First-of-its-kind Intellia data suggest CRISPR drug could be given more than once
26 Jun 2024
Clinical ResultPhase 3VaccinePhase 1
Dive Brief:
Intellia Therapeutics on Tuesday revealed data suggesting it may be able to give a person a second dose of a CRISPR-based medicine if the first one doesn’t produce a strong enough effect.
Study results disclosed at a medical meeting show that three people with the inherited disease transthyretin amyloidosis who initially received the lowest dose of an Intellia therapy in a clinical trial produced significantly less of the misshapen protein causing their disease after receiving a second, stronger dose. The additional dose was well tolerated, Intellia said.
Intellia doesn’t intend to give more participants repeat doses of the therapy as part of its clinical development program, which includes an ongoing Phase 3 trial. But the findings provide early proof that the company could, if necessary, meaning it could pursue diseases where “patients might need more than one dose to have the desired therapeutic effect,” CEO John Leonard said in a statement.
Dive Insight:
For all of the progress made with genetic medicines over the last decade, they’re still generally viewed as one-and-done treatments. The body can develop immunity or have a dangerous response to the viruses often used to deliver the complex therapies, making redosing impractical or risky.
The data Intellia unveiled Tuesday, while early and from only three people, suggest that there may be a solution. By leaning on fatty shells called lipid nanoparticles for delivery — the kind used in Pfizer and Moderna’s COVID-19 vaccinesCOVID-19 vaccines — developers may be able to administer a treatment multiple times. That means, in theory, companies could give a person several CRISPR doses to achieve an effect a single one can’t.
Intellia, for instance, initially tested its experimental treatment for transthyretin amyloidosis at lower doses before selecting the one currently being used in a late-stage trial. The first three patients enrolled received the lowest dose Intellia evaluated, and saw levels of serum transthyretin, or TTR — the protein implicated in their disease — fall by 52%.
That number is below what Leonard, in a statement, called the “target protein production level.” Onpattro, a drug approved for a form of transthyretin amyloidosis, was associated with an 80% reduction in clinical testing, an important bar for efficacy. Nearly all dose cohorts in Intellia’s Phase 1 trial had a median reduction of about 91%.
But Intellia offered study participants who didn’t reach those levels the chance to get an additional, higher dose following a prespecified two-year follow-up period. The first three enrollees did, and after four weeks, saw their TTR protein levels fall by an additional median of 90% after four weeks, or about 95%, total, from the study’s start.
“Critically, no clinically significant changes in liver enzymes, platelet counts, or coagulation parameters were reported,” wrote Myles Minter, an analyst at the investment bank William Blair. That finding supports redosing “without significant immunogenicity risk at these doses.”
The results are the first of their kind in humans with a CRISPR-based medicine and represent a potential advance for the field, showing redosing “enabled an additive pharmacodynamic effect on the target protein,” Leonard said in the statement.
Still, Blair’s Minter cautioned that, while the results have “some validity” for other developers, so far it’s only on a “product-by-product basis.” It’s also unclear if additional doses increase the potential risk of off-target, accidental edits, he wrote.
Intellia is currently enrolling patients in a Phase 3 trial testing its therapy, NTLA-2001, in people with a form of transthyretin amyloidosis that affects the heart. A similar study is planned for the rarer form of the condition that impacts the nerves.
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