Embryonic stem cells are finally helping those going blind. Human embryonic stem cells in cell culture (Wikimedia)

Embryonic stem cells are finally helping those going blind. Human embryonic stem cells in cell culture (Wikimedia)


November 17, 2015

Clinical trials for what Nobel Prize-winner Sir John Gurdon, D.Phil., recently called “one of the most successful stem cell treatments so far” are cranking into second gear.The trials give retinal pigment epithelial (RPE) cells, made from embryonic stem (ES) cells, to patients with age-related macular degeneration (AMD), the leading cause of vision impairment and blindness in the developed world.

Having shown safety—and some vision improvement—in two Phase 1 U.S. and Korea trials published in The Lancet and Stem Cell Reports, Ocata began enrolling its first Phase 2 patients this September. The London Project to Cure Blindness (LPCB) and Pfizer have launched a Phase 1 trial in the U.K., dosing its first patient in August. Cell Cure Neurosciences launched a Phase 1/2a trial in Israel, dosing its first patient this year —and scoring FDA “fast track” approval for a U.S. trial a few weeks ago. And a new University of California (UC) trial began enrolling patients last week.

“We are hopeful,” LPCB Director Peter Coffey, D.Phil., told Drug Discovery & Development.

Sir John’s warnings

At the New York Stem Cell Foundation conference last week, Sir John Gurdon made the above comment, adding that the ES-RPE work presented was “wonderful.” But he warned that regulators can cause “massive” delays “making this treatment available.” Sir John, a biologist who won a 2012 Nobel for creating stem cells from mature cells, said regulators can let lawsuit fears delay approvals. They need to see ES-RPEs are so promising, and AMD is so common, that “a great challenge is to avoid unjustified restrictions and pay attention to people suffering.”

Sir John’s comments echoed those of Geron years back, when Geron—which isolated the first ES cells in 1998—tried to get the first ES-cell trial approved. Famously, due to constant FDA requests for more data, Geron’s IND ended up 22,500 pages long. The FDA finally approved that world-first trial (of ES-derived cells for spinal cord injury) in January 2009. Geron faced similar woes in the UK in the mid-2000s.

Coffey told Drug Discovery & Development there were rough spots during his London group’s recent attempt to get the first U.K. ES-RPE trial approved. But things have changed greatly since the early days, he emphasized. When the field initially “went through the process—which, without doubt, has improved—we all were pushing barriers with regulators, who never expected stem cell therapy to move so quickly. We all needed to get educated.”

Said Coffey: “Where we (the London group) recently fell a bit afoul was during mid-submission of our application.” The group dealt with two bodies, the FDA-equivalent MHRA (Medicines and Health Care Products Regulatory Agency), and the GTAC (Gene Therapy Advisory Committee), which shifted gears to look at stem cells. “We were almost doing two different approvals, and there were conflicts between the two groups, which didn’t help.” But midway through, the government closed the GTAC, and “introduced GTAC-NRES (National Research on Ethics). That was good. They are very efficient, and a more ethics-driven authority.”

The London group’s trial was approved in 2013, after a year-long process. (An extra delay, from 2013 to 2015, was prompted by the group’s altering of manufacturing details.)

Happily, Coffey added, the U.K. science innovation minister this week reported the U.K. “will try to accelerate innovative medicine. So new therapies showing promise in early clinical stages may get accelerated approval. I think that is what John was alluding to: moving quicker.”

The U.S. regulatory process has also streamlined. Approvals for embryonic and fetal stem cells in the past did move slowly, Neuralstem CEO Richard Garr told Drug Discovery & Development. But “solutions” came with “education and experience.” The problem is less “endemic or institutional, than informational.”

Robert Lanza, CSO of Massachusetts-based Ocata, agreed. “Regulatory roadblocks haven’t been much of a problem for us,” he told Drug Discovery & Development. “Now that we have over four years of safety data, regulatory agencies seem to be much more comfortable with the use of ES-derived cells.”

One strong indicator of excitement over the approach: Astellas Pharma just agreed to buy Ocata at a 79 percent premium: $379 million.

Ocata and London Project trials

Most stem cell trials for AMD target the “dry” form, which affects 90 percent of the affected. Dry AMD involves loss or dysfunction of RPE cells, which nurture and support the photoreceptor cells that shoot light to the brain for interpretation.  RPE cell loss prompts photoreceptor death, and vision degradation.

In 2007, key studies demonstrated that “transplantation of autologous RPE, isolated from periphery of a patient’s eye into the center of the eye, may protect vision from declining further,” National Institutes of Health (NIH) ocular stem cell scientist Kapil Bharti, Ph.D., told Drug Discovery & Development. The studies offered “proof of principle data” to justify trials. But few patients have RPEs to spare. So efforts turned to making RPEs from robust ES cells.

In 2011, Ocata was first to treat AMD with ES-derived RPE cells. They completed dry AMD trials in the US and Korea (via CHA Biotech), along with a U.K. trial for Stargardt macular dystrophy. Dissociated cells were injected in suspensions.

