ARCT-032 for Cystic Fibrosis

(LunairCF Trial)

Recruiting in Palo Alto (17 mi)

+2 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Arcturus Therapeutics, Inc.

Must not be taking: Systemic corticosteroids

Disqualifiers: Recent hemoptysis, Major surgery, Transplant, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

ARCT-032-02 is a Phase 2, open-label, multicenter, multiple-ascending dose study of ARCT-032 in adults with CF who are not eligible for CFTR modulator therapy or are not taking CFTR modulators due to drug intolerance, poor response, or lack of access to modulators.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must not be taking CFTR modulators for at least 60 days before joining. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug ARCT-032 for cystic fibrosis?

Research on similar drugs, like ivacaftor and lumacaftor, shows that targeting the CFTR protein can improve its function in people with cystic fibrosis, leading to better health outcomes. These drugs have been successful in treating specific genetic mutations related to cystic fibrosis, suggesting that ARCT-032 might also be effective if it works in a similar way. ^{1 2 3 4 5}

What safety data exists for ARCT-032 or similar treatments for cystic fibrosis?

The safety of CFTR modulator therapies, which are similar to ARCT-032, has been generally well-tolerated in clinical trials, but real-world studies show a higher frequency of adverse events like respiratory issues and mental health symptoms. These treatments have been associated with drug interactions and liver injury, but overall, adverse events are comparable to those seen with placebo or other controls. ^{6 7 8 9 10}

How is the drug ARCT-032 different from other cystic fibrosis treatments?

ARCT-032 is unique because it is a gene therapy approach aimed at replacing the defective CFTR protein in cystic fibrosis patients, unlike traditional treatments that focus on managing symptoms or using small molecules to modulate CFTR function. ^{1 11 12 13 14}

Research Team

Eligibility Criteria

This trial is for adults with Cystic Fibrosis who can't use CFTR modulator therapy because it doesn't work for them, they can't tolerate it, or they don't have access. Participants should not currently be on any CFTR modulators.

Inclusion Criteria

I have been diagnosed with Cystic Fibrosis.

FEV1 between 40% and 100% of predicted value

I haven't taken CFTR modulators for 60 days due to intolerance, poor response, or lack of access.

Exclusion Criteria

I have had major surgery recently.

My liver and kidney tests are within normal ranges.

I need extra oxygen when awake or more than 2L/min when sleeping.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nebulized ARCT-032 daily for 4 weeks

4 weeks

Daily visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• ARCT-032 (RNA-based Therapy)

Trial Overview The study is testing multiple doses of a new drug called ARCT-032 to see how safe and effective it is for treating Cystic Fibrosis in adults. It's an open-label and multicenter trial, meaning both the researchers and participants know what treatment is being given.

Participant Groups

Group I: Cohort 3 Experimental Treatment 1 Intervention

Dose Level C of ARCT-032, inhaled daily for 28 days

Group II: Cohort 2 Experimental Treatment 1 Intervention

Dose Level B of ARCT-032, inhaled daily for 28 days

Group III: Cohort 1 Experimental Treatment 1 Intervention

Dose Level A of ARCT-032, inhaled daily for 28 days

Who Is Running the Clinical Trial?

Arcturus Therapeutics, Inc.

Lead Sponsor

Trials

14

Recruited

22,300+

Findings from Research

Ivacaftor, a small molecule approved in 2012, represents a significant advancement in cystic fibrosis treatment by directly targeting the CFTR gene mutations, improving chloride channel function in specific patient genotypes.

Three main therapeutic strategies have been developed to enhance CFTR function: potentiators for class III and IV mutations, correctors for class II mutations, and production correctors for class I mutations, indicating a move towards more personalized medicine in treating cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies to improve CFTR function in cystic fibrosis. Brodlie, M., Haq, IJ., Roberts, K., et al.[2022]

Cystic fibrosis treatment has advanced with personalized medicine, specifically through the development of CFTR modulators like ivacaftor and lumacaftor, which target specific genetic mutations in patients.

Ivacaftor enhances CFTR function at the cell surface for patients with gating mutations, while lumacaftor helps transport the most common mutation (p.Phe508del) to the cell surface, demonstrating tailored therapeutic approaches based on individual genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of Cystic Fibrosis with CFTR Modulators]. Tümmler, B.[2017]

The triple CFTR protein modulators (Elexacaftor-Tezacaftor-Ivacaftor) significantly improved lung function (measured by FEV1) and body mass index (BMI) in children and adolescents with cystic fibrosis, showing a mean difference of 11.80 and 16.90 respectively, based on a systematic review of ten randomized clinical trials.

These modulators demonstrated better efficacy compared to first-generation therapies, indicating they may offer enhanced treatment options for patients with the F508del_CFTR mutation, although no significant changes in CFTR channel activity were observed compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cystic Fibrosis Transmembrane Conductance Regulator Protein Modulators in Children and Adolescents with different CF Genotypes - Systematic Review and Meta-Analysis. Yousif Hamdan, AH., Zakaria, F., Lourdes Pormento, MK., et al.[2023]

Ivacaftor, a CFTR potentiator, is now approved for use in patients with cystic fibrosis who have specific class III mutations, significantly improving their CFTR protein function and overall health outcomes.

Combination therapies using both correctors and potentiators are essential for effectively treating the most common CFTR mutation, F508del, highlighting the need for ongoing research into alternative therapies and drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Bell, SC., De Boeck, K., Amaral, MD.[2022]

Current therapies targeting the CFTR protein, like ivacaftor, are limited in their effectiveness and applicability, benefiting only about 5% of the cystic fibrosis population in the US.

