HuidaGene’s LCA2 Gene Therapy Gets Orphan Drug Designation
The clinical trial of HG004 for RPE65-LCA2 dosed its first patient in February 2023.
The FDA has granted orphan drug designation (ODD) to HuidaGene’s HG004 gene therapy being investigated for the treatment of RPE65 mutation type 2 Leber's congenital amaurosis (LCA2).1
"We are pleased to have received this significant regulatory feedback from the US FDA. Receiving ODD is an important milestone as we are advancing our HG004 gene replacement therapy program to clinical trial designed to provide safe, durable, and high-quality treatment to children and adults suffering from RPE65 mutation-associated inherited retinal diseases," Xuan Yao, PhD, Co-Founder and Chief Executive Officer, HuidaGene, said in a statement.1 "It also underscores the importance of bringing this novel therapy to patients with severe visual impairment or blindness, and strongly motivates us to expedite the clinical development of HG004."
The FDA previously cleared HuidaGene’s investigational new drug application (IND) in January 2023 and the first patient was treated with a single intravitreal injection oflow-dose HG004 in February.2,3 With the 2 weeks of post-treatment follow-up available, the patient had no serious adverse events (AEs), ocular AEs, or clinically significant immune reactions.3 Although detailed data are not available, HuidaGene has stated that the patient experienced rapid and continuous improvement of visual outcome measures including dynamic visual field, full-field stimulation threshold, and best-corrected visual acuity even in low levels of light.
"At present, there is no safe and effective intervention method approved in China for the treatment of RPE65 gene mutation-related retinopathy. In the end, most patients cannot avoid the misfortune of blindness. As a clinician [I am] hoping to carry out gene therapy for patients with such diseases at an early stage and save their eyesight,” Zhao Peiquan, director, Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, and the chief surgeon that administered HG004 to the patient, said in a statement at that time.3
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HG004 uses a recombinant non-adeno-associated virus serotype 2 (non-AAV2) vector to deliver the RPE65 gene to the retina in children and adults with inherited retinal diseases (IRDs) associated with this mutation including LCA2. In preclinical studies, HG004 transduced the retinal pigment epithelium and recovered retinal functions more efficiently than AAV2-mediated gene therapy in mouse models of RPE65-related IRDs.
Based on the head-to-head preclinical comparison study of HG004 and AAV2 at the same dose, the recovery of the retinal functions was increased by 67.6% (HG004) and 35.8% (AAV2 products) when compared to the wild-type mice in the Rpe65 knockout murine model at Week 17 after a single injection, suggesting that HG004 may potentially lower the total vector doses to reduce the risk of AAV vector-associated immunogenicity or ocular adverse events in humans.
HG004 is not alone in targeting RPE65 mutation associated LCA2, with the gene therapy voretigenene parvovec (Luxturna; Spark Therapeutics) approved in the US for the indication. Another competitor in the clinical trial arena is Frontera Therapeutics’ FT-001, which is being evaluated in a phase 1/2 clinical trial that dosed its first patient in January 2023.4
