4D Molecular Therapeutics announced positive interim clinical data from the Phase 1 Dose Exploration stage (three doses, n=15) of the 4D-150 Phase 1/2 PRISM clinical trial for wet age-related macular degeneration (wet AMD).
4D-150, a novel genetic medicine that utilizes 4DMT’s evolved and customized R100 vector for intravitreal delivery to the retina, was well- tolerated at all doses.
All doses demonstrated clinical activity, including a reduction in anti-VEGF injection burden, stable or improved retinal edema and thickness, and stable visual acuity.
A dose response was demonstrated in favor of the high dose 3E10 vg/eye.
“4D-150 is the first retinal genetic medicine that is designed to inhibit all four VEGF-related molecules that drive disease in wet AMD,” said Robert Kim, MD, CMO. “We are impressed by the clinical activity reported today, especially in the high dose cohort where 80% of patients did not require anti-VEGF injections through 36 weeks. We continue to execute relentlessly on enrolling the Phase 2 Dose Expansion stage of the PRISM trial in an effort to advance this potentially transformative therapy into late-stage development as soon as possible.”
Arshad M. Khanani, MD, MA, FASRS, Managing Partner and Director of Clinical Research at Sierra Eye Associates, Clinical Associate Professor at University of Nevada, Reno, and a Principal Investigator in the 4D-150 PRISM clinical trial, added, “I continue to be encouraged by the tolerability and clinical activity of a single intravitreal injection of 4D-150 in high-need patients with wet AMD. Given the stabilization or improvements seen in retinal anatomy and maintenance of vision up to 9 months, I believe 4D-150 has the potential to be a transformative treatment for patients with wet AMD and to greatly reduce their treatment burden.”
“These clinical data on 4D-150 represent another important milestone for patients with wet AMD and for 4DMT,” said David Kirn, MD, co-founder and CEO of 4DMT. “We believe these results further validate the potential of our intravitreal R100 vector, for the safe delivery of effective transgene payloads at relatively low doses, and our Therapeutic Vector Evolution platform. These promising interim clinical data and excellent progress on Phase 2 enrollment further demonstrate the power of our product design and development engine.”
Phase 1/2 PRISM Clinical Trial for Patients with Wet AMD: Design and Baseline Characteristics
- Phase 1 Dose Exploration stage (n=15; three dose cohorts of 5 patients each at 3E10, 1E10 and 6E9 vg/eye) followed by a randomized Phase 2 Dose Expansion stage (n=50, randomized 2:2:1 to 3E10 vg/eye or 1E10 vg/eye of 4D-150 or aflibercept)
- Patients enrolled in the Dose Exploration stage of the trial were patients with high need of anti-VEGF therapy with a mean annualized injection rate between 8 and 11 per cohort in the 12 months prior to 4D-150 treatment across all three dose cohorts
- Patients received a single intravitreal dose of 4D-150. Topical corticosteroids were administered at tapering doses over 20 weeks
- All data below are as of the data cutoff date of April 3, 2023
Phase 1 Dose Exploration Interim Safety Data
- A single intravitreal dose of 4D-150 was well-tolerated through 24 weeks in all 15 patients:
- 14 of 15 patient had no inflammation reported; one patient had a single episode of asymptomatic trace mixed vitreous cells that resolved without intervention
- 14 of 15 patients completed the protocol-mandated 20-week topical corticosteroid taper and did not receive further steroids; a single patient continued beyond 20 weeks by the treating physician for asymptomatic non-inflammatory trace pigmented cells
- No dose-limiting toxicities, 4D-150-related serious adverse events (SAE) or hypotony reported
- Patients in the 3E10 vg/eye high dose cohort had extended follow-up beyond 24 weeks (n=5, with a range of 36-64 weeks); there was no inflammation, and no 4D-150-related SAEs or dose-limiting toxicities reported during this time period
Phase 1 Dose Exploration Interim Clinical Activity Data
- All three doses demonstrated clinical activity in the study, with the highest dose at 3E10 vg/eye demonstrating the greatest level of activity at 24 weeks
- In the long-term follow up for the 3E10 vg/eye cohort at 36 weeks (n=5):
- 4 of 5 patients (80%) remained supplemental aflibercept injection-free
- Mean CST showed clinically-meaningful improvement (-92 µm)
- Mean BCVA remained stable
- Of 3 patients with follow-up beyond 36 weeks, 2 of 3 patients remained injection-free at 56-64 weeks; in all 3 patients at last follow-up between 56-64 weeks, CST was improved
Phase 1 Dose Exploration Interim Aflibercept Biomarker Data
- 4D-150-mediated expression of the aflibercept transgene protein was demonstrated in the aqueous humor (AH) of the eye at 12 weeks after 4D-150 injection in 91% (10 of 11) of patient samples evaluated to date1
- Mean AH aflibercept concentrations dose-related, and predicted to be in therapeutic range for all cohorts
1) Injection-free at 12 weeks, sample results available at time of data cutoff
Future Directions for 4D-150 & Large Market Ophthalmology Portfolio with the R100 Vector
- 4D-150 in wet AMD:
- Randomized Phase 2 Dose Expansion (n=50, randomized 2:2:1 to 3E10 vg/eye or 1E10 vg/eye of 4D-150 or aflibercept) of the PRISM trial is more than 50% enrolled
- Enrollment completion expected in Q3 2023 (previously Q4 2023)
- Initial interim Phase 2 data expected in H1 2024
- 4D-150 in Diabetic Macular Edema (DME): Randomized Phase 2 SPECTRA clinical trial evaluating 4D-150 in DME
- First patient enrollment in Phase 2 SPECTRA clinical trial expected in Q3 2023
- Initial data expected in 2024
- 4D-175 for geographic atrophy (R100 + short-form human complement factor H): Program update in Q4 2023