvuttra] in patients with ATTR in clinical practice.”
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