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Axol CSO discusses the value of iPSCs for patient stratification

Axol CSO discusses the value of iPSCs for patient stratification


Using the power of iPSCs for patient stratification

On the 26th July 2023, our Chief Scientific Officer Ashley Barnes held a discussion around the value of iPSCs for patient stratification in Alzheimer’s drug discovery. Ashley was joined by Duncan Borthwick, our Head of Sales and Marketing, to discuss the current opportunities and limitations of complex in vitro disease models. In this article, we outline the main takeaways from the webinar discussion.

Recognizing the challenges facing drug discovery

Ashley and Duncan began with a summary of the current challenges in drug discovery. For one, the current failure rate is unsustainably high at over 90%, with particular challenges in the neuroscience space where the estimated failure rate is as high as 99.6% 1. Given the estimated $2.6 billion needed to get a drug to reach marketing approval 1, clearly the mantra of “fail fast, fail cheaply” needs to be reinforced. Perhaps, with a different approach.

Ashley shed further light on the situation, stating “in my 25 years working in biopharma, clinical trial failure rate has not really improved- particularly in the neuroscience space.” With drug development often lasting over a decade and large recruitment drives needed to reach adequate patient numbers, there is ultimately a heavy cost- and significant risk- with the current drug development process.

Ashley and Duncan focused on two key drivers, both ultimately stemming from a lack of human relevance.

Firstly, while animal models have provided valuable insights, there are considerable limitations (especially in the neuroscience space). For example, mice don’t get Alzheimer’s and so mice models rely on amyloid overexpression to simulate the disease. Animal models are ultimately limited in providing insights relevant to human physiology, which is why we’ve seen a persistent translational gap from model to market. From our market research, 34% of respondents are actively reducing their in vivo model usage and 87% see iPSCs as a major tool for biopharma, clearly reflecting this growing industry demand for more human-relevant models.

In my 25 years working in biopharma, clinical trial failure rate has not really improved- particularly in the neuroscience space – Ashley Barnes, CSO 

Ashley and Duncan also discussed the growing need for increased diversity in clinical trials. Representing the gender, ethnic, and race diversity of the population is key to ensuring the safety and efficacy of any potential therapies. This was emphasized by the Alzheimer’s drug donanemab which, although promising, was entered into clinical trials where 91.5% of patients were from a white background.

Clearly, there are challenges that we can work to overcome in the pursuit of better, safer therapies. And that is where human iPSCs and patient stratification comes in.

Human iPSCs could solve biopharma’s billion-dollar problem

As an expert in the iPSC space, Ashley was able to describe the value of human iPSC models succinctly: ultimately, they can enable more physiologically-relevant models for research and drug discovery. He also described that, while we recognize some of the challenges in using them (such as the potential loss of epigenetic markers in reprogramming), “the benefits certainly outweigh the negatives“.

At Axol, over the past decade, we’ve invested time and energy to develop our processes to match the quality, consistency, and standardization needed to build iPSC-derived models that can solve these challenges. With excellent compliance against the ISSCR Standards Document 2023, now is the opportune moment to take the next step with in vitro Alzheimer’s Disease models: a “clinical trial in a dish”.

How to build a robust in vitro disease model

While monoculture models offer useful data, combining multiple cell types enable cell-cell crosstalk and more human-relevant insights- after all, no cell exists in isolation in the human body.

Ashley and Duncan described the steps needed to build a complex in vitro model, comprising:

  • Multiple high-quality cell types (cortical excitatory neurons, inhibitory interneurons, astrocytes and microglia)
  • An appropriate assay format, which may take a 2D or 3D structure
  • Measurable assay data that ensures you can extract relevant data from the model

The ultimate goal is a reproducible assay format, fueled by high-quality, relevant cells, that has clear and measurable end-points.

Patient stratification and the power of a cohort-scale platform [H3]

Duncan and Ashley discussed our agreement with StrataStem which will enable us to access and commercialize a large-scale collection of iPSCs derived from StrataStem’s Alzheimer’s Disease (AD) patient samples.

Bringing everything together, we are in a position to build a robust, cohort-scale platform using human iPSCs and incorporating a wide range of patient demographics. With Axol’s investment in consistency and quality of iPSC processes, it means standardizing the processes and letting the variation come from the patient cells.

Large cohort approach to in vitro modelling

Ashley described the power of this model for patient stratification, whereby potential therapies could be tested on this cohort-scale model to find the best responders (and therefore the profile of patient that would most benefit from subsequent clinical trials). This format could also enable greater trial power to identify small signals. This could even help to identify key biomarkers to predict drug efficacy, which is currently lacking from Alzheimer’s research.

Ashley and Duncan ended with a simple request: if you’re working in the Alzheimer’s drug development space and would like to collaborate on this “clinical trial in a dish” model, then get in contact with us.

Click here to access the webinar recording

Ashley will be speaking more about this exciting area of research at The 27th CNS Therapeutics Xchange.

Counting the cost of failure in drug development – Pharmaceutical Technology (pharmaceutical-technology.com)

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