Published in Pipeline

4DMT releases positive interim data on phase 2 AMD gene therapy trial

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4D Molecular Therapeutics (4DMT) announced positive interim clinical data from the randomized phase 2 dose expansion cohort of its PRISM trial on the investigational asset 4D-150 to treat wet age-related macular degeneration (AMD).

Quick refresher on this company, please.

The Emeryville, California- based clinical-stage biotherapeutics company operates with a focus on the development of genetic medicines for rare diseases in ophthalmology, pulmonology, and cardiology.

The Therapeutic Vector Evolution, its proprietary vector discovery platform, is designed to use synthetic adeno-associated virus (AAV) capsid-derived sequences to create customized vectors for the clinical advancement of its product candidates.

Now this asset.

As a novel genetic medicine, 4D-150 uses the R100 vector (developed and customized by 4DMT) that leverages a multi-target transgene payload expressing both aflibercept and a vascular endothelial growth factor (VEGF)-C inhibitory RNA interference (RNAi).

This dual payload is designed to block four angiogenic factors responsible for wet AMD and diabetic macular edema (DME).

Note: 4D-150 is intended for single, low-dose intravitreal delivery.

And the PRISM trial?

The prospective, multicenter, randomized, controlled, and masked phase 1/2 PRISM clinical trial (NCT05197270) is enrolling a total of 150 patients (ages ≥50 years) diagnosed with wet AMD who were actively receiving anti-VEGF treatment and previously demonstrated a clinical response consistent with anti-VEGF activity within the last 12 months before the start of the trial.

The trial was split into two parts: dose exploration (escalation) and dose expansion.

What happened in part 1?

Back in May 2023, the company reported positive interim data from the phase 1 dose exploration stage of the study, which included 15 patients in three cohorts receiving a single intravitreal injection of 3E10 vg, 1E10 vg, and 6E9 vg/eye, respectively.

See here for details on that data.

And how was this second part designed?

A total of 51 patients were randomized 2:2:1 to receive either of the following single intravitreal injections every 8 weeks:

  • High (3E10 vg/eye) 4D-150
  • Low (1E10 vg/eye) 4D-150
  • Aflibercept 2 mg (control)

What was being measured?

Measured at 52 weeks, the primary outcome measures included the development and severity of treatment-emergent adverse events (TAEs) as well as serious adverse events (SAEs).

Secondary outcomes, also measured at 52 weeks, included:

  • Time to receive first supplemental aflibercept injection
  • Percentage of subjects requiring supplemental injections
  • Number of supplemental injections
  • Change from baseline in best-corrected visual acuity (BCVA) over time
  • Change from baseline in central subfield thickness (CST) over time

Findings?

Per 4DMT, a single 4D-150 intravenous dose demonstrated favorable results through the data cutoff date of Jan. 19, 2024 (with follow-up exams through up to 48 weeks).

No significant intraocular inflammation (IOI) was reported (high dose = none), as well as no 4D-150-related serious adverse events (SAEs) or study eye SAEs.

What about for the low-dose cohort?

A total of 97% of participants completed a 20-week prophylactic topical corticosteroid taper on schedule; by the cutoff date, all were off steroids.

Additionally, a single eye at Week 16 demonstrated 1+ anterior mixed (pigmented and white blood) cells, which were resolved by the following visit. By Week 26, prophylactic topical corticosteroid taper was completed, 4DMT reported.

Let’s talk about efficacy points.

At the 24-week mark, the company reported an 89% (high dose) and 85% (low dose) reduction in anti-vascular endothelial growth factor (VEGF) injection rates for 4D-150-treated participants.

Further, 84% (high) and 90% (low) of participants received either 0 or 1 supplemental injection of aflibercept. And the percentage who were supplemental injection-free were 63% (high dose) and 50% (low dose).

How about BCVA and CST?

BCVA

  • High dose
    • –1.8 Early Treatment Diabetic Retinopathy Study (ETDRS)
  • Low dose
    • +1.8 ETDRS

CST

  • High dose
    • –8.3 µm
  • Low dose
    • +29.9 µm

So what’s next?

4DMT has already completed enrollment (n = 32) for the PRISM study’s population extension cohort, which is assessing 4D-150 for wet AMD with broader disease severity (no minimum CST) and a lower treatment burden.

Per the company, interim 24-week data is expected by the second half of 2024.

Per Clinical Trials, the study’s estimated completion date is September 30, 2026.

Any plans for an eventual phase 3 trial?

Yes, actually … 4DMT is still in the planning stages, but has so far announced the study will be designed as a BCVA non-inferiority study vs aflibercept 2 mg every 8 weeks, with the high dose (3E10 vg/eye) as the study dose of 4D-150.

The trial is tentatively slated to launch in Q1 2025.

Click here for additional details.

And the significance?

According to Arshad M. Khanani, MD, MA, FASRS, director of Clinic Research at Sierra Eye Associates, Reno, Nevada, the data from both phase 1 and 2 of the PRISM study confirms that 4D-150 is well tolerated and maintains stable visual acuity in previously treated patients.

“4D-150 also significantly reduces treatment burden while effectively controlling disease activity without fluid fluctuations,” Dr. Khanani stated. “I believe 4D-150 has the potential to revolutionize the treatment approach for our patients with wet AMD.”

Dr. Khanani presented this interim data at the Angiogenesis, Exudation, and Degeneration 2024 Conference. See here for details.