CF gene therapy 4D-710 improves lung function, data show

Single dose improved or stabilized function in adults, per interim data

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by Steve Bryson, PhD |

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A single dose of 4D Molecular Therapeutics’ inhaled gene therapy candidate 4D-710 improved or stabilized lung function in adults with cystic fibrosis (CF), according to interim data from a Phase 1/2 clinical trial.

Additional data from the AEROW (NCT05248230) study, which is evaluating the therapy in CF patients who are ineligible for or intolerant to CFTR modulator therapy, demonstrated a dose-dependent increase in the production of the CFTR protein in lung samples.

Building on these data, the company is now planning a Phase 3 clinical trial in the same patient population that, if results are positive, will support applications seeking 4D-710’s approval.

“We are pleased with the widespread CFTR transgene and protein expression [production] in airway cells from all participants at all doses in the AEROW clinical trial,” Jennifer Taylor-Cousar, MD, co-director of the Adult Cystic Fibrosis Program at National Jewish Health, said in a company press release.

Taylor-Cousar reported the interim results in an oral presentation at the 47th European Cystic Fibrosis Conference in Glasgow, U.K.

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CF gene therapy targets defective protein

“The consistent widespread 4D-710-mediated CFTR expression and initial clinical activity in Phase 1 are encouraging and suggest that 4D-710 has the potential to be the first treatment option for those living with cystic fibrosis who do not currently benefit from available disease-modifying therapies,” said Taylor-Cousar, who is also the director of the Cystic Fibrosis Foundation Therapeutics Development Center at National Jewish Health.

In CF, mutations in the CFTR gene result in a missing or defective CFTR protein. Without this protein, abnormally thick and sticky mucus builds up in organs, leading to most disease symptoms.

4D-710 is a lab-made version of the CFTR gene, called a transgene, that encodes instructions for making a functioning version of the CFTR protein. It’s delivered to the lungs via inhalation using a modified, harmless viral vector (A101).

CFTR modulators are a class of therapies that enhance the functioning of defective CFTR protein in eligible patients. Still, some CF-causing mutations don’t respond to these medicines.

Phase 1 of the study was a dose-exploration stage, which tracked 10 CF patients with lung disease who were ineligible for or intolerant of CFTR modulator therapy. Before treatment, enrolled patients had a wide range of lung function, from 56% to 100% ppFEV1, the percent predicted forced expiratory volume in one second.

Participants received a single aerosolized dose of 4D-710 at one of four doses: 2.5E14 vector genomes (vg), 5E14 vg, 1E15 vg, and 2E15 vg.

Lung biopsy samples showed consistent and widespread CFTR protein production across all four dose groups. Moreover, there was a dose-dependent increase in transgene activity in epithelial cells that line the airways, ranging from 14% to 53%.

CFTR protein levels in 4D-710-treated patients were two to four times higher than in non-CF lung samples and between eight to 12 times higher than in untreated CF samples. Protein production was also seen in multiple types of airway cells, including basal cells, which are regarded as precursor cells that give rise to other cell types.

Transgene activity, clinical activity, and safety were similar regardless of pre-existing immunity to adeno-associated virus vectors, the standard vectors used in most gene therapies.

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Improvements at the 1-year mark

All participants in the two highest dose groups (2E15 and 1E15 vg) generally had stable or improved lung function one year after treatment. Two of three patients with mild to moderate lung function impairment before treatment, 40%-80% ppFEV1, showed clinically meaningful improvement in lung function at one year.

The 1E15 vg dose group had a clinically meaningful mean improvement in quality of life scores after one year, as assessed using the Cystic Fibrosis Questionnaire-Revised respiratory symptom score.

One of the four participants in the highest dose group (2E15 vg) had reported a serious adverse event of lung inflammation. This side effect was completely resolved, and the patient’s lung function improved by 6% ppFEV1 after one year. In lung biopsy samples, there was no evidence of inflammation or toxicity. Among the lower dose groups, 2.5E14 to 1E15 vg, no reported 4D-710-related adverse events were reported.

Because there was no difference in CFTR protein production in the two highest dose groups, the 1E15 vg dose was selected as the highest dose for the Phase 2 dose expansion part of the study. This second part of the trial expects to enroll up to nine patients, beginning in the second half of this year. The inclusion of a 5E14 vg dose is pending enrollment and the follow-up of the third participant in the Phase 1 portion.

An amendment to AEROW’s protocol was submitted to the Cystic Fibrosis Foundation-supported Therapeutics Development Network to evaluate 4D-710 in CF patients on CFTR modulators with persistent moderate to severe CF lung disease. Enrollment also is expected to begin in the second half of this year.

“The clinical data to date from the AEROW clinical trial continues to strongly support the advancement of 4D-710 to the next stage of development for CF lung disease,” said Alan H. Cohen, MD, company senior vice president of clinical development and therapeutic area head of pulmonology. “Based on the emerging favorable safety and clinical activity profile, we look forward to beginning our Phase 2 Dose Expansion stage in participants with mild to moderate lung function impairment, to confirm the clinical activity of the 1E15 vg dose.”

In January, the U.S. Food and Drug Administration granted 4D-710 rare pediatric disease designation. The designation aims to encourage the development of therapies for serious or life-threatening rare illnesses primarily affecting people 18 and younger.