NTLA-2002 / Intellia Therap - LARVOL DELTA

Clinical Development Plans (Intellia Therapeutics) - "Intellia’s global Phase 3, randomized, double-blind, placebo-controlled HAELO trial is ongoing to assess the safety and efficacy of lonvo-z at the 50 mg dosage. The Company announced today the HAELO trial has successfully completed screening ahead of schedule, with over half of the patients being screened in the United States. The study is no longer recruiting and Intellia will provide an update on enrollment in the future...Intellia expects to submit a biologics license application (BLA) in 2026 to support the Company’s plans for a U.S. launch in 2027."

FDA filing • Launch US • Trial status • Hereditary Angioedema

Intellia Therapeutics Announces Positive Three-Year Data from Phase 1 Trial of Lonvoguran Ziclumeran (lonvo-z) in Patients with Hereditary Angioedema (HAE) at the European Academy of Allergy and Clinical Immunology Congress (Intellia Therapeutics) - P1/2 | N=37 | NCT05120830 | Sponsor:Intellia Therapeutics | "In the Phase 1 portion of the study, a one-time dose of 25 mg (N=3), 50 mg (N=4) or 75 mg (N=3) of lonvo-z was administered via intravenous infusion and plasma kallikrein protein levels were measured along with HAE attacks. At the time of the February 12 data cutoff, patients were attack-free and treatment-free for a median of nearly two years. With up to three years of follow-up, a single dose of lonvo-z led to a mean reduction in monthly HAE attack rate of 98% over the study period, compared to pre-treatment baseline. For all 10 patients, deep, dose-dependent and durable reductions in plasma kallikrein protein continued to be observed through the latest assessment...New and longer-term data from the Phase 2 portion of the ongoing Phase 1/2 study is planned to be presented in the second half of 2025."

P1/2 data • Hereditary Angioedema

HAELO: A Phase 3 Study to Evaluate NTLA-2002 in Participants With Hereditary Angioedema (HAE) (clinicaltrials.gov) - P3 | N=60 | Active, not recruiting | Sponsor: Intellia Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Intellia Therapeutics Announces Fourth Quarter and Full-Year 2024 Financial Results and Highlights Recent Company Progress (GlobeNewswire) - "NTLA-2002...Intellia expects to present longer-term data from the ongoing Phase 1/2 study in 2025...Nexiguran ziclumeran...Intellia expects to present longer-term data from both ATTR-CM and ATTRv-PN patients in the Phase 1 study in 2025."

P1 data • P1/2 data • Amyloidosis • Cardiomyopathy • Cardiovascular • Hereditary Angioedema

CRISPR-Based NTLA-2002 Improves Quality of Life in Patients With Hereditary Angioedema (AAAAI-WAO 2025) - P1/2, P3 | "No serious adverse events were reported with NTLA-2002. Conclusions With a one-time treatment of NTLA-2002, patients experienced clinically meaningful improvements in QOL, providing the first evidence of a CRISPR-based therapy favorably impacting QOL measures in patients with HAE."

Clinical • HEOR • Late-breaking abstract • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

Intellia Therapeutics Announces Anticipated 2025 Milestones and Strategic Reorganization to Prioritize the Advancement of its Late-Stage Programs, NTLA-2002 and Nexiguran Ziclumeran (nex-z) (GlobeNewswire) - "Phase 3 HAELO study evaluating NTLA-2002 for HAE to complete enrollment in the second half of 2025; Company plans to submit a Biologics License Application in the second half of 2026....Anticipated cost savings, including a net workforce reduction of approximately 27% in 2025, support company operations into 1H 2027 and through anticipated, first commercial launch in the U.S. Nex-z for ATTR amyloidosis: Dose the first patient in the pivotal Phase 3 MAGNITUDE-2 trial for ATTRv-PN in 1Q25. Enroll at least 550 patients cumulatively within the MAGNITUDE trial for ATTR-CM."

