Clinical Strategy for Successful Cell and Gene Therapies

Industry experts

Wilson Bryan, Director at the Office of Tissues and Advanced Therapies, United States Food and Drug Administration (FDA)

Alison Moore, Chief Technology Officer at Allogene Therapeutics

Hari Pujar, Operating Partner at Flagship Pioneering

Greg Russotti, Chief Technology Officer at Century Therapeutics.

Discussion moderated by Dolores Baksh, global solutions marketing leader for Cytiva’s cell therapy business.

FDA submissions — insights from a director
Bryan: We’ve been talking about cell therapy and gene therapy for decades. And now it’s happening. How did we get here? We got here because the science has moved forward. So, if you look at the products that we have approved most recently, the science is exquisite. And if you look at products that have such strong science behind them, you see that their clinical trials have large effect sizes. And that means clinical development can proceed relatively rapidly.

These are small patient populations. The very first clinical trials provided the necessary evidence of effectiveness to support a marketing application. And this has put us into a bit of a dilemma because in many cases, the chemistry, manufacturing, and controls (CMC) aspects have not been lined up and put into place for commercialization at the time when the clinical trials are starting to show evidence of effectiveness.

We have something called a rolling biologics license application (BLA), where folks can submit their clinical, pharm-tox, and CMC modules sequentially. In the world of small molecules, the clinical module, the evidence of effectiveness, comes last. But for cell and gene therapies, the CMC module comes last. That’s because they get the clinical evidence first, while they’re still trying to get everything in place from the CMC standpoint. So, we’ve been trying to encourage our sponsors to think about the CMC issues earlier and get those lined up as much as possible, even before they get into the clinic. And then, of course, some things can’t get resolved until you’re actually in the clinic.

In the world of cell and gene therapy, most of our sponsors are academicians or small startups that sprung out of an academic lab. They don’t have the drug development experience and expertise necessary for commercialization. They get into the clinic and haven’t really thought about how to create a product that’s ready to go on the market. So, the struggles that we’re having are focused primarily on getting CMC issues in line to catch up with the outstanding clinical results that we’re seeing with some of these products.

The road to commercialization — CMC and other things to consider
Russotti: Emerging biotech companies are helping us shape what those CMC studies and process understanding need to look like to give the greatest success in the CMC package submissions. Often, you can try to have a line of sight on what commercialization would look like, designing a path to get to the clinic rather quickly. I would advise everyone, still go fast to clinic, don’t waste time pre-investing in things. But do take the time to think about things. So, think about how to make that switch later onto something that’s commercializable, and have a model that’s going to work.

No matter what the cell therapy is, it’s essential to be fast to the clinic, because if you try to get everything perfect, you’ll never get started. And we can’t learn the way we do in a clinic anywhere else. You have to get into the clinic to learn, of course, in a safe manner with something you think is going to have efficacy. But always think ahead. How am I going to get from where I am now in Phase 1 to a commercializable process and assays? Have a plan, so that when you start getting the right milestones reached, you can make a business decision on when you invest more. But you need to invest early enough so you’re not falling behind.

Moore: With novel processes, sometimes we don’t really have best practices yet. In edited cell therapy development, the technologies, pretty much all the unit operations, are what I consider to be very emergent technologies. The exciting part is there is a lot of innovation in the lab, the industry, and our supplier base. Because we get to the clinic quickly, there’s no point in making a very significant investment in CMC technologies if you don’t have a product that does what you think or hope that it might do in the clinic.

So, fast to the clinic is necessary but with some evidence of efficacy. With many of the unit operations, we learn as we practice. And since there is a lot of innovation in the field, there are superior technologies coming along. A lot of my experience is in process development. And as a process developer, it’s very interesting to think about procedures that have been, for decades, just purely molecular biology procedures, such as electroporation. And now we’re incorporating those procedures into a stream of unit operations in a good manufacturing practices (GMP) development process.

