Finding the Data for Rare, Pediatric Therapies: Q&A with Lisa Bollinger

Pharmaceutical Executive previously covered FDA’s efforts to expand the range of data allowed in clinical trials, including the use of the Bayesian method. This style of data collection allows for clinical trial data to be examined alongside existing, relevant data.

This expansion of data is especially important for clinical trials in any rare disease space that have limited patient populations. While clinical trials in this area still present unique difficulties, regulatory changes have provided solutions to issues related to limited data-sets.

Pharmaceutical Executive spoke with Lisa Bollinger, chief medical officer at Polaryx. The clinical-stage biotech focuses on treatments for rare, pediatric lysosomal storage disorders. Due to its focus, Polaryx has been able to update its trial design thanks to the previously mentioned regulatory updates.

Bollinger discusses the regulatory landscape in this area, along with the style of trial design that the company is utilizing and some of the unique challenges they still face.

Click here for the video version of this interview!

Pharmaceutical Executive: What is the regulatory landscape like at the moment for rare pediatric diseases?
Lisa Bollinger: The rare pediatric disease landscape with regulators (focusing on FDA and EU) is very robust. What we've really seen over the last couple of years is a commitment to developing therapies for rare diseases, and this is really evidenced by the formation of a rare disease review division within the centers at CBER, as well as some additional offices like the Rare Disease Hub and Rare Disease representation within the Office of the Commissioner, as well

The one reason why I say this provides evidence that the regulators are really rallying around rare disease is because when you start staffing up and putting offices together to ensure collaboration across different centers at the FDA and EMA as well, what you really see is the agencies leaning into making sure that they can adequately support rare disease drug development.

We definitely see this infrastructure at both FDA and EMA. They've advanced several guidances for industry to help rare disease companies go through the process of developing trials and studying drugs.

Pharmaceutical Executive: How are basket trials reshaping development timelines?
Lisa Bollinger: Basket trials have been around for some time, especially in the oncology space. So, I would say in oncology, where you have large populations, basket trials really didn't change the landscape at all.

But, when you look at rare oncology indications (especially in pediatrics), that's where basket trials started being used to help support rare disease development.

There are a couple of things that that are really great about a basket trial. Number one, it helps with recruitment, because usually these rare diseases are treated at the same centers. If you have a study that's set up at a center that serves a lot of the CLNs, they're able to recruit for all of the different arms of the basket study at the same time, and you can imagine this is a lot more efficient than standing up individual trials for each of these rare diseases and trying to find out what hospitals treat these specific rare diseases.

It also enhances our ability to leverage the data that comes out of those trials. So, if you have diseases with commonality and you have them all in the same basket trial and you're getting results at the same time, there is this ability to use a Bayesian approach, which really borrows known prior information across in indications. This makes it easier to recruit, and it also makes it easier to share data across indications to then provide a more robust assessment of efficacy across different populations.

There's an operational efficiency as well. In our case, for Soteria, we have four arms in our basket trial (four different indications), but it allows us to stand up a single trial at these centers, so it's much easier from an operational standpoint to set up one single trial than it is to set up four individual trials at the same sites.

Pharmaceutical Executive: What is the future of disease modifying therapies for lysosomal storage disorders?
Lisa Bollinger: The future looks bright. It's a very difficult and complex disease to treat, it's hard to address all the issues. So, when we look at lysosomal storage diseases, we know that there are more than 70 different lysosomal storage diseases, and each of them is driven by a single gene mutation.

However those single gene mutations also have multiple forms of those mutations for that single gene being mutated. How do you address the different aspects?

For example, you could have an enzyme that just doesn't work, you could have an enzyme that's not produced at all, or you could have an enzyme that's produced, but there's a protein missing in a cell membrane that doesn't allow that enzyme to get across that membrane.

It's more than just solving one single problem. So, what you need to do is think about each of those gene cell mutations, you have to come up with a modifying drug that fixes that particular single gene.

With PLX 200, our drug works high enough up in the cascade that we do think that we may see a treatment effect across different lysosomal storage diseases, but that's why we must study each different one.

They are different diseases, and so having a single disease modifying therapy is really difficult. It's hard to hit more than just one of these diseases.

Pharmaceutical Executive: How can prohibitive costs for treatments be addressed?
Lisa Bollinger: These are oftentimes very expensive therapies, especially if you think about things like gene therapy. The problem is that there is a substantial cost to developing these drugs, and with these lysosomal storage diseases, there are so many challenges.

For example, the drugs have to get into the brain, so how do you make a drug that can cross what's known as the blood brain barrier? It's a protective mechanism in our bodies that prevents a lot of foreign things from getting into a very protected site, our brain. A lot of these therapies don't have the ability to penetrate into the brain, especially when you think about things like enzymes.

When you think about gene therapy, it has to be delivered directly to the brain. So, number one, there's a substantial development cost that comes with developing these drugs. There's a small patient population, so sometimes you also must price your drug high to recoup some of that R&D expense.

At Polaryx, we're working with a repurposed drug. We're reformulating it and trying to reach a broader patient population. Maybe one of the ways to get cost down is to be able to have a therapy that can help across lysosomal storage diseases, rather than just going for a single lysosomal storage disease.

No matter what we do initially, the cost is going to be expensive, as these are small patient populations and the therapies that we're developing are pretty advanced therapies, and they have a substantial R&D cost with them.