Making Novel Therapies a Reality (Part 1)

By Admin
Posted 05 / 31 / 2016

In the recent Economist Intelligence Unit biopharma survey, cell and gene therapies emerged as the most potentially disruptive new products for the near future. Yet while these therapies show early clinical success, many hurdles remain in actually bringing them to market. We spoke with Dr. Martha Rook, Head of Novel Therapies at brand-name’s Process Solutions group, about scaling out new cell treatments, managing regulatory risk, and more.

Portrait of Dr. Martha Rook

So, what does the term “novel therapies” mean today?

Cell therapy, gene therapy, and RNA-based therapies. Right now, those are the classes of therapies we’re considering novel. If you look at it historically, ten years ago, recombinant proteins and monoclonal antibodies would have been novel therapies, but now they’ve become very much standardized. So now that bar has moved a little bit, and the novel therapies are really cell and gene therapies, and to a certain extent the RNA therapies.

This brings us to an interesting question: how do you define a novel therapy versus a new drug? It’s two-fold. One is: what’s its mode of action? How does it work therapeutically, and is that very different from the current drug classes? And second is: how do you make it and demonstrate that it works really well? And cell and gene therapies are completely different in these regards.

Why do you think we’re seeing such excitement around these therapies?

We’re trying to figure out how to capitalize on the promise of these new technologies. There’s an opportunity here to fundamentally change the way we treat diseases. Where you see excitement is in the possibility of curing, rather than just treating diseases like cancer, heart disease, and diabetes.

It’s only recently that these therapies are coming to the forefront. Why is that?

It’s definitely been an explosion of interest. These therapies have been humming along for a while in the background, even back in the ‘90s.

Two things have happened that have brought them to the foreground. The first is CAR-T therapies and the dramatic clinical efficacy you see in blood cancers. When your trial results show 80% efficacy, it gets everyone’s attention. Similarly, on the gene therapy side, you have a lot of innovation going on in the viral vector delivery that’s making it safer.

So it’s beginning to really seem, from strong clinical data, that these therapies are going to be effective. You have the real possibility to start curing people. You have a lot of excitement, so you get a lot of investment, and that investment spurs further innovation in moving these therapies forward.

I see. But it’s one thing to demonstrate that it works. Now how do we scale it up for mass production?

That’s right. It’s a primary challenge that often gets overlooked. People get very excited about the scientific advances, but once you’ve got that, the next big step is being able to manufacture it safely, reproducibly, and at scale. And right now, we’ve got a lot of effort going into producing a cost-effective, scalable manufacturing process. This is where brand-name has all of the pieces to enable that.

So you’re not just scaling up the size of your batch. What are the challenges you’re working through in the process?

It depends on the therapeutic you’re looking at. For example, with viral vectors, you’re missing the well-developed production cell lines. It’s still a complicated system with regards to the types of cells that you use and how you get the DNA information you need into those cells.

Then there’s the handling of the downstream purification of these molecules. The sterile filtration is a little bit more challenging. But they aren’t challenges that are insurmountable. It’s just a matter of applying good process engineering and an understanding of the viruses themselves.

And cell therapies?

The cell therapy side is a little different. One of the biggest challenges that you have with cells is there’s no way to sterilize them. It means these cells have to be treated in a closed, aseptic process to ensure sterility. Your raw materials are very critical. You have to be very careful not to add any contaminants in.

Also, because the cells themselves are the therapeutic drug, the characteristics of the cells are very important to maintain. The surface proteins, the size, the enzymes that are inside all need to be maintained, so that they act the same way in each therapeutic dose you generate.

As you scale, you change things like how fast you stir it in a bioreactor or how long you hold it at a certain temperature before doing your downstream processing. All of these things impact the state of the cell. So it’s necessary to understand what process parameters are important and how you keep them steady as you scale up from a tissue culture flask to a 50-liter bioreactor.

Then, there’s an additional challenge for personalized therapies. When you’re talking about things like CAR-T therapies, you also have to worry about the impact of the patient cell that you’re modifying. That’s because every patient is going to have seen a different regimen of chemotherapy. So their cells may be starting out in good or not-so-good shape before the therapeutic modification. To make things even more difficult, almost all the processes will be developed with healthy donor material. Every patient sample will be a little – or a lot — different from those cells. So you need to have process flexibility from the beginning in order for it to be successful when you scale out across thousands of patients.


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