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A Regulatory View of Personalized Therapeutics



December 18, 2019 | As Director of the Center for Biologics Evaluation and Research at the US Food and Drug Administration (FDA), Peter Marks oversees the regulation of a variety of complex biologic products, including blood products, vaccines, and cell and gene therapies.

According to Marks, the recent scope of his work includes the availability of gene therapies for rare disorders that are treating very small populations.

"To date, gene therapies have been used for small populations, traditionally considered orphan diseases, less than 200,000 in the US," Marks says. "But there are some very, very small populations, populations of perhaps less than 100 individuals per year, that might use certain gene therapies. And we're very interested in helping to have people gain access to those."

The lack of accessibility stems from a variety of factors, though Marks says the production costs of these new therapies are most pressing.

"I think what we're going to have to see is us becoming better at making these more efficiently," says Marks. "I think in some ways this is going to be something that society will have to grapple with, but we're very happy right now to try to keep these products coming towards market with the hope that the more a product is on the market, the more efficiently they're produced, the lower the prices and the more reasonably these prices will come."

On behalf of Bio-IT World, Christina Lingham spoke with Marks about the obstacles in developing gene therapies, emerging developments in the field, and the regulatory landscape surrounding personalized therapeutics.

Editor's Note: Lingham, Executive Director of Conferences and Fellow at Cambridge Healthtech Institute, is producing a track dedicated to the Renaissance of Gene Therapy and Genome Editing at the upcoming Molecular Medicine Tri-Conference in San Francisco, March 1-4, 2020. Marks will be a keynote speaker on the program. Their conversation has been edited for length and clarity.

Bio-IT World: Can you outline what are some of the greatest obstacles to developing gene therapies, and specifically for rare disorders?

Peter Marks: Obviously, obstacles can exist in various places when you're developing a product. Traditionally, we've always thought of clinical development as one of the larger areas that can be an obstacle to product development. But for gene therapies, particularly when they're targeted to a single gene disorder, the clinical development is often not as complicated. It's a matter of getting safety information on the product and then having enough people treated to know that you're having a reproducible treatment effect.

The larger problem right now is really the fact that it's challenging to manufacture gene therapies, and that's because the gene therapy vectors are not made efficiently in cell lines currently. Purifying the gene therapy products is also a relatively complex process and it's not yet fully standardized. And so one of the largest obstacles to the development of these therapies is actually getting the product made so that they actually can be tested in humans. The capacity of the system right now, at least in the United States, to make gene therapies for these small batches is not sufficiently great. In other words, there's pent up demand for making them.

What do you consider some of the most exciting emerging developments in the field?

With genome editing, one can make changes in the cells that potentially allows one to have allogeneic genetically-modified cells. That is essentially product that could be off the shelf. Therefore, once you make the multiple changes that are necessary in order to have such a potentially effective product, genome editing may also open up the realm of chimeric antigen receptor T-cells for the treatment of common oncologic diseases, as opposed to just hematologic diseases – that is solid tumors – and not just lymphomas and leukemias, which is what the current products are treating.

What are some of the novel approaches you are excited about in manufacturing or preclinical and clinical development?

Let me give you an example in each of these. I think in manufacturing, I think there may be improvements in both the cell lines and the cell culture technology to help increase the yield of these products. I also think that we may see better purification processes developed that will allow for higher quality product that will be more reproducibly efficacious. There's plenty of room for improvements in manufacturing, and I think the technologies are getting there. It's a matter of putting it all together and doing some additional work on the cell lines.

In the preclinical area, I think we see now the rising potential of human organoids, which may allow the testing for off-target effects in a way that one simply can't do in animal models. If you're doing CRISPR/Cas9 genome editing, you'd like to use a human genome and not a mouse or a baboon genome, since that's what you're really interested in. By using these organoids, we get a better idea of what's going on than using a live animal model. And then on the clinical side of things, we're really excited about people starting to apply novel clinical trial design, including starting to use a complex innovative trial designs that might involve Bayesians statistics so that one can try to come to a decision about whether a product is going to be effective or not in the smallest number of people enrolled in a trial.

Now that we are equipped with programmable and thus "personalizable" editing enzymes that are being enthusiastically evaluated for the general safety properties, how do you imagine the regulatory landscape around therapeutics that are truly personalized? For example, how will trials be conducted when tailored for patients' unique mutation?

I like to describe these therapies more as individualized than personalized. Personalized medicine we think of as medicines on the shelf that one takes off and then applies to people. Here, we're developing medicines for the individual. Nonetheless, it's a great question because one is going to potentially have the same disease entity, which is caused by multiple different mutations, that one might address with different CRISPR/Cas9 constructs. The products may all be related, with a CRISPR/Cas9 guide that will be different and some vector that will be the same. Figuring out a regulatory path forward for this is one of the important things that we're working on now. Ideally, one would like to be able to take one product and guide and bring it through with a robust clinical development package, and then have a way that the rest of the different guides might be put through, potentially even without clinical data.

If one could make a compelling case that they produce the same effect, one might get the clinical data on the back end after some of the products were in use. We still don't have anything firmed up, but we're trying to think about novel approaches where we could facilitate this—obviously making sure that safety was maintained, but also trying to make sure that we weren't making it very difficult to deal with the fact that there could be very slight changes of a few base pairs necessary in different constructs to address different mutations. This is something that we could be willing to try to consider through these novel development programs, probably with the most important information coming regarding whether there were new off target effects introduced by changing the guide.

Will this sort of medicine forever exist in investigational territory, or might it warrant a new regulatory track where preclinical testing is done in patient-derived cells in the lab to get a sense of the genomic impact before administration?

That's a great question. Our goal is to help get as many of these out of the investigational track into an approved track by facilitating the regulatory framework to allow the products to be demonstrated to be both safe and effective. Now there may be some products destined to treat very, very small populations that will perpetually be in an investigational domain. We have those now. There are products like anti-venoms that are perpetually under an investigation new drug application. That being said, ideally in this area, we'd like to see the products developed to the point that we can see both a lead product and a number of very closely related products be able to be on the market and be commercially viable.

Obviously, that's going to take some work in our regulatory framework, but I think because we have a head start on this with products are starting to be conceived of now.  I think one of the lucky things we've been able to do is get a head start on thinking about the regulatory frameworks that will be necessary to accommodate this type of commercial entity where there will be classes of products that are very closely related, all treating one disease.

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