From the President's Desk: The Three "Product" Problem of Cell and Gene Therapy

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Miguel Forte, MD, PhD
ISCT President
Kiji Therapeutics
Belgium

The “three body problem” relates to a famous unsolved problem in classical mechanics of predicting the motion of three gravitationally interacting bodies given their initial positions and velocities. It is also the title of a science fiction book, by Liu Cixin, with a television series, about a fictional past, present and future, beginning during China’s Cultural Revolution and exploring humanity’s contact with an alien civilization (1). It is about dealing with uncertainty, prediction, innovation and multiple cultural environments and needs. It has a lot of similarities with what we are experiencing with cell and gene therapy!

As with the challenges of predicting the trajectory of three gravitational bodies, it is difficult to predict with precision the evolution of the cell and gene therapy field as a whole, except for the fact that it will eventually become customary and the products part of day-to-day routine therapeutics in medicine. Nevertheless, before we reach that stage we must navigate and predict the course of multiple products and the overall evolution of the field which in recent times has proven to be difficult. The three-body-problem tells us not only about the challenges of prediction but also the challenges and opportunities when facing new developments and technology. In cell and gene therapy we are seeing huge progress but also significant product development challenges. As the success of translational science in C&GT progresses, we can expect to see those products aggregating in three clear groups for which, together and because of the interdependencies, like the three-body problem, we cannot fully predict their trajectories today.

The adoption and customization of innovative technologies takes time and goes through periods of slowness and challenges, frequently after an initial great enthusiasm. A clear recent example is the evolution of the use of biologics, monoclonal antibodies in particular. They were challenging and costly to manufacture. Adoption, despite the clear clinical benefit was slow at start, but eventually they became more and more affordable and their increasing use made them blockbusters providing value to a very large number of patients and those that develop them.

Over the last couple of years investment and commitment to cell and gene therapy products has been difficult, in the context of a global uncertain market and geo-political environment, despite the clear benefit that we continue to see with these products addressing unmet medical needs with long term value, approaching cures. Recently, at the end of September, several large pharmaceutical companies strategically moved away from C&GT projects further impacting the uncertainty in the field. Takeda (2) has decided to completely cease its activities in C&GT, exiting cell therapy research entirely. Previously with a strong commitment to the approach, the company is stepping away completely as part of a strategic re-alignment of the portfolio. A similar justification was provided by Novo Nordisk (3) that decided to stop a promising and highly valued collaboration with Heartseed on their iPSC derived cardiac cells in heart failure. Also, Galapagos has been looking for a taker to their cell therapy business with limited success so far! (4) These decisions are a signal that contrasts with what we continue to witness with the phenomenal promise of these products in up to now incurable conditions like the recent positive and encouraging results in Huntington Disease with the gene therapy from UniQure (5).

Those of us that are committed to this field continue to see and believe in the exciting science and clinical value of C&GT, but may not focus enough on the key enabling element needed for the success of these therapies, the business and commercialization model. The value proposition cannot be only based on the fantastic science and clinical efficacy. It needs to be anchored in the business case for patient access. It needs a clear focus on the concept and product proposition. Clarity also on the manufacturing, cost-of-goods, clinical convenience and adequate product launch. And this must be present in the minds of any product developer from the early stages of the translation project, when science becomes a product with a market vision well established by the target product profile, a must have tool a successful patient value proposition.

The focus should thus be on the product approach. This is where the three-product concept comes in application to cell and gene therapy. Both the present and future of cell and gene therapy products will be dominated by three types of products, all aiming at correcting or using the cell function with therapeutic objectives. The autologous, allogeneic and in-vivo product approaches. At this stage it is difficult to project the relative trajectory, like the three-body problem, of these three product approaches except, as stated before, that they will bring value to patients, will become part of routine medicine and should be based on a clear product focused development translational science.

The autologous approach is where patient cells are manipulated and mostly gene engineered ex-vivo and returned to the patient for an enhanced and targeted effect. The product here tends to be defined as the cells returned to the patient, and so characterized, but one could also consider the product as the process in itself. This opens the door to some interesting and valuable perspectives for the manufacturing and delivery of the product, the cells or the process, like a decentralized, eventually bedside, manufacturing. It's worth considering that we may have to revisit the models for development, regulatory, adoption and delivery of these products.

The allogeneic cell therapy product will use different cell types engineered for a therapeutic purpose. The cells will less and less be used from multiple donors but will be sourced from cell lines, like iPSC sourcing, and primed and engineered for a function. The cells become a raw-material, a therapeutic tool using the optimized engineered cell function for a specific effect. The product is those allogeneic cells, it is off-the-shelf and very likely centralized manufactured with a corresponding supply chain. This will continue to bring the product, the cell as a whole or their products, closer to the traditional pharma product model.

The in-vivo approach where the gene engineering aimed at correcting or enabling a therapeutic function will be delivered to the patient directly, through a vector – viral or non-viral – so that the cells will be changed inside the patient. The product here is the vector and the genetic payload, also very much aligned with the traditional concept of an off-the-shelf product in terms of manufacturing, approval and access, but with a to-the-core, gene engineered approach.

The therapeutic development must be on what the product is and how it can be optimized, not just in the biology but clearly also on the way it is produced, delivered and used. This should provide greater emphasis on the necessary focus on the key element for the success of the therapeutic proposition, concomitant with biological efficacy, which is the business commercialization model.

As the translational process is initiated, often as start-ups are created, there must be clarity of the product from a development and regulatory perspective. This involves a focus on product feasibility, scalability, automation and cost, in order to improve the business and adoption propositions together with clinical convenience and ease of use. All of this aims at an anticipated readiness for the eventual launch. The launch, adapted to the market realities, from education to cost, will be critical for product adoption – bringing value to the patient’s unmet medical needs.

It is crucial to bring confidence in the success of the cell and gene therapy field business model proposition and return on investment, alongside and for the purpose of addressing patient needs. We must consider the end game of commercialization from day one of product development. Only if we do this, can we bring back the confidence of multiple stakeholders. Particularly, those that invest (such as the venture capitalists or those that acquire or license like pharma) towards the clinically promising cell and gene therapy products.

These products represent fantastic science, and we all get bewildered by the potential they represent. However, they will only deliver the optimized clinical value to patients if we focus on delivering the optimized business model anchored, from day one, on a clear and optimized targeted product profile focus.