Variant, a biotechnology company specializing in gene therapies for orphan inherited eye diseases, announced today that it has received positive feedback from the European Medicines Agency (EMA) regarding its innovative gene replacement therapy, VAR002. The therapy targets inherited retinal dystrophies linked to mutations in the CRX gene, a critical transcription factor in photoreceptor development and function.
The EMA's scientific advice confirms that VAR002's non-clinical development plan is appropriate for advancing to first-in-human clinical trials. This regulatory milestone represents a significant step forward in addressing the unmet medical needs of patients with CRX-associated retinal diseases, which currently have no approved treatments.
Regulatory Validation Strengthens Development Pathway
The EMA's endorsement specifically validates the preclinical program, including pivotal toxicology and biodistribution studies, as adequate to support clinical translation. Additionally, the agency confirmed that the planned toxicology study design aligns with requirements for a future Marketing Authorisation Application (MAA) in the European Union.
"The EMA has highlighted the need for particular attention to the potential risks associated with CRX transgene expression outside of photoreceptor cells due to autoactivation of the hGRK1 promoter," said Denis Cayet, CEO of Variant. "These recommendations are instrumental in strengthening the robustness of our preclinical studies and, ultimately, securing the development pathway for VAR002, ensuring the highest safety and efficacy standards as we progress toward clinical trials."
The upcoming Good Laboratory Practice (GLP) compliant studies will comprehensively assess VAR002's safety, biodistribution, and potential toxicity, providing a thorough evaluation of its risk-benefit profile before human trials begin.
Innovative Mechanism Addresses Multiple Retinal Disorders
VAR002 utilizes a recombinant adeno-associated viral (rAAV) vector to deliver an unmutated copy of the human CRX gene to photoreceptor cells. The therapy was initially developed to treat three severe conditions: Leber's congenital amaurosis, retinitis pigmentosa, and cone-rod dystrophy—all linked to CRX gene mutations.
The treatment is administered as a sterile suspension of viral particles injected directly into the subretinal space, triggering expression of the therapeutic transgene in both rod and cone photoreceptors. This approach aims to restore visual function by replacing the defective gene with a functional copy.
Recent preclinical research has expanded VAR002's potential applications beyond CRX-related disorders. Studies in relevant animal models have demonstrated efficacy in treating diseases associated with defects in phototransduction pathways and ciliopathies, including CEP290-associated conditions. These findings suggest broader clinical applications than initially anticipated.
Collaborative Approach to Clinical Translation
The development of VAR002 represents a collaborative effort between Variant and the Rare Ocular Diseases Center at the University of Campania Luigi Vanvitelli (UCLV) in Naples, Italy. Variant has established a Translational Preclinical Task Team working alongside Professor Francesca Simonelli of Naples Hospital to accelerate the transition from research to clinical application.
The Centre for Rare Ocular Diseases at UCLV offers comprehensive diagnostic, rehabilitative, and therapeutic services for patients with hereditary eye diseases. The center recently established the "Telethon Advanced Ocular Therapy Unit," one of few such specialized facilities in Europe dedicated to evaluating innovative therapeutic strategies for rare ocular diseases.
This collaboration provides a pathway for patient enrollment in clinical studies once VAR002 advances to the trial phase, potentially offering hope to individuals with currently untreatable inherited retinal conditions.
Addressing Critical Unmet Needs in Ophthalmology
Inherited retinal dystrophies affect approximately 1 in 3,000 people worldwide and often lead to severe visual impairment or blindness. CRX-associated retinal diseases represent a subset of these disorders with particularly limited treatment options.
The positive EMA feedback for VAR002 marks an important advancement in the field of ophthalmic gene therapy, which has seen increasing interest following the approval of voretigene neparvovec (Luxturna) for RPE65-mediated inherited retinal dystrophy in 2017.
As VAR002 progresses toward clinical trials, it has the potential to address a significant gap in treatment options for patients with CRX-related retinal disorders while potentially expanding to benefit those with other genetic forms of retinal degeneration.
