A Look at What’s Ahead in the Rapidly Growing Cell Therapy Landscape

Pharmacy Times^® interviewed David Silverstein, JD, MS, a partner in Axinn’s Intellectual Property and FDA practice groups, on what may be coming to market in the rapidly growing cell therapy space, and the role pharmacists may play in this emerging landscape.

Alana Hippensteele: Hi, I'm Alana Hippensteele from Pharmacy Times. Today, I’m speaking with David Silverstein, a partner in Axinn’s Intellectual Property and FDA practice groups, on the FDA’s recent approval of Breyanzi, which is Bristol Myers Squibb (BMS)’s first cancer cell therapy, for the treatment of late-stage lymphoma. This approval marks the company’s entry into the rapidly growing cell therapy space.

So, David, why is this approval significant, and what does it mean for the current cell therapy landscape?

David Silverstein: Sure, well first, thank you for having me on your program. This is a very exciting time for cell therapies and immunotherapies. Breyanzi, as you said, is a treatment for late-stage lymphoma and is BMS's first approved cell therapy, so clearly it's significant for BMS, but this approval is significant in an even larger sense because it evidences a continuing growth of this class of therapeutics.

It's the fourth FDA-approved [chimeric antigen receptor T cells (CAR T)] therapy for non-Hodgkin lymphoma, and it joins treatments sold by Novartis and Gilead, so these are major players in the field. It's exciting to see yet another one added with BMS. What it shows really is the industry and FDA are working together at a quickening pace to figure out how to develop, review, and commercialize these kinds of complex therapies.

Alana Hippensteele: Right. Why do you think the cell therapy space has been rapidly developing more recently?

David Silverstein: Well, there are several reasons. I mean, for starters, there's tremendous market potential for these therapies. Over 7000 genetic diseases are estimated to be treatable using gene therapies. Currently, there are over 900 [Investigational New Drug (IND)] applications for ongoing clinical trials using these therapies, and I think as the benefits of these therapies have become more apparent to stakeholders, to biopharma, we've seen a dramatic increase in the level of investment, both from outside sources and by the developers themselves. This takes the form not only of physical capital, but also human capital in the area.

So, these therapies require quite a degree of specialization and training, and we're seeing these large pharmaceutical companies, and small ones as well, step up to the plate and get involved. With that being said, FDA's list of approved cellular and gene therapy products still fits on just a double-sided sheet of paper, so there's a long way to go still.

Another reason I think we've seen recent activity in this space in the near term, there's going to be expiration of some of the foundational platform patents in the CAR-T space, and I think with those patents soon to expire, we're going to see more and more development work underway in order to get to the market as soon as they can after this patents expire without having to take licenses or incur extra risk.

But most importantly, I think what's responsible for this increased pace and in developing these therapies is that FDA has stepped up to the plate. FDA has begun issuing guidances that provide much greater certainty to developers. If you look at FDA's list of cellular and gene therapy guidances, for example, the first going back to 1998, there was one, and then there was a large gap in time until 2007 when another one came out. Then it was about 1 or 2 a year until about 2015. We saw 3 in 2017, another 3 in 2019, culminating in 2020 when there were 7 guidances. Here we are in the second month of 2021, and there have been 2 already. So, I think it's showing that FDA is recognizing the importance of providing a clear path and for regulatory approval and the clearer that path the less risky it'll be for developers to embark on the [research and development (R&D)] processes to bring these already complex products to market.

Alana Hippensteele: What is the regulatory landscape for other innovative cell and gene therapies, and how does this landscape impact the ability for new therapies to come to market?

David Silverstein: Well, FDA has made clear that supporting the development of and approval of gene therapies is a quite significant priority for them, and they do that a number of ways. In addition to the guidance as we just mentioned, FDA encourages developers to take advantage of FDA's expedited programs. For example, seeking breakthrough therapy designation, regenerative medicine advanced therapy designation, fast track designation, and just generally priority review and accelerated approval. So, FDA is willing to work with the developers. I think that's important that FDA's willingness to engage especially in the IND stage.

It's almost more important than any other type of product where the development path, the regulatory path has already been established and well-trodden. It's important that FDA is setting out its expectations, the stakeholders are able to set out sort of their constraints, what they're able to demonstrate, what they're not able to demonstrate, and work together in concert.

One of the things that FDA is also doing is, with these therapies in general, is placing a tremendous focus on preventing off-target effects. This is something that's fairly unique to these types of therapies—cell and gene therapies—as opposed to biologics or small molecules. But FDA frankly is learning along with the industry. This is a rapidly developing field, so a lot more work has to be done on FDA's part to provide the industry the support it needs.

Alana Hippensteele: What are some of the challenges developers and the FDA are facing when seeking regulatory approval and reviewing applications for these new therapies?

David Silverstein: Well, there's numerous challenges on both industry and FDA. With these therapies, we're dealing with living drugs. There are highly complex processes involved to create them, and the generated products, the therapies themselves, are highly complex. So, with those come fairly unique set of challenges. Given the complexity of making these, it's essential to establish consistent and scalable platforms that can achieve high manufacturing yields. This isn't as simple as synthesizing a small molecule from scratch or having a cell line E. coli, for example, pump out protein of interest. These involve often viral vectors. The infection rate is very low, in short, the yield you get is very low. So that that creates a whole host of challenges. And historically there's been a lack of established and qualified processes, consistent analytics, and, as I mentioned, clear regulatory guidelines.

