Phase 1/2 Trial of 4D-710, Aerosol Gene Therapy for CF, May Soon Start

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by Margarida Maia, PhD |

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A Phase 1/2 clinical trial of an aerosol gene therapy candidate, 4D-710, in people with cystic fibrosis (CF) has been cleared by U.S. Food and Drug Administration (FDA) and is expected to start this year, its developer, 4D Molecular Therapeutics, announced.

The trial is designed as an open-label, dose-escalation and dose-expansion study, which means that all enrolled will be treated (no placebo group), and the amount of 4D-710 given will increase in each new group of participants, with more patients added as the study goes on.

It is expected to enroll about 18 patients who are either ineligible for treatment with a CFTR modulator or have stopped the therapy due to side effects. Unlike modulators that work to treat CF by addressing specific mutations that affect the CFTR protein to cause the disease, 4D-710 is reported to work regardless of a person’s mutation.

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“We believe 4D-710 has the potential to treat a broad cystic fibrosis patient population, including those patients treated with current CFTR modulators, all of which require daily dosing over the patient’s lifetime and generally result in only partial correction of lung function,” David Kirn, MD, co-founder and CEO of 4D Molecular Therapeutics (4DMT), said in a press release.

“We plan to focus initially on the approximately 10–15% of all patients whose disease is not amenable to existing modulator medicines that target the CFTR protein,” Kirn added.

4D-710 uses a harmless adeno-associated viral vector (AAV), called A101, to carry a functional copy of CFTR — the gene that encodes instructions for making the CFTR protein — called microCFTR.

The therapy is given as an aerosol — a suspension of fine particles in a gas that can be released as a fine spray — that allows direct delivery to cells in the lungs’ airways and alveoli (the capillary-rich sacs where gas exchange takes place).

A study in nonhuman primates found no significant side effects with aerosol delivery of 4D-710, and that the microCFTRgene was distributed and converted to protein throughout the lungs, the company reported on its webpage.

In the planned clinical trial, researchers want to see if 4D-710 is safe and well tolerated in patients. The team will also analyze if 4D-710 leads to the CFTR protein production by looking at lung tissue samples, and if the therapy is able to reduce disease activity by assessing lung function.

“A101 was invented not only for aerosol delivery diffusely throughout the lung airways and alveoli, but also for penetration through the mucus barrier and for resistance to pre-existing antibodies, both of which are potentially key attributes for successful treatment of these patients,” said Robert Fishman, MD, chief medical officer of 4DMT.

Antibodies against AAV — already present in some people — can render a gene therapy ineffective and limit the number of patients who may benefit from it.

“4D-710 has the potential to be a differentiated therapy for the treatment of cystic fibrosis lung disease due to its potentially corrective mechanism, expected ability to treat patients independent of CFTR mutation and resistance to AAV antibodies,” Fishman said.

The Cystic Fibrosis Foundation supported preclinical work on the therapy, with grants totaling $17.5 million given to 4DMT in 2017 and 2020. The foundation intends to purchase shares of the company’s common stock, for aggregate proceeds of about $4 million, the release stated. A portion of these proceeds will further support 4D-710’s continued development.