Disease markers stabilized or improved in cardiomyopathy patients who received a single dose of Intellia Therapeutics’ in vivo CRISPR therapy in a phase 1 trial. But the incumbents look set to fight to hold onto the market, with Alnylam Pharmaceuticals sharing early-phase data on its next-generation prospect.
Alnylam currently competes with Pfizer for the ATTR cardiomyopathy market. BridgeBio could win FDA approval for its challenger this year. The TTR stabilizers and TTR gene silencers improve outcomes, for example by lowering the risk of death and cardiovascular events, but patients need to take them for life and still experience declines in their quality of life and functional capacity.
Intellia sees an opportunity for nexiguran ziclumeran (nex-z), a drug candidate that uses CRISPR editing to inactivate the TTR gene. Nex-z is part of Intellia’s collaboration with Regeneron. The biotech shared phase 1 data on the prospect at the 2024 American Heart Association (AHA) Scientific Sessions in Chicago over the weekend. The data set included 36 patients.
Levels of serum TTR, the protein that drives ATTR cardiomyopathy, dropped 89% in the 28 days after treatment and stayed at the same suppressed level through 24 months of follow-up. Scores on the six-minute walk test (6MWT) and assessments of heart failure and function stabilized in the 12 months after treatment.
In around 80% of patients, scores on the markers of disease progression either stabilized or improved. Stabilization was the most common response, but 37% of people improved on the 6MWT. Improvements on the two heart tests were rarer but were seen in 14% and 17% of patients. Intellia also shared evidence of the stabilization or improvement in symptoms and quality of life measures.
On the safety front, the biotech saw treatment-related increases in a liver enzyme in 6% of patients but said the upticks were transient, generally mild and not indicative of liver injury. The only other treatment-related adverse event seen in more than 5% of participants was -infusion-related reaction, which affected 14% of patients.
Intellia is assessing the CRISPR therapy in a placebo-controlled phase 3 trial that will provide a truer test of its credentials as a challenger for the ATTR cardiomyopathy market. Existing options include Alnylam's Amvuttra. Alnylam used the AHA event this weekend to look beyond Amvuttra by sharing phase 1 data on its next-generation RNAi molecule nucresiran in healthy volunteers.
After a single, 300-mg dose, mean serum TTR levels fell 90.3% at Day 15, 96.5% at Day 29 and 92.6% at Day 180. The reductions were higher still in patients who received 600 mg or 900 mg of the candidate. There was little variability in the TTR reductions between patients.
Alnylam expects to share details of its plans for phase 3 development in the first quarter of next year. The biotech said the data support the potential to give nucresiran subcutaneously once or twice a year. Patients receive Amvuttra every three months. Extending the window between doses could reduce an advantage of Intellia’s one-time CRISPR therapy.