The recently approved combination therapy lumacaftor/ivacaftor is expected to help a larger group of patients who are homozygous for the Phe508del mutation, but existing therapies still play a crucial role in improving health outcomes for cystic fibrosis patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving complex medical care while awaiting next-generation CFTR potentiators and correctors: The current pipeline of therapeutics. Goralski, JL., Davis, SD.[2018]

Real-world studies indicate that while CFTR modulator therapies for cystic fibrosis are generally well-tolerated, there may be a higher frequency of adverse events (AEs) and discontinuation compared to clinical trials, particularly with lumacaftor/ivacaftor (LUM/IVA) which showed more respiratory-related AEs.

All four CFTR modulators were associated with potential mental health and neurocognitive AEs, highlighting the need for systematic monitoring and the important role of pharmacists in managing these therapies and their side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. Dagenais, RVE., Su, VCH., Quon, BS.[2022]

Highly effective modulator therapies (HEMTs) have significantly improved the management of cystic fibrosis, leading to better survival rates and health across multiple organ systems.

Despite their benefits, HEMTs are associated with serious adverse events, such as liver injury and neurocognitive symptoms, highlighting the need for long-term safety studies and careful monitoring in patients of all ages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trials and tribulations of highly effective modulator therapies in cystic fibrosis. Lieu, N., Prentice, BJ., Field, P., et al.[2023]

Lumacaftor, when used with ivacaftor, significantly increases the levels of the F508del-CFTR protein at the cell membrane, leading to improved clinical outcomes for patients with cystic fibrosis who have this specific mutation.

This combination therapy represents a major advancement in treating the underlying biochemical issues of cystic fibrosis, although it is still uncertain if similar therapies can be developed for all CFTR mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction. Brewington, JJ., McPhail, GL., Clancy, JP.[2016]

Triple combination therapy for cystic fibrosis significantly improves lung function (ppFEV1) and reduces sweat chloride levels compared to placebo and active controls, with mean differences of 13.6% and -44.13, respectively, based on six randomized controlled trials.

The therapy also enhances quality of life as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R) score, showing a mean difference of 19.8% compared to controls, while demonstrating a similar safety profile with no significant increase in adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials. Wang, Y., Ma, B., Li, W., et al.[2022]

Recent advancements in understanding CFTR gene mutations have led to targeted therapies for cystic fibrosis (CF), shifting treatment focus from just managing symptoms to addressing the underlying genetic defect.

Current CFTR modulators, including potentiators and combination therapies, are showing promise in clinical settings, but many patients still lack effective treatment options, highlighting the need for ongoing research and development of new therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis. Cuyx, S., De Boeck, K.[2020]

Genzyme is developing gene therapy and protein replacement therapies to address cystic fibrosis by replacing defective CFTR proteins, with both approaches receiving orphan drug status from the FDA.

A recent clinical trial involving 16 cystic fibrosis patients showed that a specific compound (GL-67:DOPE:DMPE-PEG5000-pCF1-CFTR) was well-tolerated and led to a 25% improvement in CF symptoms, indicating potential efficacy in treating the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Technology evaluation: cystic fibrosis therapy, Genzyme. Cockett, MI.[2017]

Trikafta, a CFTR modulator, has been shown to significantly restore CFTR function in patients with the F508del variant and even in three rare genotypes previously not eligible for treatment, indicating its broad potential efficacy.

The study utilized innovative airway epithelial stem cell models derived from CF patients to test the effectiveness of CFTR modulators, confirming Trikafta's superior clinical activity compared to older treatments and paving the way for personalized medicine approaches in CF therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells. Sette, G., Lo Cicero, S., Blaconà, G., et al.[2021]

Targeted Genetics is developing a gene therapy using an AAV vector to deliver the normal CFTR gene directly to the lungs of cystic fibrosis patients, which aims to treat the underlying cause of the disease.

The therapy has received Orphan Drug Status and has progressed to phase II trials for both cystic fibrosis and sinusitis, indicating its potential efficacy and safety in treating these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Technology evaluation: AAV-CFTR vector, targeted genetics. Tebbutt, SJ.[2012]

A new rat model expressing the human CFTR G551D variant was developed to study cystic fibrosis, allowing researchers to observe the effects of CFTR modulators like ivacaftor on lung disease characteristics.

Treatment with ivacaftor successfully restored CFTR activity and normalized airway defects, such as mucus transport and viscosity, demonstrating the potential of this model for understanding disease mechanisms and testing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. Birket, SE., Davis, JM., Fernandez-Petty, CM., et al.[2021]

References

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

Targeted therapies to improve CFTR function in cystic fibrosis. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

[Treatment of Cystic Fibrosis with CFTR Modulators]. [2017]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Cystic Fibrosis Transmembrane Conductance Regulator Protein Modulators in Children and Adolescents with different CF Genotypes - Systematic Review and Meta-Analysis. [2023]

4. England pubmed.ncbi.nlm.nih.gov

New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. [2022]

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

Improving complex medical care while awaiting next-generation CFTR potentiators and correctors: The current pipeline of therapeutics. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Trials and tribulations of highly effective modulator therapies in cystic fibrosis. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction. [2016]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Triple Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Patients With Cystic Fibrosis: A Meta-Analysis of Randomized Controlled Trials. [2022]

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

Treating the Underlying Cystic Fibrosis Transmembrane Conductance Regulator Defect in Patients with Cystic Fibrosis. [2020]

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

Technology evaluation: cystic fibrosis therapy, Genzyme. [2017]

12. England pubmed.ncbi.nlm.nih.gov

Theratyping cystic fibrosis in vitro in ALI culture and organoid models generated from patient-derived nasal epithelial conditionally reprogrammed stem cells. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Technology evaluation: AAV-CFTR vector, targeted genetics. [2012]

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

Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR. [2021]