Increasing Oral Delivery Precision For CNS Targets With Tris Pharma's Ketan Mehta

Videocast host Tom von Gunden talks with CEO Ketan Mehta of Tris Pharma about innovations in oral delivery approaches to CNS disorders, such as ADHD, pain, and addiction. They discuss dosage form options, including liquid, solid, and powder, for leveraging polymer-based particle science to deliver stable, long-acting formulations. Among the advances discussed is precision targeting of payload release locations in the GI tract for optimal absorption.

Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader:

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader, and your host for the episode.

Today, I have the pleasure of being joined by Ketan Mehta, who is Founder and CEO of Tris Pharma, a company that works on developing products targeting CNS disorders, and often by way of oral delivery, specifically liquid-based and oral solid dose forms.

Welcome, Ketan.

Ketan Mehta, Founder and CEO, Tris Pharma:

Thank you, Tom. It's a pleasure to be here.

Well, it's my pleasure to have you here.

So, Ketan, let’s start with, could you give us an overview, a historical survey and up to the current date of the landscape of patients out there with CNS [central nervous system] disorders? I know you target things like ADHD and pain and addiction and others.

And so, what has been available from a treatment perspective for those folks — with what success, with what limitations? What are the range of options that we've arrived at in today's state, and how did we get to where we are today?

Thank you, Tom. When we started, we saw a huge unmet need to deliver drugs in a long-acting, sustained-release format but having a liquid as a dosage form or having a solid, chewable tablet.

Most of the controlled release or long-acting, once-a-day types of tablets or capsules had a warning: do not crush or chew. And, in fact, there were no liquids that we knew of that were really available for patients in central nervous system disorders. And so, we thought there was really an opportunity to innovate, because if you are a very young patient, and you want to have a long-acting tablet, how are you going to deliver that? That was a big unmet need.

Also, if you want to take a very precise dose, one of the challenges of the solid dosage form is that you are pretty much set into the fixed doses: 10 milligrams, 50 milligrams, 100 milligrams, right? So, if you want to calibrate somebody in one prescription — and often in CNS conditions, you want to slowly titrate the patient up — how can you do that in a one prescription?

And that's why I thought liquid was really unique. So, it was not just the convenience of a long-acting product, but also the clinical desirability of this form that was missing when we talked about oral delivery.

And there are still a lot of things, and I'm sure we will talk as we go along, as to opportunities that have been not yet addressed, even by us. But we are very much working on those.

Gotcha, gotcha. So, thanks for giving us a bit of an overview and a history lesson, so to speak.

So, as we sit where we are today, in terms of looking at the horizon and landscape of these indications, what have we learned along the way, as an industry or you folks there at Tris Pharma, in terms of how to think about it [oral delivery] going forward in terms of making any additional advancements or innovations?

So, what we learned: So, for example, we developed a technology called LiquiXR®. Even though it says LiquiXR, it is not really focused on liquid alone. We focused on tiny particles. We essentially developed — engineered, if you will — tiny particles of drug that we complex with certain polymers. And then we deliver them in a manner — either in a liquid form or an oral solid form. Or you can even sprinkle them on a film. But they're all oral delivery of those same particles.

And that gave us a unique platform and advantages that we originally had not foreseen, frankly. For example, not only does it give you that same titratability, as I talked about, but you really give flexibility to take the same powder with any kind of liquid, as long as you are reconstituting right away before ingesting. It gives you a degree of portability and flexibility and so forth.

And so that brought a totally new opportunity. And today we have actually gotten nine of our NDAs approved thus far developing different kinds of products in this fashion.

Gotcha. So, let's dive into the science and technology of oral delivery, specifically targeting CNS disorders and conditions. So, tell us a little bit about how it works. How is it that oral administration gets to those targets?

So, let's talk about our LiquiXR technology. Even when something is in the liquid, what I generally love to say is that anything in liquid begins to sing and dance. Because it's a very fluid environment, and stability becomes a challenging aspect for it. Meaning, how can you keep something that you develop, and while you're delivering it as a liquid product, keep it stable throughout the shelf life of the product?

And we did [that in] two ways. So, what we did initially, we complexed the drug. We combined the drug by complexing it with an ionic polymer. Generally, most of our drugs are polymers; all [have] some kind of an ionic charge. And they have what you call dissociation properties. So, you take advantage of that: You ionize this product with certain polymers and combine them. And then you recover this particle and then further combine this, what I call ionic chemistry, with the sustained release science.

