FDA Recognizes CRISPR Therapy for Treatment of Hereditary Angioedema


The in vivo genome-editing therapy is the first gene therapy to be evaluated in a clinical trial for preventing HAE attacks.

The FDA has granted orphan drug designation to Intellia Therapeutics’ investigational CRISPR therapy for treating hereditary angioedema (HAE), NTLA-2002.1

NTLA-2002 is an in vivo genome editing therapy candidate designed to knockout the KLKB1 gene to reduce plasma kallikrein activity and prevent HAE attacks. It is administered intravenously and is the first single-dose therapy being evaluated in clinical trials to prevent HAE attacks. The therapy is developed with the use of Intellia’s non-viral, lipid nanoparticle platform that delivers guide RNA and mRNA to the liver to edit the genome with the CRISPR/Cas9 system.

The therapy is being evaluated in an international, open-label, single-ascending dose phase 1/2 study (NCT05120830) for safety and tolerability in adults with type 1 or 2 HAE. Pharmacokinetics and pharmacodynamics, including the measurement of plasma kallikrein protein levels and HAE attack rate will also be assessed. Two dose levels will be assessed with the goal of determining a phase 2 recommended dose level.

“Orphan drug designation represents an important milestone in the development of NTLA-2002 and underscores the importance of developing innovative, new treatment options for people living with HAE,” John Leonard, MD, president and chief executive officer, Intellia, said in a statement.1 “We hope to demonstrate in our ongoing clinical trial that NTLA-2002 can result in deep and sustained kallikrein activity reduction following a single dose, and potentially prevent the unpredictable swelling attacks caused by this genetic disease. We look forward to presenting interim data on September 16 at the 2022 Bradykinin Symposium, including safety, kallikrein reduction and HAE attack rate data.”

READ MORE: CRISPR Patents Decision Favors Harvard and MIT’s Broad Institute

Intellia also recently presented positive interim data from the phase 1 study (NCT04601051) of another CRISPR gene-editing candidate, NTLA-2001, at the European Association for the Study of the Liver International Liver Congress 2022 in June.2 NTLA-2001 is an investigational therapy for the treatment of transthyretin (ATTR) amyloidosis that is developed in collaboration with Regeneron, as opposed to NTLA-2002, which is wholly owned by Intellia.

Data presented showed that 6 patients treated at the highest dose of 1.0 mg/kg achieved a 93% mean and 98% maximum reduction in disease-causing serum transthyretin (TTR) at 28 days after treatment. These reductions remained at 6 months, with 3 patients showing no loss in TTR reductions at 9 months post-treatment. Patients in the lower dose cohorts also showed durable TTR reductions, with an 86% mean serum TTR reduction remaining durable at 6 months in the 0.7 mg/kg cohort and an 89% mean reduction sustained at 12 months in the 0.3 mg/kg cohort.

NTLA-2001 was generally well-tolerated, with mostly (73%) grade 1 severity adverse events (AEs). A serious grade 3 AE of vomiting in the 1.0 mg/kg dose group in a patient with a concomitant medical history of gastroparesis was deemed possibly related to treatment. Mild infusion-related reactions and headache, back pain, rash, and nausea were common AEs.

“Notably, the higher doses yielded even deeper serum TTR reduction, with doses of 0.3 mg/kg and above achieving mean reductions of more than 85% and the highest dose of 1 mg/kg leading to a 93% mean reduction by day 28,” David Lebwhol, MD, chief medical officer, Intellia Therapeutics, said in a conference call regarding the data that was held on June 24, 2022.3 “With this profound level of TTR reduction, it is our judgment that there is limited benefit of assessing doses beyond 1 mg/kg.”

1. 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. 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
2. Intellia and Regeneron present updated interim data from phase 1 study of CRISPR-based NTLA-2001 for the treatment of transthyretin (ATTR) amyloidosis demonstrating that deep serum TTR reductions remained durable after a single dose. News release. Intellia Therapeutics, Inc. and Regeneron Pharmaceuticals, Inc. June 24, 2022. https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-present-updated-interim-data-phase-1
3. NTLA-2001 for ATTR amyloidosis: Interim clinical results from ongoing phase 1 trial. Webcast. Intellia Therapeutics, Inc. June 24, 2022.https://services.choruscall.com/mediaframe/webcast.html?webcastid=SPVgbdeg
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