4D Molecular Therapeutics (4DMT) is pressing ahead with evaluation of its gene therapy, 4D-710, in a Phase II dose expansion trial in cystic fibrosis (CF) after the drug displayed positive tolerability and efficacy during a Phase I study.
In the early-stage portion of the Phase I/II AEROW trial (NCT05248230), 4D-710 was proven tolerable and safe, with no severe treatment-emergent adverse events (TEAEs) reported amongst patients randomised to the lower-dose cohorts.
These two patient cohorts, which received 5E14 vg and 2.5E14 vg doses, respectively, experienced mild and transient TEAEs, which generally resolved around the two-month mark.
Alongside its tolerability, 4D-710 demonstrated early signs of efficacy, with patients assigned to the lowest dose (2.5E14 vg) experiencing improvements in all additional endpoints over the course of one year.
This includes measures of forced expiratory volume and lung clearance, as well as overall quality of life. 4DMT has not yet shared specific data on these endpoints.
The 16 patients enrolled on this study were either intolerant of or ineligible for treatment with CFTR modulator therapies, which currently form the backbone of the CF treatment paradigm.
Next steps for 4D-710
Following the positive interim readout for the AEROW study, 4DMT co-founder and CEO David Kirn touted 4D-710’s potential as a “durable, redosable and variant-agonistic” therapy for CF. According to Kirn, it could also become a foundational medicine for patients with the condition.
4DMT aims to complete enrolment in the dose-expansion portion of the study by H1 2026. The biotech currently expects to give a further programme update in the second half of 2026.
4DMT plans to pursue 4D-710’s further development using a 2.5E14 vg dosing regimen. In a 13 October statement, the biotech noted that this dose is expected to remain the same for pivotal trials and subsequent commercialisation.
That same month, the Cystic Fibrosis Foundation provided 4DMT with up to $11m to support 4D-710’s Phase III trial. This takes 4DMT’s total CF programme funding accrued from the nonprofit up to $32m.
CFTR remain dominant in CF, but other modalities emerging
While CFTR modulators are currently the backbone treatment option for patients with CF, novel drug classes such as gene and mRNA therapies are also emerging.
According to GlobalData healthcare analyst Vinie Varkey, these new therapies could revolutionise the treatment landscape for CF – especially for patients who are refractory to current CFTR treatment options.
Varkey added that gene therapies such as 4D-710 could theoretically require a smaller number of doses in comparison to top-selling CFTR modulators such as Alyftrek and Trikafta, which require once and twice-daily dosages, respectively.
While this would offer notable improvements to patient centricity, she caveated that the efficacy of low-frequency dosing “remains to be proven in late-stage clinical studies”.
While Varkey sees promise in gene therapies for CF, she noted that 4D-710’s potential is only being explored in patients who are ineligible or intolerant of CFTR modulator therapies.
This means the patient group who qualifies for treatment with the gene therapy may be restricted, which could result in a “step-up treatment approach”.
Varkey also raised concerns around the price point of current CFTR modulators, which are “among the most highly priced treatment options in the pharma sector”.
In this context, she theorises that a higher price point for a gene therapy could pose as an access barrier to patients, resulting in restricted global access.
