Alnylam plans pivotal trial as Huntington’s drug notches ‘best-in-class knockdown’

 

RNAi specialist Alnylam Pharmaceuticals will advance the Huntington’s disease drug brezosiran into a placebo-controlled study in 2027 once regulatory alignment is achieved.

Alnylam is eyeing a pivotal trial for a Huntington’s disease drug after an early-stage clinical study showed “robust” reductions in the key huntingtin protein that is known to drive the difficult neurodegenerative disease.

If the therapy is ultimately approved, Alnylam could find itself with a multibillion-dollar opportunity in Huntington’s disease (HD), Oppenheimer wrote on Friday. “The severity of HD, coupled with lack of treatments, confers a significant market opportunity,” the analyst said.

In an ongoing Phase 1b clinical trial, ALN-HTT02—now to be known as brezosiran—spurred what the company called robust and dose-dependent reductions in mutant huntingtin protein (mHTT) in the cerebrospinal fluid. This was confirmed with two independent assays, Alnylam said in a Friday press release.

The data were presented in a poster at the European Huntington’s Disease Network Clinical Research Congress in Krakow, Poland. The drug is part of a longtime partnership with Regeneron, which was initially signed in 2019 and is worth upward of $1 billion.

The highest dose group saw a mean reduction of 60%–64% at three months, with the highest observed reduction reaching 83%.

The results fall in Oppenheimer’s “best case scenario,” suggesting “best-in-class knockdown,” the firm said in a Friday morning note.

But the data are early, and Alnylam did not reveal any information on the potential clinical efficacy because the follow-up period was too short, the firm noted. Stifel analysts also noted that there are many questions to be answered—and in the tough Huntington’s space, early clinical results don’t always mean the program will succeed.

“While these early results do look interesting/positive, there’s still clinical risk here in that Roche’s tominersen also demonstrated favorable CSF mHTT-lowering, which didn’t translate to a benefit,” the firm wrote on Friday morning. Roche has since abandoned the antisense oligonucleotide asset. “From a stock perspective, we know from others in HD it can take a while to prove out clinical benefit.”

Still, Alnylam was encouraged enough by the early readout to advance the program.

“The observed durability of mHTT-lowering shows the potential for a twice-yearly dosing paradigm in downstream development,” Alnylam said.

The RNAi specialist will move brezosiran into a placebo-controlled study in 2027 once regulatory alignment is achieved, according to Friday’s news release.

“We plan to evaluate our differentiated huntingtin-lowering approach in a rigorous placebo-controlled study to determine whether it can alter the course of Huntington’s disease,” Pushkal Garg, Alnylam’s Chief Research and Development Officer, said in a statement.

Brezosiran is an RNAi therapeutic developed using Alnylam’s C16 conjugate platform that aids delivery into the central nervous system. The therapy targets exon 1 of the huntingtin (HTT) mRNA transcript, which is designed to reduce production of all forms of the protein, differentiating the asset from other HD drug candidates.

Brezosiran was flagged by analysts earlier this year as a potential morale booster after the company had to cut guidance. While exciting, Stifel wants to see more from the Huntington’s program before weighing in on whether it will be a future growth driver.

“As we see it, this offers promising proof-of-concept—good safety, strong knockdown—but for the stock it’ll likely take more data to earn significant credit here, especially as we’re at a pivotal point in the TTR launch where the next couple quarters are important for investors seeing that the franchise is on track to meet ALNY’s 2030/long-term goals,” the firm wrote. Alnylam’s stock was steady around $224.54 apiece on Friday morning.

The company will present the Phase 1b Huntington’s data during a roundtable event on October 26.

Huntington’s disease is one of the toughest spaces in biopharma, with many failed assets and approaches littering the path. UniQure inspired hope last year when the gene therapy ifezuntirgene inilparvovec showed a 75% three-year slowing of the disease at three years in September 2025. That response rate has since narrowed, with more recent data showing a 44% slowing of disease progression at four years. The asset has nevertheless been filed for approval with the FDA.

https://www.biospace.com/drug-development/alnylam-plans-pivotal-trial-as-huntingtons-drug-notches-best-in-class-knockdown