Intellia’s CRISPR Gene Editing Therapy Significantly Reduces Swelling in Hereditary Angioedema, New Data Show

Intellia Therapeutics’ NTLA-2002, an investigational CRISPR/Cas9-based gene-editing therapy being evaluated in a phase 1/2 clinical trial (NCT05120830) for the treatment of hereditary angioedema (HAE), significantly reduced monthly HAE attacks by a mean of 95%, according to additional data shared from the ongoing trial during the 2023 European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress, held June 9-11 in Hamburg, Germany.¹

NTLA-2002, which is delivered systemicaly as a single-dose, is being evaluted at 3 dose-levels in the trial. As of the February 17, 2023, data cutoff, 3 participants received 25 mg, 4 participants received the 50 mg dose, and 3 participants received the 75 mg dose. Among the 10 patients treated, a mean reduction in monthly HAE attack rate of 95% was observed through the most recent follow-up (5.6-14.1 months; median 9.0). Intellia noted that the first 3 patients who received treatment reached at least 1 year of follow-up without experiencing any HAE attacks. The company also pointed out that 3 patients who had the highest respective historic monthly HAE attack rates of 16.8, 14.0, and 4.4 all remained HAE attack-free from 16 weeks posttreatment through their latest follow-up, with the longest being 11.5 months at the time of data cutoff.

The study also measured levels of kallikrein in plasma and found that all 9 patients who achieved at least a 60% reduction in plasma kallikrein remained free of HAE attacks from 16 weeks posttreatment through their latest follow-up. The 1 patient who did not achieve a 60% reduction in plasma kallikrein, who had received the trial’s lowest dose, experienced a mild HAE attack following minor hand swelling related to a sports injury after being free of HAE attacks for the previous 12.3 months. The company noted that this patient did not require medical treatment for the HAE attack and that no additional HAE attacks were observed in this patient. Furthermore, the 6 patients in the trial who had previously been engaged in long-term treatment with HAE prophylactic medications prior to receiving NTLA-2002 discontinued the prophylactic medications without experiencing new HAE attacks.

“After a single dose of our investigational CRISPR-based therapy, patients living with hereditary angioedema experienced durable elimination of their attacks,” John Leonard, MD, the president and CEO of Intellia Therapeutics, said in a statement.¹ “We are thrilled to see that the earliest-dosed patients are attack free for approximately a year or longer, with NTLA-2002 demonstrating a very favorable safety profile. These remarkable attack rate reductions have been consistent, even in patients with the most severe symptoms. While early, these unprecedented interim data from the Phase 1 study continue to reinforce our belief that NTLA-2002 could be a potential functional cure for people with hereditary angioedema. In addition, these data strengthen our view that NTLA-2002 could address the significant treatment burden that exists, despite currently available, chronically administered therapies.”

In terms of safety, NTLA-2002 was well-tolerated with the majority of adverse events (AEs) being mild. There were no dose-limiting toxicities and no AEs of grade 3 or higher reported. The most common AEs were infusion-related reactions and fatigue; the company noted that most of these cases were grade 1 and resolved in a period of 2 days. Among all of the treated patients, there were no clinically significant laboratory abnormalities reported. 

The open-label clinical trial is currently recruiting patients in the Netherlands, New Zealand, and the United Kingdom. Intellia noted that the phase 2 portion of the study has initiated and they’ve begun administration of NTLA-2002 to patients. Recruitment for this portion remains ongoing; the company anticipates the completion of enrollment before the end of 2023. In March 2023, Intellia announced that the FDA had cleared an investigational new drug application for NTLA-2002, which would enable the company to expand the phase 2 portion of the clinical trial to include patients in the United States.² Later the same month, NTLA-2002 was granted regenerative medicine advanced therapy designation by the FDA.³ It previously received orphan drug designation from the FDA in September 2022.⁴

REFERENCES
1. Intellia Therapeutics announces new positive clinical data from phase 1 study of NTLA-2002, an investigational in vivo CRISPR genome editing treatment for hereditary angioedema (HAE). News release. Intellia Therapeutics, Inc. June 11, 2023. Accessed June 12, 2023. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-new-positive-clinical-data-phase
2. Intellia Therapeutics Announces FDA Clearance of Investigational New Drug (IND) Application for NTLA-2002, an In Vivo CRISPR-Based Investigational Therapy for the Treatment of Hereditary Angioedema (HAE). News release. Intellia Therapeutics. March 2, 2023. Accessed June 12, 2023. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-clearance-investigational
3. Intellia Therapeutics anounces FDA Regenerative Medicine Advanced Therapy (RMAT) designation granted to NTLA-2002 for the treatment of hereditary angioedema. News release. Intellia Therapeutics. March 21, 2023. Accessed June 12, 2023. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-regenerative-medicine
4. Intellia Therapeutics receives U.S. FDA orphan drug designation for NTLA-2002, an investigational CRISPR therapy for the treatment of hereditary angioedema. News release. Intellia Therapeutics. September 1, 2022. Accessed June 12, 2023. https://www.globenewswire.com/news-release/2022/09/01/2508902/0/en/Intellia-Therapeutics-Receives-U-S-FDA-Orphan-Drug-Designation-for-NTLA-2002-an-Investigational-CRISPR-Therapy-for-the-Treatment-of-Hereditary-Angioedema.html