SUMMARY

• Botaretigene sparoparvovec (JNJ-74765340 or AAV5-RPGR gene therapy) is an investigational adeno-associated virus vector type 5 (AAV5) gene therapy being studied for the treatment of X-linked retinitis pigmentosa (XLRP) associated with disease causing sequence variants in the retinitis pigmentosa GTPase regulator (RPGR) gene.^1-4
• Immunogenicity data following botaretigene sparoparvovec gene therapy in RPGR-XLRP participants showed no apparent association between treatment-emergent (TE) antibody status and dose.⁵

CLINICAL DATA

Study Design

MGT009 was a first-in-human, multicenter, open-label, phase 1/2 trial conducted at 5 sites across the United States and the United Kingdom to evaluate the safety and efficacy of single subretinal administration of botaretigene sparoparvovec in participants with XLRP due to variants in RPGR gene.^1,4,6 Please visit https://www.clinicaltrials.gov (identifier NCT03252847) for additional information.

The study design was comprised of 3 parts: a non-randomized dose-escalation phase in 10 adults (given either low, intermediate, or high dose botaretigene sparoparvovec), a non-randomized dose confirmation cohort of 3 pediatric participants (intermediate dose), and a randomized controlled expansion cohort of 32 adults randomized into 3 arms (low dose, intermediate dose, or deferred treatment). In each participant, 1 eye was treated and the contralateral, untreated eye served as the control.^1,3,7,8 In the dose-escalation and dose confirmation phases, botaretigene sparoparvovec was administered to the poorer-seeing eye at baseline and the participant’s other eye served as the untreated control. In the expansion cohort, the eye in which the vector was administered was determined via randomization.^1,3,7,9 Please see Figure: Study Design of MGT009.  

Methods

Humoral immune response after botaretigene sparoparvovec administration was assessed through 26 weeks. Serum samples were collected at baseline and weeks 4, 13, and 26 for the assessment of antibodies to the AAV5 capsid, neutralizing antibodies (NAbs) to the AAV5 capsid, and antibodies to RPGR.⁵ Please see figure: Sample Collection for Assessment of Antibodies.

Immunogenicity screening assay of antibodies was performed on all serum samples and a confirmatory assay was only performed on positive screening participants. In the confirmed positive samples, antibody titers were then quantified. NAbs to the capsid were only assessed in participants identified as TE positive for antibodies to the capsid.

Participants positive for TE antibodies were defined as those with either:

• A positive sample at baseline (before administration) and a 4-fold increase of titer from baseline at any time point through week 26 (after administration)
• A negative sample at baseline (before administration) and ≥1 positive sample at any time point through week 26 (after administration), for example, treatment-induced antibodies.⁵

Please see table: Multi-Tiered Approach Used for Assessment of Antibodies

• Values for minimum required dilutions are shown in table: Minimum Required Dilutions.⁵

Results

Through 26 weeks, 21 of the 45 total participants had TE antibodies to the AAV5 capsid. Among these 21 participants, 9 were positive for TE NAbs to the AAV5 capsid. Through 26 weeks, 6 of the 45 participants were positive for TE antibodies to the RPGR protein. Summary of antibodies through week 26 are described in figure: Summary of Immunogenicity Results. For breakdown of time to treatment-emergent antibodies and neutralizing antibodies, please see figures: Time to Treatment-emergent Antibodies to AAV5 Capsid, Time to Treatment-emergent Neutralizing Antibodies to AAV5 Capsid, and Time to Treatment-emergent Antibodies to RPGR.⁵

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 20 March 2024.