When are iPS cell-based therapies ready to be tested in actual people?

It’s the million or perhaps even billion dollar question of today in the stem cell field.

I realize that perhaps it is also a dangerous question, politically-speaking, for me to ask in a public forum, but patient lives as well as potentially the progress of the entire iPS cell field are at stake.

So someone needs to start an open discussion about this topic. People are certainly talking about it behind the scenes asking questions such as:

• Are iPS cells being raced too fast to the clinic?
• Who will be the “winner” in terms of commercializing iPS cells?
• Will the iPS cell field find itself in a gene-therapy, Jesse Gelsinger kind of situation soon?

Tragically, Gelsinger and a few other patients died from what one might say was a gene therapy treatment that was not ready for prime time and from a side effect not anticipated by researchers based on animal studies. The gene therapy field was crippled for two decades.

We all want to get stem cell-based medicines to patients who need them as soon as possible, but there is such a thing as going too quickly.

There are quite a number of teams around the world working to make iPS cell-based therapies a reality in humans, but the team at the forefront is in Japan led by Dr. Masayo Takahashi.

How strong are the Japanese team’s pre-clinical data on the iPS cell-based retinal pigmented epithelial cell (RPE) therapy for macular degeneration (MD), the leading cause of blindness in the world?

No data has been published so it is a tough question to answer.

Six months ago I asked whether things were moving too fast on moving iPS cells into people? 

It is an even more apt question today in April 2013 as the first ever transplantation of the first iPS cell therapy into human patients seems ever more imminent in Japan. The proposed study has already been approved by some regulators and is awaiting approval from one last regulatory body in Japan.

Even though the pre-clinical data have not been published on this study so far, there is at least a small window into that world.

Takahashi gave a lecture at the ISSCR 2012 Annual Meeting on her lab’s pre-clinical work on iPS cell-derived RPEs for treating MD. ISSCR made the video of Takahashi’s very important talk available on the web here, but only to ISSCR members. Fortunately I watched it before its run was supposed to end.

The talk was outstanding, just not enough to support in human iPS cell studies in the near future to my way of thinking.

As mentioned above, none of the data have been published yet as well. Interestingly, three leaders in the stem cell field that I queried all essentially told me the same thing when I mentioned the lack of published pre-clinical data on safety of transplanted iPS cell-based therapies using clinically relevant transplantation paradigms:

“They do not have to publish their data and in fact why would they when that would give their competitors an advantage?”

There is a dilemma here. On the one hand, data are viewed by for-profit companies and scientists as proprietary and valuable assets. In the iPS cell field those assets could be measured in billions of dollars. On the other hand, openness protects patients and the field more generally. How do we find the right balance?

One other earlier published study by a different team was encouraging on safety based on studies in mice, but far from strong enough to support studies in humans.

Of course prior publication of pre-clinical data is not specifically required for regulatory approval to start a clinical study, but given the historic nature of what could be the first ever in human iPS cell study, it would be extremely wise in my opinion for teams to publish their work first.

Since the data is in fact not published yet, how strong were the data in Takahashi’s talk?

In her ISSCR seminar given 10 months ago, Takahashi presented some safety data from mice on the RPEs, but not from larger animals such as monkeys. To be clear, larger animal studies are not also not required, but this is an important distinction since larger animals are sometimes better models for humans and also because there were some anecdotal reports that said she had in fact presented larger animal pre-clinical safety data at the ISSCR meeting.

The only large animal data I saw in the web-broadcast of her talk was that an autologous iPS cell-based transplant into monkeys survived and there was no inflammation, but I believe that she later mentioned that this was only done on 1 monkey. Allogeneic iPS cell-based transplant in a monkey was rejected.

From murine safety studies of the iPS cell-derived, purified RPE, Takahashi reported that no tumors were observed using RPE made from 3 different human iPS cell lines. There are some major limitations to how far one can go with this data though.

Three key limitations of these safety studies come to mind:

• The studies were relatively short-term, only going out to ~6 months.
• The data presented were only on 5-7 mice, a very low number per parental iPS cell line.
• The safety testing that was presented consisted only of subcutaneous teratoma assays (assuming I understood this correctly from the talk) and not eye transplant safety data.

My understanding from Geron’s and ACT’s experience at the FDA here in the US is that the short-term nature of this iPS cell safety data along with very low animal numbers and lack of a clinically-relevant transplantation paradigm would be far from satisfying regulators here in the US that human studies should begin. Geron used thousands of rodents, while ACT used hundreds. Follow up was far longer than 6 months in some studies. Both teratoma studies as well as studies using the relevant transplantation modality (e.g. in the eye and spinal cord) were conducted.

Of course the proposed study would not take place in the US so the point is moot from a regulatory standpoint, but it still is illustrative of how minimal the data supporting the study seems to be at least from what is publicly available.

Much more data might and probably does exist, but remain private. 

Indeed, it is probable that the Takahashi team and/or affiliated for-profit teams (the latter being a key point and more on that in future posts) have more data now and/or beyond what was presented at ISSCR 10 months ago. That is my hope. If so, I encourage them to publish it all. It does not have to go into Nature or Cell Stem Cell. Just get the data out there. It is certain to be a high-impact paper regardless of the journal.

Unless there are a lot more, longer-term studies (e.g. 1 year or even longer) done on many more animals (e.g. 100s) yielding equally encouraging safety results specifically on transplants in the retina (not just sub-Q teratoma assays), I am deeply concerned as to whether the field is really ready to make the jump to transplanting iPS cell-based therapies into people any time soon.

I realize that the regulatory system in Japan is different in terms of the process for studying potential medical therapies. Takahashi is proposing a clinical study, which is perhaps more akin to a Phase 0 here in the US and to be distinguished in Japan from a clinical trial, which might come later.

But in any case the bottom line is that  patients (and the field) would be put at risk unless there is far more rigorous pre-clinical animal data.

The field has to hope that the data presented at ISSCR 2012 were just the tip of the iceberg and that much more thorough and compelling data exists below the surface. Further, it is not just the Japanese team, but also many others that are moving quickly to get iPS cell-based therapies into humans for a variety of conditions…..how strong are pre-clinical data?

Who knows. They remain generally unpublished and unavailable for informed review by anyone but regulators.

I hope the iPS cell-based therapies come to fruition as safe and effective for blindness and other diseases, which would be tremendous advances for medicine, but let’s not kid ourselves: the risks are substantial and a lack openness just increases risk further in my opinion.