Today 4D Molecular Therapeutics made a major announcement in that it would streamline its pipeline to specifically narrow its focus on getting its wet age-related macular degeneration (Wet-AMD) gene therapy 4D-150 to the finish line. That is, it would reduce its workforce by as much as 25% to accomplish this task, and this would allow it to extend its cash runway into 2028. That’s not to say that it still won’t advance other programs from the pipeline, but it just wants to make sure that it has enough cash on hand to reach the expected milestones from the wet-AMD program. It is already in good shape with this advancement because it first enrolled several patients in the first of two phase 3 studies, known as 4FRONT-1, in March of 2025. The second phase 3 study, 4FRONT-2, was just initiated last month, in June of 2025.
The purpose of these programs is to evaluate whether the use of a one-time gene therapy like 4D-150 is able to demonstrate non-inferiority in terms of best-corrected visual acuity (BCVA) from baseline to an already approved Wet-AMD drug known as EYLEA (aflibercept) from Regeneron Pharmaceuticals. However, there is a key difference in each study. The late-stage 4FRONT-1 trial is expected to only recruit 100% treatment-naive patients [no treatment for eye disease given yet], while on the other hand, the late-stage 4FRONT-2 trial is going to have 40% previously treated patients (those who have been diagnosed within the past six months) and then 60% who are treatment naive.
Wet-AMD is a type of eye disorder whereby blood vessels leak fluid and/or blood into the macula of the eye, leading to a host of vision problems for patients. The goal of 4DMT gene therapy 4D-150 is to deliver two transgenes in a single payload. This would include a transgene that encodes aflibercept (the active ingredient in EYLEA) and an RNA interference (RNAi) molecule targeting VEGF-C. The end result is inhibiting 4 key angiogenic factors involved in the progression of this disorder. Even better, the company has modified the adeno-associated virus (AAV) vector to specifically only allow continuous knockdown of the surface of the retina. In turn, this offers the ability to treat these patients in a potentially safer manner.
The company ended Q1 of 2025 with roughly $458 million in cash, which, with the 25% workforce reduction, would allow it to extend its cash runway into 2028. The reason for making such a move is because it actually expects to release data from the phase 3 4FRONT-1 and 4FRONT-2 studies in the 1st half and 2nd half of 2027, respectively. Thus, it has enough funds to reach both of these milestones, and if the primary endpoint of non-inferiority of BCVA is met with statistical significance, for one or both studies, then it will put the company in a good place to raise additional cash at a much higher stock price. Plus, it could also allow it to possibly meet with the FDA to be in a position to file a Biologics License Application [BLA] for approval of 4D-150 for the treatment of patients with Wet-AMD.
As I briefly noted beforehand, the move to streamline its pipeline doesn’t mean getting rid of other programs that it has. For example, it is in the process of developing gene therapy 4D-150 for the treatment of patients with diabetic macular edema (DME) in the phase 1 SPECTRA study. It already posted positive 32-week data outcomes showing that the 3E10 vg/eye dose was able to allow patients to sustain a gain of BCVA of +8.4 letters. Along with the fact that it reduced overall injection burden by 86%. What this means is that the patients who would receive once every 8 weeks (Q8W) EYLEA for wet-AMD, would instead see a reduction in burden of 86%. The main goal of this company is to allow for continuous targeting of the angiogenesis factor of this disorder, but at the same time reduce the number of injections needed to maintain vision.
Speaking of the use of 4D-150 for the treatment of patients with DME, the company is expected to release 52-week interim results from the phase 1 SPECTRA study at an upcoming medical conference in Q3 of 2025. The company has already engaged both the FDA and the European Medicines Agency (EMA) in order to get phase 3 studies going for this DME treatment program as well. However, the company is likely going to need sufficient funding to get phase 3 studies started in the targeting of these eye disorder patients.
Even though both phase 3 4RONT studies are not expected to have data until 2027, this doesn’t mean that there won’t be earlier data released. 4DMT is expected to release prior wet-AMD treatment 2-year data from the phase 1/2a trial and then 18-month study results from the phase 2b cohorts in Q4 of 2025. Thus, this would provide further proof of concept that the company incorporating a modified R100 AAV vector allows for deep and durable responses in patients. Lastly, it has an ongoing phase 1 AEROW study advancing gene therapy candidate 4D-710 for the treatment of patients with cystic fibrosis. As you can see, the company is not reliant on its wet-AMD treatment program entirely. However, it appears as though it wants to potentially reach the finish line for this specific program as quickly as possible. The reduction of workforce it has taken should help initially in this regard.