Editor’s highlights: Opportunities and Challenges in Translating Cell and Gene Therapy Products

Despite initial successes which have given the impression that cell and gene therapies are poised to be rolled out for everything from stroke to sickle cell anemia, the reality is that they remain challenging to discover, develop and dish out to patients. Find out what's being done to change this.

Sep 06, 2019

In their first UK meeting, the American Association of Pharmaceutical Scientists (AAPS) convened UK experts for a workshop on developing advanced therapies (4-5 September; London, UK). Below, I share my key takeaways from the 2-day meeting. 

Despite a number of initial successes which have given the impression that cell and gene therapies are poised to be rolled out for everything from stroke to sickle cell anemia, the reality is that they remain challenging to discover, develop and dish out to patients. However, if the participants of the American Association of Pharmaceutical Scientists’ (AAPS) recent workshop on Opportunities and Challenges in Translating Cell and Gene Therapy Products (4-5 September; London, UK) have anything to do with it, these challenges may be overcome sooner than we think. Below are a few of my highlights from the workshop; if you attended, I’d love to hear your conclusions! 

1. Patients as stakeholders are vital (and their comments might surprise you!) 

One of the many highlights in Anna David’s (UCL, London, UK) excellent talk on the development of a gene therapy for fetal growth restriction was inclusion of qualitative research conducted with patients. It’s easy to make assumptions on what patients may want out of a therapy, and testing anything in pregnant women is fraught with moral and ethical conundrums. However, David discussed the benefits of listening to patients, in this case indicating that they want more approved therapeutics and that they would be willing to take part in trials, to demonstrate unmet need, design meaningful endpoints and ultimately make it as easy as possible for the regulator approve any investigational product. 

2. Selecting and optimizing doses remains difficult 

The challenge of dosing was mentioned throughout the two days of presentations and was also the topic of audience questions. Route of administration, biodistribution and immune response, amongst other things, can all affect the accuracy of extrapolating doses, according to Michaela Sharp (Cell and Gene Therapy Catapult, London, UK), and sometimes an in vitro model will be more closely biomimetic than an animal model. Administering a non-effective dose of a therapy may also be mistaken for the therapy being non-effective. 

Ultimately, balancing the potential safety issues with measurably efficacy is difficult. It is likely will remain difficult until there is a large enough bank of evidence and previous research to reliable extrapolate dosing from trials. Watch this space.

3. Involving the regulator as early as possible is crucial to avoid costly and unnecessary work 

With the rapid expansion of advanced therapies under investigation, it’s not just the developers’ processes that are scrambling to keep up. However, all speakers involved in therapy development commented on the advantages they had in going to their regulator at process inception, rather than in the later stages. Whether it was advice on selecting an animal model that is more reflective of specific human physiology or reassurance that compliance with good laboratory practice (GLP) for certain bioassays would be helpful but not obligatory, considering the regulator as a partner throughout the process saved time and money in unnecessary work and ensured the eventual filing package met expectations.  

Another area where regulator input could be applied was in clinical trial design and cohort selection. Farzin Farzaneh (King’s College London, UK) made the point that if antibiotics had been subjected to the same standards as cell and gene therapies, many may never have been approved. Testing these innovative therapies in the most difficult patients may not be doing them justice, both in terms of demonstrating efficacy and in isolating adverse events as a result of the therapy. Being more aggressive in how these therapies are being trialed may demonstrate we have discovered more effective therapies than we know, but regulator support is imperative.  

4. Process development needs to happen on a case-by-case basis  

However much the developers may want it, what became clear in every case study was that in therapies and processes which are this complex, there is no ‘one-size-fits-all'. Although demonstrating efficacy in a relevant model sounds straight-forward, the nature of model, and even what efficacy looks like, can vary. A risk-based approach in process development allows you to be flexible to the needs of your particular therapy. Keeping the end point of therapy approval and clinical administration in mind at all times will ensure you are doing exactly what is necessary, rather than what you feel you should do. 

5. Allogeneic therapies are the future (but most people are still working on autologous therapies) 

Whether you are team ‘auto’ or team ‘allo’, it’s hard to deny the potential advantages of allogeneic therapies: basing a treatment on donated cells, rather than cells from the patient, could be cheaper, more reliable supply chain and less time-critical. However, I think it was telling that the majority of therapies discussed, whether approved or investigational, were autologous therapies. Autologous therapies ‘need to be taken out of GMP’ to make widespread application more realistic, possibly utilizing closed systems at point-of-care. Nevertheless, allogeneic therapies are yet to show ‘long-term efficacy or safety’ and require production of standardized and characterized cell lines before serious development can move forward.  Once therapies are being used 'off-the-shelf', we also need to understand what makes a good donor, according to Stefanos Theoharis (Cell Medica, London, UK).

As Johan Hyllner (AstraZeneca, Cambridge, UK) commented, advanced therapies such as these are a ‘dream come true’. The knowledge and insights shared at this workshop will certainly take many of the therapies discussed closer to the patient, and I’ll be following the progress of all of them closely. 

Thank you to AAPS for inviting me to the meeting, and for Charles River Laboratories (MA, USA) for supporting it.

Freya Leask

Publisher, Future Science Group

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