SUMMARY

• JNJ-1887 (JNJ-81201887; AAVCAGsCD59) is an investigational, recombinant adeno-associated viral vector (AAV) gene therapy being studied for the treatment of geographic atrophy (GA) and wet age-related macular degeneration (AMD).^1-3
• Study 1001^3-5 was a 24-month, open-label, single-center, phase 1 clinical trial (N=17) that evaluated the safety and tolerability of a single injection of JNJ-1887 in patients with GA. There were 6 events of mild ocular inflammation reported in 5 out of 17 (29.4%) patients. There was 1 unresolved event of vitritis which was managed with observation and the examination findings of ocular inflammation were resolved at the last assessment visit; the patient experienced unrelated fatal adverse event (AE) of leukemia. Two patients experienced increased intraocular pressure (IOP) associated with events of intraocular inflammation which were mild in severity and unrelated to the treatment. Two patients experienced optic nerve disorders (increase in cup-to-disc ratio) in both the eyes which were unresolved at the end of the study (not related to study treatment in 1 patient and was possibly related to study treatment in 1 patient).¹
• Study 1002 was a 24-month, open-label, multicenter, phase 1 clinical trial (N=25) that evaluated the efficacy and safety of a single intravitreal injection of JNJ-1887 in treatment naïve patients with wet AMD. There were 6 events of mild (n=4) or moderate (n=2) severity of ocular inflammation reported in 4 out of 25 (16%) patients, and all events resolved following a course of oral and topical steroids.³
• There were no dose-limiting toxicities, serious or systemic AEs, or fatal AEs related to study intervention in study 1001 or study 1002.^1,3

BACKGROUND

JNJ-1887, an investigational, recombinant AAV (AAVCAGsCD59) serotype 2 that expresses soluble cluster of differentiation (CD)59, is being studied for the treatment of GA and wet AMD. Soluble CD59 (sCD59), an endogenous protein that inhibits the formation of membrane attack complex (MAC), is intended to protect retinal cells to slow and prevent disease progression via a single, in-office intravitreal injection. Accumulation of MAC on cell surfaces, including drusen, leads to cell damage and cell death. Inhibition of MAC formation is hypothesized to protect retinal cells that are responsible for central vision and preserve functional vision.^2-5

CLINICAL DATA

Phase 1 Study 1001

Study Design

Study 1001^3-5 was a phase 1, single-center, open-label, first-in-human study to assess the safety and tolerability of JNJ-1887 in patients with GA over 24 months.¹ Please visit https://www.clinicaltrials.gov (identifier NCT03144999) for additional information.⁴

Patients (N=17) were sequentially enrolled to receive low (cohort 1 [n=3] , 3.56x10¹⁰ vg), intermediate (cohort 2 [n=3], 1.071x10¹¹ vg) or high (cohort 3 [n=11], 3.56x10¹¹ vg) doses of JNJ-1887 as intravitreal injections to a single eye, without any corticosteroid prophylaxis.¹

The duration of the main study was 26 weeks, the enrollment and treatment administration were 1 day, the safety observation period was 2 weeks, and the extended safety follow-up period was 18 months.¹

Inclusion and Exclusion Criteria

Key inclusion criteria:¹

• Adult patients (aged ≥50 years) with GA secondary to dry AMD
• Study eye with:
  • Best corrected visual acuity (BCVA) of 35 letters or worse (Snellen equivalent of ≤20/200) measured by Early Treatment Diabetic Retinopathy Study (ETDRS) charts at a distance of 4 meters for the first 3 enrolled patients
  • After enrollment of the first 3 patients (low dose cohort), the study eye had to have a BCVA of 55 letters or worse (Snellen equivalent of ≤20/80) and demonstrate favorable safety data
  • Total GA lesion size between 5 mm² and 20 mm² (approximately 2-8 disc areas); if multifocal, then at least 1 focus of GA needs to measure 1.27 mm² (0.5 disc areas)
• The fellow or non-treated eye with BCVA of ≥20/800
• If both the eyes were eligible, the eye with worse visual acuity was treated

