Co-Founder and Chief Scientific Officer Dr. Vishal Bansal: Oxeia Interviews, Part 2
Dr. Vishal Bansal is the Director of Trauma Surgery at Scripps Mercy Hospital in San Diego, California. While at the University of California San Diego, he discovered a treatment potential of OXE-103 for concussion through his work on the neuroenteric axis and brain injury. OXE-103 is a synthetic form of the hormone ghrelin that is known for stimulating appetite. Dr. Bansal is the Co-Founder and Chief Scientific Officer of Oxeia Biopharmaceuticals, which is about to launch a phase 2 clinical trial of OXE-103 as a medication for concussion patients.
We also interviewed Mr. Wyand, CEO of Oxeia, who discussed the history of Oxeia, the challenges of being the first potential drug for concussion to go through the FDA review process, and more.
Concussion Alliance Co-Founders Malayka Gormally and Conor Gormally, and Leadership team member Julian Szieff interviewed Dr. Bansal in March about his work with OXE-103 and upcoming clinical trial. The interview has been lightly edited for clarity and adapted for the Web by Shelly Seth, with additional editing by Galen Moller.
Why does OXE-103 Have an Advantage Over Other Types of Treatments Being Researched?
Malayka Gormally
We see many new, early-stage research studies looking at different substances or drugs that they could introduce into the blood and brain that would help in this acute or subacute stage. I'm sure you're aware of some other things researchers are working on. Can you speak to why you think OXE-103 has an advantage over other treatment types that you see?
Dr. Bansal
That's a great question, and this is actually where we feel the strongest. There are several reasons for that:
(1) We are using a natural endogenous hormone so that eliminates all kinds of questions about whether this is safe, and whether humans can tolerate this. If the patient is hungry right now, they have higher levels of ghrelin in their body. That's something that we know has a significant safety profile and effect.
(2) Ghrelin has been used in clinical trials in the past, but ghrelin was being used for anorexia because everyone thought, "This is the hunger hormone, so we should use it to make people hungrier and eat more." And that's true, in the ghrelin clinical trials, people ate more. The benefit of these trials for us is that in these several hundred patients who underwent ghrelin therapy, we now have a huge safety profile. In terms of drug development, safety is first and foremost. We've passed Phase 1, which is really looking at human safety. That's one huge stepping stone, and why our medication, our therapy, and our drug development is way ahead of the curve.
(3) Finally, unlike a lot of other drug developments that look good in a lab in mice, not only do we have the mouse data, we have the scientific data through a broad spectrum of neurologic diseases. Ghrelin has significant effects in Alzheimer's models, Parkinson's models, ischemic models, hypoxia models, traumatic brain injury models, mild traumatic brain injury models, and subarachnoid hemorrhage models. Ghrelin also has significant effects in a wide variety of animal species. We have also shown that in humans, there's a significant positive effect of having higher ghrelin levels. And a study that came out in 2014 in the journal Peptides looked at patients who all had a mild traumatic brain injury. Of those patients that had higher levels of serum ghrelin at the time of injury, ninety days later, they had significantly less cognitive dysfunction than those with lower levels of endogenous ghrelin.
Now, unfortunately, these researchers weren't looking very specifically for treatment. They're all looking for a biomarker to assess who will have better cognitive functions, and who wouldn't. And their assessment of cognitive dysfunction was not up to industry standard. It was various cognitive tests, memory tests, reaction time, mathematical problems, etc. Nevertheless, for patients who have higher levels of ghrelin, they looked at 15 or 16 different biomarkers in hormones, including insulin, cortisol levels, a growth hormone, etc. Out of all hormones, only higher levels of ghrelin was congruent with less cognitive dysfunction three months after your injury. And that was pretty profound, that showed that we're onto something here.
This, coupled with all of the different data, the safety profile, the safety marker, the Phase 1 data, the fact that this is a natural hormone, the fact that this has been used in numerous models of brain injury, really makes us very confident that we're going to have success in the clinical arena.
What is the Neuro Molecular Mechanism of Ghrelin in the Brain?
Julian Szieff
I was wondering if you could walk us through your understanding of the neuro molecular mechanism of ghrelin or the OXE-103 activity in the brain as you understand it?
Dr. Bansal
I think that this is also developing. The first thing I have to say is that ghrelin is a hormone. And just like other hormones in our body, it has a pleiotropic effect. A pleiotropic effect means that there is not a single mechanistic effect -- that "It does this, and this is what happens, end of story." It does many things, all of which are interconnected and related. All hormones, whether it's Synthroid, insulin, epinephrine, or norepinephrine, have multiple effects in the body. Ghrelin is by no means any exception.
