Treating Gastroparesis: From Nose To Stomach With Evoke Pharma's Matt D'Onofrio

The gastrointestinal issues stemming from delayed or restricted emptying of the stomach can lead to limited effectiveness of orally administered medications – for treating gastroparesis, specifically, as well as generally. In this episode of Sit and Deliver, Matt D’Onofrio, CEO of Evoke Pharma, talks with host Tom von Gunden about using nasal delivery to alleviate the discomfort of gastroparesis while smoothing the path for oral drug delivery to patients suffering from it.

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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 and Community Director at Drug Delivery Leader. And today, the topic for Sit and Deliver is gastroparesis and the related implications for patients who suffer from that condition. Joining me in that conversation is Matt D’Onofrio, CEO of Evoke Pharma, a commercial pharmaceutical company that focuses on gastrointestinal diseases.

Welcome, Matt.

Matt D’Onofrio, CEO, Evoke Pharma:

Hi. Thanks for having me.

My pleasure. Thanks for joining. And so, Matt, let's just go ahead and dive in. Can you tell the folks who may not be familiar with gastroparesis what it is and the kinds of patients who tend to suffer from it? And what are the implications for drug delivery, both for things to treat it and other medications those folks might need to take?

Absolutely. Gastroparesis is a disease that affects the function of the stomach. It typically occurs in people who have longstanding, poorly controlled diabetes, but it can happen in other people, as well. It's also predominantly female; unfortunately, a number of gastrointestinal diseases are. And usually, if the person does have diabetes, as an example, the nerve damage associated with that can affect many parts of the body: the kidneys, the eyes, heart, other things.

But it can also affect the stomach. And when that occurs, the stomach doesn't function in a normal fashion. So, for you and me, who may have a normal emptying process: we eat breakfast at about 8:00 in the morning. The food moves down to the stomach, and then it goes through peristalsis over the next several hours and, around noontime, four hours later or so, it empties out of the lower valve in the stomach into the intestines.

And that's where you absorb your nutrition, hydration, that kind of thing. In people who have gastroparesis, that process is stunted or halted. It becomes very unpredictable. And it can create a lot of problems for the person because they may eat a meal, and that may sit in their stomach for several extra hours and sometimes extra days.

That leads to abdominal pain, nausea, vomiting, bloating, early satiety. Those are the key symptoms that are seen most commonly and the ones we often read about. All of these factors can then lead to a number of other issues — malnutrition, dehydration being the most common. And all of these things,  because the nausea can be so horrific and then vomiting, can be so difficult.

It can lead to loss of jobs, hospitalization, and a number of other, really difficult things to deal with in terms of healthcare. It affects around 2 million to 3 million persons in the United States, we believe — at least that many are seeking treatment.

And, unfortunately, once you get it, it doesn't tend to go away. In fact, it tends to just get worse over time. It may start off being milder. And then, as the years progress, especially if there is diabetes, the nerve damage tends to continue and then eventually becomes more and more severe. And the symptoms can be triggered by really almost anything, unfortunately — everything from stress, a sickness, eating spicy food, eating too much volume of food, phase of the moon [stated in empathetic jest], menstrual cycle — a whole laundry list of unpredictable factors that can trigger a flareup of symptoms.

And those flareups can occur for a couple of hours, a couple of days, and they may occur several times a week or maybe once or twice a month. It really depends on the patient. But we do know that these people have horrific symptoms that are really debilitating, causing them not to want to eat. And as we head into the [traditionally heaviest] eating time of the year — the eating season with Halloween and Thanksgiving and the holidays and all the different things that we do around those events — it all tends to surround food.

And these people really do suffer in that they struggle with, can I try to eat? What can I eat? What type of food can I eat? That kind of thing. Or, do I just suffer through the pain?

Got it. Yeah, so for folks who suffer from this, what historically or traditionally have been ways or attempts at treating it? To what success? And then, I know [that] you folks at Evoke Pharma do work on and have alternatives. So, can you trace a little bit of the history and trajectory of what's been done, what the patient experience has been like? And then, what are you providing to them to change that?

Yes, of course. So, the first-line treatment for almost every physician is a change in diet. That can mean smaller meals in terms of volume, more liquefied meals, sometimes even more blenderized meals.

It can also mean higher fat meals, believe it or not, to help get some of those calories into the system. A number of times, these patients do have a failure to thrive. They actually are losing weight in a dramatic way. Not all patients do, but a good number do. So, the first line is diet.

And there's also a difficult issue in that patients who have diabetes have a certain diet that they're trying to follow, but that may be really counter to what the gastroparesis diet may actually require. So, a lot of times they struggle with that, as well. After that, and very commonly, they move on to drug therapy.

