NTLA-2002 for Hereditary Angioedema
(HAELO Trial)
Recruiting in Palo Alto (17 mi)
+13 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Intellia Therapeutics
Disqualifiers: Other angioedema, LNP hypersensitivity, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
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.
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.
12345Is 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.
678910How 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.
6781112Eligibility 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
1. Age ≥18 years
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
+6 more
Trial 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
Participant Groups
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.
2Treatment groups
Active Control
Placebo Group
Group I: Arm A: NTLA-2002Active Control1 Intervention
Arm A: NTLA-2002 (50 mg; single IV infusion)
Group II: Arm B: PlaceboPlacebo Group1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Allergy & Asthma Clinical ResearchWalnut Creek, CA
Asthma & Allergy AssociatesColorado Springs, CO
Optimed Research, LTDColumbus, OH
Medical Research of ArizonaScottsdale, AZ
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Intellia TherapeuticsLead Sponsor
References
Hereditary angioedema with normal C1 inhibitor in a French cohort: Clinical characteristics and response to treatment with icatibant. [2018]The clinical characteristics and icatibant-treatment outcomes of patients with hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) are limited.
Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. [2013]To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies.
Subcutaneous C1-Inhibitor Concentrate for prophylaxis during pregnancy and lactation in a patient with C1-INH-HAE. [2021]Subcutaneous plasma-derived human C1-Inhibitor concentrate (pdC1INH) may be safe and effective for long-term prophylaxis during pregnancy and lactation in hereditary angioedema patients.
An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema. [2020]Hereditary angioedema (HAE) is a genetic disorder mostly caused by mutations in the C1 esterase inhibitor gene (C1INH) that results in poor control of contact pathway activation and excess bradykinin generation. Bradykinin increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. We hypothesized that the use of RNA interference (RNAi) to reduce plasma Factor XII (FXII), which initiates the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. A subcutaneously administered GalNAc-conjugated small-interfering RNA (siRNA) targeting F12 mRNA (ALN-F12) was developed, and potency was evaluated in mice, rats, and cynomolgus monkeys. The effect of FXII reduction by ALN-F12 administration was evaluated in two different vascular leakage mouse models. An ex vivo assay was developed to evaluate the correlation between human plasma FXII levels and high-molecular weight kininogen (HK) cleavage. A single subcutaneous dose of ALN-F12 led to potent, dose-dependent reduction of plasma FXII in mice, rats, and NHP. In cynomolgus monkeys, a single subcutaneous dose of ALN-F12 at 3 mg/kg resulted in >85% reduction of plasma FXII. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular leakage, demonstrating that RNAi-mediated reduction of FXII can potentially mitigate excess bradykinin stimulation. Lastly, ex vivo human plasma HK cleavage assay indicated FXII-dependent bradykinin generation. Together, these data suggest that RNAi-mediated knockdown of FXII by ALN-F12 is a potentially promising approach for the prophylactic treatment of HAE.
Hereditary angiodema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema. [2019]To provide a comprehensive overview on clinical trial design and results of emerging therapies for the treatment of hereditary angioedema (HAE).
Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. [2022]Loss-of-function mutations in Angiopoietin-like 3 (Angptl3) are associated with lowered blood lipid levels, making Angptl3 an attractive therapeutic target for the treatment of human lipoprotein metabolism disorders. In this study, we developed a lipid nanoparticle delivery platform carrying Cas9 messenger RNA (mRNA) and guide RNA for CRISPR-Cas9-based genome editing of Angptl3 in vivo. This system mediated specific and efficient Angptl3 gene knockdown in the liver of wild-type C57BL/6 mice, resulting in profound reductions in serum ANGPTL3 protein, low density lipoprotein cholesterol, and triglyceride levels. Our delivery platform is significantly more efficient than the FDA-approved MC-3 LNP, the current gold standard. No evidence of off-target mutagenesis was detected at any of the nine top-predicted sites, and no evidence of toxicity was detected in the liver. Importantly, the therapeutic effect of genome editing was stable for at least 100 d after a single dose administration. This study highlights the potential of LNP-mediated delivery as a specific, effective, and safe platform for Cas9-based therapeutics.
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. [2022]Label="BACKGROUND">Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR.
