Vutrisiran reduces death, CV events in ATTR amyloidosis with cardiomyopathy
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Key takeaways:
- Vutrisiran lowered risk for death and recurrent CV events vs. placebo in patients with ATTR-CM.
- The results were consistent regardless of whether a patient was taking another amyloidosis drug.
Among patients with transthyretin amyloidosis with cardiomyopathy, vutrisiran, an RNA interference agent, reduced risk for death and recurrent CV events compared with placebo, according to the results of the HELIOS-B trial.
The results were consistent regardless of whether patients were already taking tafamidis (Vyndamax, Pfizer), a transthyretin stabilizer, the only drug currently approved by the FDA to treat transthyretin amyloidosis with cardiomyopathy (ATTR-CM), as well as for patients earlier in their disease.
“Vutrisiran demonstrated profound and unequivocal benefit on CV outcomes, including mortality and disease progression, in a contemporary population of patients who were also receiving multiple effective therapies, including tafamidis, SGLT2 inhibitors and diuretics,” Marianna Fontana, MD, PhD, professor of cardiology, University College London, National Amyloidosis Centre, Royal Free Hospital, London, said during a press conference at the European Society of Cardiology Congress.
For the phase 3 HELIOS-B trial, which was simultaneously published in The New England Journal of Medicine, Fontana and colleagues randomly assigned 655 patients with ATTR-CM to vutrisiran (Amvuttra, Alnylam) or placebo. The researchers analyzed the overall cohort as well as a subgroup of 395 patients who were taking vutrisiran or placebo as monotherapy. Vutrisiran is currently approved by the FDA for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis, but is not yet indicated for patients with ATTR-CM.
During the double-blind period (up to 36 months, prespecified), the primary endpoint of all-cause death or recurrent CV events occurred less often in the vutrisiran group in the overall cohort (HR = 0.72; 95% CI, 0.56-0.93; P = .01; absolute risk reduction, 9.9%) and in the monotherapy cohort (HR = 0.67; 95% CI, 0.49-0.93; P = .02; absolute risk reduction, 12.5%), according to the researchers.
Up to 42 months (prespecified), death from any cause was lower in the vutrisiran group (HR for overall cohort = 0.65; 95% CI, 0.46-0.9; P = .01; HR for monotherapy cohort = 0.66; P = .0454).
Compared with placebo, in the overall population, vutrisiran slowed decline in 6-minute walk distance (difference, 26.5 m; 95% CI, 13.4-39.6; P < .001) and in the Kansas City Cardiomyopathy Questionnaire overall summary score (difference, 5.8 points; 95% CI, 2.4-9.2), and similar trends occurred in the monotherapy population, the researchers found.
Nearly all patients in both groups experienced adverse events, whereas serious adverse events occurred in 62% of the vutrisiran group and 67% of the placebo group, according to Fontana and colleagues.
All 10 primary and secondary outcomes favored vutrisiran, and all results were consistent regardless of whether patients were taking vutrisiran or placebo as monotherapy or as an add-on to tafamidis, she said during the press conference.
That is important because tafamidis is the only approved therapy for ATTR-CM, “and if the only option doesn’t work ... there’s absolutely nothing we can do,” Fontana said during the press conference. “Now we’ve got options. The high proportion of patients who are progressing on a stabilizer, we can discuss if we should add on vutrisiran, a silencer, which has shown benefit on top of a stabilizer, or should we switch class completely. It is reassuring for patients and physicians to be able to measure TTR levels and actually be able to show that the drug is doing exactly what it is supposed to do, which is knocking down TTR production.”
In addition, the vutrisiran group was more likely to have stable or improved NYHA HF class at 30 months than the placebo group (overall population: adjusted difference, 8.7%; P = .0217; monotherapy population: adjusted difference, 12.5%; P = .0121), the researchers found.
“When I talk to patients about what does it mean for them, this drug prolongs life, and they live better. These are the two things that really matter to patients,” Fontana said during the press conference. “For me, this is a huge impact on patients and their caring physicians.”
