Gene Therapy (4D-710) for Cystic Fibrosis

(CF Trial)

Recruiting at 16 trial locations

Overseen By 4DMT Patient Advocacy

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: 4D Molecular Therapeutics

Must be taking: CFTR modulators

Must not be taking: Systemic corticosteroids, Immunosuppressants

Disqualifiers: Diabetes, Mycobacterium, Aspergillosis, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing a new gene therapy called 4D-710 in adults with cystic fibrosis who can't use standard treatments. The goal is to see if it is safe and effective. 4D-710 is part of a new generation of AAV vectors being developed for cystic fibrosis gene therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on CFTR modulator therapy, you must continue it throughout the study.

What data supports the effectiveness of the treatment 4D-710 for cystic fibrosis?

Gene therapy for cystic fibrosis has shown promise in correcting the underlying genetic defect in laboratory settings, and similar approaches have been successful in other genetic diseases. Although specific data on 4D-710 is not provided, the success of gene therapy in other contexts suggests potential effectiveness. ^{1 2 3 4 5}

Is 4D-710 gene therapy for cystic fibrosis safe for humans?

The safety of gene therapy for cystic fibrosis has been evaluated in various studies. In one study, a single dose was well tolerated but caused flu-like symptoms in some patients. Another study showed that repeated doses in sheep were well tolerated with no significant toxicity, suggesting potential safety in humans. ^{1 2 3 6 7}

How is the treatment 4D-710 for cystic fibrosis different from other treatments?

4D-710 is a gene therapy specifically designed to address the underlying genetic cause of cystic fibrosis by delivering a functional copy of the CFTR gene to the lungs, which is different from traditional treatments that mainly manage symptoms rather than targeting the root cause. ^{1 2 8 9 10}

Research Team

Alan H. Cohen, MD

Principal Investigator

4D Molecular Therapeutics

Eligibility Criteria

Adults with cystic fibrosis who can't take CFTR modulator therapy or had bad reactions to it. They must be 18+, have certain genetic mutations, and their lung function should be within a specific range. People with recent serious infections, liver disease, diabetes not well controlled, or those on chronic steroids/immunosuppressants can't join.

Inclusion Criteria

I have either two mutations in the CFTR gene or one mutation with CF lung symptoms.

I am 18 years old or older.

Sweat chloride ≥ 60 mmol/L

Exclusion Criteria

I have not had gene therapy before, except for mRNA-based treatments.

I am being treated for a severe lung allergy with steroids or antifungal medication.

I am currently being treated for an active Mycobacterium abscessus infection.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single inhalational administration of 4D-710 at various dose levels

Single dose

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• 4D-710 (Gene Therapy)

Trial Overview The trial is testing a single dose of an investigational gene therapy called 4D-710 in adults with cystic fibrosis. It's an early-stage study (Phase 1/2) to see how safe the treatment is and how the body responds to it.

Participant Groups

Group I: 4D-710 Phase 2: Dose Expansion Experimental Treatment 1 Intervention

Participants will receive a single inhalational administration of 4D-710 at the dose level(s) selected for dose expansion.

Group II: 4D-710 Phase 1: Dose Exploration Experimental Treatment 1 Intervention

Participants who are ineligible for or intolerant of modulator therapy will receive one of various dose levels of 4D-710 to identify recommended phase 2 dose(s) for further evaluation.

Group III: 4D-710 Dose Exploration (Sub-Study) Experimental Treatment 1 Intervention

Participants who are on currently available CFTR modulator therapy will receive a dose of 4D-710 at various dose levels.

Who Is Running the Clinical Trial?

4D Molecular Therapeutics

Lead Sponsor

Trials

9

Recruited

850+

Findings from Research

Significant advancements have been made in gene therapy for cystic fibrosis since the CFTR gene was identified in 1989, with various clinical trials exploring different gene transfer systems.

