Zhongmou Therapeutics has received FDA clearance for an investigational new drug (IND) application to launch a clinical study on ZM-02, its mutation-agnostic optogenetic gene therapy, for the treatment of advanced retinitis pigmentosa (RP).
Take note: This clearance reportedly marks the first IND authorization for an optogenetic therapy originating from China.
Let’s begin with this company.
Founded in 2019 and headquartered in China, the global clinical-stage genomic medicine company is developing optogenetic and gene-based therapies for three severe retinal diseases: X-linked retinoschisis (XLRS), RP, and age-related macular degeneration (AMD).
As for its scientific approach: This is based on two proprietary technology platforms:
- HOPE optogenetic protein engineering platform for designing engineered, high-sensitivity opsins
- AMAZE adeno-associated virus (AAV) vectorization platform for modular, clinically optimized gene delivery, scalable for global manufacturing
See here for details on this AAV-based gene delivery (and how optogenetic gene therapy works).
And its pipeline?
This revolves around two types of gene therapies targeting those aforementioned retinal diseases:
- Mutation-specific AAV gene therapies
- Designed to correct or replace defective genes
- Mutation-agnostic optogenetic gene therapies
- Designed to restore light sensitivity via enabling surviving inner retinal cells to respond to light
And where does this RP candidate fall under?
Utilizing Zhongmou’s HOPE platform, its lead asset ZM-02 is a next-generation optogenetic gene therapy delivered via a single intravitreal (IVT) injection.
What it does: Expresses an engineered photosensitive protein (PsCaCh2.e) in inner retinal neurons to restore light responsiveness in the blind eyes of patients with advanced retinal degeneration (such as RP).
- But more specifically: ZM-02 utilizes a clinical-grade recombinant AAV (rAAV) vector that’s designed to restore functional vision.
And as Zhongmou founder and CEO Yin Shen, MD, PhD, noted, ZM-02 addresses advanced RP’s near-complete photoreceptor loss by “bypassing degenerated photoreceptors and reactivating residual inner retinal circuits.”
And its clinical performance thus far?
Funny you should ask … the company actually recently presented data from a first-in-human (FIH) clinical trial conducted on ZM-02.
What to know about the early phase 1 study:
- Its name: zM-02's safety, tOlerability, and efficacy in retinitis pigmentOsa first-in-humaN (MOON)
- Its design: A prospective, dose-escalating, investigator-initiated trial (NCT06292650)
- Its participants: An estimated 12 patients (aged 18 to 65) diagnosed with RP (see all criteria)
- Its setup: Patient randomized to receive either one of three possible single IVT injections:
- Low-dose ZM-02, high-dose ZM-02, or a sham
- Its duration: 52 weeks of follow-up
- Its outcome measures: Measured from baseline to day 3 and week 1, 4, 16, 24, 36, and 52
- Primary outcomes were the incidence of adverse events (AEs) and serious AEs (SAEs) as well as changes in intraocular pressure (IOP)
- See here for secondary outcomes
- Primary outcomes were the incidence of adverse events (AEs) and serious AEs (SAEs) as well as changes in intraocular pressure (IOP)
What were the reported findings?
In sharing the positive 36-week data, the company noted that no drug-related SAEs or dose-limiting toxicities were observed, as well as:
- 83% of the 6 treated patients achieved ≥0.3 LogMAR best-corrected visual acuity (BCVA) at 36 weeks, with a mean gain of 0.59 LogMAR (~30 Early Diabetic Retinopathy Treatment Score [EDTRS] letters)
- Significant improvements in multi-luminance mobility testing (MLMT)—including low-light navigation (a secondary outcome)
- Rapid recovery of real-world navigation ability and “first-ever” restoration of color vision in advanced RP
- Sustained improvement in acuity, mobility, and color perception (for at least 1 year after one IVT injection)
See here for more reporting on this.
Nice! Now circling back to this IND clearance —what’s the plan?
First: Did we mention ZM-02 already received Orphan Drug designation from the FDA for RP (without restrictions on genetic subtypes)? That happened last year (details here).
As for next steps: Zhongmou is now cleared to initiate a new phase 1/2 clinical trial (dubbed PRISM) on the RP-targeted therapy.
And what do we know about this new study?
- Its design: multinational, randomized, single-masked, sham-controlled, dose-escalation
- Its purpose: To evaluate the safety, tolerability, and efficacy of a single IVT injection of ZM-02 in adult and pediatric RP patients (in both the U.S. and mainland China)
- Its outcome measures: Safety endpoints; ophthalmic exams; and functional testing using multi-luminance assays (MLMT and multi-luminance chessboard test [MLCBT] and multi-luminance shape discrimination [MLSDT])
- Its duration: Durability follow-up will continue through 52 weeks and beyond
Any timeframe yet on when this might kick off?
None so far … but stay tuned for more details in the new year!Clearance of ZM-02 marks the first optogenetic gene therapy originating from China to receive U.S. IND authorization.