Intellia Therapeutics' NTLA-2002, an investigational in vivo CRISPR-Cas9 gene-editing therapy targeting the KLKB1 gene, has shown promising results in reducing angioedema attacks in patients with hereditary angioedema (HAE). The findings, published in the New England Journal of Medicine, stem from the Phase 2 portion of an ongoing Phase 1/2 trial (NCT05120830).
The trial, led by Danny M. Cohn, MD, PhD, from Amsterdam University Medical Center, involved 27 adults who received single intravenous doses of NTLA-2002 (25-mg or 50-mg) or a placebo over a 16-week period. The primary endpoint was the reduction in monthly angioedema attack rate.
Efficacy of NTLA-2002
The results indicated a significant reduction in monthly attack rates among those receiving NTLA-2002. Specifically, the estimated monthly attack rate from week 1 to week 16 was 0.70 (95% CI, 0.25-1.98) for the 25-mg group and 0.65 (95% CI, 0.24-1.76) for the 50-mg group, compared to 2.82 (95% CI, 0.80-9.89) in the placebo group.
The mean differences in monthly attack rate with NTLA-2002 was −75% (95% CI, −95 to 27) and −77% (95% CI, −95 to 15) with the 25-mg and 50-mg doses, respectively. Notably, 40% of participants in the 25-mg group and 73% in the 50-mg group remained attack-free throughout the observation period without needing further intervention.
Furthermore, the data demonstrated a dose-related reduction in kallikrein protein levels. The 25-mg and 50-mg doses reduced kallikrein by 55% and 86%, respectively, from baseline levels, while the placebo group's values remained unchanged. These sustained reductions in plasma kallikrein protein levels are consistent with preclinical studies, suggesting the effects of KLKB1 editing have persisted through substantial hepatocyte turnover.
Safety Profile
NTLA-2002 was generally well-tolerated. Common adverse events (AEs) included headache (38%), fatigue (29%), and nasopharyngitis (29%) among participants receiving active treatment. All AEs were grade 1 or 2, except for one instance of grade 4 edema of the tongue with breathing impairment in the placebo group, which was deemed related to the underlying HAE. No serious AEs were attributed to NTLA-2002.
Two patients, one in each treatment arm, experienced infusion-related reactions (IRRs) that required a temporary pause in dosing. Symptoms included back pain, flushing, noncardiac chest pain, generalized tingling, neck pain, and tight chest. A single patient receiving the 25-mg dose reported an asymptomatic grade 2 increase in alanine aminotransferase level on day 22, which resolved by week 8.
Implications and Future Directions
"These results show the potential of a single dose of the new CRISPR-Cas9–based in vivo gene-editing therapy NTLA-2002 to be a functional cure for patients with hereditary angioedema and support continued investigation," Cohn and colleagues wrote. Intellia plans to utilize the 50-mg dose in the pivotal Phase 3 HAELO clinical trial (NCT06634420).
John Leonard, MD, the president and chief executive officer of Intellia, stated that the Phase 2 data demonstrated that a majority of patients in the 50 mg arm experienced a complete response, with no attacks and no further treatment needed after a one-time infusion of NTLA-2002. He believes this sets NTLA-2002 apart from other prophylaxis treatments, bringing the potential of being free of chronic therapy closer to reality for the HAE community.
About Hereditary Angioedema and NTLA-2002
Hereditary angioedema is often linked to mutations in the SERPING1 gene, leading to a deficiency in the C1 esterase inhibitor (C1-INH) protein. This deficiency results in an overproduction of bradykinin, causing blood vessel permeability and fluid leakage. NTLA-2002 aims to reduce bradykinin production by editing the KLKB1 gene in liver cells using Intellia's CRISPR-Cas9 technology, offering a potentially durable solution to mitigate HAE symptoms and potentially alleviate the need for ongoing interventions.
