First Patient Dosed in Trial of Aerosol-delivered Genetic Medicine

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by Steve Bryson, PhD |

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The first patient has been dosed in a Phase 1/2 clinical trial evaluating 4D-710, an investigational genetic medicine for adults with cystic fibrosis (CF), its maker, 4D Molecular Therapeutics (4DMT) has announced.

“The dosing of the first patient in the 4D-710 Phase 1/2 clinical trial in cystic fibrosis marks an important milestone for our company and for the patients we aim to benefit,” Robert Fishman, MD, chief medical officer and pulmonology therapeutic area head at 4DMT, said in a press release.

The open-label study (NCT05248230) expects to enroll about 18 participants and evaluate the safety, tolerability, and preliminary effectiveness of two 4D-710 doses. Eligible participants include adults with mutations in both CFTR gene copies, which cause CF, as well as those who are ineligible or have discontinued CFTR modulator therapies due to side effects.

Unlike modulators that treat CF in people with specific mutations that alter the CFTR protein, 4D-710 is designed to work regardless of a patient’s mutation, which may also be helpful as a combination therapy for those who do not fully respond to modulators.

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“This therapy has the potential to treat a broad range of people with cystic fibrosis independent of their specific CFTR mutations,” said Jennifer Taylor-Cousar, MD, a professor of medicine and pediatrics at National Jewish Health in Colorado and principal investigator of the trial. “It could benefit both people with cystic fibrosis who aren’t able to take CFTR modulators as well as those who have a substantial residual deficit in lung function in spite of modulator therapy.”

4D-710 was created with 4DMT’s proprietary Therapeutic Vector Evolution platform, using a harmless adeno-associated viral vector called A101 to deliver a healthy copy of CFTR — which provides instructions for the CFTR protein — referred to as microCFTR.

The A101 vector is administered as an aerosol directly to the epithelial cells that line the airways in the lungs with the aim of enhancing CFTR protein production and function. A101 was also designed to penetrate the thick mucus barrier in the lungs and resist immune responses that limit effectiveness.

In preclinical studies, 4D-710 was well tolerated in nonhuman primates; there were no significant side effects with the aerosol delivery and the microCFTR gene saw good distribution in the lungs, where it actively produced the CFTR protein, the company reported on its website.

The Phase 1/2 study’s secondary outcomes include the feasibility of detecting gene transfer and microCFTR protein production as measured in biopsies and brushings.

“4D-710 utilizes the aerosol-delivered A101 vector developed at 4DMT through our proprietary Therapeutic Vector Evolution platform,” Fishman said. “To date, our platform has produced five clinical-stage product candidates that incorporate three different proprietary and novel capsids [the shell of a virus].”

“We are seeking to unlock the full potential of genetic medicines through our platform and to fulfill the promise of transformative biotherapeutics to benefit patients,” Fishman added.

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