NTLA-2002 for Hereditary Angioedema

(HAELO Trial)

Recruiting at 31 trial locations

Overseen By Trial Manager at Intellia Therapeutics

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Intellia Therapeutics

Disqualifiers: Other angioedema, LNP hypersensitivity, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You will need to stop using long-term preventive treatments for hereditary angioedema (HAE) during the trial, but you can still use on-demand medications to treat any angioedema attacks.

What data supports the effectiveness of the drug NTLA-2002 for hereditary angioedema?

The research on ALN-F12, a similar RNA interference (RNAi) treatment, shows that reducing plasma Factor XII can decrease bradykinin levels, which are responsible for swelling in hereditary angioedema. This suggests that targeting genetic pathways, like NTLA-2002 does, could be effective in managing hereditary angioedema. ^{1 2 3 4 5}

Is NTLA-2002 safe for humans?

Research on similar treatments using lipid nanoparticles for gene editing, like NTLA-2001, has shown that they are generally well tolerated in humans, with some patients experiencing mild infusion reactions that resolved without lasting effects. These studies suggest that the delivery system used in NTLA-2002 is likely safe, but more specific safety data for NTLA-2002 itself would be needed for a definitive answer. ^{6 7 8 9 10}

How is the drug NTLA-2002 different from other treatments for hereditary angioedema?

NTLA-2002 is unique because it uses CRISPR-Cas9 gene-editing technology to target and modify the KLKB1 gene, which is involved in hereditary angioedema, potentially offering a long-lasting solution with a single administration. This approach is different from traditional treatments that typically manage symptoms rather than address the underlying genetic cause. ^{6 7 8 11 12}

What is the purpose of this trial?

This Phase 3 study aims to evaluate the efficacy and safety of NTLA-2002 compared to placebo in participants with HAE.

Eligibility Criteria

This trial is for adults with Hereditary Angioedema (HAE), a condition causing repeated swelling episodes. Participants must meet certain health criteria, but specific inclusion and exclusion details are not provided.

Inclusion Criteria

2. Clinical history consistent with HAE-C1INH-Type 1 or -Type 2

3. Ability to provide evidence of HAE attacks (confirmed by the Investigator) to meet the screening requirement

4. Must agree to refrain from the use of long-term prophylactic therapies from the start of the screening period through the end of the Primary Observation Period. PI must be in agreement that it is medically acceptable for the participant to do so.

Timeline

Screening and Run-In

Participants are screened for eligibility to participate in the trial

4 weeks

Primary Observation Period

Participants receive a single IV infusion of NTLA-2002 or placebo and are monitored for efficacy and safety

28 weeks

Regular visits for monitoring

Blinded Crossover

Participants have the option to receive a blinded, single IV infusion of the opposite treatment

Not specified

Long-Term Observation Period

Participants are monitored for long-term safety and efficacy

76 weeks

Periodic visits for long-term monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• NTLA-2002

Trial Overview The study tests NTLA-2002's effectiveness and safety against a placebo in managing HAE symptoms. A placebo group receives normal saline IV, which has no therapeutic effect, to compare results.

Participant Groups

Group I: Arm A: NTLA-2002 Active Control 1 Intervention

Arm A: NTLA-2002 (50 mg; single IV infusion)

Group II: Arm B: Placebo Placebo Group 1 Intervention

Arm B: Placebo (saline; single IV infusion)

NTLA-2002 is already approved in United States, European Union for the following indications:

Approved in United States as NTLA-2002 for:

• Hereditary Angioedema (HAE) - Orphan Drug and RMAT Designation granted, but not yet approved

Approved in European Union as NTLA-2002 for:

• Hereditary Angioedema (HAE) - Orphan Drug Designation granted, but not yet approved

Who Is Running the Clinical Trial?

Intellia Therapeutics

Lead Sponsor

Trials

10

Recruited

1,300+

Findings from Research

Patients with hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) tend to be older at disease onset and experience more abdominal and laryngeal attacks compared to those with HAE type I.

Icatibant is effective for treating angioedema attacks in both HAE-nC1 INH and HAE type I, but it takes longer to resolve attacks in HAE-nC1 INH patients, with no serious side effects reported, highlighting its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant. Bouillet, L., Boccon-Gibod, I., Launay, D., et al.[2018]

Cinryze (C1-esterase inhibitor) provided significant relief from hereditary angioedema attacks in children, with a median time to relief of 30 minutes compared to 2 hours for placebo, demonstrating its efficacy in acute management.

In prophylaxis, Cinryze reduced the frequency of attacks by about 50%, with the median monthly attack rate dropping from 3.0 to 0.39, indicating its effectiveness in preventing future episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. Lumry, W., Manning, ME., Hurewitz, DS., et al.[2013]

Subcutaneous plasma-derived human C1-Inhibitor concentrate (pdC1INH) is suggested to be a safe and effective option for long-term prevention of hereditary angioedema during pregnancy and lactation.

