Big change for stem cell field with FDA quickly issuing RMATs

The 21st Century Cures Act has some important regenerative medicine language in it. One part of that was attempting to accelerate FDA review of promising investigation regenerative medicine therapies. The mechanism for this was a new designation called Regenerative Advanced Therapy, now renamed Regenerative Medicine Advanced Therapy (RMAT) Designation.

I don’t think anyone was sure how this would play out in terms of how quickly the FDA would give RMAT designations and to how many investigational products. Already it’s clear the FDA seems to be embracing the spirit of the Cures provisions as it has given out quite a few FDA granted RMAT designations and done so quickly.

The first that I could see was given to Humacyte, which has an artificial vessel research program (see image). The artificial vessels become colonized with endogenous stem cells after implantation.Humacyte

Keep in mind that RMAT designation does not equal FDA-approval overall, but it should mean the investigational therapy has solid data behind it and is promising, together equaling a faster FDA review and then potentially in the future approval should future data be strong. If some of the RMAT therapies are ultimately proven to be safe and effective, and via RMAT they were able to get to patients and help them more quickly, with few failures amongst the RMAT group, then the RMAT regulatory experiment will be proven a big success.

Here are the approved RMATs I could find so far:

  • Humacyte (Vascular Access for Hemodialysis)
  • Enzyvant (DiGeorge syndrome)
  • jCyte (Retinitis Pigmentosa)

There may be more already given, but not yet in the public domain. If you know of others please comment on the post to let us know and I’ll add them.

Summaries of WAFSF super stem cell vision talks: Hinton, Tsukamoto, Klassen, Takahashi

Recently I was at the World Alliance Forum in San Francisco (WAFSF), a great meeting on stem cells and regenerative medicine. WAFSF had some excellent talks and I saw one session on the use of stem cells to treat vision impairment that was particularly striking.

This session’s all-star lineup included Drs. David Hinton, Ann Tsukamoto, Henry Klassen, and Masayo Takahashi. I’m going to summarize the talks below with permission of all speakers. Note that these summaries are based on rapidly scrawled notes. Together these talks show just how far the translational stem cell vision field has come in the last few years and the very real promise for the coming years in this area for major clinical impact.

David HintonThe session began with Hinton (pictured at left in USC photo) from the Project to Cure Blindness at USC, who spoke about research on treating geographic atrophy using retinal pigmented epithelial cells (RPEs). Hinton’s stem cell device is a polarized RPE monolayer. The team places 100,000 RPEs made from human embryonic stem cells (hESC) on a parylene membrane. My impression was that they are using H9 hESC for the preclinical studies, but I’m not 100% sure.

He indicated that because of the membrane there is no significant cellular migration, but there is PEDF and VEGF secretion and the RPEs appear resistant to stress. Are the RPEs functional? It seems so as there is rhodopsin phagocytosis.

For the studies he discussed, they used the RCS rat model of retinal degeneration of which there was a partial rescue by hESC-RPEs and encouragingly from a safety perspective, no teratomas.

Surprisingly, control parylene alone without cells has some rescue function, but with RPE there was substantially better organization and electrical function. One kind of cool thing from a techno perspective is that they invented a special delivery tool that gently folds the RPE sheet for insertion into the eye upon which it unfolds. It looked like it worked like a charm based on a video shown.

What does the future hold for this project?
They hope to file an IND within a few months and the target for starting a clinical trial is 2015. There was a question from audience on IP navigation. They have a license deal with WARF and they are aware of the ACT patents (now known as Ocata Therapeutics), which presumably will need to be addressed in some fashion such as licensing. Another question was on residual undifferentiated ESC. Shouldn’t be a problem, he said, because the special media that they use causes ESC death.

 

The next talk was from Ann Tsukamoto of StemCells, Inc.

They are studying the use of human CNS stem cells for treating dry eye AMD. These cells are called HuCNS-SC. After transplantation in mice the cells engraft and migrate. In RCS rats there is loss of RPEs and then 2ndary loss of photo receptors. HuCNS-SC transplanted at P21 migrate well (there’s no matrix). With transplant of HuCNS-SC they see maintenance of photoreceptors and visual acuity. What is the mechanism?

Ann Tsukamoto
One is suggested by the observation that the cells have phagocytosis function and debris is absent. They hypothesize that as a result there is preservation of synaptic connections. They have a combined phase I/II trial going, which includes a 3-month immunosuppression regimen. They have done 6-12-month follow up on 7 patients and found encouragingly no cell-related safety concerns. Best corrected visual acuity (BCVA) improved in 2 study eyes, but also in 1 control eye. They found that 6/7 treated eyes had 70% reduced geographic atrophy. I’m curious to see how this work goes as it continues to develop. HuCNS-SC may have utility to treat other diseases as well.
Henry Klassen                                                   Henry Klassen from the Gavin Herbert Eye Institute at UC Irvine spoke next (photo from UCI). Klassen’s team is studying the use of fetal retinal progenitor cells (RPC) for treating retinitis pigments (RP).
In RP there is loss of photoreceptors and loss of cones by bystander effect, Klassen said. Because of the importance of cones, the goal is to try to rescue them. This team produced their stem cell-based product here at UC Davis in the GMP facility. The RPCs, which are not immunogenic, are injected into the vitreous. They used the same RCS rat model as the first two speakers. They transplant the RPC as a single cell suspension but cells aggregate after transplant into neurospheres that float around in the vitreous and secrete cytokines. It’s like a floating pharmacy (my analogy). They observed that the RPCs rescue rods and cones in rat.
 jcyte
Their goal is to have an IND before the end of the year. They have done the work in part with funding from CIRM and interestingly have founded a company called jCyte. One pretty neat additional point was that this therapy has the potential for treating AMD too and would be complimentary with other types of therapies such as those mentioned by the first two speakers. I didn’t have a have chance, but I had hoped to ask Klassen if they thought that patients would be able to see (or not) the neurospheres like little floaters in the eye.

 

Masayo TakahashiThe final speaker of the session was Stem Cell Person of the Year, Masayo Takahashi, from RIKEN. She spoke about using RPEs made from human induced pluripotent stem cells (IPSC). She discussed treating wet AMD with the RPEs. I understood that to make IPSC they used the episomal vector approach.

They started with 24 IPSC lines, then picked the top 6 and then 3 of those lines were used to make the RPEs using a 4-month differentiation period. Of the original 6, it was notable that despite using an episomal vector, in one there was a plasmid remnant. So for all you folks out there using “transient”, “non-genetic” methods, one lesson here is to be sure to do the needed testing and validation of human IPSC lines.

They then pick pigmented clones and made sheets. It’s a lengthy and expensive process with one of the biggest expenses being the facility itself, which costs ~$500K/year just to run.

For safety testing and validation, they did their Lin28 PCR assay for residual IPSC as well as whole genome sequencing. In addition, no tumors were observed.

The RPE product, a 1.3 x 3 mm wide device, was just transplanted recently into the first human AMD patient. I think everyone is on the edge of their seat in this field to see how this clinical study progresses.

Looking to the future, Takahashi mentioned that allogeneic transplantation is an option and teams are moving in that direction. An IPSC cell bank with a variety of HLA types could be helpful to many patients in an allogeneic manner.

She also discussed the regulatory situation in Japan including the novel concept of adaptive licensing (see below the overview of the current regulatory system in Japan).

Japan stem cell regulatory system

She mentioned that it is a fast system, but acknowledged that it has risks too. She also said they are planning photoreceptor transplantation in 5 years for RP.

Overall these four talks were very encouraging for the future of treating various forms of vision impairment using stem cells.