One thing that we know about ghrelin is that it binds to a specific receptor on most cells. That receptor is called "the ghrelin receptor" or "GHS-R receptor." That receptor tends to be mostly concentrated in the brain, specifically the hippocampus, the brain's central memory region, which is very interesting. When looking at MRI imaging in athletes with concussions, it's the hippocampus that is probably the most affected in terms of degeneration. So it is very interesting that ghrelin has many receptors, and the richest receptors are in the hippocampus in the brain. By binding to these specific receptors, ghrelin, a G-protein coupled reaction, increases the number of mitochondria in the brain.
Now, why is that important? Mitochondria is essential for regulating energy consumption of the brain. [An aspect of concussion pathophysiology] is hyperactivity of mitochondria in the affected brain, leading to an increase in reactive oxygen species, which then causes free radical formation and brain damage that you won't necessarily see on imaging. But, you certainly see this in the symptoms: ongoing headaches, difficulty sleeping, and memory problems.
We see three reactions from increased ghrelin:
(1) Ghrelin checks that process by increasing the number of mitochondria, thereby decreasing the overall ratio of bad [hyperactive] mitochondria to healthy mitochondria and leading to improved overall homeostasis in the brain.
(2) Ghrelin causes a direct increase in hippocampal synaptic density. In several animal models, we've seen that when ghrelin is introduced, the hippocampus itself has increased connectivity and increased neuronal health. Ghrelin has a direct effect on hippocampal activity and hippocampal health.
(3) We're beginning to see more and more data on the axonal connections. Ghrelin increases axonal connectivity, not just in the hippocampus, but also in the midbrain and in the cerebrum.
So ghrelin produces a combination of reactions. Ghrelin improves the overall glucose homeostasis and energy homeostasis in mitochondria, increases the hippocampal synaptic density, and increases synaptic and axonal connectivity. I think those are probably the three most likely bio pathophysiology mechanisms of ghrelin, all three of which, by the way, are affecting concussion.
What Effect Does Ghrelin Have on the Blood-Brain Barrier?
Julian Szieff
I've also been looking at studies talking about the blood-brain barrier. How did the actions you've just talked about relate to the blood-brain barrier? Are these two different mechanisms?
Dr. Bansal
When I first started doing this research, that was actually a very important aspect. We looked at the blood-brain barrier, specifically looking into whether it varied in relationship to ghrelin. This is because we've shown that the connection in the gut and the stability of the gut is actually improved by ghrelin following severe TBI as well. I focused my attention to the blood-brain barrier, and we found and published that ghrelin reduces blood-brain barrier extravasation [leakage of blood and serum into the brain]. We think it may have to do with secondary inflammation, but we're not entirely sure. It also may have to do with two specific proteins, ZO-1 and Occludin, that help maintain blood-brain barrier stability.
We think ghrelin has an effect on these proteins. The exact effect on why that occurs is a little bit unclear to us, but ghrelin definitely increases blood-brain barrier stability after TBI. There are lots of different occludins and ZO-1s, so we look at those specific molecules related to the blood-brain barrier. We also looked at Aquaporin 4, which was the one that really seemed to have an effect by ghrelin. We published those results in the Journal of Neurotrauma back in 2012.
Julian Szieff
Fascinating. We're still working out a little bit more of our understanding of how that is mediated, but the thought is that it is mediated through those proteins is very interesting.
Dr. Bansal
Yes, we definitely saw those proteins mediated in the gut. We're presuming that those proteins would have some effect in the actual blood-brain barrier itself. When we looked at the blood-brain barrier stability, we were mostly looking at blood-brain barrier dysfunction, which is to say the degree of extravasation of blood and serum into the brain after TBI. Ghrelin definitely reduced that for sure.
Conor Gormally
I saw that the ghrelin basically reduced a three-fold increase in vascular permeability back to sham levels in one of your earlier mice studies.
Dr. Bansal
Exactly.
Malayka Gormally
I remember that several recent studies show that people with persistent post-concussion symptoms have dysfunction in their blood-brain barrier. [See our 7/9/20 and 12/12/19 newsletter editions, in the Diagnostics section.]
Dr. Bansal
That was the point. DTI [Diffusion tensor imaging] is looking exactly at that. That's why there is a great deal of excitement in DTI.
What is the Clinical Trial Design and Target Sample Population?
Julian Szieff
We were wondering why the clinical trial is designed this way? Specifically with the 14-day parameters and which measures you're specifically looking at with your patients.