Thinking about what technologies are really suitable for much larger-scale editing is very interesting. And fortunately, we have had good innovation in the third-party landscape that is bringing forward addressing technologies. But that’s an example of where I think the CMC developers have a real challenge. As Dr. Bryan already pointed out, they can get into the clinic with a process that might be a little more academic. But it’s almost inevitable, then, that components of that process will have to be revised so that it can be characterizable, created in a robust way. And that we can eventually try to achieve an adequate control strategy. So, that’s why I often refer to the emergent dynamics of our field. And that absolutely requires the partnership of our regulatory colleagues to help us to get to those kinds of landmarks.

Data and science — what does ‘good’ look like?
Russotti: Having that process understanding is so important. It’s always important to invest early in what I like to call process characterization. You don’t know in Phase 1 if your product’s going to go further. But you do usually have an opportunity at that point to do two things:

1.    Start preparing for the next phase in terms of scale-up and what process changes you’re going to make.
2.    Understand how your process behaves, which you’ll need for scale-up.

You need to understand how those input parameters on any unit operation affect the key attributes. And you’re still learning about the key attributes.

Doing that allows you to get a design space, so when you change the unit operation or scale it up, you have a sense of what works and what doesn’t. Then, no matter what unit operation you’re in, when you understand how inputs affect cell behavior and then ultimately cell attributes, it eventually gives you the data you need for that validation package.

Moore: A conversation about potency comes up because the production process for a lot of cell therapy processes is smaller scale. And if you’re running those processes routinely, that certainly can have challenges. But you might find that the bigger challenges are in method development and execution, because trying to understand what you’re growing, producing, and releasing is really where you have an enormous learning opportunity.

People often overlook things like method performance. Even if you have a method that you quite like, and you’re starting to understand what it really tells you, do you understand the routine method performance? We all calculate the variance of our methods, but do we understand what the method performance drivers are, and how related that is to our process performance? So for me, in addition to having the ability to deeply observe the production process, I also want to have some of those analytical methods close at hand, too, so that we can understand all of the data coming out. That interrogation of the process understanding with the robustness around the analytic profile of your process is certainly part-and-parcel in understanding how your process evolves, and ultimately how potency is achieved in the manufacturing process as well.

Manufacturing — how to reduce risk
Russotti: All your critical process parameters, you really need to tear them apart. First, you need to find out what they are. There are no best practices here. We’re all learning, which makes it a lot of fun. But you need to tear all that apart.

Another big factor for autologous and maybe some allogeneic therapies is that you’re going to change donors. In certain autologous therapies, it’s a different donor every time. So, you need to understand that variability as well. You need to understand process variability separate from donor variability. So, it’s quite a large data package. I don’t think anybody has great comfort at a BLA, because there’s always more you could do. But then there’s a risk-benefit ratio. If the product works so amazingly well clinically, how much risk are you willing to take? You’ll want to do smart things in the CMC, so you can reduce at least the key risks.

Bryan: We don’t have that experience to know what manufacturing changes are going to make a difference. There’s going to come a day when we’re going to have hundreds, if not thousands, of cell therapies and gene therapies on the market for treating a wide variety of diseases. And in developing these and bringing them forward into the marketplace, we’re going to figure out which changes in manufacturing make a difference with regards to safety and effectiveness. We’ve certainly seen products that made changes in manufacturing that have had substantial impacts and surprised us. Trying to characterize these products to figure out the critical process parameters and critical quality attributes, that’s not a small task. And tying these things to clinical safety and effectiveness is not a small task.

When each product is different, getting a good potency assay has held up the development of several products. We’ve looked at applications that are very close to ready for approval or BLA submission. We’ve looked at the data for the potency assays and didn’t know if there was enough science to support that the proposed potency assays were good enough.

Where to manufacture — CDMO, in-house, or both?
Pujar: Unfortunately, for small companies, particularly in the early stages of development, we’re not able to invest the capital dollars required to equip a manufacturing facility, get it qualified, and get it up and running, all in time to make Phase 1 clinical material. So, the use of contract development and manufacturing organizations (CDMOs) is necessary.

