Early Signals of Efficacy With Cystic Fibrosis Gene Therapy

Jennifer L. Taylor-Cousar, MD, MSCS

4D Molecular Therapeutics’ 4D-710 is an investigational gene therapy currently being evaluated for the treatment of cystic fibrosis (CF) in the phase 1/2 AEROW clinical trial (NCT05248230). Data from the trial were presented at the 47th European Cystic Fibrosis Conference, held in Glasgow, United Kingdom, in June 2024.

In an interview with CGTLive®, principal investigator Jennifer L. Taylor-Cousar, MD, MSCS, Professor, Departments of Medicine and Pediatrics, and codirector, Adult Cystic Fibrosis Program, and Director, Cystic Fibrosis Foundation Therapeutics Development Center, National Jewish Health, who presented the data, discussed 4D-710 and the results. She shared cautious optimism for the therapy’s efficacy, having seen at least 1 participant experience clinically meaningful improvements in lung function.

CGTLive: Can you discuss unmet needs in CF?

Jennifer Taylor-Cousar, MD, MSCS: CF is a disorder that was originally described back in 1938 and at that time people died as young children. We have progressed forward with treatments so that now the median predicted survival for somebody is 61 here in the United States. But there is a large group of people who either can't tolerate the new therapies that we have for CF or are ineligible for those therapies. For that reason, there is a very large unmet need for people who see all of their friends and family members who maybe qualify for these drugs or can take them, but they actually can't benefit from the drugs that were approved in 2019 in the US. We really do need to develop therapies for them.

Can you talk a little bit about 4D-710 and how this therapy could potentially improve outcomes for these patients?

4D-710 is a drug that's comprised of an adenovirus associated virus (AAV) vector. It's been really optimized to penetrate mucus and be resistant to preexisting antibodies, which was a problem for AAV vectors in the past. So with 4D-710 we're hoping that we can actually use this drug to replace the gene that's abnormal in people with CF, and specifically replace that gene with a corrected copy in the airways, where most people actually are affected by CF.

Can you give an overview of the AEROW clinical trial?

The AEROW trial is a first-in-human trial that's designed to test the safety of 4D-710 and hopefully to give us some early signs of at least biological efficacy. People are screened to come into the trial at this point. Only people who are not on CFTR modulators have been allowed into the trial. We have dosed 10 people to date in 4 different cohorts because we're trying to figure out what the optimal dose is—the highest dose that's both tolerated and effective.

To date, we have dosed 10 participants at 4 different dose levels. We've actually shown that with the highest dose, which was 2x10⁵ vector genomes (vg), it showed an expression profile that was beyond what we had hoped to actually target. There was actually message in the interstitium, which is not part of the target profile of the drug. We really want it only to go into airway cells, so we are not advancing the 2x10⁵ vg dose. But we have dosed people in lower doses, and those have all been very well tolerated by participants. The next step is for us to really finish these lower dose cohorts and then determine what dose should be advanced into the next phase, where we look more closely at that specific dose to determine whether it's showing early signs of clinical efficacy, meaning we see improvements in lung function in addition to quality of life, for example, in a larger number of people.

Can you discuss the updated data that was recently presented?

With the lower doses of 4D-710, including 1x10¹⁵ vg, 5x10¹⁴ vg, and 2.5x10¹⁴ vg we've shown that with each of those we were actually able to get really great expression in the airways, both by in situ hybridization (looking at mRNA expression) and by immunohistochemistry (looking at protein expression). So both of the lower doses, and in fact all 3 doses, showed good expression in the airway. In those cohorts that were dosed at these lower doses, we also showed that people tolerated the drug, and that we saw at least at the 1x10¹⁵ vg dose, at least 1 person who had a clinically meaningful improvement in their percent predicted lung function. We think that's very promising for looking at that dose or other lower doses in further participants.

Is there anything else you want to share?

For the people with unmet need in CF, it's critically important that we develop therapies that are agnostic to which CFTR mutation (or, in other words, variant) that they have. A therapy like gene therapy will correct the gene no matter what variant someone has. I think that's a very important concept for people to understand. Our goal with all of these nucleic acid-based therapies, whether it's gene therapy, mRNA therapy, or antisense oligonucleotide therapy—all of those are directed for people who have no effective therapy, the way we have for other people who have CFTR modulators. We are very, very excited about the opportunity to be able to help those people.

Transcript edited for clarity.

REFERENCES
1. 4DMT Presents Positive Interim Data from Phase 1/2 AEROW Clinical Trial of Aerosolized 4D-710 for Modulator-Ineligible/-Intolerant Cystic Fibrosis at 47th European Cystic Fibrosis Conference. News release. 4DMT. June 6, 2024. https://www.cgtlive.com/view/4dmt-aligns-path-forward-cystic-fibrosis-gene-therapy-4d-710
2. 4DMT Announces Update on Regulatory Interactions and Development Path for 4D-710 for Treatment of Cystic Fibrosis. News release. 4DMT. March 28, 2024. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-update-regulatory-interactions-and-development