FDA clears HuidaGene's IND for CRISPR RNA-editing nAMD therapy

HuidaGene Therapeutics announced the FDA has granted clearance to an investigational new drug (IND) application for HG202, intended for neovascular age-related macular degeneration (nAMD).

Notably: HG202 is the first-ever clinical-stage clustered regularly interspaced short palindromic repeats (CRISPR)/Cas13 ribonucleic acid (RNA)-editing and only clinical-stage RNA-targeting therapy for nAMD.

First up, HuidaGene Therapeutics.

Based in Shanghai and New Jersey, the global, clinical-stage biotechnology company specializes in developing CRISPR-based—gene-editing technology—genetic medicines.

In ophthalmology, its pipeline includes investigational candidates for three inherited retinal dystrophies (IRDs):

• HG202 (our topic of choice)
  • Disease: nAMD
    • RNA editing
• HG004
  • Disease: RPE65 mutation-associated IRDs (RPE65-IRDs)
    • Gene replacement
    • To note: The FDA previously granted this candidate Rare Pediatric Disease and Orphan Drug designations.
• HG301
  • Disease: Rhodspin (RHO)-associated retinitis pigmentosa (rho-adRP)
    • RNA editing

And what’s the basis for its technology platform?

Adeno-associated virus (AAV)—which can be engineered to deliver DNA to target cells.

• Specifically: The company has developed its three ophthalmic investigational candidates (encompassing gene replacement and genome editing) to deliver therapeutic genes to cells via AAV vectors.
  • See more on this AAV screening platform.

Let’s focus on HG202.

As an RNA-targeting therapy, this candidate is designed to address nAMD via a partial “knock down” method of vascular endothelial growth factor (VEGF)-A messenger RNA (mRNA).

• About these nAMD patients: These patients have either developed a resistance to anti-VEGF treatment and/or are “responsive to current standard anti-VEGF therapies," according to HuidaGene.

To note: HG202 is packaged in a single AAV vector independently developed by the company’s HGPRECISE platform.

• About that platform: The proprietary CRISPR-based HuidaGene – Platform for Rational Engineering of CRISPR-Cas Identification by Synergic Expertise (HGPRECISE) platform was designed to develop “potentially curative genome medicine.”

Put this therapeutic’s purpose in plain terms, please.

Essentially, HG202 is designed as a one-time,“once-and-done” treatment intended to fill the current unmet treatment need for those nAMD patients who:

• Have developed a resistance to anti-VEGF treatment
• Are non-responsive to current standard anti-VEGF therapies

This one-time treatment is a stark contrast to standard anti-VEGF therapies, which require frequent repeated intravitreal injections and typically lead to decreased long-term efficacy and increased risk for complications.

And its clinical performance?

In preclinical in-vitro and in-vivo studies, HG202 was found to effect an 87% decrease in choroidal neovascularization (CNV) area in laser-induced CNV mice.

• What this means: Its performance for this metric was superior to both aflibercept and AAV vector-based anti-VEGF gene therapy (47% and 70% reductions, respectively).

Plus: A single injection of H202 achieved a durable therapeutic effect for at least 13 weeks, investigators reported.

And has there been any other research into this yet?

Indeed. HuidaGene noted that preliminary data was reported earlier this year from the first-in-human (FIH) SIGHT-1 clinical trial (NCT06031727), which dosed its first participants with HG202 in September 2023.

The study details:

• Participants: Aged 50 to 80; diagnosed with CNV secondary to AMD in the study eye
  • See full inclusion and exclusion criteria
• Setup: Participants receive a single unilateral subretinal injection
• Duration: An estimated 52 weeks for each patient

When reporting the data in April 2024, HuidaGene Co-Founder and CEO Alvin Luk, PhD, MBA, CCRA, previously stated that the company was particularly encouraged by animal and human data on the therapy, which indicated “that HG202 may stabilize blood vessels and reduce fluid in the retina to potentially treat nAMD patients who are either (resistant) or non-responsive to anti-VEGF agents.”

Nice! So what’s next for HG202?

With this IND clearance, the company is preparing to initiate a new open-label, multiple-cohort, dose-escalation phase 1 study: BRIGHT (NCT06623279).

Its official name: Open-laBel Dose-escalation Study for CRISPR/​cas13- Rna TargetInG THerapy for the Treatment of Neovascular Age-related Macular Degeneration in Phase I Trial (BRIGHT).

The setup:

• Participants: 15 (aged 50 to 85) with active macular CNV secondary to nAMD in the study eye
• The design: Up to three study cohorts, with each administering one unilateral subretinal injection of:
  • Low dose HG202
  • Middle dose HG202
  • High dose HG202
• Study duration:
  • 4-week screening period, enrollment visits, and treatment visit
  • 52-week follow-up period
  • 4-year long-term follow-up (extension study)
• Outcome measures (measured at 52 weeks):
  • Primary: Ocular and systemic adverse events (AEs), including serious AEs and DLTs
  • Secondary:
    • Mean change in best-corrected visual acuity (BCVA)
    • Mean change in annualized rate of supplemental injections

When is that study expected to kick off?

Per Clinical Trials, the interventional trial is slated to commence in April 2025—and its conclusion is estimated for February 2031.