Key exclusion criteria:¹

• GA secondary to non-AMD etiologies
• Ongoing inflammation in either eye
• Active or uncontrolled glaucoma
• Study eye with:
  • Prior or active choroidal neovascularization (CNV)
  • History of (<3 months from enrollment) or likely to undergo intraocular surgery
  • Acute or chronic infection
  • History of inflammation
  • History of uveitis

Primary and Secondary Endpoints

The primary objectives were safety and tolerability of JNJ-1887, which included assessment of ocular and non-ocular treatment-emergent adverse events (TEAEs) over 24 months. The ocular and non-ocular TEAEs included:¹

• AEs
• Serious adverse events (SAEs)
• AEs leading to study discontinuation
• AEs by severity graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v4.0
• AEs by causality to JNJ-1887
• Death

Secondary objectives:¹

• Change in area and rate of growth of GA lesions in eyes with dry AMD
• Incidence of conversion of dry AMD to wet AMD

Results

Demographics

A total of 17 patients received JNJ-1887 and were included in the safety analysis set, of which 16 (94.1%) patients completed 2 years of follow up. The demographics and baseline ocular characteristics of the patients enrolled were balanced across the cohorts and were consistent with the GA population. See Table: Demographics and Ocular Baseline Characteristics of the Study Eye (Study 1001). All patients enrolled in the study had foveal center-involved GA, and no CNV was noted in the treated eye. In the treated eye, the mean (standard deviation [SD]) visual acuity was 37.3 (13.8) ETDRS letters and the mean (SD) IOP at baseline was 13.8 (3.1) mmHg. Mean (SD; range) baseline GA lesion size in the treated eye was 11.1 (4.2; 5.5-19.5) mm² and was similar across the 3 cohorts.¹

Safety

There were no dose-limiting AEs in any cohort. There were no serious, systemic, or fatal AEs related to JNJ-1887, and no related AEs led to study discontinuation. See Tables: Summary of Systemic TEAEs Over 2 Years (Study 1001) and Summary of Study Eye Ocular TEAEs Over 2 Years (Study 1001).¹

A total of 13 (76.5%) patients experienced ocular TEAEs, which were balanced across all cohorts; none were SAEs or led to study discontinuation. There were 6 events of mild ocular inflammation related to JNJ-1887 in 5 (29.4%) patients, which resolved in 4 patients by the end of the study with either topical steroids (n=2) or observation (n=2). The ocular inflammation did not recur through 2 years of follow-up in these patients. Topical steroids were used in 2 patients (1 with an AE of anterior chamber inflammation [cohort 2] and 1 with vitritis [cohort 3]), at the investigators’ discretions. No patients required oral corticosteroids to manage inflammation. There was 1 unresolved event of vitritis which was managed with observation and the examination findings of ocular inflammation were resolved at the last assessment visit; the patient experienced unrelated fatal AE of leukemia. Two patients experienced increased IOP associated with events of intraocular inflammation (onset at days 28 [cohort 2] and 34 [cohort 3]), which were mild in severity and deemed unrelated to the treatment by the investigator. Both events resolved (1 required IOP lowering drops) and IOP returned to baseline in both patients. Two patients experienced optic nerve disorders (increase in cup-to-disc ratio) in both the eyes, and they were unresolved at the end of the study (not related to study treatment in 1 patient [cohort 2] and was possibly related to study treatment in 1 patient [cohort 3]). Visual acuity was reduced in 3 (17.6%) patients from cohort 3; all were unrelated to study treatment. Two of the 3 patients had resolution with vision at or near baseline at the end of the study. None of the patients had occlusive or non-occlusive retinal vasculitis, endophthalmitis, or new onset of CNV in any treated eye. Over 24 months, there was no difference in the ganglion cell layer in the treated eye, compared to the fellow eye.¹

Rate of Geographic Atrophy Lesion Growth

Among all the dosing cohorts, the GA lesion growth from baseline was similar. In the high dose cohort (cohort 3), GA lesion growth rate continued to decrease in each 6 months interval up to 24 months (final measurement).¹ See figures: Change from Baseline in GA Lesion Area and GA Lesion Growth Rate Over Time for Cohort 3.

