E77: Ophirex: Biting Back

About this Episode

Imagine you're exploring the great outdoors when, out of nowhere, you feel the fangs of a snake - a poisonous snake - breaking through your skin. Medical care is nowhere in sight, so you're left with the terrifying prospect of venom slowly infecting your body's critical functions.

This is the reality that roughly five million people face annually. From that number, approximately 500,000 either die, are permanently maimed, or suffer long-term cardiovascular/neurological impairments.

However, Drs. Rebecca Carter and Matt Lewin are working to change that. Their work at Ophirex revolves around further developing Varespladib, a repurposed drug, as an accessible and affordable oral treatment to instantly combat venomous snakebites. By ingesting a small tablet or capsule, victims can buy time to seek out more advanced care, giving them a better chance to limit complications and prevent death.

Join us as we explore the impacts snake venom has on the body, how Drs. Carter and Lewin discovered Varespladib, how collaborations and partnerships have benefited their development of this treatment, and what can be done to improve its accessibility, especially in remote areas of the world.

Show Notes

• Ophirex Lifesaving Antidotes
• Antivenoms - World Health Organization
• Interventions for the Preventing Reactions to Snake Venoms - National Institute of Health

• Podcast Transcript

  Mary Parker (00:00:00):
  Did you know that Charles River has a sister podcast, Eureka's Sounds of Science? Hi, I'm Mary Parker, the voice of Sounds of Science. Starting in the fall, Vital Science will fold into Sounds of Science, forming a unified podcast. We look forward to sharing more scientific, patient and advocacy perspectives on trending issues in drug discovery and development. You can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts.

  Rebecca Carter (00:00:30):
  Over 150,000 people every year die from venomous snakes, and three times that number - so somewhere around 450,000 people, are permanently maimed or have long-term complications as a result of snake bite. So wrapping your head around that number can be really hard for some people. Half a million people every year, a half a million people globally are either killed or have their lives permanently changed by result of an encounter with a venomous snake. And the reason that of Ophirex is here, our mission is to change that stat. We've looked at that stat internally and we've said "this is not acceptable." We have made significant advances in so many areas of medical care and have advanced our ability to care for many, many diseases, but not this one. The gold standard anti-venom has been around for over 125 years. It's great, it saves a lot of lives, but still we have this big unmet medical need.

  (00:01:46):
  And Ophirex was established because of that unmet need. And Matt's real idea, again, was to create a solution that was portable, that was oral, so you can take it. It can be taken regardless of the snake species and is able to provide a period of time for people to get to the hospital and to get advanced care. And we are all passionate is a word that is thrown around a lot, but sometimes passions fade and can change. And we are passionate. But I want to say we're committed. We are committed, and we get up every day to resolve this problem.

  Mary Parker (00:02:44):
  Imagine you're out on a hiking expedition, you've just been bitten by a venomous snake and realize that your closest chance at treatment is a week's travel to the closest clinic today. This is the stark reality for populations in many parts of the world. But what if you could reach inside your pocket and take a small tablet or capsule, one that could begin counteracting the venom before significant toxicity can occur? I'm Mary Parker, and in this episode of Vital Science, we sit down with Dr. Matt Lewin and Dr. Rebecca Carter of Ophirex, a biotech company developing an oral portable drug to treat snake bites around the world. We discuss why snake bites are a global crisis, the benefits of being a public benefit corporation, and how the Ophirex team hopes to save countless lives with their novel approach to snake bite treatment. Welcome to Vital Science, Dr. Rebecca Carter and Dr. Matt Lewin. We're honored to have you.

  Rebecca Carter (00:03:43):
  Thank you. We're happy to be here.

  Mary Parker (00:03:46):
  So can you tell us about both yourselves and your role at the company Ophirex?

  Rebecca Carter (00:03:53):
  Rebecca Carter. My background is in vascular physiology and I spent a good bit of my career as an active duty Air Force officer, and in that role I was responsible for developing medical solutions for special operations medical teams in their deployment capabilities. And that's really how I met Matt. So Matt,

  Matt Lewin (00:04:20):
  That was a very abbreviated Becky intro. Thank you.

  Mary Parker (00:04:24):
  Why don't you give us more details, Matt? We'd love to hear about it.

