Published in Pipeline

FDA clears 4DMT's IND for genetic GA treatment

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4 min read

The FDA has cleared 4D Molecular Therapeutics’ (4DMT) investigational new drug application (IND) for its intravitreal genetic medicine 4D-175, clinically designed to treat patients diagnosed with geographic atrophy (GA).

Let’s start with 4DMT.

Founded in 2013 and based in Emeryville, California, the clinical-stage biotherapeutics company is developing genetic medicines for rare diseases in three key therapeutic areas:

  • Ophthalmology
  • Pulmonology
  • Cardiology

Central to these medicines: the Therapeutic Vector Evolution Platform.

Explain this, please.

The proprietary vector discovery platform develops and uses synthetic adeno-associated virus (AAV) capsid-derived sequences to create customized vectors and deliver genetic material for the clinical advancement of its product candidates.

  • How it’s used: The platform utilizes the synthetic capside to match with a target vector profile (TVP) that then defines the cell types and intra-organ distribution that can be targeted by:
    • The vector (and within it, a product candidate)
      • R100
        • 4D-150 (wet age-related macular degeneration [nAMD]; diabetic macular edema [DME])
          • See here for positive interim phase 2 data
        • 4D-125 (X-linked retinitis pigmentosa [XLRP])
        • 4D-110 (choroideremia)
        • 4D-175 (GA)
      • A101
      • C102
    • Route of administration
    • Specific dose range for delivery
    • Any resistance to pre-existing antibodies within the human population

Now dive into 4D-175.

As a novel genetic medicine, 4D-150 uses the R100 vector (developed and customized by 4DMT) along with a codon-optimized transgene encoding a highly functional shortened form of human complement factor H (sCFH)—which we’ll explain below.

Give me the rundown on sCFH.

First thing to know: sCFH is an engineered and optimized version of CFH that fits into AAV vectors “with robust expression and full functionality.”

It’s also been confirmed in human cells in vitro (plus in preclinical animal models and species in vivo), according to 4DMT.

What restoring CFH function means: When restored via a targeted delivery of sCFH transgene (ie: 4D-175), it may not only restore normal complement regulation, but also potentially reduce retinal injury (ie: GA).

Gotcha. So just to recap…

The sCFH payload purpose: To restore normal complement regulation

And the overarching purpose of 4D-175: To provide durable transgene expression within the retina without significant inflammation—possibly slowing GA progression

  • Note: 4D-175 is intended to be administration via a single, low-dose intravitreal (IVT) injection

And any clinical data?

Preclinical trial findings concluded that IVT administration of 4D-175 at two doses (1x1010 to 5x1011 vg/eye) was deemed safe and well-tolerated, resulting in “robust transgene expression in the retina and retinal pigment epithelium (RPE)/choroid.”

See here for a full recap on 4DMT’s preclinical data on the use of 4D-175 in vitro and in vivo.

So what’s next for 4D-175?

The phase 1 GAZE clinical trial is expected to evaluate the use of 4D-175 among patients diagnosed with GA secondary to AMD.

  • Study type: Open-label, sequential cohort, dose-exploration stage
  • Setup: Participants will receive a single injection of 4D-175 at one of three dose levels
  • Objectives:
    • Determining safety and tolerability of 4D-175
    • Identifying optimal dose level(s) for phase 2
    • Evaluating transgene expression and biological activity

Note: The study has yet to be assigned an NCT number via

What’s the timeline for it?

No specifics as of yet; however, this IND clearance has officially enabled 4DMT to initiate enrollment.

Their tentative plans: H2 2024, according to Co-Founder and CEO David Kirn, MD.

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