Dr. Bansal
We've been going back and forth for three years, trying to find the ideal trial for ghrelin and OXE-103. The real problem is trying to figure out the metrics to measure successful therapy. Around 80% of patients that suffer concussions, their symptoms resolve within seven days. That resolution makes it even more difficult to identify which patients would benefit from therapy and see its effects. So it took us a long time to find the best way to do this trial effectively.
We finally concluded that those that would benefit are those with the highest burden of symptoms. The data and the literature continuously and consistently report that those who continue to have high levels of symptoms at the seven-day mark and beyond are those who likely will have the highest level symptoms at 30 days and beyond. And that, after all, is the target population that we want to see the effect on; those patients are hampered in their daily living activities, who continue to have symptoms and are no longer able to go to work or have effective schooling. So that's why we chose what we called a "subacute population."
We are not looking at PCS [post-concussion syndrome]. We are looking at potentially preventing PCS and or ongoing clinical symptomatology that could affect daily lives. So this is what I would call the subacute or Pre- PCS population. And specifically, we are targeting those patients with a significant burden for whom this drug would have a great deal of beneficial effects.
Malayka Gormally
The 5th Consensus Statement on Concussion in Sport defines persistent symptoms as those lasting longer than two weeks in adults and four weeks in youth. And you mentioned that 80% of patients have their symptoms resolve in seven days. So are all those numbers what you're looking at?
Dr. Bansal
Yeah, I would say it is that. We have to be careful about what the international organization says vs. what we see clinically. When we see patients entering the clinic arena but have a high symptom burden, we have to put a stake in the sand and go with it, which was at the 14-day mark. If you do not see a significant drop in symptoms after that mark, then that's the target population that we want to use for our drug. Biologically, the brain's ongoing effects are still in the acute scenario where the brain is still adding significant metabolic dysfunctions, significant mitochondrial activity, significant glucose, and glucose energy dysfunction at the cellular level. So this all works biologically and fits well with our thesis that ghrelin affects the metabolic activity of altered neurons and axons following concussion. If a patient is having ongoing symptoms, we believe the metabolic alterations of the brain are ongoing. Ghrelin, via its mitochondrial activity, improves these alterations.
Will the Clinical Trial Make Use of Imaging?
Conor Gormally
We talked a little bit with CEO Michael Wyand about the study's structure and the cognitive measurements that you guys are taking with the iPad tools. And he also mentioned some symptomatology and imaging. We'd be interested to hear what kind of imaging you're planning.
Dr. Bansal
The imaging is definitely a moving target. The problem is as follows: I have been in the TBI research space for the better part of 15 years. In general, outside of CT scans for looking at hemorrhage, and MRI ... for diffuse axonal injury, imaging has been relatively unuseful for the majority of concussions. It's still very much in the research space. Rather than target and look at imaging as one of our endpoints, we decided to use imaging for any other clinical criteria.
So our clinical partners would continue to use imaging for the clinical need. For instance, let's say a patient is now having significant ongoing headaches for 14 days, more so than they reported in the past. That might be indicative of a delayed bleed in the brain. So that patient would undergo a CT scan, which would be part of the image captured in the trial, but not specifically an endpoint. And that is the specific imaging that we would necessarily have as part of the trial.
Julian Szieff
It sounds to me like you guys are using imaging to rule out other things like brain bleeds, other things you would be worried about.
Dr. Bansal
That's exactly right. The majority of the patients that we're going to capture will have already presented to an emergency department immediately after their injury. In the initial presentation, if there is any change in the sensorium (the definition of what a concussion is), I'm going to get a CT scan of those patients.
[In medical discourse, sensorium refers to "the unique and changing sensory environments perceived by individuals. These include the sensation, perception, and interpretation of information about the world around us by using faculties of the mind such as senses, phenomenal and psychological perception, cognition, and intelligence." Also, "Captured" patients mean that they have already been identified for expedited inclusion into the study.]
I don't think there's a single patient that I've ever not gotten a CT scan on when there's a change in sensorium. But, there are a select few patients where we do see intracranial hemorrhage. We want to know about those because they can worsen, and they can be followed. The vast majority of these patients we'll be seeing and enrolling in our trial will have had a concussion based on their clinical presentation. So I would suspect that many of these patients will have a CT scan.
How will Oxeia Recruit Participants for the Clinical Trial?
Julian Szieff
I know that the idea is to pull from an emergency population and have them work with an outside neurologist. So I'm wondering if you guys have any worries about your recruitment of those patients who just had a concussion? Most likely, it's their first concussion -- would they want to immediately enroll in a clinical trial?
