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Therapy led to higher than expected activity of CFTR protein in lung cells
Written by Marisa Wexler, MS | Nov. 3, 2023
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Treatment with the inhaled gene therapy 4D-710 led to clinically meaningful quality of life gains for people with cystic fibrosis (CF) in a clinical trial, according to data announced by 4D Molecular Therapeutics (4DMT), the therapy’s developer.
Treatment also led to high expression of the CFTR protein in lung cells, at levels exceeding what 4DMT was expecting.
“4D-710 … has the potential to address the limitations of prior aerosol gene therapies. Initial results from the AEROW study showed that 4D-710 resulted in CFTR expression in lung airways that significantly exceeded our target profile,” David Kirn, MD, co-founder and CEO of 4DMT, said in a company press release .
CF is caused by the dysfunction of the CFTR gene, which provides instructions for making the CFTR protein. 4D-710 is designed to deliver healthy copies of the gene to lung cells so they can produce functional CFTR. It specifically delivers a version of the gene called CFTRdeltaR , which is optimized to allow high production of the protein.
The therapeutic gene is delivered by an adeno-associated viral vector called A101, which has been designed to get through the sticky mucus of the lungs.
4DMT is running AEROW (NCT05248230) , a clinical trial that’s testing 4D-710 in people with CF who aren’t eligible for or don’t tolerate CFTR modulators .
“Participants with cystic fibrosis in this clinical trial do not have the option of treatment with currently available disease-modifying therapies and therefore have high unmet need,” said Jennifer Taylor-Cousar, MD, lead principal investigator on the AEROW study. “By delivering copies of the CFTR[delta]R transgene to the lung epithelium with a novel aerosolized AAV and achieving high levels of CFTR protein expression in airway cells, 4D-710 has the potential to provide durable benefit in these individuals and potentially all individuals affected by CF.”
Goal of new collaboration is novel non-viral gene therapy to treat CF
Data from AEROW clinical trial
New data was announced from the first seven AEROW participants.
The first three patients were treated with 4D-710 at a dose of 1E15 (one quadrillion) vector genomes, a measure of how many particles of the therapeutic virus are present. They have been followed for at least a year.
Two patients had mild to no lung disease before treatment, based on a measure of lung function called ppFEV1, or percent predicted forced expiratory volume in one second. The ppFEV1 scores of both have remained stable a year after treatment.
The third patient had moderate lung impairment before treatment and this person’s ppFEV1 scores increased by 1 to 10% a year with 4D-710.
Lung-related life quality was measured in all three patients by the Cystic Fibrosis Questionnaire-Revised respiratory domain symptom score (CFQ-R-RD). A change of at least 4 points on this score is considered a meaningful difference. A year after receiving gene therapy, the average score improved by more than 8 points in these three.
The other four patients were given a higher dose of 2E15 vector genomes. Lung function and life quality data are not available yet, but 4DMT did present analyses of safety and biomarker data.
Safety data showed 4D-710 has generally been well tolerated, with no clinically significant acute safety issues among any of the seven patients. During the follow-up, one patient had a serious lung infection that might have been related to the gene therapy. No long-term safety issues were noted, otherwise.
“We are pleased with the safety and tolerability of 4D-710 in participants in the AEROW study to date,” Taylor-Cousar said.
CFTR protein expression is high
Data from 34 biopsies or brushings of lung tissue from the seven patients have shown a robust expression of CFTR protein. At both doses tested so far, at least 98% of epithelial cells that line the airways had detectable CFTR protein, and CFTR levels were more than four times higher than what’s typically seen in normal lungs and roughly 10 times higher than what’s typical for a CF patient.
Based on these data, the next group of AEROW patients will test a lower dose of 5E14 vector genomes. The first patient in this group has been dosed, according to 4DMT. Participants are still being recruited at sites in the U.S.
“The high CFTR expression levels and durable clinical activity of 4D-710 as demonstrated by improvements in quality of life and stability in ppFEV 1 through 12 months in Cohort 1 have never been achieved with any gene delivery in CF, making a dose reduction feasible,” said Alan Cohen, MD, 4DMT senior vice president, therapeutic area head of pulmonology.
The CF Foundation has supported the development of 4D-710 since 2016. The company recently completed an agreement with the foundation to provide an additional $2.8 million to support the development of 4DMT’s gene delivery vectors, bringing the total commitment to $6.3 million.
4DMT said it’s also expecting U.S. Food and Drug Administration feedback on development plans for 4D-710 early in 2024. Feedback is expected to use 4D-710 as a monotherapy and with approved CF modulators.
“I’m excited to work closely with the CF Foundation, CF community, and regulatory agencies to advance the development of 4D-710,” Cohen said.
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