Alnylam to no longer pursue US approval of Onpattro for ATTR-CM

FDA rejects therapy despite positive opinion by its own committee

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Many hands are seen giving the thumbs down sign against the backdrop of a red circle.

The U.S. Food and Drug Administration (FDA) has rejected Alnylam Pharmaceuticals‘ application seeking the expansion of its Onpattro (patisiran) label to include treatment of people with ATTR amyloidosis with cardiomyopathy (ATTR-CM), or heart damage.

Based on the regulatory rejection, Alnylam has decided to no longer pursue an approval of Onpattro for this indication in the U.S., according to a company press release.

The commercial availability of Onpattro for adults with familial amyloid polyneuropathy (FAP), a related condition for which the therapy has been approved since 2018, will not be affected.

In a complete response letter to the company — which is not a final decision — the FDA said there was insufficient evidence to establish the clinical meaningfulness of Onpattro’s efficacy in ATTR-CM. No issues with safety, trial conduct, or quality and manufacturing were identified.

However, the negative decision was issued despite a positive opinion last month from from one of the FDA’s own advisory committees, which by a 9-3 vote found that the treatment’s benefits outweighed its risks for ATTR-CM. While the agency considers such committee opinions in its decisions, they are not binding, as was seen in this case.

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Onpattro shows benefits for 1.5 years in ATTR cardiomyopathy trial

Alnylam now working to develop Amvuttra for ATTR-CM

Alnylam, which called the FDA decision disappointing, said it plans to maintain treatment access to Onpattro for ATTR-CM patients already receiving the medication as part of an ongoing trial.

That means that participants in the open-label extension (OLE) period of the Phase 3 APOLLO-B clinical trial (NCT03997383) — whose data had supported the request for the label expansion — will still be able to continue on the therapy.

Treatment also will be maintained for those in a U.S. expanded access protocol (NCT05505838) that was assessing the long-term safety of Onpattro in ATTR-CM patients through a review of adverse events, or side effects.

“First and foremost,” said Yvonne Greenstreet, CEO of Alnylam, “our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating and fatal disease and face significant unmet need. While we are disappointed by this decision, we are committed to supporting them and are well positioned to address their needs with continued innovation that can potentially help improve their outcomes and treatment experience.”

First and foremost, our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating and fatal disease and face significant unmet need. … We are disappointed by this decision.

For this patient group, the company will continue developing another of its therapies, Amvuttra (vutisiran).

Approved for FAP last year, Amvuttra has the same mechanism as Onpattro, but a different route of administration. Instead of intravenous or into-the-vein infusions, given every three weeks, Amvuttra is administered via subcutaneous, or under-the-skin, injections every three months.

Indeed, Greenstreet noted in a company conference call about the regulatory rejection that Alnylam had in large part been developing Onpattro for ATTR-CM as part of a “bridging strategy to unlock the cardiomyopathy opportunity” of the medication.

“Our eyes ultimately [were] on bringing our next generation product, Amvuttra, to cardiomyopathy patients,” Greenstreet said.

A Phase 3 trial (NCT04153149), dubbed HELIOS-B, now is testing Amvuttra against a placebo among 655 ATTR-CM patients — nearly double the number of participants in APOLLO-B.

HELIOS-B’s main goal is to assess whether Amvuttra, at a dose of 25 mg, is superior to a placebo at reducing a composite outcome of mortality and cardiovascular events over 2.5 years.

“We remain confident in the HELIOS-B Phase 3 study of [Amvuttra] and look forward to sharing topline results in early 2024,” Greenstreet said.

“If successful, we believe [Amvuttra] will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits,” she said.

ATTR amyloidosis encompasses a group of rare diseases in which the transthyretin (TTR) protein forms toxic clumps in the body’s tissues. FAP is a hereditary form of the disease characterized mainly by nerve damage — but it also can affect the heart and other tissues. In ATTR-CM, which is sometimes hereditary, TTR accumulates in the heart, causing damage.

Onpattro works to reduce TTR protein levels by interfering with an intermediate molecule involved in its production. That in turn prevents the protein from clumping, and case ease symptoms of ATTR amyloidosis.

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AAN 2023: Amvuttra and Onpattro show similar efficacy in Phase 3 trial

Results of Onpattro for ATTR-CM were ‘very encouraging,’ per Alnylam

Alnylam’s application to expand the therapy’s indication for ATTR-CM was supported by data from the Phase 3 APOLLO-B trial, which “was designed in consultation with the FDA,” Greenstreet said in the conference call.

A total of 360 adults with ATTR-CM were enrolled and randomly assigned to receive either Onpattro (3 mg/kg) or a placebo once every three weeks for a year. The main goal was to assess changes in how far a person could walk in six minutes — the six-minute walk test, or 6MWT, is a standard functional measure in heart disease trials — Greenstreet noted.

The results showed that Onpattro significantly slowed declines in 6MWT by 62% compared with a placebo after a year of treatment, meeting its main goal. It also met a key secondary goal related to improvements in health status and life quality relative to a placebo, with a similar safety profile as in previous studies.

Participants then were able to enter APOLLO-B’s OLE phase, in which all are receiving Onpattro for as long as three more years. Data recently presented indicated that the benefits of Onpattro were sustained through two years of treatment.

While the trial was not designed to directly assess changes in heart-related outcomes, favorable trends were observed in terms of survival, hospitalizations, and urgent heart failure-associated hospitalizations, Greenstreet noted in the conference call.

Given these positive findings from a trial with an FDA-approved design, and the positive recommendation by the agency’s committee, Anlylam was “quite surprised” with the regulatory rejection, Greenstreet said, noting in the conference call that the trial data were “very encouraging.”

“[We want to] express our deepest gratitude to patients, clinical investigators, investigators, and study staff that participated in the APOLLO-B study,” Greenstreet said.

Alnylam also is exploring another treatment candidate, called ALN-TTRsc04, for forms of ATTR amyloidosis. The once-yearly therapy has the potential to reduce TTR protein levels by more than 90%, according to the company.

A Phase 1 trial (NCT05661916) is underway to evaluate the therapy’s safety, tolerability, and pharmacological properties among healthy adults at a single site in London.

“Beyond [Amvuttra], we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen,” Greenstreet said in the release.