Challenges in clinical translation and commercialization of HLA-typed iPS cell banks

by Alexey Bersenev on September 25, 2014 · 0 comments

in embryonic/iPS

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Potential cost of iPS cell-based therapies is extensively discussed topic. Even though, development of autologous iPS cell therapies considered by many professionals as cost prohibitive, allogeneic HLA-typed iPS cell banks viewed as very promising approach. Currently, proposals for allogeneic iPS cell banks development backed-up by Yamanaka’s name and cheered by many. However, many practical aspects of creation of such HLA banks, their maintenance and usability are not discussed and/ or assessed.

Christopher Bravery – a consultant on advanced biologicals from UK, in the recent critical analysis, argues that investment in allogeneic HLA-typed clinical iPS cell banks does not make commercial sense (at least now). I really like his thoughtful analysis and I would highly recommend to read it. He highlights requirements for derivation of research- versus clinical-grade iPS lines, differences between single and multiple allo- iPS cell lines for generation of clinical products. One of unique challenges for clinical allo- iPS cell banks is necessity for introduction and characterization of multiple master cell banks (MCB). We cannot avoid this issue, because HLA-matching will be required in order to avoid potentially harmful immunogenicity. Also, single MCB will be exhausted at some point, after generation of multiple therapeutic cell products. Obviously, we will need extensive comparability and validation studies, to address inherent donor variability, differences between facilities, differences between manufacturing processes, differences between final therapeutic products and so on. Theoretically, single MCB from single donor, manufactured by single facility will be more beneficial, because of consistency. In such model, however, there is a great risk for lack of availability of therapeutic product. On the other side, public repositories could possess “a significant business threat if access to the same iPS lines by others was possible”.

Manufacturing risks in clinical allo- iPS cell banks, could be related not only to comparability/ validation issues, but also to complexity of raw materials and huge cost:

The cost of generating, testing and expanding research iPSC lines is estimated to be between US$10,000 and US$20,000 per line and requiring clinical use these figures escalate, bringing the likely cost per line in the order of US$0.8 million (personal communication, G.Stacey) due to the need for a GMP environment testing and
evaluation of tumorigenic hazards. While such cost might be envisaged from public or/or private consortia, developing CTP from a repository of HLA-typed iPSC would require commercial funding.
For each CTP it would be necessary to prepare one or a series of product MCB for each iPSC line at a similar cost each, but also to undertake extensive comparability to demonstrate equivalence of each iPSC line used in any CTP process. This likely brings a plausible estimate of the cost per iPSC line to well-over US$1M, and at least some banks would need to be prepared before preclinical development could be started.

So, while idea of using repositories of HLA-typed iPS cell lines for generation of clinical products is interesting, it seem to me we cannot afford it with current regulatory requirements. Practical challenges, related to creation and maintenance of such allo- banks, are underappreciated and should be critically discussed. I’d like to cite some of Bravery’s conclusions:

… the sheer complexity of developing such products and maintaining a continuous supply once authorised brings unprecedented uncertainties and risks. The number of uncertainties suggests it would be prudent to await evidence that CTP based on single iPSC lines can be safe and effective in the clinic before embarking on such an ambitious project. This combination of scientific and commercial uncertainties combined with investment costs suggests it is unlikely that any investor would consider the risks acceptable.
… the cost just to prepare the iPSC banks is likely prohibitive, let alone the cost of developing CTP from them, and with so much uncertainty around their future utility, these lines would likely have low prospects of returning significant investment from expended public money.

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