ATTR-CM therapy shows consistent effects across treatment groups

In people with transthyretin amyloid cardiomyopathy (ATTR-CM), treatment with the approved therapy Amvuttra (vutrisiran) may help reduce the risk of death and serious heart problems, with similar trends seen in patients who were and were not taking Vyndamax (tafamidis) at baseline, a new analysis suggests.

Alnylam Pharmaceuticals, the company that markets Amvuttra, presented the analysis at the European Society of Cardiology (ESC) Congress recently held in Germany. The findings were simultaneously reported in a study titled “Effect of Vutrisiran According to Baseline Tafamidis Use in Transthyretin Amyloidosis With Cardiomyopathy: Insights From HELIOS-B,” published in the Journal of the American College of Cardiology.

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Two ATTR-CM treatment approaches target TTR in different ways

ATTR-CM is a disorder in which a protein called transthyretin (TTR) forms toxic clumps that build up and damage the heart. In recent years, several new ATTR-CM treatments have been developed. These medicines fall into two main categories: gene silencers like Amvuttra, which reduce the production of the TTR protein, and protein stabilizers like Vyndamax, which help prevent TTR from misfolding and contributing to the buildup of toxic clumps.

Gene silencers and stabilizers work in complementary ways, but neither approach is complete on its own: some TTR production continues despite gene silencing, while protein stabilization is not absolute. This raises the possibility that using the two approaches together could provide added benefit. However, clinical evidence testing combination treatment remains limited. According to an editorial published alongside the study, whether or not this combination offers added benefit “is now one of the most pressing unanswered questions in the field.”

Approvals of Amvuttra for ATTR-CM were based mainly on data from HELIOS-B (NCT04153149), a Phase 3 clinical trial that tested the therapy against a placebo in more than 600 people with the disease. About 40% of participants in HELIOS-B were taking Vyndamax at the start of the study; the therapy had already been approved at that time. HELIOS-B was funded by Alnylam, and two study authors were company employees.

The main goal of HELIOS-B was to see if Amvuttra would decrease the risk of a composite outcome that included death from any cause and recurrent heart-related health events. The study met its goal: the risk of death or recurrent heart-related events was lower in patients given Amvuttra compared with placebo. In the total study population, this difference was statistically significant, meaning that mathematically it’s highly unlikely that the difference can be explained by random chance.

In this new analysis, researchers compared the effects of Amvuttra in patients who were or were not taking Vyndamax at the start of the study. The researchers found directionally consistent effects in both groups — in other words, the risk of death and/or heart events tended to be lower in patients given Amvuttra whether or not they were taking Vyndamax at baseline. However, the study was not designed to definitively determine Amvuttra’s benefit specifically in patients taking Vyndamax at baseline, so the findings in that group remain uncertain.

Amvuttra preserved walking ability across treatment groups

Data also showed that Amvuttra helped preserve walking distance on the six-minute walk test in both treatment groups. The test is a common measure of exercise capacity. Health-status questionnaire scores also favored Amvuttra, although the effect relative to placebo was smaller among patients who were taking Vyndamax at the start of the study.

Overall, the data “raise the possibility of incremental benefit of concomitant [Amvuttra and Vyndamax use] over [Vyndamax] alone,” the researchers wrote. However, they stressed that the results are not definitive, emphasizing a need for further studies to determine the best way to use gene silencers and protein stabilizers for the best clinical outcomes in ATTR-CM.

In other presentations at ESC, Alnylam shared multiple post hoc analyses of HELIOS-B, meaning additional analyses that were not included in the trial’s original analysis plan. These analyses indicated that patients given Amvuttra were less likely than those given placebo to experience decline in intrinsic capacity, a measure of physical and mental abilities important for day-to-day functioning. A separate analysis found fewer adverse events overall with Amvuttra than with placebo.

In addition to ATTR-CM, Amvuttra is also approved to treat hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), a related condition where TTR protein clumps mainly accumulate and damage nerves. In another ESC analysis, researchers pooled data from four Phase 3 studies involving patients with ATTR-CM or hATTR-PN. The goal was to see whether treatment effects differed according to biological sex, and results showed that treatment effects were consistent between males and females.

“These data add to the deep and consistent evidence base supporting [gene] silencing in ATTR-CM,” Teresa Trenkwalder, MD, senior physician at TUM University Hospital German Heart Center, said in a press release from Alnylam. “Across patient populations, treatment settings, and manifestations of disease, the analyses of [Amvuttra] demonstrate the clinical benefit that can be achieved by reducing TTR production at its source.”