For example, you are coating them with the different kinds of polymers, and you achieve the desired release profile. And then you deliver them, if you are delivering a liquid in a liquid environment, which gives them a stable ionic profile. So, you're not releasing the drugs while they're in the bottles. They only start reacting, or rather, releasing the drug once you ingest them.

And if you are doing that in a tablet form, it brings a slightly different challenge. But you similarly overcome [that] by making sure that they are stable in the tablet form. And they start opening up, if you will, once you have ingested them, and release the drug.

Gotcha. Let’s pick up the thread of what you just mentioned in terms of challenges. So, any way you want to come at this. I'll name a few, and if any of those stick, feel free to take off with those, or just go in a different direction.

I'm interested in anything that's front of mind right now for you and the other folks at Tris Pharma when it comes to additional problems to solve, questions to answer, challenges to overcome: anything from efficacy to absorption to bioavailability to patient safety to patient adherence. Anything to move the dial on?

So, you're actually bringing up something that we have just submitted in NDA. This is a very unique challenge. So, what we did, we combined two different platforms. We have this LiquiXR platform, and then we combined it with what we call RaftWorks™.

Now, there is a drug which has a very short half-life, almost less than one hour. And this drug requires that you deliver the drug in a very specific area of the GI tract to be absorbed. On top of that, when patients are taking this drug, this is actually for inducing sleep. So, when you take this drug, you actually have to put an alarm to take the second dose in the middle of the night. So, imagine, you don't get to sleep. That's why you take this drug, but then you're forced to wake up in the middle of night to take a second dose.

We developed a once-a-night version of this drug by doing two things. We combined the drug with a polymer where we got the right complexation properties. But because it was very short half-life and a very specific area of absorption in the GI tract, we needed to deliver it to the right area.

So, we combined it with certain excipients, such that when you take this particular composition, it actually swells, expands, and forms something like a raft, if you will. And it floats in the stomach. And the drug particles are entrapped into this raft. And after sudden predetermined time, this raft starts to disintegrate.

What it is doing is slowly allowing initial release of the drug to be absorbed right in the upper intestine area, where it needs to be absorbed. And as time goes by, it eventually disintegrates and allows the bolus of drug to be administered at the end, so you get a long duration, and the patient can sleep for the whole night.

So, we combine LiquiXR with the RaftWorks. And this product is — right now, the NDA has been submitted. We think this is going to be standard of care in this particular category. And it will hopefully really be a great success story for drug delivery, as well as patient outcomes.

Great, great. Well, it all sounds very promising.

So, I'd like to turn to a look forward; I like to end these conversations in this way.

And so, I know [that] across the range of what we would consider to be central nervous system disorders, there are different kinds of patient populations with different sorts of conditions, from ADHD to pain to addiction to whatever. I know that not every example is going to prompt the same thought about them.

But as you look out over that landscape, and should these advances and innovations that you and the folks there are working on take hold in the market for any of those conditions, how do you envision either the treatment regimen or the success in terms of cures or management of chronic conditions? What might that look like in a future state?

So, some of the things we are focused on are some of the big challenges in oral delivery [that] still remain, even though we are gaining on solving some of these challenges. For example, until recently, large peptide drugs were not easy to deliver orally. In fact, you may see that Ozempic has just come up with their own oral version, and they've successfully delivered that. And that was a great advancement.

But there are some other [challenges]. How do you, for example, go about what we call selective receptor targeting? Meaning, how can you actually target or block certain receptors, which are more problematic in drug-drug interactions or [have] some of the untoward side effects?

There are certain receptors that we want to have more concentration or efficacy. And so, you are able to do this also now by drug delivery. And it really opens up all kinds of opportunities.

And those are some of the things that we are looking at, how we're going to do that. I don't have a product that I can tell you and say, this is when we're going to deliver, but we are encouraged by what we are seeing in the lab, and we are continuing to work on that.

Another area that's of interest to us is how do you avoid first-pass metabolism? And how do you maximize the absorption of the drugs that are very much prone to first-pass metabolism.

Gotcha, gotcha. Well, thanks for walking us through some of those additional focus areas for you, and the advancements that you're pushing on there. I appreciate the work. And so, Ketan, I'd like to thank you for joining me for this episode of Sit and Deliver to update our audience about the work that's being done there. And to that audience, I'd like to thank you for joining for another episode of Sit and Deliver. And we'll see you next time.