And there has only been one product that's been approved by the FDA in the United States to treat these persons. It is trademarked or trade-named Reglan, otherwise known as Metoclopramide. It has been on the market since about 1980, so, believe it or not, a very long time. Apart from that, there have not been any other approved medications to treat gastroparesis or diabetic gastroparesis.

There have been other medications that are used to try to help with some of the symptoms. Very often, because these patients, their number one symptom that goes along with this is nausea, they'll have some kind of an antiemetic that's commonly given to them. Most often today it seems to be Zofran, which is now generic Ondansetron, which is a pretty potent anti-nausea medication.

And then they'll move on to other things, like erythromycin, which is an old antibiotic that has a side effect associated with motility that can be sometimes helpful in a very short term. And then after that, for the abdominal pain, they'll oftentimes, unfortunately, end up on some kind of opiate, which is really difficult because opiates, in and of themselves, slow down the GI tract.

And this delayed gastric emptying, which is what gastroparesis is, can be further delayed by that opiate to help treat with the abdominal pain. So, it becomes a bit of a downward spiral, unfortunately. All of these medications and others as well, they're all pills; they're all basically generic tablets. And all of these medications can have a difficult time being absorbed because they can't migrate through this dysfunctional gut, this dysfunctional stomach, to get into the intestines. And that's where we absorb medications; we absorb medications in our intestines.

There are really only a couple of handfuls of actual medications [that] are absorbed locally in the stomach. So, it's a bit of a misnomer. So, these patients suffering from these symptoms actively are trying to treat themselves with medications that are prescribed by their physicians. But then either a) they vomit out the medications before they get absorbed, which happens all too often. We read about these stories in online blogs. Oftentimes, they're difficult trying to get those things in.

Or b) they may sit in the stomach for hours, days, visiting physicians and talking to a gastroenterologist. They will frequently scope the patients to see what's going on in the stomach. And the protocol, as we all may know, is, you typically don't eat for about 24 [to] 48 hours. And there's a volume of liquid that's swallowed ahead of time to help clear out the whole GI system.

And these physicians report finding yesterday's breakfast and a whole stack of different medications, still sitting in the gut. And so, when you have this combination, the patient is suffering. They're trying to be compliant, but their stomachs are not being compliant. And that is really a difficult thing for these people.

The only other thing I'll say is, while these patients may be taking two, three, four medications just for gastroparesis, they're oftentimes dealing with other diseases or problems, as well, especially if this person has neuropathy associated with diabetes. They may be on antidiabetic medications, oral medications for that, thyroid pills, cardiac pills, a whole laundry list of other things.

And in our own Phase 3 clinical trials, the patients were on 12 different medications each, on average, all of which are being held hostage by this stomach that is not compliant. So, there's a laundry list of issues that can be exacerbated, we believe, because the stomach is not allowing the medications to get in and help treat those patients’ issues.

Gotcha. So, go ahead and tell us about the route of administration and mechanism of action for what you folks provide.

Sure. So, here at Evoke, we spent over a decade developing a nasal spray version of Metoclopramide. The oral tablet, we knew when it could get into the system, which these patients do often when they get in the hospital, they get this medication via IV, being fed directly into the vein.

We know [that] when it gets in, it can be effective. And so, by developing a nasal spray, we felt very convinced that a non-oral route would have, not just a benefit in terms of it being convenient, but a real clinical benefit to the patient that potentially could improve their chances of getting treatment. And, in fact, after we had developed this and had it on the market, we more recently have conducted what's called a real-world evidence [RWE] trial.

We went to a retrospective database analysis of patients who were on the nasal spray version, about 250-some-odd patients on nasal. And then we compared them to another 250 mirror-imaged oral patients. And over six months of time, the difference in the usage of hospitalizations and ER visits and other, what we call healthcare resources, was dramatically different.

The patients who were on the nasal spray went to the ER specifically 60% less than the persons on the oral, and then also went to be admitted into the hospital 68% less, both of which were very statistically significant: 0.005, 0.007 as a p value. These are incredibly strong results, indicating that just by changing the route of administration for this particular disease, you can actually have a real clinical benefit for the patient.

It's not something that's typically thought of because the vast majority of our medical practice and medical activity revolves around providing oral medications to treat whatever it is. But for the person who suffers from delayed gastric emptying, or gastroparesis, it may have a direct, situational event occurring so that those people are not being able to be treated correctly.

So that's why Gimoti^®, which is the branding of our product, we believe is really important. And it really highlights the concept of the need for alternative delivery as a concept for the topics that you discuss on your platform.

