Aerosol gene therapy safe, heightens CFTR protein levels in cystic fibrosis

Key takeaways:

• Patients given aerosolized 4D-710 had elevated CFTR protein levels that went over normal levels.
• Over 12 months, lung function and quality of life improved with one of the assessed doses.

Receipt of 4D-710, an aerosolized gene therapy, resulted in high cystic fibrosis transmembrane conductance regulator protein expression levels in patients with cystic fibrosis, according to a company press release.

These data, presented at this year’s North American Cystic Fibrosis Conference, also showed that patients who received one of the doses of 4D-710 (4D Molecular Therapeutics) had stable/improved lung function and improved quality of life over 12 months.

“We are pleased with the safety and tolerability of 4D-710 in participants in the AEROW study to date,” Jennifer L. Taylor-Cousar, MD, MSCS, lead principal investigator, professor in the departments of medicine and pediatrics, co-director of the Adult Cystic Fibrosis Program and director of the Cystic Fibrosis Foundation Therapeutics Development Center at National Jewish Health, said in the release. “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.”

In an ongoing phase 1/2 clinical trial, Taylor-Cousar and colleagues assessed seven patients with cystic fibrosis who received aerosolized 4D-710 either as 1E15 vg (n = 3) or 2E15 vg (n = 4) to evaluate safety and tolerability of the therapy, as well as changes in lung tissue biomarkers.

At baseline, researchers noted that percent-predicted FEV₁ impairment in the population was generally mild.

In terms of safety, 4D-710 was generally well tolerated during dosing, 4 hours after dosing and 4 to 17 months after dosing. Further, an assessment of lung biopsies taken during follow-up showed that no inflammation existed, according to researchers.

Out of the total cohort, one patient from the 2E15 vg group experienced a serious adverse event (pneumonitis) that may have been related to the drug.

Researchers amassed 34 airway biopsy and brushing samples from the study population, and an analysis of airway epithelium cells 4 to 8 weeks after the patients received the aerosol showed “robust and reproducible 4D-710-mediated CFTR protein and RNA expression.”

Compared with normal lung samples, the mean percentage of airway cells that had CFTR protein was higher among both dosage groups (1E15 vg, 98%; 2E15 vg, > 99% vs. healthy control, 44%).

Further, patients given the aerosolized therapy demonstrated average CFTR protein expression levels about 450% of levels in normal lung samples by immunohistochemistry, with an even higher average (~ 1,000%) found when compared with CF lung samples.

According to the release, positive signal for the CFTR[delta]R transgene expression in airway epithelial cells was found in 40% of the 1E15 vg samples and 53% of the 2E15 vg samples by in situ hybridization.

Researchers also looked at changes in lung function from baseline to 12 months among those who received 1E15 vg and found stable percent-predicted FEV₁ in the two patients who had mild/no lung impairment, as well as 1% to 10% improvement in the one patient with moderate lung impairment.

Additionally, after the 3-month mark, none of these patients reported an exacerbation up through 17 months.

CF Questionnaire-Revised respiratory domain symptom scores taken at baseline and over 12 months also showed a benefit of the 1E15 vg dose, with a mean increase of 8.4 points to 11.1 points and scores that went over the minimal clinically important difference of ± 4, according to the release.

At this point, lung function and quality-of-life assessments among the 2E15 vg group are pending.

Notably, the release provided a few insights on what is next in the development of 4D-710, including that the 1E15 vg dose will be moving into phase 2, a lower dose (5E14 vg) is being tested in phase 1 and more measures have been added to the study to evaluate changes with the therapy (high-resolution CT, lung clearance index, mucociliary clearance index, number and severity of bacterial pulmonary exacerbations).

“By delivering copies of the CFTR[delta]R transgene to the lung epithelium with a novel aerosolized [adeno-associated virus] 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,” Taylor-Cousar said in the release.

According to the release, researchers are anticipating feedback from the FDA in quarter 1 of 2024 on a development plan for monotherapy and approved CF modulator combination regimens.

References:

• 4D-710 AEROW phase 1/2 interim clinical data – November 2023. https://ir.4dmoleculartherapeutics.com/static-files/c2590461-dc15-4253-b3fd-0c138037e157. Accessed Nov. 2, 2023.
• Taylor-Cousar JL. S14.2- Building the path to the cure: the role of AAV therapy. Presented at: North American Cystic Fibrosis Conference; Nov. 2-4, 2023; Phoenix.