Stem Cells in Ophthalmology Update 27: ACT Interim Clinical Results Are Outstanding

Having treated 36 patients in two clinical trials for Stargardt’s Macular Dystrophy (SMD - 24 patients to date) and for dry Age-Related Macular Degeneration (AMD - 12 patients to date), Advanced Cell Technology reported the interim results obtained with 18 of these patients (9 in each trial) in the US-based studies. Both trials (NCT01345006 - Stargardt’s, and NCT01344993 - AMD) began in July 2011, giving the company up to three-year’s data for the earliest patients, and a median of 22 months followup for all. The interim results were reported in The Lancet, published online October 14, 2014 in: “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies”.

An additional Stargardt’s trial, being conducted at two clinics in the United Kingdom, with 12 patients enrolled (NCT01469832), along with 3 of the 4 patients treated in each of two trials with better vision candidates, as part of the two clinical trials in the publication (Phase IIa), were not included in The Lancet results.

As noted by Paul K. Wotton, Ph.D., President and Chief Executive Officer of Advanced Cell Technology, "These study results represent an important milestone and strengthen our leadership position in regenerative ophthalmology. We would like to thank the patients for their willingness to participate in these studies. Our findings underscore the potential to repair or replace tissues damaged from diseases. We plan to initiate comprehensive Phase 2 clinical trials for the treatment of both AMD and SMD, two disease states where there is currently no effective treatment."

Editors Note: As announced on October 15th by the company, the Phase II dry AMD clinical trial (50 Patients) will start during the 1st Half of 2015 and is expected to be completed in the middle of 2016, taking place at 10 Trial Sites across North America. The Phase II SMD clinical trial (100 patients) will start during the 4th Quarter of this year or by the end of the year. It will take 18-24 months to complete, taking place at 30 sites across North America and Europe.

Robert Lanza, M.D., Chief Scientific Officer of ACT and co-senior author of the paper, commented, "Diseases affecting the eye are attractive first-in-man applications for this type of investigational therapy due to the immune-privileged nature of the eye. Despite the degenerative nature of these diseases, the vision of 10 of 18 patients showed measurable improvement at the six month follow up, after transplantation of the RPE cells. Furthermore, the cells have been well tolerated for a median period of 22 months with two of the patients treated more than three years ago. We are pleased that there have been no serious safety issues attributable to the cells observed in any of the patients."

Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute, principal investigator and co-lead author of the publication said, "The data published in The Lancet support the potential safety and biological activity of stem cell-derived retinal tissue. Once again, surgical access to the subretinal space has proven safe. However, for the first time in humans, terminally differentiated stem cell progeny seem to survive, and do so without safety signals. Combined with the functional signals observed, these data suggest that this regenerative strategy should move forward. This is a hopeful and exciting time for ophthalmology and regenerative medicine."

These two studies provide the first evidence of the mid- to long-term safety, survival, and potential biologic activity of pluripotent stem cell progeny into humans with any disease. In addition to showing no adverse safety issues related to the transplanted tissue, anatomic evidence confirmed successful engraftment of the RPE cells, which included increased pigmentation at the level of the RPE layer after transplantation in 13 of 18 patients.

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. Thirteen (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt’s macular dystrophy.

Figure 3: Change from baseline in best-corrected visual acuity in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B) Median change in best-corrected visual acuity was expressed as number of letters read on the Early Treatment of Diabetic Retinopathy Study visual acuity chart in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B). Red lines show treated eyes and blue lines show untreated eyes of patients during the first year after transplantation of the cells derived from human embryonic stem cells. Green lines show the difference between the treated and untreated eyes. Patients who underwent cataract surgery after transplantation are not included in the graph. There was a significant difference in the letters read in transplanted eyes of patients with age-related macular degeneration versus non-transplanted controls at 12 months (median 14 letters vs –1 letter; p=0·0117). There was an increase in letters read in transplanted eyes of patients with Stargardt’s macular dystrophy versus non-transplanted controls at 12 months (median 12 letters vs two letters, although the sample size was too small to allow reliable calculation of the Wilcoxon signed-rank test).

The SMD and dry AMD trials are prospective, open-label studies designed to evaluate the safety and tolerability of human embryonic stem cell (hESC)-derived RPE cells following sub-retinal transplantation into patients at 12 months, the studies' primary endpoint. Three dose cohorts were treated for each condition in an ascending dosage format (50,000 cells, 100,000 cells, and 150,000 cells). Both the SMD and dry AMD patients had subretinal transplantation of fully-differentiated RPE cells derived from hESCs.

Dr. Anthony Atala, a surgeon and director of the Wake Forest Institute for Regenerative Medicine at Wake Forest University in an accompanying commentary in The Lancet said:

"It really does show for the very first time that patients can, in fact, benefit from the therapy.

That allows you to say, 'OK, now that these cells have been used for patients who have blindness, maybe we can also use these cells for many other conditions as well, including heart disease, lung disease and other medical conditions.' "

Human embryonic stem cells have the ability to become any kind of cell in the body. So scientists have been hoping the cells could be used to treat many diseases, including Alzheimer's, diabetes and paralysis. But the study is the first human embryonic stem cell trial approved by the Food and Drug Administration that has produced any results.

"It is really a very important paper."

The co-authors of the study summarized their interpretation of their results in this way:

“The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that human-embryonic-stem-cell-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.”

My takeaway from reading The Lancet article (and several of the accompanying writeups about the study) is, the use of RPE derived from embryonic stem cells is safe and efficacious, particularly in the eye. But most of all, this important study shows that Advanced Cell Technology is able to safely stop the progression of to-date untreatable dry AMD and SMD retinal diseases (17 of 18 patients) and to improve the vision in those who have lost considerable sight (10 of 18 patients).

Finally, the two clinical trials that are reported on in The Lancet, were done on patients with nothing to lose (with vision no better than 20/400), whereas patients in the Phase IIa study, still in progress, have vision no worse than 20/100. It is anticipated that even better results will be shown with this better vision group.

References:

1. ACT Announces Positive Results from Two Clinical Trials Published in The Lancet Using Differentiated Stem Cell-Derived Retinal Pigment Epithelium (RPE) Cells for the Treatment of Macular Degeneration, ACT Press Release, October 14, 2014

2. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies, Schwartz, SD, Lanza R, et al, The Lancet, Online, October 14, 2014.

Other Resources:

Encouraging New Paper on ACT Stem Cell-Based Trial for Macular Degeneration, Paul Knoepfler, Knoepfler Lab Stem Cell Blog, October 14, 2014

Embryonic Stem Cells Restore Vision In Preliminary Human Test, Rob Stein, NPR Health Blog, October 14, 2014

Disclosure: As of September 17, 2014, I own a small number of shares of the company’s stock.