Both cationic liposome and adenoviral-based methods have been tested for safety and efficacy, but the results have been variable, indicating that while progress is being made, challenges remain in achieving consistent therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for cystic fibrosis: which postman, which box? Middleton, PG., Alton, EW.[2019]

Over the past 20 years, 26 clinical trials involving around 450 patients have been conducted to explore cystic fibrosis gene therapy, primarily focusing on safety and proof-of-concept rather than direct clinical benefits.

The first trial specifically designed to assess clinical efficacy of gene therapy in cystic fibrosis, using AAV2-CFTR, was completed in 2014, indicating a shift towards evaluating actual improvements in lung function rather than just molecular corrections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cystic Fibrosis Gene Therapy in the UK and Elsewhere. Griesenbach, U., Pytel, KM., Alton, EW.[2022]

MRT5005, an mRNA treatment for cystic fibrosis, was found to be generally safe and well tolerated in a Phase 1/2 study involving 42 adults, with mild to moderate febrile and hypersensitivity reactions reported in some participants.

Despite the treatment being safe, there were no significant improvements in lung function (FEV1) observed after administration, indicating that while MRT5005 is tolerable, its efficacy in enhancing lung function needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. Rowe, SM., Zuckerman, JB., Dorgan, D., et al.[2023]

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]

A gene therapy approach using a recombinant adenovirus vector to deliver the normal CFTR gene has been developed, showing successful transfer and expression of the gene in airway epithelial cells for at least 6 weeks in preclinical studies.

The first human trial for this gene therapy in cystic fibrosis began in 1993, with preliminary evidence indicating that it is feasible to express the normal CFTR gene in patients, paving the way for potential treatment of respiratory symptoms associated with CF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for the respiratory manifestations of cystic fibrosis. Korst, RJ., McElvaney, NG., Chu, CS., et al.[2012]

The plasmid vector pGM169, when delivered with the cationic lipid GL67A, was well tolerated in sheep with no significant adverse effects on health or lung function after nine monthly doses, indicating its potential safety for future use in cystic fibrosis patients.

Molecular analysis showed successful delivery of pGM169 DNA to the airways, with transient increases in immune cell numbers that returned to baseline, suggesting that the treatment does not cause cumulative inflammation or lung damage over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep. Alton, EW., Baker, A., Baker, E., et al.[2022]

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]

Cystic fibrosis is caused by a malfunctioning chloride channel in epithelial cells, leading to severe respiratory issues, making gene therapy a promising treatment option due to the well-characterized gene involved.

Current research is focused on developing effective gene delivery mechanisms and vectors, with early clinical trial results starting to emerge, indicating progress in potential treatments for this genetic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cystic fibrosis gene therapy. Colledge, WH., Evans, MJ.[2019]

Gene therapy is being explored as a treatment for various lung diseases, particularly cystic fibrosis (CF), which is a promising candidate due to the lack of effective treatments available.

The success of gene therapy depends on selecting the right gene transfer vector for the specific lung cell types affected by the disease, highlighting the complexity of lung structure and the need for tailored approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for cystic fibrosis: an example for lung gene therapy. Griesenbach, U., Geddes, DM., Alton, EW.[2020]

Recent advancements in gene therapy for cystic fibrosis (CF) have focused on improving the efficiency of gene transfer to the airways, which is crucial for clinical benefit.

Innovative strategies, including RNA repair and stem cell gene therapy, are being explored alongside viral and non-viral gene transfer methods to enhance treatment options for this monogenic disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in gene therapy for cystic fibrosis. Griesenbach, U., Alton, EW.[2012]

References

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

Gene therapy for cystic fibrosis: which postman, which box? [2019]

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

Cystic Fibrosis Gene Therapy in the UK and Elsewhere. [2022]

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

Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. [2023]

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

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

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

Gene therapy for the respiratory manifestations of cystic fibrosis. [2012]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep. [2022]

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

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

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

Cystic fibrosis gene therapy. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Gene therapy for cystic fibrosis: an example for lung gene therapy. [2020]

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

Recent progress in gene therapy for cystic fibrosis. [2012]