Dr. Bansal
I'm always worried about recruitment. It doesn't matter what study I'm doing. I've been part of several drug trials—both as a principal investigator and a sub-investigator in participation—and enrollment is always an issue. I'm always worried about enrollment; therefore, feasibility is extremely important. As a company of our size, which is small, we have to have a feasibility trial. Our upcoming Phase 2 trial will function as this, as well as being a proof of concept. So that's an important caveat that you mentioned. And I'm happy you mentioned that.
To clarify, we are not enrolling patients directly from the emergency department. We are enrolling patients who have already been through the emergency department and are now seeing our clinical neurologist. This clinical neurologist is part of a large concussion center and a concussion foundation. These are patients who have already gone through the emergency department setting, have already been referred to a neurologist, and are seeing this neurologist as an outpatient. So we've already crossed that emergency room barrier. These patients have already cleared the kind of logistical hurdles and clinical hurdles, and therefore, they were prescreened. That was a huge barrier that we as a company crossed.
Further, subjects must be screened for seven days after they enter the concussion clinic. If they have ongoing symptoms, they are eligible for enrollment. Subjects must have sustained a concussion within 28 days before enrollment. We finally got to the point that those enriched patients* have ongoing symptoms that are already captured in a concussion expertise office with a specific concussion neurology expert. That made a massive difference in terms of feasibility. This is a large, well-respected concussion center. We have numbers that we feel we'll be able to meet at enrollment, and we plan to finish the trial within 12-16 months, being very conservative. We're optimistic that we'll be faster. So we think the numbers will be quite good, and we will take numbers of only about a 40 to 50 percent recruitment rate. So we're already being very conservative in our numbers.
["Enriched" patients are those that have been selected for a specific characteristic; in this case, symptoms lasting 14 days after injury.]
Conor Gormally
Michael mentioned two trials that you guys are looking at running. And the first trial is the one that you were just talking about with the established, pre-logistically cleared patients in that subacute phase without any signs of spontaneous symptom resolution. He also mentioned a potential second trial that sounded like it was much more focused on acute and directly from the ER.
Dr. Bansal
That's correct. Initially, our goal was to do our study through the emergency department or an emergency setting. But because of the variety, the variability, and all the factors I mentioned, we thought that would be less feasible as an opportunity than a captured concussion population. So that's why we're starting with our folks. We raise money adequately and have everything ready to go for the subacute concussion population.
Still, it is our goal as a company, once we have the funds, to go ahead and target that acute population. Knowing that we'll have to recruit from multiple centers and emergency departments because of the issue mentioned before about recruitment, and the fact that the population is so diverse, we'll probably have a certain degree of attrition. That study would be study number two and would require additional fundraising and additional clinical partners. We have the partners already identified, and we're developing the protocol as we speak. So we're excited once we raise the money to do so, to do that second trial.
Conor Gormally
I'm sure that the timeline on data collection on that second trial would have to be probably much more expansive than on the first trial because you have to anticipate so much loss of follow-up and trouble with recruitment. I can imagine people saying, "Oh, I just got this concussion today -- I want to see if it resolves first."
Dr. Bansal
I totally think that's the case.
What gives OXE-103 an Advantage in the Clinical Arena?
Conor Gormally
We were looking through preliminary stuff from your research on ghrelin in the mice models, in your animal models. We noticed that at least in four different studies, you were working with a weight drop model, and it's specifically creating severe TBI in mice. I know there's a huge amount of transition from animal trials to the human clinical trial just in anything. But, I'm wondering if you have any concerns about treatment mechanism, efficacy, transitioning from an animal model to a human model, and from a severe TBI model to a mild TBI model.
Dr. Bansal
We started looking at ghrelin more clinically; we thought ghrelin would be better suited for a mouse model of a mild patient population rather than a severe patient population, because of the need and the number of concussion patients. I actually switched my research and started using the close cortical impact model that basically uses a small little gun instead of a weight drop model. This model specifically and directly impacts the brain in a mild fashion. You can adjust the impact to what's considered a standard mild model. We presented that data showing that ghrelin significantly decreases reactive oxygen species in a mild TBI model at the 24th Military Health System Research Symposium in 2016. We kept that on the back burner as we didn't want it to get published until we secured our patent, but that has now been published and made public.
To further go with your human concept. This goes back to the several scores of manuscripts that have been showing how ghrelin has significant effects on human mental well-being, whether that be improving overall cognitive function or improving overall balance and motor scores, or improving sleep. So, we have strong human evidence that ghrelin is a therapeutic treatment. Now the question is how significantly will ghrelin help with a post-concussive population. All the science and the data make it very exciting, and we're optimistic that it's going to have a profound effect on patients following mild TBI.