Commercial • Enrollment closed • FDA filing • Amyloidosis • Hereditary Angioedema

Distinguished Industry & Late-breaking Oral Abstracts - Session 1 (ACAAI 2024) - "Learning Objectives Objective 1: Discuss lebrikizumab’s efficacy up to 52 weeks among patients with atopic dermatitis with or without atopic comorbidities. Observe that participants with hereditary angioedema treated with a single dose of NTLA-2002 in Phase 2 of a Phase 1/2 study saw robust, sustained reductions in attacks and plasma kallikrein levels, with no new safety signals...To educate on the efficacy and safety of Dupilumab in a randomized, placebo-controlled, double-blind 24-week phase 3 trial compared dupilumab to placebo treatment in omalizumab-naive patients with symptomatic CSU despite standard-of-care H1-antihistamines treatment (up to 4-fold approved dose)...Understand the efficacy and safety profile for barzolvolimab from the first large, randomized placebo-controlled study to achieve a successful outcome for chronic inducible urticaria. This data allows advancement of the program to registrational studies."

Late-breaking abstract • Allergic Rhinitis • Atopic Dermatitis • Cardiovascular • Chronic Spontaneous Urticaria • Complement-mediated Rare Disorders • Conjunctivitis • Dermatitis • Dermatology • Hereditary Angioedema • Immunology • Inflammation • Ocular Infections • Ocular Inflammation • Ophthalmology • Urticaria

RESULTS FROM A PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF CRISPR-BASED THERAPY NTLA2002 FOR HEREDITARY ANGIOEDEMA (ACAAI 2024) - P1/2 | "A single dose of NTLA-2002 25mg or 50mg led to robust, sustained reduction in attacks and total plasma kallikrein levels and was well-tolerated with no new safety signals."

Clinical • Late-breaking abstract • P2 data • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hereditary Angioedema • Infectious Disease • Pain

CRISPR-Based Therapy for Hereditary Angioedema. (PubMed, N Engl J Med) - P1/2 | "NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema. These results support continued investigation in a larger phase 3 trial. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830; EudraCT number, 2021-001693-33.)."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Genetic Disorders • Hereditary Angioedema • Infectious Disease • Pain

HAELO: A Phase 3 Study to Evaluate NTLA-2002 in Participants with Hereditary Angioedema (HAE) (clinicaltrials.gov) - P3 | N=60 | Recruiting | Sponsor: Intellia Therapeutics

New P3 trial • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

NTLA-2002 in Adults With Hereditary Angioedema (HAE) (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Intellia Therapeutics | Trial completion date: Dec 2025 ➔ Mar 2026

Trial completion date • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Reduction of plasma kallikrein by in vivo CRISPR-based gene editing of KLKB1 does not alter coagulation in patients with hereditary angioedema (ISTH 2024) - "At the time of analysis, median duration of follow-up was 9.0 months. The most frequent adverse events (AEs) were infusion-related reactions and fatigue. No treatment-emergent serious AEs or ≥Grade 3 AEs were observed."

Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hematological Disorders • Hereditary Angioedema

ITL-2002-CL-999: Long-Term Follow-Up (LTFU) of Subjects Treated With NTLA 2002 (clinicaltrials.gov) - P=N/A | N=100 | Enrolling by invitation | Sponsor: Intellia Therapeutics | Not yet recruiting ➔ Enrolling by invitation

Enrollment open • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

NTLA-2002 in Adults With Hereditary Angioedema (HAE) (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Intellia Therapeutics | Recruiting ➔ Active, not recruiting | N=55 ➔ 37

Enrollment change • Enrollment closed • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

Kallikrein inhibitors for angioedema: the progress of preclinical and early phase studies. (PubMed, Expert Opin Investig Drugs) - "ATN-249 is an oral drug that has shown promising results in preclinical and Phase I studies, and good tolerability in the prophylactic treatment of attacks. KVD900 is also an oral agent developed for the on-demand treatment of HAE attacks...The third drug, IONIS-PKKRx, is an antisense oligonucleotide targeting plasma prekallikrein mRNA...STAR-0215 is a long acting anti-activated kallikrein monoclonal antibody...Lastly, NTLA-2002 is an investigational gene-editing therapy. The targeted treatment of the dysregulated kinin-kallikrein system with specific inhibitors is promising for the prevention of angioedema attacks. Ongoing phase III studies will provide further insight into the efficacy and long-term safety of these novel therapies, potentially expanding treatment options for HAE treatment."