A Single Administration of CRISPR/Cas9 Lipid Nanoparticles Achieves Robust and Persistent In Vivo Genome Editing. [2022]The development of clinically viable delivery methods presents one of the greatest challenges in the therapeutic application of CRISPR/Cas9 mediated genome editing. Here, we report the development of a lipid nanoparticle (LNP)-mediated delivery system that, with a single administration, enabled significant editing of the mouse transthyretin (Ttr) gene in the liver, with a >97% reduction in serum protein levels that persisted for at least 12 months. These results were achieved with an LNP delivery system that was biodegradable and well tolerated. The LNP delivery system was combined with a sgRNA having a chemical modification pattern that was important for high levels of in vivo activity. The formulation was similarly effective in a rat model. Our work demonstrates that this LNP system can deliver CRISPR/Cas9 components to achieve clinically relevant levels of in vivo genome editing with a concomitant reduction of TTR serum protein, highlighting the potential of this system as an effective genome editing platform.
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]Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a progressive fatal disease characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TTR) protein in tissues, resulting in cardiomyopathy and heart failure. Approximately 50,000 people have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis globally, leading to poor quality of life and high morbidity, resulting in death within a median of 2 to 6 years after diagnosis. However, data on the prevalence of ATTR-CM is limited and poorly characterized. NTLA-2001, an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum by knocking out the TTR gene, has been shown to be effective, presenting a new therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration has not been yet demonstrated. Study and results: The first-in-human in vivo CRISPR/Cas9 trial of TTR Gene editing by NTLA-2001 in patients with Transthyretin Amyloidosis and cardiomyopathy was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic responses to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis and cardiomyopathy. Twelve subjects received NTLA-2001 (three NYHA I/II subjects at 0.7 mg/kg, three subjects at 1.0 mg/kg, and six NYHA III subjects at 0.7 mg/kg). Serum TTR levels were reduced from the baseline in all subjects (mean>90% after 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA III at 0.7 mg/kg = 94% (1%) maintained through 4-6 months. Two of the 12 patients (16.7%) reported a transient infusion reaction. One patient experienced a grade 3 infusion-related reaction that resolved without any clinical sequelae. Lessons learned: This study showed a significant and consistent reduction in serum TTR protein levels after a single admission, while being generally well tolerated, representing a potential new option for the treatment and improvement of the prognosis of cardiac ATTR amyloidosis. Further research into the long-term safety and efficacy of NTLA-2001, particularly in higher-risk patients, including continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term, is essential. Evaluation of the potential effects of markedly reduced TTR levels on patients' clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential. The analysis of the use of this technology for an array of other diseases is vital.
Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice. [2023]CRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.
Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina. [2023]Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modified PEG-lipids, and neutral unmodified PEG-lipids (LNP). Subretinal injections of LNPa containing Cre mRNA in the mouse show tdTomato signal in the retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx and LNPz show 27% and 16% photoreceptor transfection, respectively, with striking localization extending from the photoreceptor synaptic pedicle to the outer segments, displaying pan-retinal distribution in the photoreceptors and RPE. LNPx containing Cas9 mRNA and sgAi9 leads to the formation of an oval elongated structure with a neutral charge resulting in 16.4% editing restricted to RPE. Surface modifications of LNPs with PEG variants can alter cellular tropism of mRNA. LNPs enable genome editing in the retina and in the future can be used to correct genetic mutations that lead to blindness.
In Vitro CRISPR/Cas9 Transfection and Gene-Editing Mediated by Multivalent Cationic Liposome-DNA Complexes. [2023]Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease 9 (Cas9) gene-editing offers exciting new therapeutic possibilities for disease treatment with a genetic etiology such as cancer, cardiovascular, neuronal, and immune disorders. However, its clinical translation is being hampered by the lack of safe, versatile, and effective nonviral delivery systems. Herein we report on the preparation and application of two cationic liposome−DNA systems (i.e., lipoplexes) for CRISPR/Cas9 gene delivery. For that purpose, two types of cationic lipids are used (DOTAP, monovalent, and MVL5, multivalent with +5e nominal charge), along with three types of helper lipids (DOPC, DOPE, and monoolein (GMO)). We demonstrated that plasmids encoding Cas9 and single-guide RNA (sgRNA), which are typically hard to transfect due to their large size (>9 kb), can be successfully transfected into HEK 293T cells via MVL5-based lipoplexes. In contrast, DOTAP-based lipoplexes resulted in very low transfection rates. MVL5-based lipoplexes presented the ability to escape from lysosomes, which may explain the superior transfection efficiency. Regarding gene editing, MVL5-based lipoplexes achieved promising GFP knockout levels, reaching rates of knockout superior to 35% for charge ratios (+/−) of 10. Despite the knockout efficiency being comparable to that of Lipofectamine 3000® commercial reagent, the non-specific gene knockout is more pronounced in MVL5-based formulations, probably resulting from the considerable cytotoxicity of these formulations. Altogether, these results show that multivalent lipid-based lipoplexes are promising CRISPR/Cas9 plasmid delivery vehicles, which by further optimization and functionalization may become suitable in vivo delivery systems.