This finding supports the use of pdC1INH in managing hereditary angioedema in pregnant and breastfeeding patients, ensuring both maternal and fetal safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous C1-Inhibitor Concentrate for prophylaxis during pregnancy and lactation in a patient with C1-INH-HAE. Andarawewa, S., Aygören-Pürsün, E.[2021]

A new treatment using RNA interference (RNAi) to reduce plasma Factor XII (FXII) has shown promise in preventing excessive bradykinin generation, which causes swelling in hereditary angioedema (HAE).

In studies with mice, rats, and cynomolgus monkeys, a single dose of the siRNA treatment (ALN-F12) resulted in over 85% reduction of plasma FXII and significantly decreased vascular permeability, indicating its potential effectiveness for HAE management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. Liu, J., Qin, J., Borodovsky, A., et al.[2020]

Emerging therapies for hereditary angioedema (HAE), including C1 esterase replacement, kallikrein inhibitors, and bradykinin receptor 2 antagonists, have shown promise in phase 1 and phase 2 trials, indicating their potential effectiveness in treating HAE.

The clinical trials are well-designed, being double-blind and placebo-controlled, and they focus on patients with confirmed low C1 inhibitor levels, suggesting a robust approach to developing new treatments for HAE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hereditary angiodema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema. Frank, MM.[2019]

The study developed a lipid nanoparticle delivery system that effectively delivered CRISPR-Cas9 components to knock down the Angptl3 gene in the liver of mice, leading to significant reductions in harmful blood lipids like LDL cholesterol and triglycerides.

This delivery platform demonstrated high efficiency and safety, with no off-target effects or liver toxicity observed, and the therapeutic benefits lasted for at least 100 days after a single treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Qiu, M., Glass, Z., Chen, J., et al.[2022]

NTLA-2001, a CRISPR-Cas9 based gene-editing therapy, demonstrated a significant reduction in serum transthyretin (TTR) protein levels in patients with hereditary ATTR amyloidosis, achieving a mean reduction of 87% with the higher dose after 28 days.

The treatment was well-tolerated, with only mild adverse events reported in a small group of six patients, indicating a favorable safety profile for this innovative therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. Gillmore, JD., Gane, E., Taubel, J., et al.[2022]

A lipid nanoparticle (LNP) delivery system successfully enabled over 97% reduction in serum transthyretin (Ttr) protein levels in mice after a single administration, with effects lasting for at least 12 months.

The LNP system was biodegradable, well tolerated, and effective in both mouse and rat models, demonstrating its potential as a safe and effective platform for CRISPR/Cas9 genome editing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. Finn, JD., Smith, AR., Patel, MC., et al.[2022]

The first-in-human trial of NTLA-2001, a CRISPR/Cas9 gene-editing therapy for transthyretin amyloidosis, demonstrated a significant reduction in serum TTR levels (over 90%) in all 12 participants after 28 days, indicating its potential efficacy in treating this progressive disease.

The treatment was generally well tolerated, with only 16.7% of patients experiencing transient infusion reactions, suggesting a favorable safety profile for NTLA-2001 as a new therapeutic option for patients with ATTR amyloidosis and cardiomyopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy. Kotit, S.[2023]

The study developed a mouse model that allows for tissue-specific activation of target genes using a CRISPR-based system, which can enhance the understanding of gene functions in living organisms.

By optimizing delivery methods like Lipid Nanoparticles and Adeno-Associated Virus, the researchers successfully modulated gene expression in vivo, demonstrating the potential of this system for disease modeling and drug discovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice. Hunt, C., Hartford, SA., White, D., et al.[2023]

Lipid nanoparticles (LNPs) modified with different PEG-lipids can significantly alter their ability to deliver mRNA to specific retinal cells, with LNPx and LNPz achieving up to 27% and 16% photoreceptor transfection, respectively.

These modified LNPs not only enable efficient gene delivery but also facilitate genome editing in the retina, suggesting potential for future treatments of genetic mutations that cause blindness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina. Gautam, M., Jozic, A., Su, GL., et al.[2023]

The study developed two types of cationic liposome-DNA systems for delivering CRISPR/Cas9 gene-editing tools, with MVL5-based lipoplexes showing significantly higher transfection efficiency in HEK 293T cells compared to DOTAP-based lipoplexes.

MVL5-based lipoplexes achieved over 35% knockout efficiency for a target gene, comparable to commercial delivery systems, but also exhibited higher cytotoxicity and non-specific gene knockout, indicating a need for further optimization for safe in vivo applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro CRISPR/Cas9 Transfection and Gene-Editing Mediated by Multivalent Cationic Liposome-DNA Complexes. Sousa, DA., Gaspar, R., Ferreira, CJO., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Subcutaneous C1-Inhibitor Concentrate for prophylaxis during pregnancy and lactation in a patient with C1-INH-HAE. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Hereditary angiodema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. [2022]

9. Qatar pubmed.ncbi.nlm.nih.gov

Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina. [2023]

12. Switzerland pubmed.ncbi.nlm.nih.gov

In Vitro CRISPR/Cas9 Transfection and Gene-Editing Mediated by Multivalent Cationic Liposome-DNA Complexes. [2023]