  Matt Lewin (00:04:27):
  Well, we can do so just by way of background, I'm an emergency physician by training and a PhD in neurophysiology. I got involved in this through being an expedition physician for almost 20 years and thinking about the types of hazards that occur in remote areas, which actually in parallel is very similar to Becky's background who could have unbeknownst to either of us working kind of along the same lines of what happens if personnel in the military get bitten by a snake, which is kind of the similarly hazardous and chaotic situations that could occur. So I founded this company because a predecessor of mine at the California Academy of Sciences was killed by a snake. And while preparing for expeditions, I was thinking, what am I going to do in this situation if somebody's bitten by a snake, there's no anti-venom or remote setting. And at the time I was just thinking about the expeditions and then became aware that this was a much bigger problem and by fortune met Becky at a cool sounding conference called Venom Week, and she said that she'd been thinking about this for a long time and having seen the data that I had at the time, would I be interested in working with her group to advance this?

  So I think it is been a really kind of a cool story of parallel lines meeting.

  Rebecca Carter (00:05:58):
  It was interesting while he was starting to think about this, I also was working, I was at the time in the Air Force working on medical solutions and I had a special operations team member that had recently been deployed to Africa and they came back and said, there's got to be a better way. We need a better solution than what's out there right now. At the time, Sanofi was considering stopping their production of Fab Aric, which was the primary anti-venom for Africa. And it was a major problem not just for military members but for everyone in that region of the world, the WHO, the World Health Organization was also considering making snake byta neglected tropical disease. And when I first heard about this problem, I really didn't understand the extent of the global health issue, but as I learned more about it, it really became an intriguing issue.

  (00:07:06):
  Anti-venoms are the gold standard and really have saved many lives for lots of years. But when Matt and I talked, we decided there had to be a better way. And Matt's idea, foundational idea of really turning the concept, the paradigm of snake bite treatment on its head and providing a treatment that can be administered at or near where victims are bitten rather than requiring victims to come to treatment as they have to with anti-Venom really caught my attention and as Matt said, we met in 2014 and we've been working together on this problem ever since.

  Mary Parker (00:07:57):
  So Becky, you mentioned that you have vascular physiology training, and Matt, you have neuro training and I know snake venoms behave in different ways, but from each of your different backgrounds, how does snake venom affect the body in those systems? Matt, you want to go first?

  Matt Lewin (00:08:16):
  Sure. So clinically what you see, and depending on the type of snake that's bitten, you can see something that's purely neurotoxic, which is sort of the bent I come from, which is what happens when transmission between nerves and muscles is interrupted and the patient will become weak and in a severe bite will die without treatment. Or you might see something more in Becky's realm of expertise, which would be cardiovascular collapse or bleeding. And some of the venoms are mixed, so you'll see both weakness and bleeding or tissue destruction. And so these are very complex problems. There are hundreds of different venomous snakes along this spectrum of pure neurotoxic, pure he MotoX or bleeding causing bleeding or abnormal clotting or you see a lot of them right in between. And so at least our areas of expertise are quite complimentary in this and fortunately we have somewhat different interests so we can easily keep each other's interests alive.

  Rebecca Carter (00:09:30):
  I think that's right, Matt. I think it was certainly not intended that we came at this problem from different areas of science background, but it has been very helpful to us over time that Matt has had really firm foundation in the neurotoxic areas and my specialty has really been more associated with the hemotoxicity and cardiovascular collapse.

  Mary Parker (00:09:58):
  Today, Ophirex is a biotech company with a mission to develop an affordable, accessible oral treatment for venomous snake bites. But it didn't happen overnight. The company began when Dr. Lewin discovered a promising molecule for treating snake bites. He published a paper on the molecule but unfamiliar with the complexities of drug commercialization, soon realized that he would need partners to help him obtain a patent and establish a business structure. In joining forces with Dr. Carter and later CEO Nancy Koch, Ophirex became a public benefit corporation, or PBC, with a dual mission to make a drug that is both commercially viable and globally accessible. The PBC structure assures stakeholders that the company's mission to provide accessible treatment is genuine as it is ingrained in their DNA. This foundation was crucial in gaining support and moving Ophirex forward. Let's hear more about how Ophirex hopes to make its drug both accessible and portable.

