Interim safety and clinical activity data from the Phase 1/2 clinical trial of intravitreal 4D-125 in patients with advanced X-linked retinitis pigmentosa (XLRP) was presented in a late-breaking presentation at the American Society of Retina Specialists (ASRS) 39th Annual Meeting.
The data described are from the first-in-human, on-going Phase 1/2 dose escalation and dose expansion clinical trial assessing intravitreal 4D-125, 4DMT’s targeted and evolved R100-based product candidate for XLRP. As of the data cutoff date (September 1, 2021), eight patients with clinically advanced XLRP due to RPGR gene mutation had been enrolled. A standard 3+3 dose escalation design was used, followed by a dose expansion cohort. Patients were enrolled in one of three dose cohorts: dose-escalation cohort 1 (3E11 vg/eye; n=3), dose-escalation cohort 2 (1E12 vg/eye n=3) and the dose expansion cohort (1E12vg/eye; n=2 to date). Patients enrolled in the dose escalation cohorts of the first-in-human clinical trial had clinically-advanced XLRP, with patients having limited or no measurable remaining photoreceptor area or retinal sensitivity. As of the data cutoff date, two dose escalation patients (n=1 at 3E11 vg/eye; n=1 at 1E12 vg/eye) were evaluable for clinical activity defined as having both measurable ellipsoid-zone area (EZ Area) by spectral domain optical coherence tomography (SD-OCT) and retinal sensitivity by microperimetry in both the treated and untreated control eye with at least six months follow-up; dose expansion cohort patients (n=2) had not yet reached six months follow-up but are expected to be evaluable with sufficient follow up. On-going enrollment in the dose expansion cohort is expected to enroll patients with less advanced disease than those enrolled in dose escalation, and who we expect to be evaluable for clinical activity based on central reading center confirmation at screening.
Interim Safety Data Summary
- 4D-125 was well-tolerated in all eight XLRP patients, including in five patients at the top dose level of 1E12 vg/eye.
- No dose-limiting toxicities or serious adverse events were observed.
- No chronic inflammation was observed.
- Transient, grade 1+ anterior chamber and/or vitreous cells were observed in two of the eight patients at a single protocol-defined assessment timepoint (SUN1 & NEI2 grading scales)
- One patient had grade 1+ vitreous and anterior chamber cells
- One additional patient had grade 1+ vitreous chamber cells
Interim Clinical Activity Summary
In the two dose escalation patients who were evaluable for clinical activity in both the treated and untreated control eyes, interim data from both patients demonstrated anatomical retina preservation as measured by EZ Area progression, a measurement of intact photoreceptors, in the treated eye as compared to the untreated control eye in the same patient. In addition, interim data from both patients demonstrated functional improvements as measured by increases in the mean retinal sensitivity in the treated eye, and a greater number of loci gaining ≥ 7 dB sensitivity in the treated eye, as compared to the untreated control eye in the same patient.
Patient 3 (3E11 vg/eye cohort – 9 months follow-up): Decreases from baseline EZ Area were -12.4% in the treated eye compared to -16.2% in the untreated control eye (~23% lower relative progression rate). An increase in mean retinal sensitivity was demonstrated, with an increase of +1.65 dB in the treated eye from baseline compared to +0.25 dB in the untreated control eye. The number of loci gaining greater than ≥ 7 dB sensitivity were six in the treated eye compared to one in the untreated control eye.
Patient 5 (1E12 vg/eye cohort – 6 months follow-up): Decreases from baseline EZ Area were -20.2% in the treated eye compared to -28.7% in the untreated control eye (~30% lower relative progression rate). An increase in mean retinal sensitivity was demonstrated, with an increase of +0.90 dB in the treated eye from baseline compared to +0.10* dB in the untreated control eye. The number of loci gaining greater than ≥ 7 dB sensitivity were three in the treated eye compared to zero in the untreated control eye.
*note: microperimetry data for this patient’s untreated eye were evaluable at 4 months but not available at month 6 due to an inability to fixate with the untreated control eye at that visit.
1. Standardization of Uveitis Nomenclature Grading Scheme – SUN Working Group 2005 (Jabs et al., 2005)
2. National Eye Institute Grading System for Vitreous Cells – (Mahendradas, Khanna, Kawali, & Shetty, 2014)