Why is the Trial Focusing on Improvement of Symptoms Rather Than Biomarkers?
Malayka Gormally
I follow Dr. Chris Giza's Twitter feed, and he tweeted about a study by Roh-Eul Yoo et al. that was published in European Radiology, saying that the blood-brain barrier may be disrupted in patients with PCS. I know you're not studying ghrelin for longer-term persistent symptoms, but are you thinking that down the road that it could have some value for what is either called PCS or persistent post-concussion symptoms?
Dr. Bansal
For sure. It's one of those things where we have to decide what we're going to do at some point. And it gets so exciting when you think about all these potential avenues. I'll tell you a funny story. Back in the old days, when we first started this company, we were thinking of CTE [chronic traumatic encephalopathy]. And we thought that maybe we should start measuring GFAP [glial fibrillary acidic protein] right now, look at CTE, and look at CTE's myofilamentation process. We also wanted to look at the tau protein.
Then we started to scale back our excitement and thought, "What's really going to make our company succeed? What's going to allow us to get the FDA funding we need for the real trials?" And at the end of the day, the FDA cares about one thing: the improvement of symptoms. They don't care about imaging or blood biomarkers. It's nice that we have it, but if you're not helping the patient, it is almost irrelevant what their imaging or blood shows. So that's why we started to focus on symptomatology and specifically in the subacute concussion.
Dr. Bansal
Obviously, the first thing anyone is talking about to anyone these days is COVID-19. I'm the Chief of Trauma at Scripps in San Diego, and we have one patient in the ICU with COVID-19. Everyone is talking about chloroquine, right? This malarial drug that we've had for ten years. People were saying, "Oh, let's start the patient on chloroquine." And I sat at the meeting and said, "OK. We can absolutely start it, but what's your metric that this is improving the patient's overall symptoms?" And someone said, "Well, you know, that there are these great biomarkers that have shown that the biomarkers of inflammatory profiles of Interleukin 6 go down on a patient receiving chloroquine as published in China." And I said to myself, "yeah, but that was no effect of actually improving patients and patient outcomes. You might show that these biomarkers are dropping, but that has no relationship to whether patients are going to get home faster or sooner." And in that respect, we're talking about the same thing.
In this situation, there are drugs, therapies, and treatments that show an increase or decrease in biomarkers in a lab or a clinical setting. But if someone told you that your s100b level is better, your GFAP level is better, but you still feel like garbage, then it's almost irrelevant.
What are Oxeia's Challenges and Opportunities Moving Forward?
Conor Gormally
For you, what do you see as the biggest challenges to the trial in terms of potential, worries about side effects, or showing effects, or getting funding, or clinical adoption, or things of this nature that you feel might be barriers that you're looking at how to circumvent?
Dr. Bansal
I'm not worried about the side effects of the drug because it's well-established. So that's actually less of a concern for me. We already talked about recruitment. That's always a concern with any clinical trial; even though we're confident in the numbers we've seen, weird things happen. You know, COVID-20 could happen, COVID-50 could happen. That could affect recruitment and our clinical trial in numbers. Finally, number three goes back to our metrics that we're using for concussion improvement. Are our metrics appropriate? You know, after all the discussion we've had for the last five years, are we on the right track with metrics? Is the symptom reduction score the best score to use? Is the BrainCheck score the best cognitive test to use? We really don't know. We think it's the best, but we don't think there's anything better out there that we've seen, researched, studied, or discussed. But at the end of the game, we are establishing a new goal post here. Therefore, we could be wrong. I don't think we're wrong, but it would be arrogant of me to think that that's not a possibility.
Malayka Gormally
I understand that you don't want to disclose the clinic that you have lined up at least till you do a press release. It does make me wonder about the location because COVID-19 is hitting certain areas particularly hard.
Dr. Bansal
I think we have no problem divulging where we're going to do that. The only reason that we haven't is really more so than anything that the final documents have yet to be signed off. We just have to do a couple of paperwork and bureaucratic stuff. And then at that point, we have no problem at all discussing with you and telling you everything. I think the sophistication of your group will be very, very happy and very impressed.
Conor Gormally
Awesome. So glad to hear that.
Dr. Bansal
Once you get there, the story behind it is a great story.
Conor Gormally
We would love to hear it.
Dr. Bansal
It's these kinds of stories that make you think we're going to be successful because there's so much serendipity that goes into inventions and in terms of development. So this is one of those serendipitous moments that made us excited.