4DMT shares data from Phase 1/2 PRISM clinical trial, 4FRONT Phase 3 study design

(Image credit: AdobeStock/Ziyan)

4D Molecular Therapeutics has announced data based on the longest interim follow-up from Phase 1/2 PRISM clinical trial and 4FRONT Phase 3 study design. These results are a part of the company’s 4D-150 Wet AMD Development Day.

In the press release¹, David Kirn, MD, co-founder and CEO of 4DMT noted the progress and timeline of this candidate, saying, “We continue to build support for 4D-150 with positive interim data from PRISM showcasing potential durable, multiyear clinical benefit with an emerging safety profile comparable to approved anti-VEGF agents. In addition, we have assembled an exceptional senior leadership team with deep late-stage drug development, regulatory and commercial experience in large market ophthalmology to design and execute our upcoming pivotal studies. We expect to initiate 4FRONT-1, our first 4D-150 Phase 3 study in wet age-related macular degeneration (wet AMD), in Q1 2025. We look forward to continuing the rapid advancement of this potentially paradigm shifting product candidate that addresses the limits of current treatment options for patients with wet AMD.”

Robert Kim, MD, CMO of 4DMT added to these comments, saying, ““As prudent medicines developers we began our clinical development program for 4D-150 in the most severe wet AMD patients in the Phase 1/2a portion of PRISM. After observing favorable tolerability and clinical activity results, we and our investigators felt confident in 4D-150’s potential across a broad range of wet AMD patients and designed the Phase 2b cohort. We believe our interim data from Phase 2b presented today demonstrates strong clinicalactivity, especially in more recently diagnosed patients.”¹

4D-150 Wet AMD Development Day Key Highlights

Positive Interim Data from 4D-150 Phase 1/2 PRISM Study

Clinical Activity (based on data cutoff of September 3, 2024)

1. Robust and durable treatment burden reduction observed in all PRISM populations studied with the planned Phase 3 dose of 3E10 vg/eye of 4D-150
   1. Phase 1/2a Severe (n=24, through 52 weeks):
      1. 83% overall reduction in annualized injections
      2. 52% received 0 or 1 injection*
      3. 44% injection-free*
   2. Phase 2b Broad (n=30, through 52 weeks):
      1. 89% overall reduction in annualized injections
      2. 80% received 0 or 1 injection*
      3. 70% injection-free*
   3. Phase 2b Recently Diagnosed** (n=15, through 52 weeks):
      1. 98% overall reduction in annualized injections
      2. 100% received 0 or 1 injection*
      3. 87% injection-free*

*Based on Kaplan-Meier method for calculating endpoint with follow-up through 52 weeks (Phase 1/2a) and variable follow-up through 32–52 weeks (Phase 2b)

**Defined as diagnosed ≤6 months

1. Central Subfield Thickness(CST): sustained anatomic control with fewer fluctuations
2. Mean best corrected visual acuity (BCVA): Stable (Phase 1/2a) or sustained improved (Phase 2b)

Safety (based on data cutoff of August 23, 2024):

1. 4D-150 continues to be well tolerated with favorable safety profile
   1. Wet AMD:
      1. 2.8% (2 of 71) had 4D-150–related IOI at any timepoint
         1. 2 patients had transient 1+ vitreous cells
         2. 99% (70 of 71) completed steroid prophylaxis taper on schedule
         3. 97% (69 of 71) remained off steroids completely
   2. Diabetic Macular Edema (DME; SPECTRA trial):
      1. No patients treated at any dose (n=22) have experienced IOI events at any timepoint
2. No 4D-150–related hypotony, endophthalmitis, vasculitis, choroidal effusions or retinal artery occlusions observed to date across both the wet AMD and the DME programs

4FRONT Wet AMD Planned Phase 3 Program Key Design Elements

• Company planning for global 4FRONT Phase 3 development program comparing a single dose of 4D-150 3E10 vg/eye to on-label aflibercept 2mg Q8 weeks:
  • Initiation of 4FRONT-1 clinical trial (N=500) in treatment naïve wet AMD patients expected in Q1 2025
• Program expected to include two double-masked, randomized, controlled noninferiority trials:
  • Primary endpoint: noninferiority in BCVA
  • Randomization requires on study demonstration of aflibercept responsiveness
  • Sham controlled to support masking
  • All patients randomized to receive 3 total loading doses per aflibercept label
• Supplemental aflibercept injection criteria for 4D-150 arm optimized to protect primary BCVA endpoint and to maximize reduction of supplemental treatment burden; no supplemental injections allowed in control arm
• Study design has been aligned with feedback from U.S. Food and Drug Administration (FDA) under RMAT designation
• Alignment ongoing with European Medicines Agency (EMA) under PRIME designation

Carlos Quezada-Ruiz, MD, FASRS, SVP, Therapeutic Area Head, Ophthalmology of 4DMT added, “Given the consistent emerging safety profile and strong signs of promising clinical activity across a broad range of wet AMD patients, we are excited to rapidly advance 4D-150 into Phase 3. We have worked closely with global regulatory agencies and our Ophthalmology Advisory Board to maximize the probabilities of clinical, regulatory and commercial success of the 4FRONT Phase 3 program. In partnership with the retina community, we are eager to begin enrollment in 4FRONT-1 and potentially bring a paradigm shifting treatment option to patients.”¹

Arshad M. Khanani, MD, MA, FASRS, Director of Clinical Research at Sierra Eye Associates and Clinical Professor at University of Nevada, Reno also gave his thoughts on this news in the press release¹, saying.“Our patients with wet AMD require frequent life-long treatment with intravitreal injections, leading to a high treatment burden and suboptimal outcomes in the real world compared to clinical trials. Based on the data to date, 4D-150 has the potential to decrease treatment burden and control wet AMD with a safe, single routine intravitreal injection while maintaining vision and anatomy. I am looking forward to working with the 4DMT team, ophthalmology advisory board, and investigators on the 4FRONT Phase 3 global development program to advance this potential treatment option for all our patients with wet AMD.”

4D-150 Wet AMD Development Day Webcast Details

Title: 4D-150 Wet AMD Development Day

Date/Time: Wednesday, September 18, 2024 from 4:15 pm to 6:15 pm ET

An archived copy of the webcast will be available for up to one year by visiting the “Investors & Media” section of the 4DMT website: https://ir.4dmoleculartherapeutics.com/events.

Reference:

1. 4DMT highlights robust and durable clinical activity for 4D-150 along with design for 4FRONT phase 3 program at 4D-150 wet AMD development Day. 4D Molecular Therapeutics. September 18, 2024. Accessed September 18, 2024