Russotti: At Century, we’re fairly small, very well-funded, but very early. We did make a commitment to do in-house from the get-go. We’re fortunate to have a partner. FUJIFILM Cellular Dynamics has an in-house manufacturing facility ready to go. We’ll make our first products with them, and then we’re building our own as well. So, it was a conscious decision to do that in-house from the get-go. The advantages are many. Some small companies don’t have the time, money, or expertise to build in-house. It’s a lot of expertise. You need to know how to build it and have the right infrastructure in place to run it. You need quality systems in manufacturing, and quality control (QC) teams in development.

Having development and operations all on the same team working together helps you solve problems much more quickly. It helps you make changes in a forward-looking way. And you have control of all that. When you think about most of your development experiments, you’re always adjusting parameters and looking at edge effects and interactions. Even though you think the process may run great down the middle, it doesn’t always run great. Interesting things can happen. Those are learning opportunities. And having your own operational staff doing that brings you that learning opportunity. We made that conscious decision at Century.

Pujar: I think for companies that have a little bit of a pipeline where they’re not reliant
on one asset, it’s important to think about building a facility. And these days the building of a new facility is significantly streamlined relative to what it was 20 years ago. Most of these are manufacturing using single-use components, so it’s a cleanroom type of a situation. And so  that would be the time to think about building. Or even going to a facility and renting it out with your own operators and your own equipment. That way you have even more control than with a CDMO. So, that would be the ideal scenario for a small company with a little bit of a pipeline on a single platform technology.

Russotti: At Celgene we were considered mid-sized in 2006. We had 700 employees, and about 100 were in the cell therapy division. So, we were fortunate that Celgene took a chance with the acquisition of Juno and then the work with Bluebird in the autologous CAR T space. We made a decision then to have our own in-house facility from the very first trial. I’ve always done in-house. I was at Merck before that. Merck had great resources to do everything in-house if they wanted to.

Moore: Allogene is currently work with a CDMO. And I think that’s been really advantageous for us. At the same time, we’re almost complete on construction of our own manufacturing capacity. I couldn’t agree more with the major reasons for wanting to have that close, so we do have Allogene staff there with the CDMO. And the purpose is to create that connectivity.

Pujar: With large companies it’s less of an issue. They typically already have cleanrooms that they can deploy to different platforms, and so that is easily taken care of.
 
Phase I — how to plan and get through it
Russotti: With biologics, a lot of times people make the investigational new drug application (IND)-enabling batch at the same time they make the Phase 1 batch. And that’s a great luxury to have. Because with biologics, you have a platform to plug into, and you can just bang out that product quickly. The reactor you’re making it in could be 1000 liters. And you need to get in and out, because more products are coming through the pipeline. You need to get out of that space for the next product.

The difference with cell therapies is you typically don’t have a platform. And if you wait for that platform and for your Phase 1 process to be all ready to go, you’re going to be very late to the clinic, because you’re going to be later to your IND. So, I think the key is you need to have a process and a product that is representative of what’s going to go into Phase 1 when you make it for your animal IND-enabling studies. For those in vivo studies, you need to have confidence that what goes into those animals is the right product, and it’s representative of what you’re going to make later. But it doesn’t need to be quote-unquote “Phase 1 material.” It just needs to be representative.

It doesn’t need to be in the same facility. It doesn’t need to be exactly the same process. But it should be darn close. That’s a challenge, but it’s a challenge that most of us have to take. Because, again, we don’t have the resources to just plug something into a Phase 1 process. We’re learning as we go.

Wilson: Too often companies get stuck in the science too much. And they’re always changing things, and they never get moving forward to the clinic. And sometimes they get stuck in Phase 1 and keep doing Phase 1 over and over again.

It’s very important to develop what we call a target product profile. Big drug companies and medium-sized companies always do this. They figure out the path that they’re on and how they’re going to get that product into the marketplace. And to do that, all the disciplines have to be talking to each other. You can’t design your preclinical program unless you’ve got your product in line. And you can’t design your preclinical program unless you have an idea of what you’re planning to do in the clinic.