References:
- Alnylam presents detailed results from the positive HELIOS-B phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy at the European Society of Cardiology Congress. https://via.tt.se/pressmeddelande/3592981/alnylam-presents-detailed-results-from-the-positive-helios-b-phase-3-study-of-vutrisiran-in-patients-with-attr-amyloidosis-with-cardiomyopathy-at-the-european-society-of-cardiology-congress. Published Aug. 30, 2024. Accessed Aug. 30, 2024.
- Fontana M, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2409134.
Perspective
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HELIOS-B is one of the most positive trials I have ever seen. The two primary endpoints were positive, as were 10 out of 10 secondary endpoints. There were significant reductions in all-cause death or recurrent CV events in the overall cohort and the tafamidis-naive population, and a 35% reduction in all-cause mortality with vutrisiran, which is huge. Quality of life and 6-minute walk test were among the endpoints improved with vutrisiran, and the results were independent of subgroups. It did not matter whether a patient had hereditary vs. wild-type ATTR, etc.
We knew most of those things when the top-line results were released, but we learned some new things from the presentation. No. 1, where was the separation of the curves. In the ATTR-ACT trial of tafamidis, the event curves separated at around 20 months. In the ATTRibute-CM trial of acoramidis (BridgeBio Pharma), the curves separated around 10 months. Here, we see an earlier separation, at around 6 months. That is very positive for vutrisiran.
No. 2, we wanted to know about combination therapy — vutrisiran plus tafamidis. In the future, cardiologists would like to prescribe silencers plus stabilizers. Keeping in mind that the trial was not powered for this comparison, the combination of vutrisiran and tafamidis seems to be better than vutrisiran alone. Those who received combination therapy had a 22% reduction in all-cause death or recurrent CV events and a 40% reduction in all-cause mortality. Directionally, this looks promising.
All the subgroups and biomarkers told a similar story. Vutrisiran improved levels of troponin and N-terminal pro-B type natriuretic peptide, as well as TTR, which means the patients are more stable. It also improved functional capacity and quality of life. In addition, there were no safety concerns.
The question from now on is when you have a patient with ATTR, should you prescribe tafamidis, acoramidis or vutrisiran? In the short term, the deciding factor is going to be insurance approval. Because patients who need tafamidis have usually been getting it, that may be tried first. But patients who cannot be stabilized with tafamidis may be switched to acoramidis or vutrisiran.
Perspective
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Jose A. Alvarez-Cardona, MD, FACC, FHFSA, FICOS
Vutrisiran is an RNA interference therapeutic that is administered subcutaneously every 3 months and is currently FDA approved for the treatment of hereditary ATTR polyneuropathy. In contrast, tafamidis is an oral TTR stabilizer that is currently FDA approved for the treatment of wild-type or hereditary ATTR cardiomyopathy.
The results of this study highlight the importance of early diagnosis and initiating treatment as soon as possible. There was a significant reduction in all-cause mortality and CV events with vutrisiran, regardless of the baseline use of tafamidis.
If approved, vutrisiran will provide a new treatment option for patients with wild-type ATTR-CM who are currently limited to one FDA-approved drug, tafamidis.
If vutrisiran is approved, clinicians will need to decide where this therapy will fall in the treatment armamentarium with respect to TTR stabilizers, and if there is sufficient evidence to support monotherapy or combination therapy, especially in patients with both cardiomyopathy and neuropathy.
Although wild-type ATTR amyloidosis has been primarily associated with cardiomyopathy, neurological symptoms are being increasingly recognized in these patients. I look forward to seeing what the effects of vutrisiran will be in terms of neuropathy in wild-type ATTR.
It will be important to make it available to patients considering cost and accessibility.
Collapse
Fontana M, et al. Hot line 1. Presented at: European Society of Cardiology Congress; Aug. 30-Sept. 2, 2024; London (hybrid meeting).
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