  This one I might go over to Becky for, since you have experience out in the field and you know how difficult it can be in chaotic situations, I imagine that a big goal was to create something that was going to be portable, something that could be used right away. I understand time is of the essence if someone gets bitten. So I assume that the treatment involved isn't something that needs to be handled with kid gloves, so to speak.

  Rebecca Carter (00:11:23):
  Right? You put it very well and really synthesized a lot of what we're working on in order to give you and your audience, I think a better context as we go into this. It's important to really recognize the global health need for snake bite in general here in America. And for those of us who came to snake bite, for example, when I came to snake bite, I thought, well this isn't a problem. Why are we dealing with this? And here in America? And then frankly in many, many developed nations, we have ready access to medical care. We do have venomous snakes, but we have good anti-venoms available and it's not an issue that many of us think about, but globally, this is a big public health problem. Over 150,000 people every year, every year die from venomous snakes and three times that number - somewhere around 450,000 people are permanently maimed or have long-term complications as a result of snake pipe.

  (00:12:34):
  So wrapping your head around that number can be really hard for some people. Half a million people every year, a half a million people globally are either killed or have their lives permanently changed by result of an encounter with a venomous snake. And the reason that Ophirex is here, our mission is to change that stat. We've looked at that stat internally and we've said "this is not acceptable." We have made significant advances in so many areas of medical care and have advanced our ability to care for many, many diseases, but not this one. The gold standard anti-venom has been around for over 125 years. It's great, it saves a lot of lives, but still we have this big unmet medical need and Ophirex was established because of that unmet need. And Matt's real idea again was to create a solution that was portable, that was oral, so you can take it, it can be taken regardless of the snake species and is able to provide a period of time for people to get to the hospital and to get advanced care. And we are all passionate is a word that is thrown around a lot, but sometimes passions fade and can change and we are passionate, but I want to say we're committed. We are committed and we get up every day to resolve this problem.

  Mary Parker (00:14:20):
  I mean, I think that leads perfectly into the next question: what drives the important work at Ophirex? But like you said, it's the people that need it.

  Rebecca Carter (00:14:31):
  It is. I think Kofi Annan, the former Secretary General of the United Nations may have put it the best and he called snakebite the biggest public health crisis you have never heard of. And what drives not just us, but our partners is the desire to resolve this problem. And I do firmly believe that we have the ability to make a difference in people's lives and that's why we're here. Ophirex is a very small company and the majority of people are kind of like Matt and I, who have come to Ophirex from other careers and we have either retired or stopped our previous career and come into this job to say this is our mission, this is what we're doing and we're not going to stop until we've resolved it.

  Mary Parker (00:15:30):
  That's amazing. So let's start with Matt on the next one. What accomplishment are you most proud of at Ophirex?

  Matt Lewin (00:15:37):
  I would have to say the team that's been recruited, it's astonishing If you work in any sort of situation anywhere you work, there's always, it is hit or miss how you put a team together. So I have to say as a person who's not experienced at this, I feel like I've been incredibly lucky to be able to recruit the people we've recruited and build the team and then have that team build their teams and see this cohesion run through the company. I would say is for me certainly the most unexpected. I think scientifically I feel pretty confident, but in terms of building a program, I'd never done it. And so I think the early decisions that were made, which to bring in Nancy into bring in Becky, would have to qualify as a real achievement.

  Mary Parker (00:16:31):
  So this goes back to your previous point, Becky, but I'd like to hear from both of you on this. So globally there are several populations and communities that live in proximity to venomous snakes. Can you share your perspective of the bigger problem, which it sounds like the bigger problem is that not enough people are aware of the situation?

  Rebecca Carter (00:16:50):
  That's a great question. Certainly when you consider the amount of work that has been done in other areas, the amount of support that snakebite has gotten has been low and that is a problem, although I think that's changing. One of the things that Matt did very early on was focus on ensuring that not just what we are working on as a company, but what others are working on to transform medical care for snake bite received a higher platform. And we started talking about this in better ways and he has done a great job with that, as have others. I think that the problem to your point globally tends to be unfortunately in lower and middle income areas, in areas where people do not have access to medical care or have very poor access to medical care, they tend to be agrarian. Many of victims are actually children or women and it affects the entire family. When people are bitten by snakes,

