Researchers from Amsterdam UMC, in collaboration with other hospitals, have successfully completed the first-ever Phase 3 study of an in vivo CRISPR therapy. In this large-scale, double-blind Phase 3 trial, 80 patients with hereditary angioedema were randomized to receive either the CRISPR therapy or a placebo. CRISPR therapy is a medical technique that allows doctors to precisely modify errors in cellular DNA to treat specific hereditary diseases. Danny Cohn, leader of the research, is highly enthusiastic: "The study demonstrates that the therapy is genuinely effective and safe. This confirmation is exactly what regulatory authorities need to approve the very first in vivo CRISPR gene editing treatment for the market."

The findings were presented today at the annual congress of the European Academy of Allergy and Clinical Immunology in Istanbul, and simultaneously published in The New England Journal of Medicine.

Significant Reduction in Attacks

The study evaluates a one-time CRISPR treatment for hereditary angioedema, a rare disorder characterized by recurrent and potentially dangerous swelling. Internist Danny Cohn explains: "This is the first time CRISPR therapy has been applied in vivo within a large, double-blind, international Phase 3 trial. A total of 80 patients were randomized to receive either lonvoguran-ziclumeran or a placebo."

The primary outcome was measured between weeks 5 and 28 following a single intravenous infusion. The results heavily favored the active treatment, showing an 87% relative reduction in attacks. Furthermore, 62% of treated patients remained attack-free without any maintenance therapy, compared to just 11% in the placebo group. Key secondary outcomes were also strongly positive: the need for on-demand treatment fell by 89%, moderate-to-severe attacks decreased by 91%, and quality-of-life scores showed a distinctly greater improvement compared to the placebo.

Cohn notes that trial participants tended to take medication at the earliest sign of a potential swelling. "Consequently, we cannot be certain if all reported swellings were actual attacks," Cohn says. "We anticipate that the number of completely attack-free patients will rise now that participants know they received the active treatment. This awareness will likely give them the confidence to forego on-demand therapy."

A Single, One-Time Treatment

The implications for patients are profound, suggesting that a severe, chronic condition can potentially be managed long-term with a single intervention. Cohn: "Patients may no longer need continuous preventative medication, sparing them from the associated side effects. Furthermore, this can alleviate treatment burden, reduce drug dependency, lessen the anxiety of future attacks, and ultimately improve quality of life."

Paving the Way for Future Genetic Therapies

In terms of safety, the treatment appears to be well-tolerated. The most frequent side effects were mild infusion-related reactions, headache, fatigue, and back pain, all of which resolved quickly. No serious adverse events were reported in the treatment group.

"This makes the results exceptionally relevant; it is not just effective, it is safe," Cohn emphasizes. He adds that data from 37 participants from the Phase 1 and 2 trials show the treatment remains just as effective and safe four years after administration. "This study opens doors to in vivo CRISPR treatments for patients with other hereditary disorders. Inserting, deleting, or repairing a gene—it is all possible with CRISPR technology."

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