Vutrisiran Sodium

Encouraging early clinical data from Alnylam Pharmaceuticals and Intellia Therapeutics presented at the American Heart Association’s (AHA) scientific sessions over the weekend hinted at significant progress in developing novel treatments for transthyretin amyloidosis (ATTR).While Alnylam’s next-generation siRNA therapeutic, nucresiran, demonstrated rapid and durable reduction of serum transthyretin (TTR) in healthy participants, a one-time administration of Intellia’s Regeneron-partnered CRISPR-based gene editing therapy, nexiguran ziclumeran (nex-z), showed disease stabilisation or improvement, alongside TTR lowering in a cohort of ATTR amyloidosis with cardiomyopathy (ATTR-CM).Robust siRNA-induced TTR knockdownIn one ongoing Phase I study, 48 healthy participants were randomised to receive a single ascending dose of nucresiran in the range of 5 mg to 900 mg, or placebo. Results showed that a ≥300-mg nucresiran dose achieved rapid and consistent knockdown of serum TTR, with mean reductions >90% by day 15, peaking >96% by day 29, and sustained through day 180. For the 300-mg dose, TTR reductions remained >70% at day 360. Moreover, nucresiran demonstrated low inter-patient variability in TTR reductions at all doses by day 29. Safety remained favourable across all doses, with no injection site reactions or liver-related signals identified. “Nucresiran utilises our IKARIA platform, which has now demonstrated the potential to achieve durability supportive of biannual or annual dosing, representing a potential new paradigm in the treatment of ATTR amyloidosis,” remarked Pushkal Garg, chief medical officer of Alnylam.Garg noted that the company will unveil Phase III development plans for the drug early next year. Subject to successful late-stage testing and approval, nucresiran would become the third addition to Alnylam’s siRNA portfolio for ATTR, which includes Onpattro (patisiran) and Amvuttra (vutrisiran), approved by the FDA in 2018 and 2022, respectively.CRISPR therapy alters ATTR-CM progressionMeanwhile, Intellia’s Phase I study is investigating nex-z in two cohorts: a 36-participant ATTR-CM arm and a 33-participant ATTR with polyneuropathy (ATTRv-PN) arm. Results for the ATTR-CM arm at the August 21 data-off showed that a single dose of nex-z led to a 90% reduction in serum TTR by month 12, which was sustained in 11 participants reaching the 24-month follow-up. Notably, the treatment also demonstrated disease-modifying effects, with 81%, 94% and 77% of participants achieving significant improvements on cardiac markers such as NT-proBNP, high sensitivity Troponin T and 6-minute walk test, respectively. On the safety front, nex-z was well tolerated, with no instances of treatment-related discontinuation.“The stability or improvement…in multiple markers of cardiac disease progression is remarkable, especially considering the high proportion of patients with cardiomyopathy who had advanced heart failure,” explained John Leonard, chief executive of Intellia. The company also noted positive and consistent trends, reflecting a disease-modifying effect in the ATTRv-PN cohort. Intellia is currently recruiting for the Phase III MAGNITUDE study of nex-z for ATTR-CM and is set to commence the MAGNITUDE-2 study for ATTRv-PN. The latest findings for nex-z could spell good news for the biotech, whose stock tumbled over 20% last month after investor concerns persisted despite positive mid-stage results of another CRISPR-based therapy, NTLA-2002, for hereditary angioedema.

In one of the most closely-watched arenas in biotech, Intellia says its gene editing treatment for a heart muscle disease can stabilize or improve outcomes where other treatments have only been shown to slow the disease’s progression. But results are from a small, early-stage study with no comparison group and must be replicated in a larger Phase 3 trial. On Saturday, the Cambridge, MA-based company presented the first clinical outcomes from 36 patients in a Phase 1 study of its gene editing treatment nex-z for ATTR amyloidosis with cardiomyopathy, a disease in which misfolded proteins build up in the heart. On the six-minute walk test, a common tool used in heart and lung disease trials, patients who received nex-z saw a median 5-meter improvement one year after treatment. In addition, Intellia reported that 92% of the patients saw either improvement or no change in their New York Heart Association class. Intellia CEO John Leonard highlighted that the patients enrolled in the Phase 1 study saw disease stasis — or, in some cases, improvement — despite how a greater proportion of patients had more advanced disease compared to key studies of other therapies that have been shown to slow down the progression of ATTR cardiomyopathy. That includes Alnylam’s pivotal trial readout earlier this year of an RNA silencing drug for ATTR cardiomyopathy, which was dubbed by some to be the biggest biotech readout of 2024. “This is encouraging, but it does not yet rise to a level where we would say, ‘OK, there is a very clear signal that we are actually improving how patients are doing.’ That’s because of the open-label nature, the small sample size,” said Ahmad Masri, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University. “Nonetheless, it is very exciting,” he added. Masri was not involved with the Phase 1 study, but is an investigator on a Phase 3 study that’s currently ongoing. The Phase 1 outcomes were presented at the American Heart Association scientific meeting on Saturday and concurrently published in the New England Journal of Medicine . Intellia is now running a much larger 765-patient Phase 3 study called MAGNITUDE comparing nex-z to placebo in ATTR cardiomyopathy. “This is, in a way, the first time ever we have a treatment that can suppress TTR to this degree. Whether this extra suppression of TTR is adding value or not — that’s where the question is, and that’s what the MAGNITUDE trial hopefully can answer,” Masri said. At one year, the mean TTR reduction in the Phase 1 study was 90%. Intellia’s treatment nex-z is designed to use gene editing to inactivate the gene that encodes for a protein called transthyretin, which is behind the buildups that accumulate in the heart. Currently, Pfizer’s tafamidis, which is marketed as Vyndamax or Vyndaqel, is the only drug approved to treat ATTR cardiomyopathy and last year generated $3.3 billion in sales. But two new drugs are expected to reach the market soon — BridgeBio’s acoramidis and Alnylam’s vutrisiran. AstraZeneca and partner Ionis are also running a Phase 3 study of an experimental treatment for the heart muscle disease. Intellia also shared additional data on nex-z in the form of the disease that causes nerve damage, called ATTR polyneuropathy. In 33 patients who received a dose of 0.3 mg/kg or higher, the mean TTR reduction was 91%. Intellia likewise pointed to early trends in clinical measures that suggested the disease stabilized or improved in a small group of patients. Intellia is developing nex-z as part of a larger collaboration with Regeneron.