The Ocata trials, designed to assess safety, did so, many agree. Furthermore, all 31 patients (with AMD or Stargardt) receiving the cells over four years saw vision improve or stabilize. But the improvement was not dramatic. “The problem was two-fold, I think,” Coffey told Drug Discovery & Development. “The earlier Ocata trials dealt with end-stage disease for both AMD and Stargardt. It helped ensure safety. But it didn’t give a true read-out of efficacy.”

Coffey’s group—with University College London—gives cells earlier, before major vision loss, in “wet” AMD, where vision drops more suddenly. “Ocata dealt with more end-stage (dry) AMD, so only safety was tested. In our case, with wet AMD, we can look for both safety and efficacy, as our patients have good vision. We have a window in which to keep the vision maintained.”

Another problem, Coffey said, may have been “this issue of suspension versus cells on a membrane. We believe you probably need to give the cells physical support, as they are polarized. They need to be pointed in the right direction, anchored to a membrane. We give them that. Ocata injects suspensions. That may be useful for earlier stages, not later stages of severe visual change. Ocata probably won’t see the major benefit of their procedure until they treat patients with less severe visual problems.”

Lanza told Drug Discovery & Development that, in Ocata’s new Phase 2 trial, some patients will, indeed, be treated earlier, with more cells.

“Whether monolayers may lead to more success than suspension depends on who you speak with,” Lanza said. “Clearly, scaffolds [monolayers] require a larger retinotomy. And mechanically unrolling them in the subretinal space can be quite problematic, which increases risk of retinal detachment, and egress of cells into the vitreous cavity, which can then form pre-retinal patches and adversely impact vison–especially in better vision patients.”

Further, Lanza said, “the scaffold can migrate, and any potential therapeutic value lost entirely. [But] dissociated cells may not attach well to old Bruch’s membrane, although those are likely to be areas where there are no photoreceptors left to rescue. There are pluses and minuses for each approach.  For the moment, the sheet approach is mainly being used for wet AMD.”

The Ocata ES-RPE Phase 2 trial for dry AMD launches at Los Angeles’ Jules Stein Eye Institute, and Philadelphia’s Wills Eye Institute. Coffey’s ES-RPE monolayers were given to the London group’s first wet AMD patient in at Moorfields Eye Hospital. If the patient remains stable, ten will be dosed next year.

Both Lanza and Coffey are trying to turn ES cells into photoreceptor cells, too. Coffey’s group just saw “a bit of a breakthrough,” he said. “The optimal solution might be treating AMD before a majority of photoreceptors die,” Bharti told Drug Discovery & Development. As that won’t always be possible, RPE/photoreceptor mixes may be key. And right now, Bharti said, early transplant safety is unknown.

Six more trials

A third group, Cell Cure Neurosciences, enrolled its first patient in a dose-escalation study of ES-derived RPE’s this year. Its cell suspensions treat the most severe dry AMD, geographic atrophy (GA), at Jerusalem’s Hadassah Medical Center (HMC). Cell Cure, also given US FDA fast-track approval, was co-founded by stem cell pioneer Benjamin Reubinoff, M.D., Ph.D. Reubinoff was a member of the second group in history to isolate human ES cells.

A 20-patient trial led by UC Santa Barbara eye stem cell expert Dennis Clegg began enrolling this week. Monolayers of ES-cell derived RPEs will be given to two groups of dry AMD patients—one with severe GA, one with less severe disease—in Beverly Hills and Los Angeles.

Last year, a Japanese group led by Riken Laboratory for Retinal Regeneration head Masayo Takahashi, Ph.D., gave an RPE monolayer, made from a patient’s induced pluripotent stem cells (iPSCs), to a wet AMD patient. The patient is fine. But the trial is on hold until 2017. Six mutations were found: three single nucleotide variations, and three copy-number variants, says Nature. None were driver mutations, Takahashi said on the blog of UC Davis scientist Paul Knoepfler. So the hold is largely due to new Japan regulations favoring marketable allogeneic cells (and marketing approval based on safety alone). She is switching to the partially matched allogeneic iPSC-derived cells of Nobel-prize winning iPSC-inventor Shinya Yamanaka. She and Healios K.K.—a biotech, formed to market Yamanaka cells, whose IPO raised $59 million in June—plan a US AMD trial (with suspensions) in 2017.

Takahashi agrees with Coffey suspensions may suit early-stage AMD; monolayers, late-stage.

Also in 2017, a group led by the NIH’s Bharti hopes to launch a trial of RPE monolayers made from dry AMD patients’ own iPSCs, he told Drug Discovery & Development.

And Stem Cells Inc. is enrolling patients with dry GA AMD in a different kind of Phase 2 trial—of adult fetal neural stem cells—in California, Texas, Arizona, New York, Michigan, and Utah. In their encouraging earlier trial, “the majority of patients exhibited improved visual acuity,” Stem Cells Inc. Executive Vice President Ann Tsukamoto, Ph.D., told Drug Discovery & Development.


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