Aerow hits the mark for 4D Molecular

An early success with its cystic fibrosis gene therapy brings the company up.

The most advanced inhaled gene therapy for cystic fibrosis just advanced a little further. An update on the first three patients in a trial of 4D Molecular Therapeutics’ 4D-710 shows lung function improvement in the sickest patient, as well as quality of life benefits.

The company’s stock rose 12% this morning, though this does not quite recoup the 20% value destruction that followed the release of disappointing data on its wet AMD candidate in April. But data on more patients in the cystic fibrosis trial will come at the end of this year, and could change the situation further.

Interim data from the first three patients in the phase 1/2 Aerow trial, released at the end of last year, showed 4D-710 had successfully delivered the CFTR gene. A new cut in the same three subjects, released at the annual meeting of the European Cystic Fibrosis Society late yesterday, included actual functional data. 

Two of the Aerow participants were ineligible for existing CFTR modulators such as Vertex’s Trikafta, and the third intolerant of them. They all received a single 1x1015vg dose of 4D-710. The main efficacy measure was percent predicted forced expiratory volume in one second (ppFEV1), and here two of three maintained or saw improvement in pulmonary function; lung function would be expected to decline in these patients.


The most severely ill patient, who had moderate disease and baseline ppFEV1 of 69%, saw a seven-point increase nine months after treatment with 4D-710. In a May note Evercore ISI analysts had said that a 10-point improvement in this patient would be a “big win”, while a five-point increase “might be compelling” if it was accompanied by quality of life benefits. 

It was. The measure 4D used for quality of life was the cystic fibrosis questionnaire-revised respiratory symptom score (CFQ-R-R), and all three patients had “meaningful improvement”, 4D said. 

Also positively, 4D-710 was well tolerated at 9-12 months follow up, with no therapy-related adverse events or dose-limiting toxicities.

Biomarker analyses demonstrated widespread CFTR gene and protein expression, which could be a good sign for the company’s other pulmonary gene therapy, 4D-725. This uses the same AAV-based delivery vector as 4D-710, and is in preclinical research for alpha-1 antitrypsin deficiency lung disease.

Source: company presentation.

The trial had no control arm and patient numbers so far are clearly tiny. But Evercore ISI analysts wrote that the FEV1 and quality of life benefits, plus the evidence of CFTR protein expression, suggest that 4D’s therapy might be able to play a role in patients not suitable for Trikafta – a population of around 7,000 patients in the US. Vertex’s drug usually delivers an FEV1 benefit of more than 10 points, the analysts wrote.

The trial continues apace. More interim data on these three patients, and from patients in cohort two receiving a 2x1015vg dose, are expected at the North American Cystic Fibrosis Conference in November. Dose selection for, and initiation of, the phase 2 part of Aerow will start in the second half of this year, and the company intends to talk to the FDA about the potential regulatory path and design of a pivotal trial in the fourth quarter. 

Several other groups are contesting the inhaled CF therapy space. The closest behind 4D is Splisense, whose antisense project SPL84 is in a phase 1/2 trial in healthy volunteers. It is not clear when this might report. 

As for 4D’s other activities, the phase 2/3 Prism trial of 4D-150 in wet AMD could yield more data in the first half of 2024. The company has three more clinical-stage projects. 

4D Molecular's pipeline
Project Vector Status
A101 (aerosol)
Ph 1/2 Aerow trial in 21 CFTR modulator-ineligible cystic fibrosis pts ongoing; in preclinical research for modulator-eligible CF patients
R100 (intravitreal)
Ph 1/2 Prism trial in wet AMD ongoing; in preclinical research for diabetic macular oedema 
C102 intravenous)
Ph1/2 trial in Fabry disease; ph1/2 trial in pts with Fabry disease and cardiac involvement; project on FDA clinical hold
R100 (intravitreal)
Ph1/2 trial in X-linked retinitis pigmentosa ongoing
R100 (intravitreal)
Ph1 trial in choroideremia ongoing
A101 (aerosol) In preclinical research for alpha-1 antitrypsin deficiency lung disease
R100 (intravitreal)
In preclinical research for geographic atrophy
Source: company website,

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