Alnylam gearing up for Phase 3 trial of nucresiran in FAP late this year
Details of TRITON study design still being discussed with global regulators
Alnylam Pharmaceuticals is planning to launch a Phase 3 clinical trial toward the end of this year to test its therapy candidate nucresiran in people with familial amyloid polyneuropathy (FAP) — though details on the trial’s design are still being discussed with global regulators.
That’s according to pipeline updates announced by the company in a press release and an R&D Day event last week.
Like Alnylam’s Onpattro (patisiran) and Amvuttra (vutrisiran) — both approved in the U.S. to treat adults with FAP — nucresiran is a TTR silencer. The medication is designed to silence, or shut off, the production of the TTR protein that can cause FAP and other forms of ATTR amyloidosis.
“As we advance our flagship TTR franchise, we are excited to share Phase 3 development plans for our next-generation TTR silencer, nucresiran, which has best-in-class potential,” Pushkal Garg, MD, Alnylam’s chief medical officer, said in the release.
The trial is expected to enroll about 1,200 patients.
Nucresiran expected to be more effective, reduce treatment burden
ATTR amyloidosis is a group of diseases in which the TTR protein builds up as toxic clumps that damage tissues. In FAP, the toxic clumps mainly damage the nerves outside the brain and spinal cord, leading to neurological symptoms.
When TTR clumps, or aggregates, build up mainly in the muscles of the heart, they cause heart damage, medically known as cardiomyopathy, and the disease is then called ATTR amyloidosis with cardiomyopathy, or ATTR-CM.
Onpattro, Amvutta, and nucresiran are small interfering RNA (siRNA) therapies, which use short strands of genetic material to target and break down messenger RNA (mRNA), the intermediate molecule derived from DNA that guides protein production.
Designed to specifically target the mRNA of the TTR gene, which codes for the TTR protein, all three therapies aim to reduce TTR protein production and slow disease progression in FAP and other forms of ATTR amyloidosis.
But unlike Onpattro or Ambuttra, nucresiran is expected to be more convenient for patients to receive. Onpattro is administered intravenously, or directly into the bloodstream, every three weeks, while Amvuttra is given as an under-the-skin, or subcutaneous, injection every three months. Nucresiran, meanwhile, is expected to be more effective with just two subcutaneous doses a year.
In an ongoing Phase 1 trial (NCT05661916), the developer is testing the third-generation RNAi therapy against a placebo in as many as 180 healthy adults. Preliminary data from 48 participants showed that a single subcutaneous injection of nucresiran, at a dose of 300 mg or higher, reduced blood TTR levels by at least 90% for up to six months compared with the placebo. All tested doses were also found to be safe and generally well tolerated.
Participants in Phase 3 trial will get 300 mg dose, but just twice per year
Alnylam is now preparing the launch of the Phase 3 TRITON program of nucresiran, which will comprise a Phase 3 trial in people with ATTR-CM, dubbed TRITON-CM, and a Phase 3 study in FAP patients, called TRITON-PN.
In both trials, participants will receive 300 mg of nucresiran, twice a year.
“We believe that this regimen provides the optimal combination of rapid, deep, and sustained TTR reduction and patient convenience,” John Vest, MD, Alnylam’s senior vice president of clinical research, said during the R&D Day event.
The placebo-controlled TRITON-CM study, expected to start in the upcoming months, will assess differences between the nucresiran and placebo groups in a composite measure of all-cause death and cardiovascular events for at least two years. Participants completing the placebo-controlled part of the trial may continue on, or roll over, into an open-label extension portion in which all will receive nucresiran for up to two years.
If the results are positive, nucresiran could potentially be approved for the treatment of ATTR-CM patients by about 2030, Vest said.
We believe that this regimen provides the optimal combination of rapid, deep, and sustained TTR reduction and patient convenience.
But with a goal to “bring nucresiran to patients as quickly as possible,” Vest said, Alnylam believes there’s a “potential opportunity” for nucresiran to be approved to treat FAP “several years in advance of our assumed launch in [ATTR-CM].”
While full details on the design of the TRITON-PN study were not disclosed, Vest said the company is “currently exploring efficient designs in consultation with global regulators and we look forward to sharing more on this in due course.”
Per the release, the company’s therapies are “potentially transformative” for patients.
According to Garg, “Alnylam is driving the field of RNAi therapeutics into the future, with a sustainable innovation engine that continues to generate transformative medicines while simultaneously expanding what’s possible for RNAi with platform advances.” Garg said.
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