Journal • Preclinical • Review • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

Long-Term Follow-Up (LTFU) of Subjects Treated With NTLA 2002 (clinicaltrials.gov) - P=N/A | N=100 | Not yet recruiting | Sponsor: Intellia Therapeutics

New trial • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema. (PubMed, N Engl J Med) - P1/2 | "In this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.)."

Journal • Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Genetic Disorders • Hereditary Angioedema

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema. (PubMed, J Allergy Clin Immunol Pract) - "Donidalorsen is an investigational GalNAc-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein...ADX-324 is a GalNAc-conjugated siRNA being investigated in HAE...NTLA-2002 is an investigational in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based therapy designed to knock out the prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Gene Therapies • Hereditary Angioedema

CRISPR/Cas9 editing of KLKB1 in Hereditary Angioedema Patients: Updated Results from a Phase 1 Study (ACAAI 2023) - "All 6 patients who were taking concomitant long-term prophylaxis at study start were able to withdraw treatment and remain attack-free post-withdrawal. Conclusion A single dose of NTLA-2002 was well-tolerated and led to dose-dependent, durable reductions in plasma kallikrein protein, with clinically significant reduction in attack rate observed across all cohorts."

Clinical • P1 data • Cardiovascular • Complement-mediated Rare Disorders • Fatigue • Hereditary Angioedema

Intellia Therapeutics Announces First Quarter 2023 Financial Results and Highlights Recent Company Progress (GlobeNewswire) - "Upcoming Milestones: The Company has set forth the following expected milestones for pipeline progression: NTLA-2002 for HAE: Present additional clinical data from the ongoing first-in-human study of NTLA-2002 in 2023. Complete enrollment in the Phase 2 portion of the Phase 1/2 study in 2H 2023; AATD Franchise: Submit an IND or IND-equivalent application for NTLA-3001 for AATD-associated lung disease in 2H 2023. Complete IND-enabling activities for NTLA-2003 for AATD-associated liver disease by year-end 2023."

IND • P1/2 data • Trial status • Alpha-1 Antitrypsin Deficiency • Genetic Disorders • Hereditary Angioedema

In vivo CRISPR/Cas9 editing of KLKB1 in Patients with Hereditary Angioedema: A First-in-Human Study (ACAAI 2022) - P1/2 | "Conclusion A single 25 mg dose of NTLA-2002 has been well-tolerated to date, meeting pre-specified criteria for advancement to phase 2 with reduction in plasma kallikrein levels and HAE attack rate maintained throughout the 16-week period following infusion. Safety, pharmacodynamic and HAE attack rate data for both cohorts will be presented."

P1 data • Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

NTLA-2002: CRISPR-Mediated Gene Knockout of KLKB1 as a Potential Single-Dose Treatment for Hereditary Angioedema (HAE) (BSACI 2022) - "In mice, NTLA-2002 led to protection from captopril-induced vascular leakage. Preclinical data indicate that NTLA-2002 elicits high levels of KLKB1 gene editing with robust and durable reduction in kallikrein protein at well tolerated doses in multiple animal models. A first-inhuman clinical trial has been initiated with the first patient dosed in December of 2021. Enrollment is ongoing"

Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

CRISPR/Cas9-mediated KLKB1 Gene Editing and Serum Kallikrein Reduction by NTLA-2002 Remains Durable in Humanized Mice Following Liver Regeneration after Partial Hepatectomy (AAAAI 2022) - "KLKB1 editing and serum kallikrein reduction is retained at both dose levels following PHx-induced liver regeneration, demonstrating the permanence of CRISPR-Cas9-induced genetic editing. These data further support the development of NTLA-2002 as a potential single-dose treatment for patients with HAE."

Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema