SUMMARY

• Botaretigene sparoparvovec 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.^1,2
• An open label, multicenter, phase 1/2, dose escalation, dose confirmation and randomized, controlled dose expansion clinical trial (N=45) evaluated the safety and efficacy of botaretigene sparoparvovec as the primary and secondary endpoints, respectively.²
  • A total of 37/45 patients experienced ≥1 treatment-emergent adverse event (TEAE), including all the participants in the treatment group and 5/13 participants in the control group. There were no reported dose-limiting events (DLEs). Most adverse events (AEs) were transient and related to the surgery and resolved without intervention. Two serious AEs (SAEs) were reported with immediate treatment cohort (retinal detachment and uveitis).
  • Improvements in retinal sensitivity, functional vision and visual function were observed compared to the concurrent control group at week 26. A similar trend was observed at week 52.
• The LUMEOS study, a phase 3 clinical trial of botaretigene sparoparvovec, is ongoing.³

BACKGROUND

Botaretigene sparoparvovec (AAV5-RPGR) is an investigational AAV5 gene therapy being studied for the treatment of XLRP caused by variants in the RPGR gene.^1,2 The AAV5 capsid contains a linear single strand of human RPGR-ORF15 deoxyribonucleic acid (DNA) with an in frame deletion in the purine-rich tract in the ORF15 region. The transgene is driven by human rhodopsin kinase promoter (hRKp) to drive expression.^2,4

CLINICAL DATA

Study Design

MGT009¹ was an open label, multicenter, phase 1/2, dose escalation, dose confirmation and randomized, controlled dose expansion clinical trial conducted at 5 sites across the United States and the United Kingdom, that evaluated the safety and efficacy of subretinal botaretigene sparoparvovec in males with RPGR-XLRP. The study was initiated on July 31, 2017, and was completed on November 18, 2021 (last follow up).² Please visit https://www.clinicaltrials.gov (identifier NCT03252847) for additional information.¹

In the dose escalation phase, adult participants were administered with 1 of 3 doses of botaretigene sparoparvovec (low, intermediate, or high dose) in the worse seeing eye. In the dose confirmation phase, pediatric participants were administered intermediate dose. In the dose expansion phase, only adult participants were enrolled. Participants were randomized in a 1:1:1 ratio to the low dose, intermediate dose, or deferred (concurrent control group randomized for treatment after 26 weeks) group. The treatment eye was randomized in a 1:1 ratio. Participants who completed the week 52 visit for the treatment group and those who completed the week 26 visit for the deferred group were considered to have completed the study.² Please see Figure: Study Design.

Inclusion and Exclusion Criteria

Key inclusion criteria:²

• Males aged ≥5 years
• XLRP diagnosis associated with a disease-causing missense or null variant in RPGR
• Had relatively symmetrical retinal disease (defined as <15 letter best corrected visual acuity [BCVA] difference between eyes)
• Evidence of relative retinal structure preservation at the macula, determined by discernable ellipsoid zone observed on spectral-domain optical coherence tomography
• Evidence of impaired navigation in dim illumination in both eyes (tested monocularly), determined by a mobility assessment completion time of ≥12 seconds at low illumination (either 1 or 4 lux)
• Able to undertake age-appropriate clinical assessments

Exclusion criteria:²

• Had a known allergy to any antibiotics, steroids, or proton pump inhibitors used in the trial
• Participated in another research study involving an investigational medicinal therapy for ocular disease within the previous 6 months
• Had any condition considered to be inappropriate for entry into the trial (e.g., uncontrolled hypertension, diabetes mellitus, or heart failure; history of tuberculosis; chronic kidney disease; immunocompromised state; osteoporosis; active peptic ulcer disease or uncontrolled gastroesophageal reflux).

Primary and Secondary Endpoints

The primary endpoint was safety, defined as the absence of any of the following 5 DLEs possibly related to botaretigene sparoparvovec and occurring during the 9 weeks after surgery:²

• Reduction in visual acuity (VA) by ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) chart letters
• Severe unresponsive inflammation, defined according to Standardization of Uveitis Nomenclature Working Group grading system (anterior chamber cells 3+, anterior chamber flare 3+, or vitreous haze 3+ failing to improve by 2 steps [or to grade 0] during a 6-week period)
• Infective endophthalmitis
• Ocular malignancy
• Grade ≥3 non-ocular serious adverse reaction

The secondary objective included assessment of slowing or halting of progressive deterioration in retinal structure or visual function in participants receiving botaretigene sparoparvovec and improvement in retinal and visual function as well as quality of life. Secondary efficacy endpoints were grouped into functional vision, retinal function, and visual function. The functional vision efficacy assessment included the vision guided mobility assessment (VMA) at screening, and weeks 13, 26 and 52, which evaluated the participant’s navigation ability through a maze at various illumination levels. The efficacy assessment of retinal function included static perimetry testing with the Octopus 900 device, mean retinal sensitivity (MRS) on Octopus static perimetry in the central 10 degrees (excluding scotomata), and microperimetry data using Macular Integrity Assessment (MAIA) at baseline and weeks 13, 26, and 52. Visual function assessments included ETDRS BCVA, and contrast sensitivity (CS), measured using the Pelli-Robson chart.²

Results

A total of 49 participants were enrolled in the dose escalation phase (adult male, n=10), dose confirmation phase (child male, n=3), and randomized, controlled dose expansion phase (adult male, n=36; discontinued prior to botaretigene sparoparvovec administration, n=4). The mean (range) age of the participants was 28.1 (11-61) years and 91.9% (n=41) were white. One participant in the intermediate dose group of the dose expansion phase inadvertently received treatment with the high dose and was included with the other 3 participants in the high dose group for the safety analysis and in the intermediate dose group for the efficacy analysis. Of the 49 participants enrolled, 45 received botaretigene sparoparvovec and were included in the safety analysis set, of whom 43 completed the study. One participant in the intermediate dose group (due to mental health issues) and 1 participant in the high dose group (for unspecified reasons) discontinued the study prior to completing the week 52 visit.²

Safety

No DLEs related to botaretigene sparoparvovec administration and no TEAEs leading to study discontinuation were reported throughout the study. Of the 45 participants, 37 experienced ≥1 TEAE. Among the participants treated with low, intermediate and high doses, the most common AEs were conjunctival hemorrhage (n=8 [72.7%], n=11 [64.7%], n=4 [100%], respectively), reduced VA (n=6 [54.5%], n=8 [47.1%], n=2 [50.0%], respectively), and the presence of anterior chamber cells (n=4 [36.4%], n=9 [52.9%], n=3 [75.0%], respectively).²

The TEAEs experienced by most of the participants in the treatment and control group were mild (n=11; 29.7%) or moderate (n=22; 59.5%) in severity, and 4 (10.8%) TEAEs were considered severe. A total of 19/32 (59.4%) of the participants in the treatment groups reported AEs deemed related to botaretigene sparoparvovec. Most of the participants (31/32, 96.9%) in the treatment groups reported an AE that was related to surgery, transient, and resolved without intervention. Two SAEs were identified in the immediate treatment cohort (low dose group of the dose escalation phase): 1 retinal detachment (related to surgery and resolved after surgical correction, with no sequelae) and 1 uveitis (related to botaretigene sparoparvovec).²

Twenty-five participants in the treatment cohort experienced ≥1 ocular inflammation-related TEAE (principal AE of interest), most of which were mild or moderate in severity. One participant in the dose confirmation phase (intermediate dose group) and 1 participant in the dose escalation phase (high dose group) experienced chorioretinitis and severe uveitis, respectively, both of which were either recovering or resolved at study completion. Following the implementation of a modified prophylactic corticosteroid regimen (sub-Tenon’s capsule injection of triamcinolone acetonide) in the dose expansion phase, there was a reduction in the frequency and severity of inflammation related AEs.² See Figure: Participants with Ocular Inflammation-Related AEs by Severity of AE.

Increased intraocular pressure (IOP) was reported in 16/45 participants, of which 2 events (1 in low dose group and 1 in intermediate dose group) were considered related to botaretigene sparoparvovec and 4 (2 in low dose group and 2 in intermediate dose group) were considered related to surgery. All events of increased IOP were treated medically with standard of care or observation and resolved.²

Efficacy

Functional Vision

Improvement in functional vision with botaretigene sparoparvovec in the pooled low and intermediate dose group was seen across treatment cohorts (from dose escalation and dose expansion phase), compared with control group. Nominal improvements in change in walk time in the VMA was observed at the lower lux levels. See Figure: Improvement in Walk Time at Week 26 Compared With Baseline for walk time at 1, 4, 16 and 64 lux in the pooled (low/intermediate) treatment and concurrent control cohorts, at week 26 compared to baseline. The least square (LS) mean differences between the treatment and control group on week 26 at 1, 4, 16 and 64 lux was -36.96 (95% CI, -68.10 to -5.82; nominal P=0.022), -19.48 (95% CI, -39.62 to 0.65; nominal P=0.057), -5.58 (95% CI,
-10.85 to -0.31; nominal P=0.039), and -2.16 (95% CI, -5.18 to 0.86; nominal P=0.153) seconds, respectively.²

Retinal Function

Participants treated with botaretigene sparoparvovec showed improvement in retinal functional assessment compared with the control group. The percentage of responders in point-by-point static perimetry analysis within the full (photopic) visual field at week 26 was 26.1% for the treatment group vs 20% for the control group (odds ratio: 1.41; 95% CI, 0.23-8.61; P=1.000). This further increased to 47.8% at week 52 in the treatment participants. The MRS within the central 10 degrees (excluding scotomata) showed static perimetry improvement with botaretigene sparoparvovec administration. At week 26, the LS mean difference between the treatment and control group was 1.96 dB (95% CI, 0.59-3.34; nominal P=0.006). Improvement in scotopic microperimetry MRS was also observed. At week 26, the LS mean difference between the treatment and control group was 1.06 dB (95% CI, 0.05-2.07; nominal P=0.041).²

Visual Function

The administration of botaretigene sparoparvovec showed improvements in visual function and stability in BCVA assessments.² The retinal and visual function efficacy are presented in Table: Retinal and Visual Function Efficacy Assessments.

Bleb Overlay Subanalysis

The topographically treated area of the retina (within the bleb) was assessed for functional improvement over time compared to the untreated surrounding area, measured by photopic static perimetry of all tested loci (patients in study MGT009 received 0.3-0.8 mL of botaretigene sparoparvovec subretinally at 1 of 3 doses to the worse-seeing eye in the dose-escalation phase).⁵ The location and extent of blebs were documented with intraoperative video and delineated by the operating surgeon. The hill of vision (HOV) surface was flipped 90 degrees vertically along the horizontal axis and superimposed onto the color fundus image. The visual field center grid point in the HOV map was aligned with the fovea location, and the 15-degree temporal point was aligned to the center of the optic nerve. The HOV volumes were calculated within/outside the blebs within 30-degree hill-of-vision (V30) at baseline through 6 and 12 months using fully automated custom software.⁶

Two intermediate dose patients, 005 and 007 (male; 33 and 27 years of age, respectively) were analyzed. Patient 005 received therapy in a single bleb while patient 007 received 4 blebs.⁵ At month 12 (compared to baseline), V30 in total in the treated eye improved in patient 005 (7.56 dB-sr vs 9.50 dB-sr, +25.7% improvement) and in patient 007 (9.54 dB-sr vs 10.18 dB-sr, +6.7% improvement). Within the bleb areas within V30 there were improvements in patient 005 (1.94 dB-sr vs 2.60 dB-sr, +33.8%) and patient 007 (3.85 dB-sr vs 4.06 dB-sr, +5.4%). Outside of the bleb area within V30, HOV improved in patient 005 (22.9%) and patient 007 (7.5%).⁵ Please see examples of V30 Bleb Overlay: 6 months in Patient 01-005 in the Escalation Cohort, Patient 02-022 in the Expansion Cohort, and Patient 02-028 in the Expansion Cohort.

Use in Pediatrics

Among 45 subjects treated with botaretigene sparoparvovec throughout the MGT009 study, 3 male children (aged 11, 14, and 15 years) in the pediatric dose confirmation cohort received intermediate dose, while 10 adult males in the dose escalation cohort received low (n=3), intermediate (n=4), or high (n=3) dose, and 32 adult males in the expansion cohort received either low or intermediate dose.^7,8 The Phase 3 Study MGT021 is currently ongoing with an actual enrollment of 97 male or female subjects 3 years and older. Please visit https://www.clinicaltrials.gov (identifier NCT04671433) for additional information.³

Long-Term Data

Michaelides et al (2021)⁹ reported on 10 participants from a previously performed natural history study (MGT011) of patients with XLRP that were enrolled in the dose escalation phase of MGT009. Participants included males aged 5 years and older with retinitis pigmentosa (RP) caused by disease-causing variants in RPGR and spectral domain optical coherence tomography (SD-OCT) evidence of relative preservation of retinal structure at the macula. Retinal function was assessed through 12 months post-treatment. Changes in MRS and V30 were examined up to 48 months pre-intervention (MGT011) and 12 months post-intervention (MGT009). Baseline characteristics of these 10 patients are described in Table: Baseline Characteristics of MGT011 Participants Enrolling in MGT009 (Dose Escalation Phase).

At month 12 post-intervention the safety profile of botaretigene sparoparvovec was as expected and has been previously reported. In the low and intermediate dose cohorts, 6 participants showed improvement or stability in treated-eye retinal sensitivity while no improvement was shown in the high dose cohort.

At month 12 in the intermediate dose group, the treated eye demonstrated improvements in MRS derived from Octopus perimetry, achieving levels observed ≥24 months prior to intervention based on a linear regression model. The treated eye in this dose group also showed improvements in perimetry-derived V30, achieving levels observed ≥24 months prior to intervention based on a linear regression model. In the overall group, V30 in the untreated eye decreased at a similar rate to patients in the natural history study (MGT011).

Ongoing Long-Term Data

Safety and efficacy were evaluated at various time points in the phase 1/2 Study MGT009,¹ and these subjects will be followed for up to 60 months in follow-up study MGT010 (NCT04312672).¹⁰

The phase 3 Study MGT021 the primary outcome will be measured at 52 weeks,³ and then the subjects will be followed for an additional 60 months in the longer-term follow-up study MGT022 (NCT04794101).¹¹ This study design is consistent with FDA Guidance for Industry which recommends long-term follow-up to monitor safety and evaluate durability of the clinical effect of gene therapy.^12,13

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, DERWENT^® Drug File (and/or other resources, including internal/external databases) was conducted on 21 May 2024.