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LONDON -- Vutrisiran (Amvuttra) improved functional and disease outcomes as well as survival in transthyretin amyloidosis cardiomyopathy (ATTR-CM), according to findings from the HELIOS-B phase III trial.

And the benefits in comparison with placebo were seen regardless of background use of TTR stabilizer tafamidis (Vyndamax, Vyndaqel), as Marianna Fontana, MD, PhD, of University College London, reported at the European Society of Cardiology (ESC) meeting in London. The findings were simultaneously released in the .

For the primary composite endpoint of death from any cause and recurrent cardiovascular events, the RNA-interfering therapy reduced relative risk by 33% in those taking it as monotherapy and by 28% overall when including the 40% of patients who were on tafamidis at baseline (at least one event in 39% vs 53%, P=0.02, and 38% vs 48%, P=0.01, respectively).

Secondary endpoints showed similar reductions for vutrisiran over placebo in the overall cohort:

• All-cause mortality at 42 months (18% vs 26%, HR 0.65, 95% CI 0.46-0.90)
• Decline in 6-minute walk distance at 30 months (6MWD, least-squares mean difference 26.5 m, 95% CI 13.4-39.6)
• Decline in quality of life score on the Kansas City Cardiomyopathy Questionnaire at 30 months (least-squares mean difference 5.8 points, 95% CI 2.4-9.2)

What Fontana called "profound and unequivocal" efficacy results were widely seen as likely to lead to FDA approval of an expanded indication in treating ATTR-CM beyond just polyneuropathy from the disease. In from HELIOS-B, drugmaker Alnylam said it was "moving with urgency to file these compelling data with regulators."

If approved, Fontana said, "vutrisiran has the potential to become the standard of care for newly diagnosed patients and those progressing on stabilizing therapy ... We had only one stabilizer [tafamidis], and we didn't know what to do in patients who were progressing. So for me when I'm going to see patients in clinic, if the drug is going to be approved, this is a very suitable treatment option as first line."

The findings contrasted with the small gains in 6MWD and quality of life (difference of 14.7 m and 3.7 points at 12 months) in the with patisiran (Onpattro) versus placebo that weren't enough to gain it a similar expansion in indication.

Unlike those findings that had been criticized by FDA advisors as not clinically meaningful, vutrisiran showed meaningful impacts on outcomes patients care about, Fontana told 木瓜直播 at an ESC press conference.

"This is certainly more impressive," agreed Dipti N. Itchhaporia, MD, of Hoag Heart and Vascular Institute in Newport Beach, California, and a past president of the American College of Cardiology, suggesting "potential to become the new standard of care."

"If you can have a drug that's going to help with the polyneuropathy but also the progression of the amyloid cardiomyopathy, it seems to me like that would be very appealing," said Itchhaporia, who was not involved in the trial. "Obviously, we're going to have to see about the cost."

included 655 adults with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. They were randomized to double-blind treatment with 25-mg vutrisiran or placebo subcutaneously once every 3 months during a double-blind treatment period of up to 36 months. After that, both groups could get vutrisiran in an open-label extension period. After randomization, 21-22% of patients in both treatment groups initially on monotherapy started taking tafamidis.

Vutrisiran met all 10 primary and secondary endpoints and for all patient subgroups. "A trend toward particularly large effect was seen in patients with early disease, highlighting the need to begin the most effective treatment as early as possible," Fontana said.

She also called the safety profile "acceptable and consistent with previously published data from the HELIOS-A trial and from postmarking authorization."

What the study couldn't do is compare vutrisiran monotherapy against tafamidis monotherapy. Nor were patients randomized to the combination or vutrisiran monotherapy.

"Do we really need to do two drugs? That's going to be an important piece of information, of course," Itchhaporia noted. Another question is longer term safety and whether there is any drop-off of the effect after a period of time. "You know, 36 months is a good amount of time, but we still need 5-year data and longer-term data."

Practically speaking, "I see measuring the TTR levels as one of the advantages of a silencer, for example, over a stabilizer," Fontana noted. "It's also very reassuring for patients and physicians to measure the TTR levels and actually being able to show that the drug is doing exactly what it's supposed to do."

Overall, the results also marked the improvements in prognosis that have occurred with the available treatments and earlier diagnosis, said ESC session study discussant Sarah Cuddy, MD, of Brigham and Women's Hospital in Boston.

"Look what we've done in a disease space in 6 years. We've taken [it from] where a placebo going into a trial had a 30-month survival of 57%, and now we've shifted this to over 80%. This is such a win for this disease."

Other gene silencers and novel agents are in the works for ATTR-CM as well, including anti-ATTR amyloid antibodies that would remove rather than just stabilize amyloid. "So I think this space will continue to be hugely exciting in the years to come," Cuddy concluded.

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