While many of us were in quarantine, the annual ARVO 2020 meeting delivered some exciting news as promised. Christopher Riemann, MD, delivered results from Lineage Cell Therapeutics’ phase 1/2 study evaluating stem cell-derived retinal pigment epithelium (RPE) transplantation into the subretinal space for patients with advanced geographic atrophy (GA). The study design is interesting because it looks at different doses of transplanted cells and 2 different techniques of cell delivery into the subretinal space. We asked Roger Goldberg, MD, MBA, and Chirag Shah, MD, to weigh in on the study findings. Also, unique to allogenic transplants (and something retinal specialists don’t frequently consider), immune suppression becomes important to prevent rejection. We asked Dr. Riemann to discuss the immune suppression regimen in this study, requisite duration of suppression, and possible alternative options. Finally, we are privileged to have the CEO of Lineage Cell Therapeutics comment on future directions as the company embarks on a multicenter clinical trial.

Roger A. Goldberg, MD, MBA
Bay Area Retina Associates

Geographic atrophy, with its concomitant loss of RPE and overlying photoreceptors, would appear to be a disease tailor-made for regenerative medicine approaches to treatment. If the RPE could be replaced or regenerated, perhaps we could not only stop or slow down the progression of this relentless disease, but also reverse the vision loss that comes with it. Enter Lineage Cell Therapeutics, which recently reported updated interim phase 1/2 results from its human embryonic stem cell-derived RPE (which the company calls “OpRegen”) in patients with advanced GA.

As with any early stage investigation, the primary results are focused on safety. It was a dynamic trial design that requires a little explanation: The first 12 patients were 20/200 or worse, and were treated with traditional pars plana vitrectomy, with injection of the stem cell-derived RPE cells through a retinotomy into the subretinal space. The next 5 patients had less advanced disease, and all received a freeze-thaw version of the cells; 3 had the cells delivered by vitrectomy and transretinal bleb, while 2 patients had the Orbit subretinal delivery system, which uses a specialized cannula advanced through a sclerotomy and the suprachoroidal space, and then delivers the cells transchoroidally into the subretinal space.

Why strive to avoid a vitrectomy and retinotomy? Well, 13 of the 15 patients treated with the transretinal approach developed epiretinal membranes (one was deemed to be severe), and 1 patient developed a retinal detachment. This is consistent with reports of other types of stem cell-derived cells being injected into the eye. These complications were avoided in the 2 patients treated with the SDS system, though they did develop small subretinal hemorrhages at the choroidal puncture site, which resolved without treatment. Importantly, the cells themselves seem to be safe once in the appropriate location, and they seem to persist for a long time.

The company reported some early indications of efficacy, but it is too early to tell how functional these cells are, or how they might be functioning (eg, as true replacement cells, or in a paracrine fashion to support adjacent sick but not dying RPE and photoreceptor cells). Importantly, one patient reportedly had reversal of an area of GA with restoration of outer retinal structures on multimodal imaging. Certainly, the early results are encouraging, and larger studies with more patients are warranted to better understand the surgical approach, the optimal patient selection, and the safety and possible efficacy of this technology.

Chirag Shah, MD
Ophthalmic Consultants of Boston

The OpRegen phase 1/2a trial is currently evaluating human embryonic stem cell-derived RPE transplantation for atrophic AMD. Keep in mind that phase 1/2a studies are designed to evaluate the safety, tolerability, and appropriate dose of a drug. Though the sample size is small, such studies can also suggest some degree of effectiveness, helping to justify progression to a larger phase 2b trial designed specifically to assess efficacy. It is human nature to attribute too much credibility to the efficacy observed in phase 1/2a, even though the great majority of such trials evaluate drugs that will not come to market.

