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CLEVELAND -- In a surprise Monday morning move, the FDA declined to expand the indication for anti-amyloid agent patisiran (Onpattro) in treating wild-type or hereditary transthyretin amyloid cardiomyopathy (ATTR-CM, or cardiac ATTR amyloidosis), not just polyneuropathy from the condition.

Drugmaker Alnylam Pharmaceuticals it had received a complete response letter citing insufficient evidence of clinical meaningfulness, but no clinical safety, study conduct, drug quality, or manufacturing issues.

The company said it would keep the gene silencer on the market for its current indication in ATTR-CM polyneuropathy but abandon efforts to expand the indication, focusing instead on another ATTR-CM drug candidate, vutrisiran.

The denial was unexpected, since the FDA's advisory committee in September had voted 9-3 that patisiran's benefits outweigh its risks for the expanded indication. However, the panel appeared unimpressed by the magnitude of the gene silencer's benefits, which didn't meet subjective thresholds for clinical significance compared with placebo.

The decision "is disappointing for the patients who were taking it and felt there was a clinical benefit," said Mathew Maurer, MD, of Columbia University in New York City.

Over the weekend, he presented findings at the Heart Failure Society of America meeting in Cleveland from mid-term follow-up of the APOLLO-B pivotal trial extension study.

For the primary endpoint of 6-minute walk distance, loss in this measure of functional capacity was stable from the end of the main 12-month trial to 24 months (-8.1 vs -7.8 m from baseline) among patients who remained on the drug.

Those who switched from placebo to patisiran had stabilization but not recovery (-25.4 m at 12 months to -26.0 m at 24 months).

While clinical outcome curves continued to separate between the groups out to 24 months, the differences remained statistically nonsignificant for that underpowered comparison of the composite of all-cause mortality, hospitalization, and urgent heart failure visits.

No new safety signals emerged in the open-label extension, Maurer noted. "So the overall risk-benefit of patisiran, we think continues to be favorable through 24 months."

Even if it had been approved, "there's still cost and a lot of other things we have to steer around a little bit," noted session co-moderator Jeff Teuteberg, MD, of Stanford University Health Care in California.

The extended phase data doesn't change much from the , he told 名媛直播. "But it is at least nice to see that even when you wait and people have gotten worse in front of your eyes, at least there's some stabilization. Was it a gigantic study? No, but at the same time, it's just kind of one more drop in the bucket of evidence that seems to favor its use."

Maurer agreed: "I do think this data adds to the confidence that the effects we saw at 12 months are sustained for 24 months. That's a good thing. I think if it slipped, everyone would be a little concerned."

The phase III APOLLO-B trial included 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries. Participants were randomized 1:1 to receive patisiran (0.3 mg/kg) or placebo intravenously every 3 weeks. After 12 months, 334 patients got patisiran in an open-label extension to month 24.

An exploratory analysis showed that cardiac biomarkers improved in the group that switched from placebo to patisiran to reach a similar level as seen in those who remained on the drug.

One limitation was the lack of longer-term follow-up, Maurer told 名媛直播. "It's a 1-year study. There's a lot to expect in a disease that most other trials went for longer. So hard endpoints take longer to accrue."

There was no analysis on what factors identified better responders, Maurer said.

"I can tell you practically, in my site there were people [who] learned what they were on in the double-blind period. They definitely, whether true or not, felt better. I have a patient who fell apart in the double-blind period ... and he's not the same patient," he said.

While disappointing that the drug won't be available for these patients, "we wait for potentially easier drugs to administer with potentially better data that has more hard endpoints to feel more confident about," Maurer said.

Without any predictive factors or predictive scores, it's going to be hard to find the sweet spot for patient selection with transthyretin stabilizers like tafamidis (Vyndaqel or Vyndamax), Teuteberg said. "Can we give these medicines to every single person who has amyloids? Probably not."

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