Reviewing the state of play on cell and gene therapies, with the FDA’s Peter Marks

These are billed as being exciting times for cell and gene therapies, but seasoned observers of the pharmaceutical industry would be forgiven for taking that billing with a pinch of salt.

One such observer is Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA), who recalls the same sort of hype – and questions from the doubters – coming up when he made the move from academia to industry two decades ago.

'We're going to see product after product come along'

So now that a handful of these advanced therapies have reached the market, does Dr Marks believe that they will start to transform patient outcomes across multiple disease areas in the near future?

“I think, in certain areas, we’re going to see much more reach the market,” he told The Pharma Letter. “In the area of genetically modified cell therapies, I think we’re going to continue to see product after product come along. That is the way of controlling issues that have been challenging with gene therapy – CAR-T – where you are doing your genetic modification in a very controlled manner and giving them back.

“My prediction is that as we see them start to move from the autologous to the allogeneic world of CAR-T, we’ll potentially see these start to move into the realm of solid tumors. Obviously, we don’t know that for a fact yet but I think it’s possible. I also think we’ll start to see some of the genetically-modified hematopoietic stem cell therapies, potentially for sickle cell disease, beta thalassemia, come along, so I do think there we will see robust progression.

“I would answer the issue of directly-administered gene therapies a little more cautiously because there, I think, is an area where if we proceed very carefully, very thoughtfully, very scientifically, working to understand and learn from what we are seeing as we move into gene therapies for hemophilia, and for other disorders where we are seeing immune responses, issues with the amount of vector we need to give, the type of vector we are giving, as we learn from those, and build upon them, we will continue to see acceleration there. That’s an area where, from my perspective especially as a regulator, I’m excited because if we can help direct things on track that will be very helpful, so I’m pretty upbeat.”

An enhanced regulatory role

Because of the fast-changing nature of the technology, it is not just drugmakers that are having to be innovative in their approach. As well as performing the basic function of providing regulatory clarity on pathways for therapies to reach market, the FDA is helping in other ways, such as by aiding the advance the manufacturing technologies for cell and gene therapies.

“I think we need to be able to see these therapies be manufactured more consistently, and more easily, at lower cost, so that’s something we’re very interested in,” Dr Marks said. “We’re also very interested in helping developers study their products most efficiently.”

For example, allowing companies to design clinical trials so that they can reduce the number of individuals needed to make a showing of safety and efficacy. This is one area where drugmakers can be helped to bring down costs, which Dr Marks accepts remains the major challenge in the cell and gene therapies field.

“I think there is a lot of concern for return on investment for what you put into these products,” he said. “If we could see the cost come down to manufacture, be that start-up costs or cost of production, that would be very helpful. Somewhat inter-related are what it costs to develop a product for a rare disease when you have to go to multiple regulatory environments in order to have enough patients to become commercially viable – if you have 30 patients in the USA, 30 in the European Union, 30 in Japan and 30 in Australia, you have four different regulatory paradigms you have to negotiate, to the extent that we can harmonize – we’re very interested in doing that, we’re working with the World Health Organization to try to work in that direction, that’s a work in progress.”

Reducing cost a priority

The payers that ultimately have to reimburse drug companies will have a big role to play, too, especially in the USA where there is no single payer and questions around whether something will be paid for does lead to uncertainty for high-priced treatments, especially for gene therapies that are not an outright cure because there could potentially be arguments about whether they are worth their while.

When these and other complexities with the ecosystem will be ironed out to the extent that these therapies become a major part of mainstream medicine is not a simple question but, in the case of cell-based gene therapies, Dr Marks believes it could be as little as five to 10 years.

“I can imagine at some point, once the cost factor is addressed and the scalability issues and potentially with allogeneic CAR-Ts and allogeneic T-cells, you could imagine that people will start to use these,” he said. “They could prove to be useful in eliminating minimal residual disease and that’s no small feat because remember that’s what kills people in breast cancer and lung cancer, particularly lung cancer because even with localized or relatively localized stage two lung cancer, about half the people still relapse with lung cancer because of micro-metastatic disease, which you don’t see. This is potentially what the immune system can possibly do really well. It’s like smart bombs, it can target and eliminate cells so I think that’s where we make the largest growth, if people decide they want to go there and if the manufacturing issues, the cost can be brought down, I would say that’s the here and now.”