At ARVO 2020, researchers released preliminary data on the first 17 patients enrolled in the OpRegen study, including 12 patients in cohorts 1-3, and 4 patients in cohort 5. Cohort 1 had 50,000 cells transplanted, compared to 200,000 cells for cohorts 2 to 4. All patients were immunosuppressed with tacrolimus and mycophenolate 1 week before and 6 weeks or 3 months, respectively, after transplantation. The surgical transplantation technique involved vitrectomy with subretinal injection of stem cells through a retinotomy, creating a subretinal bleb adjacent to macular atrophy. Two of the 5 patients in cohort 4 had implantation via suprachoroidal delivery utilizing the Orbit SDS device; no vitrectomy or retinotomy was performed in these patients.

Every patient had at least 1 adverse event, although most of these were mild. One of 17 developed a retinal detachment, but none had PVR or significant inflammation, as described in prior stem cell transplantation trials. Thirteen patients did develop an epiretinal membrane. Both patients undergoing suprachoroidal delivery developed subretinal hemorrhage, though they were asymptomatic with spontaneous resolution.

In terms of efficacy, and again take these results with a grain of salt, there was suggestion of treatment effect. The patients in cohorts 1 to 3 did not lose vision, while all 5 patients in cohort 4 noted visual improvement. There was reduction of drusen within the area of the OpRegen transplant bleb, improved reading speed, and asymmetric progression of atrophy, with less progression toward the transplanted cells.

In summary, subretinal stem cell-derived RPE transplantation with the OpRegen product appears to have a reasonable safety profile with some suggestion of efficacy in this small cohort. We still have to wait for complete enrollment and completion of this phase 1/2a study before researchers can decide to proceed with a phase 2b study.

In my opinion, although treatment for atrophic AMD is badly needed, there will be challenges if patients require immunosuppression, given our present pandemic and the other health concerns of this older patient population. Further, some retinal specialists might not have enough operating room access to effectively serve their populations, and may need to think creatively and/or build their own surgical centers. Nonetheless, an effective treatment for atrophic AMD is desperately needed and the OpRegen drug is one of many that gives us hope.

Christopher Riemann, MD
Co-principal investigator, Lineage Cell Therapeutics

All allogeneic cell therapies have a potential risk of immune rejection. However, given the unique immune privilege of the eye, the need for immunosuppression is likely far less than that required for more conventional tissue or organ transplants. The current use of immunosuppression regimens are likely due, in part, to previous and outdated knowledge employed in earlier cell therapy studies. To Dr. Shah’s point, it is undoubtedly in the best interest of our patients to limit exposure and duration of immunosuppression, pandemic notwithstanding. We currently use systemic (PO) tacrolimus (0.01 mg/kg daily, adjusted to reach a circulating concentration of 3-7 ng/mL), mycophenolate mofetil (PO) (up to 2 g daily), and a course of topical steroid therapy (prednisolone 1% or dexamethasone 0.1% drops 4-8 times daily, with gradual taper) over the course of up to 6 weeks, all of which can be discontinued at the discretion of the treating physician. It is the belief of many that ultimately some form of perioperative dexamethasone intravitreal implants, or equivalent, may be sufficient to mitigate the risk of rejection while limiting risk to patients. If systemic immunosuppression does prove essential to transplanted cell survival, it should be for as short a duration as possible and at the lowest dose required.

Brian Culley
CEO, Lineage Cell Therapeutics

As Drs. Goldberg and Shah correctly noted, numerous products show early signals of efficacy yet do not reach later-stage trials. However, we are encouraged by the preliminary data from the OpRegen clinical trial and plan to begin enrolling patients next year in a larger, multicenter comparative trial. OpRegen appears to be well tolerated and, in addition to early suggestions of efficacy described elsewhere, a recently reported case study of retinal tissue restoration leading to a reduced area of GA at 9 months is exciting and worthy of substantial further study and peer review. We look forward to receiving data from additional patients, particularly those with better baseline vision and smaller areas of GA, as well as developing additional experience with delivering RPE cell via a new subretinal delivery device. RP