Phase 1 Study 1002

Study Design

Study 1002 was a multicenter, open-label, phase 1 clinical study conducted to evaluate the safety and tolerability of a single intravitreal injection of JNJ-1887 in treatment naïve patients with wet AMD over 24 months.³ Please visit https://www.clinicaltrials.gov (identifier NCT03585556) for additional information.²

Patients (N=25) received a single baseline anti-vascular endothelial growth factor (anti-VEGF) injection (bevacizumab 1.25 mg, ranibizumab 5 mg, or aflibercept 2 mg) on day 1 followed by a single intravitreal injection of JNJ-1887 at a low (3.56x10¹¹ vg/eye, n=22) or high (1.071x10¹² vg/eye, n=3) dose 7 days later, along with an oral corticosteroid prophylaxis regimen started on day 30 of the study. The corticosteroid prophylaxis regimen consisted of a 7 day taper of prednisone 40 mg for 2 days, 30 mg for 2 days, 20 mg for 2 days and 10 mg for 1 day.³ All eyes were treated with intravitreal anti-VEGF monthly as needed based on disease activity.²

Inclusion and Exclusion Criteria

Key inclusion criteria included:³

• Diagnosed with wet AMD with CNV with presence of intraretinal and/or subretinal fluid on optical coherence tomography (OCT), with no evidence of subretinal fibrosis under the fovea (2 patients were enrolled with extrafoveal subretinal fibrosis at baseline)
• Treatment naïve
• BCVA Snellen equivalent between 20/25 to 20/400 in the study eye, as measured by ETDRS charts

Key exclusion criteria included:³

• CNV secondary to non-AMD etiologies
• Subretinal hemorrhage that interfered with the ability to adequately measure visual acuity or follow retinal or subretinal fluid collection on OCT
• Serious pigment epithelial detachment that was >50% of the CNV lesion
• Presence of a retinal pigment epithelial tear, previous macular laser photocoagulation for CNV, photodynamic therapy, ocular radiation, or subretinal surgery for CNV in the study eye

Primary and Secondary Endpoints

The primary objective was the number of intravitreal anti-VEGF injections from month 1 through month 12 following intravitreal injection of JNJ-1887 at day 7.²

The secondary objectives were number of patients with:²

• Change in vision of ≥15 letters measured at 12 months
• Inflammation, endophthalmitis, IOP>30, retinal detachment, cataract, and systemic AEs measured at 24 months

Results

Demographics

See table: Demographics and Ocular Baseline Characteristics of the Study Eye (Study 1002) for breakdown of patient demographics and breakdown of ocular baseline characteristics of the study eye. Ocular concomitant medications were administered in 24/25 (96%) patients, with anti-VEGF injections being the most administered.³

Safety

There were no dose-limiting toxicities or serious or systemic AEs, and no fatal AEs related to JNJ-1887.³ Please see tables: Summary of Systemic Treatment-emergent AEs (Study 1002) and Summary of Study Eye Ocular AEs (Study 1002).

Eleven out of 25 (45%) patients had a total of 20 study eye ocular AEs; none were considered serious. Four out of 25 (16%) patients experienced 6 events of ocular inflammation, 4 mild events and 2 moderate events, all of which resolved following a 7 day oral steroid taper and varied duration of topical steroids. Two patients experienced singular events of reduced visual acuity which were both considered mild in severity and unrelated to study treatment; 1 event resolved and 1 event was ongoing at the end of the study. Two patients had subretinal fibrosis which were both mild in severity; 1 event was resolved and 1 event was ongoing at the end of the study. One serious incidence of acute kidney injury after a fall was reported in the low dose cohort and was unrelated to the study treatment.³ Please see table: Summary of Study Eye Ocular AEs of Interest in the Wet AMD Study (Study 1002).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 27 March 2024.