FDA approves vutrisiran for ATTR amyloidosis with cardiomyopathy
Key takeaways:
- The FDA approved vutrisiran for the treatment of transthyretin amyloidosis with cardiomyopathy.
- Approval was backed by the HELIOS-B trial results of vutrisiran as an add-on to tafamidis or alone vs. placebo.
Alnylam announced the FDA approval of its supplemental new drug application for vutrisiran, an RNA interfering small molecule transthyretin stabilizer, for the treatment of transthyretin amyloidosis with cardiomyopathy.
Vutrisiran was previously FDA-approved for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis.
Vutrisiran (Amvuttra) is now approved for the prevention of CV mortality, CV hospitalizations and urgent HF hospitalization in adult patients with wild-type or hereditary transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM), according to a company press release.
The drug is administered in four subcutaneous doses per year and reduces transthyretin production, decreasing deposition of transthyretin fibrils. These fibrils form the amyloid protein, which is associated with CV damage and premature mortality in patients with ATTR-CM.
The approval is based on the results of the phase 3, double-blind HELIOS-B trial, for which 655 patients with ATTR-CM were randomly assigned to vutrisiran or placebo.
As Healio previously reported, compared with placebo, vutrisiran was associated with lower all-cause death or recurrent CV events in patients already taking tafamidis (Vyndamax, Pfizer; HR = 0.72; 95% CI, 0.56-0.93; P = .01; absolute risk reduction, 9.9%) and in those taking vutrisiran alone (HR = 0.67; 95% CI, 0.49-0.93; P = .02; absolute risk reduction, 12.5%). All primary and secondary outcomes of the HELIOS-B trial favored vutrisiran, regardless of whether patients were taking vutrisiran alone or as an add-on to tafamidis, previously the only drug approved by the FDA to treat ATTR-CM.
“This FDA approval provides an opportunity to further transform ATTR-CM treatment with a new mechanism of action. The HELIOS-B clinical trial found that vutrisiran allowed patients to live longer, experience fewer hospitalizations, and improve how they function and feel,” Ronald Witteles, MD, professor of medicine at Stanford University School of Medicine, co-director of the Stanford Amyloid Center and co-investigator on the HELIOS-B trial, said in the release. “The trial enrolled patients who mirror the real-world population with this disease, and I am very encouraged by vutrisiran’s ability to demonstrate meaningful clinical benefits across both cardiovascular outcomes and multiple measures of disease progression. This is a very exciting day for patients with this challenging disease.”
Editor’s note: This is a developing news story. Please check back soon for more details.
Perspective
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It is no surprise that vutrisiran received FDA approval given that the HELIOS-B trial met its primary endpoint of a reduction in CV death and HF hospitalization. It met the same bar for efficacy as tafamidis in ATTR-ACT and acoramidis (Attruby, BridgeBio) in ATTRibute-CM. FDA approval was absolutely appropriate.
The million-dollar question — sadly, somewhat literally — is how to choose among the expanding landscape of therapeutic options for ATTR-CM: a TTR stabilizer, tafamidis or acoramidis, or TTR silencer, vutrisiran, or both. Clinical trials cannot currently help us answer these questions. All are clearly effective, but relative efficacy cannot be inferred from these placebo-controlled trials given the vast differences in trial populations. Participants are healthier in successive eras due to earlier diagnosis and better general HF management, as indicated by their lower baseline N-terminal pro-B type natriuretic peptide, longer 6-minute walk test and lower event rates even in the placebo group.
As for comparing silencers with stabilizers, this is tough too. While HELIOS-B had 40% of patients on tafamidis at baseline and 20% who started it during the trial, when they are published, these underpowered comparisons will have to be interpreted with caution.
It's difficult to say based on evidence how to choose therapies. It's also difficult to say based on mechanism of action. If vutrisiran has 80% TTR knockdown, do you still need to stabilize the remaining 20% of TTR? No one knows. Should TTR levels be used to guide therapy? No one knows, and it's tricky, as stabilizers raise levels, which can be a marker of better outcomes, while silencers lower them. If a patient is progressing on one type of therapy, should you switch to another? Again, no one knows.
In this data-free zone, we'll have to rely on clinical judgment and shared decision-making. My sense is that if cost is not an issue for patients — societal health economics of very expensive therapies aside — they will want "everything" because it stands to reason that everything is better than something. Insurers may end up being the gatekeepers in the decision of stabilizer vs. silencer vs. both, but I'm not sure what reliable data can be used for guidance.
Ultimately, the future is bright for patients with ATTR-CM due to increased recognition and earlier diagnosis. The survival curve for patients in HELIOS-B on treatment approached age-related mortality of patients without ATTR-CM. We may be entering an era where patients may die with, but not from, ATTR-CM. The embarrassment of riches is a good problem to have. We know there are three effective therapies, and now we need to figure out how and when to use them. We can't forget, however, none of these therapies reverse disease. Both stabilizers and silencers just slow progression. So the holy grail of TTR depleters is the next exciting field to watch, with fingers crossed for confirmation of safety and efficacy from ongoing trials.
Professor of Medicine, Smidt Heart Institute at Cedars-Sinai
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