Another thing that's fairly unique to these types of therapies is, for safety reasons, it's essential to observe how these genetically modified cells behave over time. That by default expands the development timeline for these therapies to years or decades even. That's not really found in developing other products. On the manufacturing side, simply put, I think there's a general consensus we just don't have enough manufacturing capacity to produce these therapies for many of the diseases that could benefit from having them developed.

There's—with the viral vectors, for example—tremendous challenges in bringing these therapies to market is the scale up for clinical trial use, not to mention commercial scale. To address this, limitation gene therapy makers are exclusively partnering with or even buying outright [Contract manufacturing organizations (CMOs)], and what we'll see is there's only limited capacity available to begin with, and it's being scooped up by the forerunners in this space. We're going to see a little bit of a lull as the industry struggles to sort of fill in for that need of CMOs. It's akin to a layperson. They wonder, “Well how is it we have so many pharmaceutical companies, but we only have a handful that have come out with COVID-19 vaccines.” The reality is these aren't the run-of-the-mill products that the host of pharmaceutical companies can just turn on a switch and start making. It takes specialized equipment, takes specialized know-how.

Then once the company gets into the business of making these, quality control is a challenge. The requirements are incredibly high, as they should be. FDA is vigilant and will not hesitate to put clinical holds in place. This happened, for example, back in 2018 with Sarepta’s phase 1 and phase 2 trial for micro dystrophin gene therapy. There were trace amounts of DNA that were found in in the plasmids, and FDA put a hold on. So those are challenges that exist that, especially when the development isn't completely vertically integrated, when you're working with partners, CMOs, or development partners, it poses its own challenges of ensuring quality control, ensuring everybody's on the same page with regard to what impurities are tolerated, what deviations are tolerated.

Another factor, I would say, is limited talent pool. These are specialized equipment, requires specialized training to use. There's definitely a relatively small talent pool for skilled workers who can oversee the manufacturing operations for these therapies. Not only does this impact industry, but it also has an impact on FDA. FDA needs the same skill set to review applications, to inspect sites, and so that's something I think we'll see that will be met. It's great job opportunities for pharmacists in training or at any stage in their career. I think this is an exciting area that's up and coming, and there's only going to be greater, greater demand on it.

In a nutshell, I guess FDA is in the industry getting up to speed on these new technologies. As we said, with the rolling out of more and more guidances, that'll provide clarity to the industry with increasing the talent pool, increasing manufacturing capacity. That'll create opportunities for industry to meet the needs that the market is showing is there.

Alana Hippensteele: What are you keeping your eye on in the cell therapy field in 2021?

David Silverstein: I think the first thing comes to mind—the natural extension of these 4 CAR T therapies that have been approved for treating lymphoma would be extending those to treat solid tumors. I think that would be tremendously beneficial to patients. Solid tumors are a tough nut to crack when it comes to existing therapies, and so extending CAR Ts to that would be very exciting. I think that's kind of a natural next step for the companies that are there already with CAR T.

But I think, outside of CAR T, I think we're going to see a number of [clustered regularly interspaced short palindromic repeats (CRISPR)]-based technologies and therapies come into clinical trials and eventually be submitted as BLAs. That's a very hot field. A lot of R&D money is being spent on it, and it's getting a lot of attention. Speaking of talent pool, it's attracting a lot of talent. So, I think that's going to be one to watch as well. I don't think we'll see anything necessarily is in the pipeline to come to market in 2021, but I think we'll see R&D programs embarked upon, we'll see even clinical trials start. I think it's an exciting field.

Alana Hippensteele: Yeah, and is there anything important for pharmacists to understand about the cell therapy field today?

David Silverstein: I think, as I'm saying with the skills required, it is a specialized field, but it’s coming. This will become more and more mainstream as time goes on, and there's a tremendous role for pharmacists to play.

Some of the roles that pharmacists can play, for example, with CAR T, their cell therapy are involved in policy development, electronic medical record billing, patient and staff education, patient selection, procurement, and storage and handling. I failed to mention it earlier, but one of the challenges in cell therapies in particular is they have to be made near where they're used. So there's tremendous regulatory hurdles, import restrictions, if they're made abroad and imported because these are living cells, viruses are involved, and so it's much simpler to have these made locally, so to speak, within the United States for the US market. So, pharmacists will have an involvement in procurement, storage, and handling these products. They have to maintain, just like the COVID-19 vaccines, low temperatures, handled the appropriate way so they're not adulterated, or even inactivated before use.

Other areas where pharmacists will have involvement are medication administration, supportive care, management of adverse reactions, naturally, and quality tracking. So there's a lot to be done. I think, while these may seem sort of niche specialist, specialty products right now, I think given their potency and the potential to be really tremendously effective against these horrible diseases, I think we're going to see more and more of these in the coming years. So there's a lot for pharmacists to get involved with.

Alana Hippensteele: Fantastic, thank you so much for taking the time to speak with me today, David.

David Silverstein: My pleasure.