Stem cells for dry AMD with GA show promise in early study

August 14, 2020

Subretinal transplantation of human embryonic stem cells (hESC)-derived retinal pigment epithelial (RPE) cells in patients with AMD and geographic atrophy (GA) appears well tolerated, according to date presented during ARVO 2020.

Subretinal transplantation of human embryonic stem cells (hESC)-derived retinal pigment epithelial (RPE) cells in patients with age-related macular degeneration (AMD) and geographic atrophy (GA) appears well tolerated, according to Christopher D. Riemann, MD, Cincinnati Eye Institute and University of Cincinnati.

He presented interim results of a phase I/IIa trial investigating OpRegen for the treatment of dry AMD with GA during ARVO 2020 (NCT02286089).

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OpRegen is administered as a cell suspension, initially in balanced salt solution, but now in a thaw-and-inject formulation that uses CryoStor 5.

The U.S. Food and Drug Administration has already granted OpRegen Fast-Track Designation, Dr. Riemann said.

RPE cell replacement is important, as loss of RPE cells impairs drusen clearance, leading to the development of macular degeneration and the corresponding central vision loss.

The primary objective of the phase I/IIa trial was to assess the safety and tolerability of subretinally transplanted STEM cell-derived RPE cells in patients with dry AMD and GA. The secondary objective looked at the survival of the cells and possible effects of OpRegen treatment by assessing changes in retinal structure and function.

Related: Vision-related quality of life: Impacts of advanced AMD

Study design and procedure
The trial includes four cohorts with advanced dry AMD and GA. Cohorts 1-3 include 12 legally blind patients (visual acuity, <20/200); Cohort 4, which will include patients with better visual acuity and smaller atrophy (average visual acuity, 20/125), is still recruiting, with 5 of 12 patients enrolled. (See the Table for full cohort data.)

ParameterCohortsCohort 4 (ongoing)
Subretinal Dose Delivered Cohort 1: 50K cells Cohorts 2-3: Up to 200K cellsUp to 200K cells
Surgical Approach (PPV and retinotomy or Orbit SDS)12 patients, PPV and retinotomy 3 patients, PPV and retinotomy; 2 patients, Orbit SDS
GA size – Central Reading Assessment ≥ 1.25 mm2 and ≤ 17 mm2≥ 1.25 mm2 and ≤ 17 mm2 ≥ 4 mm2 and ≤ 11 mm2
Mean GA Area12.7 mm27.9 mm2
Mean Age78.3 years74.6 years
Historical GA GrowthN/ASQRT per year of > 0.25 mm
Cataract StatusNot definedPseudophakic or phakic with Orbit SDS

Abbreviations: PPV, pars plana vitrectomy; SDS, subretinal delivery system; GA, geographic atrophy; N/A, not available; SQRT, square root.

Patients underwent short-course, perioperative systemic immunosuppression prior to the procedure.

The eyes with worse vision were implanted with 50,000 to 200,000 OpRegen cells subretinally in suspension either through a standard pars plana vitrectomy and retinotomy approach or using the Gyroscope Therapeutics Orbit Subretinal Delivery System.

“The Orbit Subretinal Delivery System is a new surgical procedure using novel instrumentation,” Dr. Riemann said. “A sclerotomy is created, a special cannula is placed tangentially into the suprachoroidal space and advanced posteriorly toward the target area in the macula, adjacent to the geographic atrophy.”

Related: Intraoperative surgical methods hold key to AMD treatment

Once the target area is reached, “a screw drive advances a needle through the choroid into the subretinal space” and a leading balanced salt solution subretinal bleb is created, Dr. Riemann explained. “Once we confirm a subretinal bleb, we turn a valve and switch from balanced salt solution to cells, and deliver the OpRegen into the subretinal space. The subretinal injection is accomplished without a vitrectomy or retinotomy.”

Efficacy results
Patients in Cohorts 1-3 had no marked, sustained reductions in visual acuity.

The 5 patients in Cohort 4, however, had improved vision up to the 1-year follow-up period, including one patient who experienced a 10-letter gain that was sustained for 15 months.

“Improvements in drusen retinal outer layers and retinal pigment epithelium within the area of OpRegen transplant were observed and have persisted in some patients,” Dr. Riemann said. “Asymmetrical progression of geographic atrophy in the treated areas has been observed. The change in the total area is trending toward slower growth in treated versus fellow eyes. Better visual acuity and improved reading speed has been observed in some early cohort patients and all Cohort 4 patients after OpRegen.”

Related: ASRS 2020: PDS with ranibizumab signals paradigm shift in treatment of neovascular AMD

Adverse events
There were no reports of acute or delayed inflammation or increases in interocular pressure, but all patients reported at least one adverse event. For systemic adverse events, asthenia and malaise were reported by four patients.

“Subretinal pigmentation was common and presented in 11 out of 17 patients,” Dr. Riemann said. “While the significance of this remains unclear, we feel as if it may represent a potentially positive finding as evidence of long-term survival of the subretinally transplanted OpRegen cells.”

Of note, in patients operated with the vitrectomy and retinotomy approach, one patient had a retinal detachment (successfully repaired) and 13 of 15 patients developed or experienced an exacerbation of an existing epiretinal membrane, one of which resulted in a temporary reduction in vision and required a vitrectomy, after which vision was restored.

Related: Stem cell transplantation: Restoring vision in AMD may be possible

“While visual acuity improved after the peeling, the need for the vitrectomy to remove the epiretinal membrane is important,” Dr. Riemann said. “Though the cause of these epiretinal membranes remains unclear, we felt as if a possible etiology may have been migration of the OpRegen cells through the retinotomy in the vitreous cavity post-transplantation, and this was an important underlying reason for us to explore the Orbit Subretinal Delivery System for transplantation of the OpRegen cells without a vitrectomy or retinotomy.”

Neither of the two cohort 4 patients operated with the Orbit Subretinal Delivery System have developed epiretinal membrane, macular pucker, lamellar hole, retinoschisis, or retinal detachment.

However, patients in the Orbit Subretinal Delivery System group developed small, asymptomatic subretinal hemorrhages that resolved on their own. The significance of that adverse event is unknown.

Recruitment for Cohort 4 is ongoing, he said.

Read more by Michelle Dalton