Gene Therapy (4D-710) for Cystic Fibrosis

(CF Trial)

Recruiting at 18 trial locations

Overseen By 4DMT Patient Advocacy

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: 4D Molecular Therapeutics

Must be taking: CFTR modulators

Must not be taking: Systemic corticosteroids, Immunosuppressants

Disqualifiers: Diabetes, Mycobacterium, Aspergillosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Single dose

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy called 4D-710 for individuals with cystic fibrosis, a condition that affects the lungs and makes breathing difficult. The goal is to explore the effectiveness of different doses and determine the best dose for future studies. It includes participants who either cannot use current treatments or have stopped them due to side effects, as well as those already on other cystic fibrosis medications. Candidates may be suitable if they have cystic fibrosis with frequent lung issues and have had trouble with available treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new 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.

Is there any evidence suggesting that 4D-710 is likely to be safe for humans?

Research shows that 4D-710 holds promise for safely treating cystic fibrosis. Studies have found that patients tolerate this gene therapy, delivered as an inhalable mist, well. Reports indicate that patients receiving 4D-710 had increased levels of CFTR protein, crucial for healthy lungs. Over 12 months, no major safety issues arose, and patients experienced improved lung function and quality of life.

Initial findings suggest that 4D-710 is safe for humans, with no significant side effects reported. Although this gene therapy remains under study, these results are early but encouraging. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for cystic fibrosis?

4D-710 is unique because it offers a gene therapy approach for treating cystic fibrosis, unlike the standard treatments that primarily involve CFTR modulators like ivacaftor or lumacaftor. This therapy uses an inhaled method to deliver a new functional copy of the CFTR gene directly into the lungs, which could potentially address the root cause of the disease rather than just managing symptoms. Researchers are excited about 4D-710 because it may benefit patients who are ineligible for or intolerant of current modulator therapies, giving hope for broader treatment options in the future.

What evidence suggests that 4D-710 might be an effective treatment for cystic fibrosis?

Research has shown that 4D-710, a gene therapy for cystic fibrosis, holds promise. Early results suggest this treatment can improve lung function, as evidenced by meaningful increases in lung capacity for some patients. Specifically, this improvement was observed at 12 months in individuals with mild to moderate lung problems. Additionally, the therapy was well tolerated, with no serious side effects related to the treatment. Designed to work for different genetic mutations in cystic fibrosis, 4D-710 could potentially benefit many patients. These early signs indicate it could become an important new option for those with cystic fibrosis. Participants in this trial will receive 4D-710 at various dose levels to determine the most effective dose for further evaluation. ^{1 2 3 6 7}

Who Is on the Research Team?

Alan H. Cohen, MD

Principal Investigator

4D Molecular Therapeutics

Are You a Good Fit for This Trial?

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.

Sweat chloride ≥ 60 mmol/L

I can't take CFTR modulator therapy or stopped it due to side effects.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• 4D-710

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05248230

NCT05248230 | 4D-710 in Adult Patients With Cystic Fibrosis This Phase 1/2 trial will evaluate the safety, tolerability, and preliminary efficacy of 4D-710, an investigational gene therapy, in adults with cystic ...

2. ir.4dmoleculartherapeutics.com ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-interim-data-aerosolized-4d-710-phase-12

4DMT Presents Positive Interim Data from Aerosolized 4D ... 4D-710 has the potential to treat a broad range of patients with cystic fibrosis, independent of the specific CFTR mutation, and is designed for ...

3. 4dmt.gcs-web.com 4dmt.gcs-web.com/news-releases/news-release-details/4dmt-presents-positive-interim-data-phase-12-aerow-clinical-0

4DMT Presents Positive Interim Data from Phase 1/2 AEROW ... Clinically meaningful improvements in ppFEV1 at 12 months observed in 2 of 3 participants with mild to moderate baseline lung function ...

4. cgtlive.com cgtlive.com/view/early-signals-efficacy-cystic-fibrosis-gene-therapy

Early Signals of Efficacy With Cystic Fibrosis Gene Therapy 4D-710 is an investigational gene therapy currently being evaluated for the treatment of cystic fibrosis (CF) in the phase 1/2 AEROW clinical trial.

5. cysticfibrosisjournal.com cysticfibrosisjournal.com/article/S1569-1993(23)00211-4/fulltext

interim results from a phase 1/2 clinical trial Initial clinical data indicated that 4D-710 treatment was well tolerated, with no 4D-710-related adverse events subsequent to aerosol delivery, no serious ...

6. biospace.com biospace.com/press-releases/4dmt-advances-4d-710-to-phase-2-with-additional-funding-and-support-from-the-cystic-fibrosis-foundation

4DMT Advances 4D-710 to Phase 2 with Additional ... Cystic Fibrosis Foundation to provide up to $11 million in additional funding to accelerate development of 4D-710 for cystic fibrosis, ...

7. healio.com healio.com/news/pulmonology/20231108/aerosol-gene-therapy-safe-heightens-cftr-protein-levels-in-cystic-fibrosis

Aerosol gene therapy safe, heightens CFTR protein levels ... Patients given aerosolized 4D-710 had elevated CFTR protein levels that went over normal levels. Over 12 months, lung function and quality ...