  Mary Parker (00:18:08):
  Certain regions are particularly vulnerable to snake bites. India often called the snake bite capital of the world has seen over a million deaths from snake bites in the last 20 years. This statistic isn't due to a lack of effort or medical care, but rather the critical delay between being bitten and receiving treatment. Africa also faces severe challenges with snake bites. Many people must travel long distances to reach medical facilities and there's a shortage of anti-venom which many clinics and hospitals lack. For instance, the Mesi Snake Bite Clinic is one of the few facilities in central Tanzania that has anti-venom. During a recent visit, a man arrived for treatment after a snake bite having traveled nearly a week from the other side of Lake Victoria to find experienced caregivers with the necessary anti-venom. These long delays in receiving care mean that the effects of snake bite venom become more severe and harder to treat, highlighting the urgent need for accessible and timely therapeutic solutions like the ones of Ophirex aims to provide. Let's hear more about how snakebites are currently handled in remote areas. Correct me if I'm wrong, but places that are agrarian or many developing countries or places that don't have a strong transportation infrastructure probably also have the most diversity of venomous snakes in the area and the largest populations of snakes because they haven't been driven out by urbanization.

  Rebecca Carter (00:19:35):
  That's right. That's exactly right.

  Mary Parker (00:19:37):
  So of the 450 species of venomous snakes, how many have a matched anti-venom?

  Matt Lewin (00:19:45):
  It is significantly less than half. And even if the anti-venom is matched to the species, it doesn't mean it will actually be effective. And to understand this, for example, in India, all the anti-venoms are manufactured using venoms from the south southern part of India.

  (00:20:07):
  Well those snakes in Southern India are millions of years apart from their snakes in the north that look just the same. But the venom has changed or the venom composition has changed. And so while they nominally might be the same, it doesn't mean that there is potent or as effective against venoms from a region. It doesn't mean that they will be as effective as if they were perfectly matched to a local snake from the south where the venoms were originally collected because the venoms evolve a lot faster than the snakes. So they do change over time.

  Mary Parker (00:20:44):
  I had never thought about that, but that is a really good point. I mean even snakes of the same species, there might be subspecies that have totally different venoms and therefore less effective.

  Matt Lewin (00:20:55):
  That's exactly correct. A match in name is not necessarily a match in efficacy.

  Mary Parker (00:21:04):
  So you mentioned earlier people having long-term effects. So what consequences exist if an anti-venom treatment is delayed?

  Matt Lewin (00:21:13):
  This is one I can speak from personal experience of treating patients. As Becky alluded to, far more people are maimed than killed, but 75% of the people that die from snake bite die before they get to care.

  (00:21:29):
  In my experience, of course most people don't die and we think, okay, you survived the snake bite, good luck. See you later. But those patients have long lasting effects. When I've started following patients for long periods of time, almost none of them recover immediately. We have good care in the emergency department, they get discharged from the hospital months or years of pain or scarring issues or swelling in the limb can affect them. And so I think Becky said it really nicely not long ago, he said, you can't judge the venom by lethality alone. So I think that not just the lack of effective anti-venoms, it's lack of access. That's the gap we're trying to fill. And I think Becky, maybe you can talk about that a little bit because I actually think it's a fascinating and largely I would say almost completely ignored area in the field of snake bite research because we were all fixated on survival, but that's actually not the most common. Death is not the most common outcome. It's actually disability infinitely more common.

  Rebecca Carter (00:22:41):
  Quality of life Following snakebite is a tremendously important topic that most of us haven't reached yet. We're very focused on getting people to the hospital and getting that immediate care. How do we do that? And then maybe we can take on quality of life after.

  Mary Parker (00:23:00):
  So as you said, under the current standard, a snake bite victim must quickly reach a hospital that has the correct anti-venom if it exists, and it has to match the snake responsible for the bite to the species, to the anti-venom. If the snake can be identified, leaving out the fact that someone who's just been bitten by a snake might not be able to tell the difference between a black snake with brown stripes or a black snake with brick red stripes. How does ovex revolutionize care in this space when there's a large unmet need?

