Oral Peptide Delivery with Protagonist Therapeutics' Dinesh Patel

To stab or to swallow? For treating conditions in the I&I (immunology and inflammation) space – think psoriasis, as one common example – some see the holy grail of delivery as moving from injectable to oral administration. In this inaugural episode of Sit and Deliver, host Tom von Gunden invites Dinesh Patel, president and CEO at clinical stage biotech company Protagonist Therapeutics, to deliver the rationale for targeting I&I diseases and other therapeutic areas with oral peptides.

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Deilvery Leader:

Welcome to Sit and Deliver, the series that provides timely updates from leading thinkers in drug delivery. My name is Tom Von Gunden, Chief Editor and Community Director at inline information exchange Drug delivery Leader. Today, I am joined by Dinesh Patel, President and CEO at clinical-stage biotech company Protagonist Therapeutics.

Welcome, Dinesh.

Dinesh Patel, President and CEO, Protagonist Therapeutics:

Thank you so much, Tom. And I would really like to thank you on behalf of the entire Protagonist team. It's a privilege for us to be here and participate in this forum.

We're privileged to have you. So, let's go ahead and dive in. So, in the world of peptide-based drugs and therapeutics, and specifically around the delivery of those, can you go back and trace some of the history and trajectory of the space? In other words, what have been some of the therapeutic areas that peptide-based therapies and drugs have traditionally targeted?

Our industry has evolved. In the early days, we were focused on small molecule oral drugs. You discover a new small molecule chemical entity, you convert it into a pill, and there you go, whether it is aspirin or cholesterol-lowering agents like statins. And that was okay for the first 50 or so years. But after that, when we had picked all the low-hanging fruit, then we went towards more complicated targets which could not be addressed by small molecules, because now you're trying to obstruct or intervene big proteins, big biologics.

So, that is where the big antibodies came into play, and they did a wonderful job for a number of decades. Now, antibodies are big and, by virtue of that, they are also injectables by nature. So just a sharp contrast to the small molecules, which are oral.

Then, over the last decade or two, people started paying a lot of attention to peptides, which are in the in-between space. So, if you think about a small molecule as a half a kilodalton chemical entity with, let's say, three points of binding interactions, the big biologics or antibodies are, a few hundred times bigger and will have, let's call it 30-to-40 points of interaction. Peptides are in between. They are a little bit bigger than small molecules — around two three kilodaltons, would be the average size —but much smaller than the antibodies.

And the idea would be that with peptides, can you then go and tackle those big protein targets, which are not accessible by small molecules and are only accessible by the big biologics? So that is how, for example, Protagonist Therapeutics started, in 2008. We are focused exclusively on peptide therapeutics. And our mantra was, let's try to grab this in-between space, and go after those biological targets that are not addressed adequately either by small molecules or the big biologics.

And that is how we came up with the ideas of quote unquote, peptides. But very quickly we realized that peptides are also, for the most part, injectables. So, if you think of insulin, it's like a five kilodalton peptide. But even today, insulin is largely injectable. So, for us to cause a true differentiation, we came up with a very different philosophy, saying, hey, just pitching an injectable peptide versus an injectable antibody is not going to be a big distribution.

Of course, peptides are smaller in size, so they can have better tissue distribution. And they may have an advantage that you would find out later on in the late stages of clinical development. But we wanted an advantage that was very obvious, and clear, and simple but profound. So, we said, instead of injectable peptides, what if you came up with oral peptides?

Now we are talking about oral peptides versus injectable antibodies. So then the best utility for oral peptides could be going after those biological targets or pathways that have been successfully intervened by injectable antibody drugs.

So, Dinesh, as oral peptides continue to develop in effectiveness and deliverability, what benefits may ensue for patients? And in what therapeutic areas?

So the benefit for patients would be simple but very profound, which is that you are taking an oral pill, an oral tablet or capsule, instead of an injection. I will use Psoriasis as an example: 30% of psoriasis patients eligible for treatment opt against targeted therapies, simply because they don't like what is out there. And the prominent reason is these are injectables. So, it is just human nature, right? We don't like to be pricked or poked.

Whereas taking a pill in the morning is the easiest thing to do. Also, if something goes wrong with an oral peptide, the discontinuation is easy. You stop taking it. Whereas with an injectable, which you typically will take every week or every four weeks, you kind of get stuck with the drug. So that's the simple but profound advantage of an oral.

And the places where it has found the maximum use so far is in the inflammation and immunomodulatory (I&I) space. So here you are talking about diseases like rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease. These are immune disorders and the largest selling drugs of modern times like Humira®. That's a prime example of an I&I target like tumor necrosis actor (TNF).

Now these are all injectable. So you better get a lot out of them via that sort of thing. So that is where we felt, at Protagonist, that if we come up with an oral peptide that goes after the same biological pathways, then that would be a huge differentiation.

So Dinesh, what's next on the horizon in terms of advancements and targets in oral peptide delivery?

So, in the inflammation and immunomodulatory space, we already have our hands full. We have delivered an orally administered interleukin-23–receptor antagonist, JNJ-2113, to Johnson & Johnson.

[But] in I&I there are other biological targets. For example, IL-17a or interleukin 17 is another target. That is where Protagonist is focused, as well. But I think there is another game changer in the space. As you know, in our sector these days, anything and everything that people want to talk at professional level or even in social circles is about the obesity drugs.

There are two drugs out there, one from Eli Lilly, and the other from Novo Nordisk. These are both –- guess what -- injectable peptides. So it's almost like this is calling us. This is pulling us in that direction. And not just Protagonist, because we have the expertise in it, but as you can imagine, a lot of pharmaceutical discovery innovation, drug delivery innovation is gearing in that direction towards oral peptides in the obesity space.

So finally, Dinesh, to make some of these additional advancements in the oral delivery of peptides, what challenges and needs and problems may need to be addressed? And how will that happen?

Yeah, there are multiple challenges in coming up with an oral peptide. Number one, you have to match the potency of the antibody. I believe, at Protagonist, we have mastered that. We know how to do that.

Number two, when you swallow a pill, now the peptide is exposed to the various digestive enzymes. It is their job to break down these peptides. So you have to come up with orally stable peptides that would withstand that kind of treatment from the enzymes that are prevailing in the GI tract. I think that is also something we at Protagonist have mastered.

But the third and the absolute challenge is, okay, fine, your peptide is potent, it is stable. But now it needs to get into the blood compartment. It needs to have oral bioavailability. It needs to get to the site of action. So that is where oral delivery comes into play. And that is a science that is evolving very rapidly and very broadly.

And that is one area where Protagonist is building its expertise. But let's face it, it takes a village. So, while we are learning the craft, at the same time, we are also joining hands with other specialized oral delivery companies so that we can work in a synergistic fashion and then achieve our end goal of coming up with successful oral peptides, for these kind of biological targets in the shortest possible time.

So, oral delivery is one of the main challenges that peptide drugs are facing in this day and age. And it's good to see that so many companies with special expertise are coming up in this space. And, we will just have to see how it unfolds and where we land after a few years.

But right now, it seems like the industry is really gearing up towards tackling this challenge of oral delivery of peptides. And of course, we are very happy and fortunate to be part of this big undertaking.

Well, excellent coverage. Dinesh, I want to thank you for joining me on this episode of Sit and Deliver and sharing your perspective.

Thank you so much for the opportunity.