1. In this randomized controlled trial, gene-editing therapy targeting the kallikrein B1 gene (KLKB1) led to a significant reduction in plasma kallikrein levels among adults with hereditary angioedema (HA).
2. Trial participants also saw a reduction in angioedema attacks in the following 16 weeks and had no severe adverse events.
Evidence Rating Level: 1 (Excellent)
Study Rundown: HA is a rare autosomal dominant genetic disease characterized by unpredictable and potentially fatal attacks of swelling in the gastrointestinal tract, the larynx, and tissues throughout the body. The pathophysiology of HA involves the dysregulated production of bradykinin, leading to its hyperactivity and increased contact activation pathway. Plasma kallikrein, the precursor of which is encoded by KLKB1, is a key enzyme in bradykinin activation and a validated therapeutic target for HA. This current study was a phase one trial investigating NTLA-2002, an in vivo liver-targeting CRISPR-Cas9 therapy designed to permanently downregulate KLKB1 through gene editing for adults with HA. NTLA-2002 at escalating doses was not associated with dose-limiting toxicity or serious adverse events. It resulted in dose-dependent reductions in total plasma kallikrein. Correspondingly, NTLA-2002 recipients were observed to have reduced angioedema attacks from baseline at week 16. Given its early phase, this study was limited by its small size, limited duration, and lack of placebo control or randomization. Nevertheless, the results demonstrated that NTLA-2002 may be safe in providing long-term management of HA.
Click here to read the study in NEJM
Relevant Reading: Inhibition of Prekallikrein for Hereditary Angioedema
In-Depth [randomized controlled trial]: This study was the phase one open-label dose-escalation portion of the combined phase one/two trial of NTLA-2002 in adult HA patients. Patients 18 years of age or older with a diagnosis of type one or type two HA and a history of at least three attacks within 90 days before screening were eligible for inclusion. Exclusion criteria included a concurrent diagnosis of other types of angioedema and a history of hypersensitivity to the lipid nanoparticle component of NTLA. Three patients received a single dose of 25mg of NTLA-2002, four received 50mg, and three received 75mg. The primary outcome of this trial was the safety and adverse effect profile of NTLA-2002. Patients’ angioedema symptom diary and samples for pharmacodynamic and pharmacokinetic assessments were obtained throughout. No dose-limiting toxicity was observed, while the most common adverse events were infusion-related reactions (in 70% of patients) and fatigue (in 60%). No severe adverse events (grade 3 or higher) were reported. Elevations in alanine aminotransferase and aspartate aminotransferase levels were observed in 60% of patients but were all low-grade and transient. Notably, total plasma kallikrein level was reduced from baseline in treated patients in a dose-dependent manner: mean percentage change of -67% among the 25mg recipients, -84% among the 50mg recipients, and -95% among the 75mg group. By 16 weeks, the mean percentage change in the number of angioedema attacks per month from baseline was -91% for the 25mg recipients, -97% for the 50mg recipients, and -80% for the 75mg recipients for an overall average of -95%. In summary, these results showed that NTLA-2002 had an acceptable safety profile for adults with HA and could offer a potential long-lasting management of this condition.
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