Working with regulators — why early is better
Wilson: People need to be talking to each other really early in the process. And we encourage you to include us, the regulators, in those conversations. So, we’ve been pushing for pre-IND meetings. And more recently for what we call pre-pre-IND meetings, or what has been renamed an INTERACT meeting, which stands for Initial Target Engagement for Regulatory Advice on Center for Biologics Evaluation and Research (CBER) Products. These meetings are meant to  help streamline the development process preclinically so the CMC data you’re getting, the CMC characterization of the product and the animal studies, are necessary and you aren’t wasting a whole bunch of animals along the way, which can cost time and money. So, I want to push for the INTERACT meetings, the pre-IND meetings, and also for the target product profile to be sure that you’re on the right path.

Moore: There are not too many detailed regulations for gene editing in the cell therapy space. We’re all learning how to execute those activities while ensuring that we have safe outcomes. Those technologies are extremely interesting. But how do we make sure we’re committing to them in a way that’s ultimately headed toward something that can be defended, controlled, and approved? I think it’s very dangerous for us to try and make those decisions unilaterally. And so it must be a tremendous challenge at CBER. But it’s great to have the opportunity to partner in those discussions with, of course, adequate thought and data coming forward, and just having some dialog about whether this looks like a suitable path forward.
Because also, some of these new technologies are incredibly expensive.

We need to consider new supply chain and raw materials for highly edited cell therapy processes, and if we also have viral vector transduction, we’re starting to have multiple raw materials per batch that could be hundreds and hundreds of thousands of dollars. So, executing a batch, even a full-scale batch, which is very small, is a commitment. We strive to have good small-scale models, which is also a little bit challenging. So, for us to set up the right experimental paradigm, it requires some commitment that we’re headed down the right path. That’s why it’s critical for startups working in novel areas to partner and discuss with our regulatory colleagues outside of the context of submissions.

How to move forward — take hold of the reins
Russotti: With novel processes, there really are no best practices. I think that’s what kind of makes it fun early on. It’s really the scientific approach you have to take to something, and say, “What regulations are out there that may apply? Why are they written the way they are?” Let’s think about the spirit of the law, not the letter of the law, so we can apply them appropriately.

Let’s make good decisions about how we construct our product and our process. Draw upon the big-company experience, like having the right quality systems in your manufacturing facility, so you have good-quality product appropriate for Phase 1.

How do you have reliable assays? But the bigger questions are: What are the right assays? And then, how do you run the process in a way that gives you confidence you’re making the same product each time? These are the harder decisions. Each of these cell therapies is a little different. And that’s probably what makes it fun for the FDA, too, or maybe challenging. But at the same time, they’re seeing things that are so different, and one set of rules does not always apply to all products. So, that’s what gets me motivated to do this job.

Pujar: We’re heading upstream to the central dogma of molecular biology. We’ve been dealing with small molecules for 150 years, proteins for 40 years, and now we’re moving up the chain to RNA and DNA. And so most startups these days are focused on some version of RNA, DNA, or even cells. And as such, they all require high-quality reagents initially to get their preclinical work done. Fortunately, a number of providers have emerged in that space to provide high-quality reagents. And again, that space will continue to evolve and improve.

But immediately thereafter, I think it’s very important for the startup to bring the CMC activities in-house, to learn the correlation between, in the old days structure-function, or in the new world process-function, and start to in-source a lot of that activity. And I think we’re seeing more and more of that as the costs and methods of producing these newer reagents get more and more well-established.

And then, once you get through Phase 1, you need to start thinking about in-sourcing even manufacturing and become a fully integrated company. But I think it’s an exciting time for startups. There’s a lot of interest on the part of the investment community in biotechnology that, frankly, is unprecedented relative to what it was even five years ago. So, it’s a great time for startups, and it’s a great time for companies that are thinking about playing in the upstream parts of the central dogma of molecular biology.

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