CRISPR therapy helped hereditary angioedema in phase I trial
American, British, Dutch and New Zealand researchers reported the success of the first phase I in vivo clinical trials of CRISPR therapy for hereditary angioedema. The publication appeared in The New England Journal of Medicine.
Hereditary angioedema (HAE) occurs in one in about 50,000 people. This dangerous disease is associated with mutations in the SERPING1 (encodes an inhibitor of the C1 component of the complement system) or F12 (encodes clotting factor XII) genes. Both lead to uncontrolled elevation and release of kallikrein and consequently kinins. Clinically, this is manifested by severe swelling of the arms, legs, face, larynx and abdominal organs, which can lead to life-threatening conditions such as choking and acute abdomen (for more on HAE, see "Ancestral Edema"). Such attacks are treated only in the hospital, for their management use concentrates of C1-inhibitor, fresh frozen plasma, bradykinin receptor antagonist ikatibant, kallikrein inhibitors ecallantide, berotralstat and lanadelumab, but the effectiveness of these drugs is limited, and they (except plasma) are not available in all countries.
The drug NTLA-2002, developed by Intellia Therapeutics, is a CRISPR/Cas9 system components packaged in lipid nanoparticles that, when injected into the body, turn off the KLKB1 gene encoding plasma prekallikrein (a precursor to kallikrein). A single administration should provide a lifelong effect.
In the wing of a phase 1 combined phase 1 and phase 2 clinical trial conducted by Hilary Longhurst of the University of Auckland with colleagues from the UK, the Netherlands, New Zealand and the US, three adult patients with type 1 or type 2 HAE received an intravenous infusion of 25 milligrams of NTLA-2002, four received 50 milligrams and another three received 75 milligrams. To prevent acute reactions to the complex biologic drug, they were administered twice a glucocorticoid and once histamine H1- and H2-receptor blockers before infusion. The participants' initial observation period lasted 16 weeks, followed by a long-term observational period of 88 weeks.
At the time of the last evaluation at the end of the observational period, there was an average 67 percent decrease in plasma kallikrein concentration at the 25 milligram dose, 84 percent at the 50 milligram dose, and 95 percent at the 75 milligram dose compared with baseline. By the end of the primary observation period, the average number of angioedema attacks per month decreased at these dosages by an average of 91, 97, and 80 percent, respectively. By the end of the observational period, the rate averaged 95 percent among all participants.
No serious adverse events or clinically significant laboratory abnormalities were observed at all doses that would limit the use of NTLA-2002. Of the side effects, the most common were reactions to drug administration and increased fatigue.
Thus, in Phase I trials, a single administration of NTLA-2002 resulted in a sustained dose-dependent reduction in plasma kallikrein levels without serious side effects, as well as a marked reduction in the frequency of disease attacks in all dosing regimens. Phase I/II trials are ongoing, with global Phase III trials scheduled to begin in the second half of 2024.