Despite success in improving visual acuity, a study on CNTO-2476 was discontinued due to safety concerns.
Subretinal doses of CNTO-2476 (palucorcel) carry risk of retinal detachments and perforations due to the subretinal delivery procedure, according to a recent study.
Although the novel cell therapy, which uses human umbilical tissue derived cells, “was well-tolerated and may be associated with improvements in visual acuity” for patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD), the high percentage of adverse events (AEs) associated with the procedure led researchers to suspend the trial.
Allen C. Ho, MD (pictured), of the Wills Eye Hospital and Mid Atlantic Retina of Philadelphia, led the phase 1/2a, multicenter, open-label, dose-escalation, fellow-eye controlled study of subretinal palucorcel in 35 patients with bilateral GA and exudative neovascular (wet) AMD, who had no other ophthalmic conditions, and were suitable candidates for ophthalmological surgery. Ho and colleagues from California and Pennsylvania selected participants over 50 years of age with GA caused by AMD.
For each participant, an "intervention eye" was determined by "worse visual acuity." The worse eye in each phase of the study (1 and 2a) was screened by fundis autofluorescence (FAF) and determined to have more than 1 GA lesion with a diameter of ≥360 micrometers (median 14.26 mm2 in intervention eye), and best corrected visual acuity (BCVA) of no greater than 20/200 in phase 1 (median and 20/80 in phase 2a).
In the first phase of the study, 29 participants received a single, subretinal dose of palucorcel of either 27 μl (3.03 X 105 viable cells, given over 16 seconds), 50 μl (6.03 X 104, 1.23 X 105), or 50 μl (5.63 X 105 viable cells, given over 30 seconds) via an ab externo approach, superior to the macula adjacent to the GA lesion.
In the phase 2a portion of the study, suspended after only 4 subjects were enrolled, participants received 1 to 2 doses of palucorcel at 27 μl (3.03X105 viable cells, given over 16 seconds) or 50 μl (6.0 3 104 viable cells, given over 30 seconds) based on results from the phase 1 study. Ophthalmologic safety assessments and changes to visual acuity and function were recorded at baseline and follow-ups.
Patients receiving palucorcel injections showed significant improvementsin visual acuity. Ho and colleagues reported that BCVA at 12 months from baseline was "4.5 (-41 to 32) letters in the intervention eye and —0.5 (-30 to 15) letters) in the fellow eye," and that 30% of subjects had a gain of ≥10 letters at 3, 6, and 12-month follow ups, versus only 13% improvement in the fellow eye.
There were also significant improvements in low-luminance BCVA in the intervention eye (increase median of 5.5 letters) versus the fellow eye (increase median 0 letters) at the 12-month follow up.
Despite improvements in visual acuity, palucorcel injections carried significant risk with 97.1% of patients (n=34) experiencing more than one adverse event associated with the injection. Of 33 participants receiving subretinal palucorcel injections, 36.4% experienced retinal perforation, 30.3% experienced conjunctival hemorrhage, 15.2% experienced retinal detachment, and 15.2% experienced retinal hemorrhage.
Ho and colleagues linked these adverse events to the eye surgery in 75.8% of the patients, and the delivery system in 58% of the patients. Only 15% of the patients had adverse events related to palucorcel alone, and those may have been exacerbated by the surgery and delivery as well, according to the study. Ho and colleagues wrote that the delivery method “led to an unacceptably high rate of retinal perforations and retinal detachments."
Dr. Ho told MD Magazine that given the high percentage of AEs associated with the ab externo procedure, they are "changing the surgical procedure to reduce risk,” and have "an entirely new surgical approach that is promising."