So, Matt, it might be helpful if you could describe a common scenario in the patient landscape, an actual experience from a patient perspective.

Yes, absolutely. I'm really fortunate in that we do get a number of descriptions of patients from our sales force and from the physicians that they're working with to try to help these persons. More recently, we just heard a story about a young man in his 20s who — he was under 100 pounds and had been to the hospital like eight times in the recent six months, or something of that nature.

And he and his mother were really at wit’s end. He was diabetic. He was having trouble ingesting food, a failure to thrive. There was just — he was losing weight and very, very, symptomatic. And the nurse practitioner, I believe, had put the patient onto Gimoti^® and two months had gone by when he returned back for follow up, and the staff was floored.

He had gained nine pounds over that two months’ time frame which, if you're under 100 pounds, that's really dramatic and really showing that he's starting to actually be able to capture calories. And he had not been back to the hospital. And that was two months, which the prior time he had been in and out frequently. So, the family was thrilled, from what was reported to me. And hopefully, he's now being able to launch into his young adulthood.

We hear these kinds of stories, especially [that] patients are nauseated, vomit quite frequently. There’s another example of a person who was wheeled into an office with literally a bucket on her lap, and she was vomiting into the bucket as she was being wheeled in to see her gastroenterologist.

And they had a sample of Gimoti^® in the office. They gave her a dose there. And it did stop the symptoms pretty quickly. Now, these are all anecdotal. There's not a lot of — our clinical trials aren't capturing things in terms of an immediate basis. But these are just things that help show that having an alternative delivery for these people who had tried oral medications, they didn't work, you can get benefit by trying something that's not oral.

Well, it sounds reassuring and inspiring. So, thanks for sharing those examples. As we look either broadly across the current landscape or out onto the horizon of the future in terms of patient needs and therapeutic areas, are there other things you're looking at or other possibilities and opportunities out there that some of these advances in delivery could address?

Well, I think we're seeing that happen already. There are examples today. Even in the nasal spray category, we're seeing some other medications come forward. The neffy^® is the product name associated with anaphylactic reactions — peanut allergy, these kinds of things. So, instead of using an injection or things of that nature, it's much more — it's a nasal spray that's come onto the market.

So, there are other of these alternative treatments that are being looked at. There are different rationales to do so, and I think it makes a lot of sense. A lot of times, nasal sprays enter the bloodstream much faster than oral medications. This was given, by example, boy, many years ago when it came to migraine products that were given as oral medications.

In fact, as another example, migraine patients: They go through what's described as a gastroparesis-like event. When they go through a migraine, their stomach kind of shuts down, which is why it's so important for migraine patients who are taking oral medications to try to get them in very early, or as early as possible, because if they don't, it won't get into the system in time, which is why they developed both the nasal spray and injectable versions of Imitrex and other migraine products many years ago.

And it was really directly because of the delayed gastric emptying issue that the stomach can create in these situations. So, I do believe that there is a real need for examining a patient clinically and the specific disease for this delayed gastric-emptying scenario.

The other piece of this that's coming forward today is GLP-1s. GLP-1 medications, better known as Ozempic^® or Mounjaro^®: It has been pretty well characterized that these medications do, in part, act by creating delayed gastric emptying in those patients. It may help them to be a little more satiated and not feel as hungry as quickly. But we also have seen that there has been a significant rise in gastroparesis awareness or diagnosis because of it.

And the gastroenterologists that we call on through our sales force report seeing a number of patients who are diabetic, maybe had gastroparesis, where this now unmasks it. And so, because of the numbers — the huge volumes of people who were taking GLP-1s — I think we need to be careful about thinking about those patients, how we treat them with what medications, and especially what route of administration if their stomach is not emptying.

This is already being addressed through anesthesiologists who are concerned about certain surgical procedures, especially elective procedures, and how they usually have to have the patient make sure they're not aspirating food in their gut. So, there's a number of implications around GLP-1s and delayed gastric emptying.

And we believe that, especially the most recent data we showed, once again, Gimoti^®, our product, way outperformed the oral product in helping those patients stay out of the hospital, stay out of the offices and things of that nature, by using the nasal versus the oral. So yet again, delayed gastric emptying, I think, is something we need to be aware of, especially with the GLP-1s taking over the market space.

All right. Great. Well, I want to thank you, Matt, for joining me to share your perspective with our audience on treating gastroparesis and other potential applications of nasal spray delivery, and advances in that route of administration. And with that, we'll close. And I want to thank our audience for joining us for Sit and Deliver. We'll see you next time.