4DMT presents positive interim data from Phase 2 PRISM clinical trial of intravitreal 4D-150 for wet AMD

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4D Molecular Therapeutics has announced positive interim data from the Phase 2 PRISM clinical trial evaluating intravitreal 4D-150 in wet age-related macular degeneration (wet AMD) patients with severe disease activity and a high treatment burden.

Arshad M. Khanani, MD, MA, FASRS, presented data at the Angiogenesis, Exudation, and Degeneration 2024 Conference outlining 24-week landmark results from the randomized Phase 2 Dose Expansion cohort of the PRISM clinical trial.¹

David Kirn, MD, co-founder and CEO of 4DMT, noted during a webcast today that the drug has the potential to preserve vision. He pointed out in a news release the positive interim results also validate 4D-150’s potential as a safe, convenient, durable and transformational intravitreal therapeutic for wet AMD patients, with a goal of preserving vision for the longer term.

“We believe 4D-150 has the potential to disrupt the current treatment paradigm in these patients and that these results continue to highlight the power and value of our intravitreal R100 vector invented at 4DMT,” Kirn said in the news release. “I would like to thank the patients and investigators who are participating in the PRISM trial who helped to achieve this important milestone.”

Robert Kim, MD, the company’s chief medical officer, noted that the 4DMT was buoyed by the clinical activity demonstrated in this severe disease activity patient population with high treatment burden.

“We believe these positive interim Phase 2 results demonstrate a differentiated product profile for the treatment of wet AMD, including in these most difficult to treat patients that have not been studied adequately in prior clinical trials,” Kim said in a news release. “We look forward to discussions with regulators to align on a Phase 3 development plan expedited by FDA RMAT and EMA PRIME designations to advance 4D-150 with the goal of providing a compelling new treatment option for millions of patients suffering from these blinding VEGF-driven retinal diseases.”

Khanani explained that wet AMD is a chronic disease, and many of the patients require long-term, frequent intravitreal injections. He noted during the webcast that 4D-150 met a favorable safety profile with no significant or recurring intraocular inflammation. 

“Unfortunately, under-treatment and suboptimal disease control contribute to vision loss in the real world," said Khanani, who is director of Clinic Research at Sierra Eye Associates in Reno, Nevada. "I am encouraged by the potential of a one-time intravitreal injection of 4D-150 for treating wet AMD. Results from the Phase 1 and interim results from Phase 2 cohorts of the PRISM study confirm that 4D-150 is well tolerated and maintains stable visual acuity in previously treated high-need patients.”

Moreover, Khanani pointed out in the company’s news release that 4D-150 also reduces treatment burden while effectively controlling disease activity without fluid fluctuations.

PRISM details

The Dose Expansion cohort of the PRISM study is a randomized, controlled Phase 2 clinical trial evaluating 4D-150 in previously treated wet AMD patients with severe disease activity (≥ 325 µm central subfield thickness (CST) measured by optical coherence tomography (OCT) and presence of subretinal or intraretinal fluid) and a high treatment burden (≥6 anti-VEGF injections in the prior 12 months).¹

The trial enrolled 51 patients with severe disease activity and treatment burden:

PRISM Phase 2 interim results

A single intravitreal dose of 4D-150 demonstrated favorable safety results through the data cutoff date (all ophthalmic exams through up to 48 weeks of follow-up):

PRISM Phase 1 Long-Term Follow-Up

• Safety results maintained in all 15 patients treated to date (up to 104 weeks of follow-up) with no new inflammation and no change in steroid status
• Three patients treated with high dose (3E10 vg/eye) 4D-150 were previously reported to be injection-free after 52 weeks of follow-up; all 3 patients remained injection-free through 80–104 weeks (up to 2 years) of follow-up

Additional 4D-150 Program Updates

• 110 patients have been enrolled and dosed to date with 4D-150 in the following cohorts: PRISM Dose Exploration (N=15), Dose Expansion (N=41, excluding control arm), Population Extension (N=32), and SPECTRA Dose Confirmation (N=22)
• No clinically significant treatment-emergent inflammation reported
• Enrollment completed ahead of schedule in Phase 2 PRISM Population Extension cohort evaluating 4D-150 in wet AMD patients with broader disease severity (no minimum CST) and lower treatment burden (1-6 anti-VEGF injections in prior 12 months, ≥1 in last 12 weeks), with 32 patients dosed with 3E10 or 1E10 vg/eye of 4D-150
• Pivotal study planning ongoing with FDA and EMA under RMAT and PRIME designations
• 4DMT plans for the first Phase 3 study to be a BCVA non-inferiority study vs aflibercept 2 mg every 8 weeks; 3E10 vg/eye has been selected as study dose
• Application of preliminary Phase 3 eligibility criteria for BCVA and CST to the PRISM Dose Expansion Phase 2 study (16 of 20 in high dose 4D-150 arm and 6 of 10 in aflibercept arm met criteria) demonstrated:
• BCVA: +3.3 letters favoring high dose 4D-150 vs. aflibercept
• CST: –99.0 µm favoring high dose 4D-150 vs. aflibercept
• Anti-VEGF treatment burden: 90% reduction in annualized injection rate (88% received 0 or 1 injection, 63% were injection-free)
• Enrollment and dosing completed in Phase 2 SPECTRA Part 1 Dose Confirmation cohort evaluating 4D-150 in diabetic macular edema (DME), with 22 patients dosed with 3E10 or 1E10 vg/eye of 4D-150

Upcoming 4D-150 Milestones

The company noted that additional FDA and EMA interactions planned in Q2 2024, with an update expected in Q3 2024.

Moreover, according to the news release a Phase 2 PRISM Population Extension cohort evaluating 4D-150 in wet AMD patients with broader disease severity: Initial interim 24-week landmark data analysis is expected in H2 2024.

The Phase 2 SPECTRA Part 1 Dose Confirmation cohort evaluating 4D-150 in DME: Initial interim 24-week landmark data analysis is expected in H2 2024, and the initiation of the first Phase 3 study is expected in Q1 2025.

According to the company, 4D-150 comprises its customized and evolved intravitreal vector, R100, and a transgene cassette that expresses both aflibercept and a VEGF-C inhibitory RNAi. The company noted this dual-transgene payload inhibits 4 angiogenic factors that drive wet AMD and DME: VEGF A, B, C and PlGF.

Moreover, the company also noted R100 was invented at 4DMT through its proprietary Therapeutic Vector Evolution platform; we created this platform utilizing principles of directed evolution, a Nobel Prize-winning technology. 4D-150 is designed for single, low-dose intravitreal delivery.

Closing thoughts

As research continues, Kim noted that since wet AMD can impact the fellow eye, and that issue will also be considered going forward.

Kirn said the company produces all of its clinical trial materials inhouse and it will continue to do that throughout the study at commercial scale and process.

“As a busy retina specialist, I am happy to see these results,” Khanani said in the webcast. “I believe 4D-150 has the potential to revolutionize the treatment approach for our patients with wet AMD, and I am looking forward to participating in planning of the Phase 3 trials.”

Reference

1. 4DMT Presents Positive Interim Data from Randomized Phase 2 PRISM Clinical Trial of Intravitreal 4D-150 Demonstrating Favorable Tolerability & Clinical Activity in Wet AMD | 4D Molecular Therapeutics. 4D Molecular Therapeutics. Published 2024. Accessed February 5, 2024. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-presents-positive-interim-data-randomized-phase-2-prism