4D Molecular Therapeutics has linked its gene therapy to a 90% reduction in treatment burden in wet age-related macular degeneration (AMD), emboldening it to start planning to enter phase 3 next year.
4D-150 uses an adeno-associated virus vector to deliver transgenes encoding aflibercept, the molecule that Regeneron sells as Eylea, and RNAi that inhibits VEGF-C. The idea is to free patients from the need to receive frequent injections of Eylea and, through the RNAi, counter the upregulation of a protein that may contribute to drug resistance.
4DMT tested that theory in a phase 2 dose-expansion cohort that randomized 51 wet AMD patients to receive a single shot of one of two doses of 4D-150 or injections of aflibercept every eight weeks. The patients had severe disease, as assessed by central subfield thickness (CST), and, on average, received 10 anti-VEGF injections in the year prior to the study.
By the 24-week analysis, 4DMT had tracked an 89% and 85% reduction in annualized anti-VEGF injection rates in the high and low 4D-150 dose arms, respectively. Between 84%, on the high dose, and 90%, on the low dose, of participants received zero or one supplemental aflibercept injections. Almost two-thirds of patients on the high dose were injection free.
4DMT also looked at visual and retina anatomic outcomes. The biotech tracked reduced CST variability, a factor that predicts legal blindness, in the high-dose arm. Vision, as measured using the BCVA test, was stable across the three arms. Aflibercept numerically beat the high, but not the low, dose at Week 24. No patients had significant intraocular inflammation.
The biotech plans to start a phase 3 trial in the first quarter of next year to show the noninferiority of the high dose to aflibercept on BCVA. 4DMT will finalize its plans based on regulatory interactions but is currently looking at enrolling 225 patients per arm, covering a broader swath of the wet AMD population than the phase 2 expansion cohort.
4DMT is trailing Regenxbio and AbbVie’s ABBV-RGX-314 in the race to bring a wet AMD gene therapy to market. AbbVie is aiming to get two pivotal trials to primary completion next year, although 4DMT’s use of the VEGF-C inhibitor gives it a potential point of differentiation. While noninferiority is the planned goal of the phase 3, 4DMT CEO David Kirn, M.D., has discussed a “real opportunity for superiority.”
Shares in 4DMT rose around 30% to above $22 in premarket trading.