During the 2019 American Academy of Ophthalmology Retina Subspecialty Day program in San Francisco, California, Pravin Dugel, MD, presented data from the Reneuron phase 1/2a study on retinitis pigmentosa. The study investigated Reneuron’s human retinal progenitor cell (hRPC) cells for the treatment of retinitis pigmentosa. Retinal Physician asked retina specialists to weigh in on the data, and for a representative of the company to respond.

Jordi Monés, MD, PHD Institut de la Màcula, Barcelona, Spain

The data presented so far have been quite intriguing, although, like many open-label studies, not entirely consistent. There have been 3 subjects that have demonstrated a rapid and profound increase in their ETDRS visual acuity (mean 25 letters, range 12-37 letters) and this response has been maintained for at least 6 months. There have been 5 subjects that have experienced a more gradual and moderate improvement in ETDRS visual acuity (mean 5.8 letters, range 2-11 letters), which has also been sustained. Finally, 2 subjects experienced loss of vision; however, this was secondary to surgical complications, which are known to occur in patients in the population who undergo subretinal injection.

The take-home point is that there have been clinically significant improvements in visual acuity that have occurred in a patient population for which there are currently no known treatments, and for which the slow and inevitable loss of vision is the norm. There has been no drug-related toxicity at the 1 million cell dose. I look forward to seeing further data, as there is definitely a signal. I suggest that better defining the patient population and increasing the dose may help clarify the efficacy signal.

Michael Singer, MD Medical Center Ophthalmology Associates, San Antonio, Texas

The hRPC cells studied in the Reneuron phase 1/2a trial are isolated from fetal retina and have the ability to differentiate into retinal cells. The advantage of these cells is that they are cryopreserved, so they are able to have a 9-month shelf life and, unlike for other stem cell therapies, no immunosuppression is required. The mechanism of action involves their physical integration into the retina as well as their innate paracrine effects. These cells are injected directly into the subretinal space via pars plana vitrectomy. Interestingly, unlike other therapies, these cells are agnostic to genetic subtype or disease.

The phase 1 study tested multiple doses of the hRPC cells ranging from 250,000 to 1 million to assess safety and maximum tolerated dosage level. The phase 1 study was performed on 12 patients at 1 clinical site by Jason Comander, MD, PhD, at Massachusetts Eye and Ear in Boston, Massachusetts. In this phase 1 study, the visual acuity ranged from light perception to 20/800. As a result of the first study, a phase 2a study tested the highest dose, 1 million cells, in 10 additional patients at 2 sites (Dr. Comander at Massachusetts Eye and Ear and Pravin U. Dugel, MD, at Retina Research Institute in Phoenix, Arizona). Visual acuity for the phase 2a study ranged from 20/640 to 20/80. The primary endpoint of the phase 2a study is the change in EDTRS letters from baseline to 24 months. The patient are being examined at interim visits: 1, 2, 3, 6, 9, 12, and 18 months. The cells are being delivered into the subretinal space via a pars plana vitrectomy similar to the phase 1 study.

The data presented at the meeting were the phase 1/2a safety data and early efficacy data (Table 1). In terms of safety, 22 patients were dosed in both studies. All doses were generally well tolerated, with dose escalation to 1 million cells. There was no evidence of inflammation or proliferative vitreoretinopathy. There were 2 ocular serious adverse events unrelated to the rHPC cells on 2 subjects. The first subject had progression of a preexisting epiretinal membrane. The other subject had persistent subretinal fluid secondary to the surgical retinotomy. There were 2 events leading to vision loss: one patient experienced retinal pigment epithelium tear, and the other patient (mentioned above) had persistent fluid secondary to the retinotomy. In terms of visual acuity, 6 of 8 patients had some improvements in visual acuity at 90 days with a mean change from 13 letters to 17.8 letters in those who improved. The visual improvement in some patients was very rapid and profound, and in others it was slower. The study is still ongoing.

I believe this therapy is very intriguing. The fact that it is disease agnostic means it will have more versatility to treat a larger number of patients in a typical retinal physician’s practice. In addition, because the cells are cryopreserved and not fresh, they will be much more adaptable to different types of surgical situations including both hospital based and ambulatory surgical centers. The fact that immunosuppression is not required increases the pool of possible patients who can be treated. Although the data are preliminary and the study is ongoing, it is encouraging that patients with debilitating visual prognosis might have hope for some visual restoration and increasing quality of life.

Yoshihiro Yonekawa, MD Mid Atlantic Retina, Wills Eye Hospital, Philadelphia, Pennsylvania

Cell and gene therapy are “hot” topics in our field, and both treatment paradigms bring hope for previously untreatable retinal diseases. Between the 2 modalities, gene therapies overall have made more advancements toward later stage trials and regulatory approvals. Whether it’s via gene replacement therapy for rare genetic malfunctions or production of therapeutic proteins for more common diseases, genetic manipulation has made positive headlines.

Cell therapies take a different approach, where they aim to treat or prevent the common late-stage atrophic/degenerative state of various retinal diseases, and therefore hopefully will be able to help a broader patient population. That’s what’s really exciting about cell therapy. However, we don’t fully understand yet whether, and how, stem cells will help degenerating photoreceptors — whether by regeneration, secretion of neuroprotective factors, or other mechanisms.

Unlike gene therapies, cell therapy has not yet advanced past early clinical trials. So how is Reneuron’s phase 1/2a trial different from previously failed stem-cell studies? One important distinction is that the study uses retinal progenitor cells isolated from fetal retina, which may more likely differentiate into appropriate outer retinal architecture than pluripotent stem cells. That the cells have a 9-month shelf life is also attractive.

I think we need to pay attention to Reneuron’s study results. Treatment overall resulted in improved vision, and this is exciting. However, there are factors we should keep in mind:

1. Most patients also improved vision in their untreated eye (not as much as the treated eye), especially the 2 patients with the highest gains in the treated eye. It would be great to characterize what was unique about these 2 patients, and what the visual acuity curves would look like without these 2 possible outliers.
2. (On the other end of the spectrum, 2 patients lost vision, apparently from surgery-related complications: 1 from an RPE tear, and 1 with persistent subretinal fluid and patent retinotomy. Subretinal bleb formation is relatively challenging in eyes with diffuse atrophy and pigmentary degeneration, so there will always be some risk associated with the surgery. Nevertheless, we should continue to optimize this surgical technique.
3. Remember that these are preliminary results, and the readout of short-term outcomes is still pending. But overall it looks like the cells are safe to deliver into the subretinal space.

I look forward to the finalized data, which are expected this year. More granular structural and functional data will give us more information also.

Richard L. Beckman, MD Chief Medical Officer, Reneuron

We at Reneuron are very excited regarding the signal of efficacy that we have seen in this patient population, for whom the vast majority have no available treatment, and who are losing vision in the prime of their lives. We look forward to the accrual of additional data from current clinical trial subjects and to the next group of patients who will undergo treatment in the near future. RP