Gene-Editing Therapy for Hereditary Angioedema Cleared for US Phase 2 Sites

The FDA has accepted Intellia Therapeutics’ investigational new drug application (IND) for NTLA-2002 for the treatment of hereditary angioedema (HAE), enabling the company to include the United States in the global phase 2 portion of its ongoing phase 1/2 study (NCT05120830).¹

“The FDA’s acceptance of our IND application to initiate clinical evaluation of NTLA-2002 brings us one step closer to introducing a potentially paradigm-shifting treatment for people living with hereditary angioedema,” John Leonard, MD, president and chief executive officer, Intellia, said in a statement.¹ “The NTLA-2002 IND clearance marks an important milestone for Intellia as we continue our track record of execution as the leader in the genome editing field. We are thrilled to advance the development of NTLA-2002 in the US and are working to rapidly enroll patients in the phase 2 portion of the study. We look forward to presenting additional data from the first-in-human, phase 1 portion of the study later this year.”

NTLA-2002 is a CRISPR-based, in vivo genome editing therapy designed to inactivate the kallikrein B1 (KLKB1) gene to reduce plasma kallikrein protein activity and prevent HAE attacks. The phase 1/2 study most recently reported data cut off as of September 28, 2022, from 10 participants from the dose-escalation phase 1 portion of the study.² Participants received single doses of 25 mg (n = 3), 50 mg (n = 4), or 75 mg (n = 3) of NTLA-2002 via intravenous infusion. At latest follow-up, the 25 mg cohort had a mean 64% plasma kallikrein reduction as of week 32, the 50 mg cohort had a mean 81% plasma kallikrein reduction as of day 22, and the 75 mg cohort had a mean 92% plasma kallikrein reduction as of week 16.

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HAE attacks also reduced from baseline; in the 25 mg cohort, which had a baseline attack rate of 1.1 to 7.2 attacks per month, patients were attack free for 5.5 to 10.6 months as of the cutoff date. This cohort had a 91% mean HAE attack rate reduction from weeks 1 to 16 and an 89% reduction from weeks 5 to 16. The 75 mg cohort, which had a baseline attack rate of 4.0 to 5.9 attacks per month, has been attack-free for 2.3 to 4.2 months, and had a 78% mean HAE attack rate reduction from weeks 1 to 16 and an 89% reduction from weeks 5 to 16.

“We see early evidence that our one-time CRISPR-based investigational therapy may offer patients suffering from hereditary angioedema a functional cure for their disease,” Leonard said in an earlier statement.2 “Based on the extended data across multiple dose cohorts, we are strongly encouraged that all patients who received a single dose of NTLA-2002 subsequently became attack-free. In the patients with the longest follow-up to date, their attack-free interval has been maintained 5 to 10 months from their last attack. Importantly, the safety data from all 10 patients are highly encouraging, further supporting NTLA-2002’s potential to change the future HAE treatment paradigm.

Intellia's other lead CRIPSR/Cas 9 gene editing candidates, NTLA-2001, is targeting transthyretin (ATTR) amyloidosis with cardiomyopathy. Similar to NTLA-2002, the company recently announced plans to move forward with an IND to expand study sites into the US for a pivotalphase 2 study.³ Intellia also plans to launch a phase 3 study to evaluate NTLA-2001 in ATTR amyloidosis with polyneuropathy, making it the only gene therapy candidate currently in clinical trials for this indication.

REFERENCES

1. 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. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fda-clearance-investigational
2. Intellia Therapeutics Presents New Interim Data from First-in-Human Study of NTLA-2002 for the Treatment of Hereditary Angioedema (HAE) at the American College of Allergy, Asthma & Immunology 2022 Annual Scientific Meeting/ November 12, 2022. https://www.einpresswire.com/article/600986799/intellia-therapeutics-presents-new-interim-data-from-first-in-human-study-of-ntla-2002-for-the-treatment-of-hereditary-angioedema-hae-at-the
3. Intellia Therapeutics highlights strategic priorities and anticipated 2023 key milestones. News release. Intellia Therapeutics. January 5, 2023. https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-highlights-strategic-priorities-and-1