Intellia’s investigational CRISPR-Cas9 gene-editing therapy NTLA-2002 reduced monthly attacks by more than 70% in both tested dose arms.
Danny M. Cohn, MD, PhD
(Credit: Amsterdam UMC)
Data from the phase 2 portion of an ongoing phase 1/2 trial (NCT05120830) evaluating NTLA-2002 (Intellia Therapeutics), an investigational in vivo CRISPR-Cas9 gene-editing therapy targeting the KLKB1 gene in patients with hereditary angioedema (HAE), have been published, suggesting that a single dose of therapy reduced angioedema attacks and resulted in strong and sustained reductions in total plasma kallikrein levels.1
Published in the New England Journal of Medicine after topline data were presented at the 2024 American College of Allergy, Asthma & Immunology Scientific Meeting, held October 24 to 28, in Boston, Massachusetts, these results are ultimately supportive of exploration of NLTA-2002 in a larger phase 3 study, according to the investigators.Intellia also announced that it will utilize the 50 mg dose in the pivotal phase 3 HAELO clinical trial (NCT06634420).2
Published by Danny M. Cohn, MD, PhD, a staff vascular medicine specialist at Amsterdam University Medical Center, and colleagues, the trial consisted of 27 adults and assessed the efficacy and safety of single intravenous doses of NTLA-2002, comparing 25-mg and 50-mg dose levels to a placebo over a 16-week observation period. “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.
The primary end point—defined as the reduction in monthly angioedema attack rate—demonstrated a favorable outcome in those receiving NTLA-2002. From week 1 to week 16, the estimated monthly attack rate was 0.70 (95% CI, 0.25-1.98) for the 25-mg group (n = 10) and 0.65 (95% CI, 0.24-1.76) for the 50-mg group (n = 11), compared with 2.82 (95% CI, 0.80-9.89) in the placebo group (n = 6).
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, with similar results observed for the monthly attack rate (measured from week 5 through week 16). The mean percent change from baseline in monthly attack rate was –78.1% (±30.4) with 25 mg, −79.5% (±42.0) with 50 mg, and −16.3% (±41.6) with placebo.
Additionally, a portion of participants—40% (n = 4) in the 25-mg group and 73% (n = 8) in the 50-mg group—remained attack-free throughout the observation period without the need for further intervention. The data also suggested that there was a dose-related reduction in kallikrein protein levels for treated individuals, with the 25-mg and 50-mg doses reducing kallikrein by 55% and 86%, respectively, from baseline levels, while the placebo group’s values remained unchanged.
“Updated data from the phase 1 portion of the trial, with a median follow-up time of 20.1 months, suggest that NTLA-2002 provides a sustained, long-term benefit,” Cohn and colleagues wrote, adding that the plasma kallikrein protein reductions in phase 1 patients have remained stable, and that the monthly attack rate had decreased by 98% from baseline as of last follow-up, with 8 of 10 patients have remained attack-free. Additionally, none of the phase 1 participants had resumed long-term prophylaxis.
“These sustained reductions in plasma kallikrein protein levels are consistent with the findings from preclinical studies of NTLA-2002 and suggest that the effects of KLKB1 editing have persisted through a substantial amount of hepatocyte turnover, given that a recent study showed that approximately 19% of hepatocytes are replaced each year in a healthy human liver,” Cohn et al wrote.
No new safety signals or concerns were identified. NTLA-2002 was generally well tolerated, with mild-to-moderate adverse events (AEs) such as headache (38%), fatigue (29%), and nasopharyngitis (29%) reported by participants receiving active treatment at a rate of at least 25%. All AEs were deemed grade 1 or 2 except for 1 instance in the placebo group of grade 4 edema of the tongue with breathing impairment, which was deemed related to the underlying HAE. There no serious AEs attributed to the investigational therapy.
There were 2 patients—1 in each treatment arm—who experienced infusion-related reactions (IRRs) that required a temporary pause in dosing, but those symptoms resolved without lasting effects. Symptoms of IRRs included back pain, flushing, noncardiac chest pain, generalized tingling, neck pain, and tight chest.
A single patient who received a 25-mg dose NTLA-2002 reported an asymptomatic grade 2 increase in the alanine aminotransferase level on day 22—deemed by the trial site investigator to be possibly related to treatment—but this level decreased to a grade 1 level by day 28 and returned to normal by week 8. No clinically significant laboratory results were recorded for any patients.
HAE is typically linked to mutations in the SERPING1 gene, resulting in a deficiency of the C1 esterase inhibitor (C1-INH) protein. This deficiency causes an overproduction of bradykinin, a protein responsible for blood vessel permeability and fluid leakage. By using Intellia’s CRISPR-Cas9 technology to edit the KLKB1 gene in liver cells, NTLA-2002 aims to reduce bradykinin production, offering a potentially durable solution to mitigate symptoms. NTLA-2002 is designed as a 1-time treatment, potentially alleviating the need for ongoing interventions.
“These positive NTLA-2002 Phase 2 results underscore the tremendous potential of our in vivo CRISPR gene editing therapy to be a functional cure and redefine the treatment paradigm for HAE,” John Leonard, MD, the president and chief executive officer of Intellia, said in a statement in October 2024.2 “The phase 2 data demonstrated that a majority of patients in the 50 mg arm experienced a complete response—no attacks at all and no further treatment needed—after a one-time infusion of NTLA-2002 through the latest follow-up, consistent with the long-term phase 1 data. We are highly encouraged by these results, which we believe sets NTLA-2002 apart from other prophylaxis treatments. What was previously an unimaginable potential to be free of chronic therapy is one step closer to becoming a reality for the HAE community.”
