Intellia data suggest CRISPR drug may be repeatable

Intellia Therapeutics has presented promising new data indicating the potential for administering multiple doses of its CRISPR-based therapy. This advancement could benefit individuals whose initial dose does not elicit a sufficiently strong response. The findings were disclosed at a recent medical conference, where Intellia shared results from three participants with transthyretin amyloidosis, a genetic disease. These participants, who had initially received the lowest dose in a clinical trial, showed significant reductions in the faulty protein responsible for their condition after receiving a second, stronger dose. Importantly, the additional dose was well tolerated, according to the company.

While Intellia does not plan to offer repeat doses to more participants within its current clinical development program, which includes an ongoing Phase 3 trial, the results suggest a new possibility. The company now has early evidence that it could, if necessary, administer additional doses to achieve the desired therapeutic effect. This could be particularly relevant for diseases where a single dose may not be sufficient, said CEO John Leonard in a statement.

Historically, genetic medicines have been seen as one-time treatments. The human body can develop immunity or adverse responses to the viral vectors often used to deliver these therapies, making repeated dosing risky or impractical. However, Intellia’s new data offers a potential workaround. The company uses lipid nanoparticles for delivery, similar to the technology employed in COVID-19 vaccines from Pfizer and Moderna. This method may allow for multiple administrations of the therapy, thereby potentially achieving effects that a single dose cannot.

Initially, Intellia tested its experimental treatment for transthyretin amyloidosis at lower doses before deciding on the dose used in the current late-stage trial. The first three patients, who received the lowest dose, saw their serum transthyretin (TTR) levels—implicated in their disease—drop by 52%. While this reduction was significant, it fell short of the target protein reduction level. For comparison, Onpattro, a drug approved for a form of transthyretin amyloidosis, achieved an 80% reduction in clinical trials. Nearly all dose cohorts in Intellia’s Phase 1 trial had a median reduction of about 91%.

To address this, Intellia offered those participants an additional, higher dose after a predetermined two-year follow-up period. The first three enrollees accepted and, four weeks later, their TTR protein levels showed an additional median drop of 90%, culminating in an overall reduction of about 95% from the start of the study. The safety and efficacy of the additional dose were in line with observations from a single higher dose. Only mild side effects were reported, including a mild infusion reaction and a Grade 2 infection, but no significant changes in liver enzymes, platelet counts, or coagulation parameters, noted Myles Minter, an analyst at William Blair investment bank. This supports the possibility of redosing without significant immunogenicity risks at these doses.

These results are groundbreaking, marking the first instance in humans where a CRISPR-based medicine has shown the potential for redosing, leading to an additive effect on the target protein. Leonard called this a potential advance for the field. However, Minter cautioned that these findings might only be valid on a product-by-product basis and it remains unclear whether additional doses could increase the risk of unintended genetic edits.

Intellia is currently enrolling patients in a Phase 3 trial to test its therapy, NTLA-2001, in individuals with a form of transthyretin amyloidosis that affects the heart. A similar study is planned for the rarer form of the condition impacting the nervous system.