Nucresiran, a next-generation RNAi therapeutic, showed potential as a treatment for transthyretin amyloidosis cardiomyopathy (ATTR-CM), Alnylam Pharmaceuticals said recently in reporting phase 1 trial results.
A single dose of 300 mg or more achieved rapid reductions in levels of transthyretin (TTR), exceeding 90% by day 15, with the effects sustained for at least six months, the company said in a news release. The therapy introduced the possibility of biannual or annual dosing, offering a new approach to managing the challenging condition, it added.
What is ATTR-CM?
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare progressive disease of the heart muscle that leads to congestive heart failure. It occurs when the transthyretin protein produced by the liver is unstable. Symptoms include fatigue; shortness of breath; irregular heart rate or palpitations; swelling of the legs, ankles and stomach; brain fog; wheezing; and dizziness. It often goes underdiagnosed because of a lack of awareness and knowledge of the disease. There is currently no cure for ATTR-CM.
For patients with ATTR, the potential for reduced dosing frequency and durable reduction of TTR represents a promising possible advance. By addressing the disease’s underlying mechanism and offering a tolerable safety profile, nucresiran may simplify treatment and improve long-term outcomes.
Read more about ATTR-CM therapies
ATTR is a severe and often underdiagnosed disorder caused by misfolded TTR proteins, which form harmful deposits in organs such as the heart and nerves. Currently, patients face progressive symptoms, including polyneuropathy and cardiomyopathy.
Nucresiran directly targets the root cause by reducing both mutant and wild-type TTR, slowing the disease’s progression, the company said. Nucresiran’s durability further allowed for a less frequent dosing alternative compared to existing therapies, the company said.
“We are very excited by these new Phase 1 data with nucresiran, our next-generation TTR-targeting RNAi therapeutic, which demonstrated that a single dose of ≥ 300 mg achieved rapid knockdown of TTR greater than 90% from day 15 that was sustained to at least six months,” said Dr. Pushkal Garg, chief medical officer at Alnylam. “Furthermore, we are encouraged by the potential of nucresiran to reduce interpatient variability in TTR lowering.”
The Phase 1 study involved 48 healthy participants and assessed doses ranging from 5 mg to 900 mg. For doses of 300 mg or higher, TTR reductions exceeded 96% by day 29, with levels remaining 90% lower than baseline at day 180, the company said.
Even at day 360, TTR remained reduced by 70% in the 300 mg group, and data for higher doses is forthcoming. Notably, the treatment displayed consistent results across patients, with low variability in the reduction of TTR.
Safety findings showed that across all doses tested, nucresiran was well tolerated, with most adverse events mild and unrelated to the treatment. No injection site reactions or liver-related issues were observed, addressing a common concern with new therapies.
Alnylam said it anticipated sharing Phase 3 development plans in early 2025 to confirm nucresiran’s benefits and bring it closer to regulatory approval.