  Rebecca Carter (00:23:31):
  I'll start this and then turn over to Matt. I think one of the things that I frequently have to say is we are not developing an anti-venom. The drug that we are is not anti-venom. It is not a biologic. It is not antibody based. It is not species specific. Anti-venoms are biologic. They are antibody based. They are produced based on the specific species that you have collected venom from and then injected that venom into large animals and isolated antibodies. Therefore, their scope of ability, their therapeutic bandwidth is a little bit narrow. We're developing raib and raib, as I mentioned, is very different. It is a synthetic drug, so it is not biologic and rather than being based on an antibody match to a specific venom, it is a direct inhibitor of secretory phospholipase-A2, which is a major toxin that is found in about 95% of the world's venomous snakes.

  (00:24:48):
  Therefore, what this means to you as a victim is you don't have to identify the snake. Most of us are not herpetologists, to your point, we can't identify a snake, we can't tell if that snake was a cobra or something else. And we are panicked and certainly many people also just want to say, I'm bitten by snake, just I don't care. Just give me what I need. In addition, as we mentioned, it is orally available. So we're developing this drug to be a tablet and this tablet you can carry in your backpack. You can imagine it in a kind of local care facility or clinic that may be in a more rural setting that would not normally have access to anti-venom. It's very easily administered and taken and will allow people time to get to the hospital. In addition, the drug that we're working on is very stable. It can be stored at any environmental conditions and doesn't require special environmental care like refrigeration.

  Matt Lewin (00:26:04):
  The only thing I would add is that when I started to think about the problem, these were the sort of criteria I was looking for. Something safe with a broad effect, easy to use could be manufactured at a cost that would allow it to be accessible once it was produced and of course would need to be stable in tropical and hot dry environments. So that was sort of how I went about looking for a molecule that could perform this task.

  Mary Parker (00:26:35):
  Varespladib is a repurposed molecule, yeah? It has an extensive development and safety record. And I see here that it was originally developed by Eli Lilly as an anti-inflammatory. So the FDA granted it fast track designation for the treatment of snake bites in 2022. How did you find this drug? What were you looking for that led you to this candidate?

  Matt Lewin (00:26:57):
  So again, I had what are the attributes of a molecule I'm looking for to avoid an accident like what occurred with the California Academy of Sciences expedition in which one of the scientists was killed by a snake. So okay, I need something as portable, broad spectrum, safe, stable. And the question I think you're really getting at is how would, and of course you have a disease that nobody's thinking about and that nobody's commercially interested in. And so for me, I was looking for a drug that was also either already FDA approved and nobody had recognized had the potential for this use or what's the next best thing, a drug that almost made it and there are a lot of data behind it and could serve this purpose. And so I couldn't find a drug that had been FDA approved and could easily be converted into a treatment. The compounds that I tested, this one really kept showing up as really promising. This was really what we were after and I think it helped move things along as they believed in our mission and were willing to support it. And so we got tremendous help from both those companies.

  Mary Parker (00:28:14):
  It sounds like the purpose of the drug is to control the symptoms long enough to get the person the correct treatment. Is that correct?

  Matt Lewin (00:28:26):
  Again, the gap we're filling right now is this immediate event you've been bitten, now you need to get to care and you need to have either a bridge to survival or better outcome. I think the true potential of the drug has not yet been fully realized or recognized. We don't know, right?

  (00:28:44):
  There are some venoms for which you can imagine this thing is loaded with phospholipase-A2 and maybe that someday will prove to be sufficient. We don't know that yet. For other venomous snakes there's less phospholipase-A2 and other toxins. Maybe we need to develop a second drug to go along with this one to better bridge that gap. But as a starting point to change how snake bites are managed, this is really keeps coming up as the drug that is recognized for accelerated development past this first hurdle as a field treatment and then we can incrementally improve it by adding other compounds and then maybe that gap gets that time to care gets better. You can have a little bit longer and in some circumstances someday in the future maybe it serves as a standalone, but we don't know that yet. That's why we have to do the science, right.

  Mary Parker (00:29:42):
  If it can get people to at least a week, then they can get from one side of Lake Victoria to the other like you mentioned. So that would be an improvement for sure. So what is Varespladib's mechanism of action?

  Matt Lewin (00:29:56):
  So interestingly, this gets to one of these things where luck plays a pretty good role in your scientific, you can't be proud of it, you just feel lucky, right? So when I first thought, okay, there's this target and it's got an enzymatic activity, you can block the enzymatic activity. And so the drug does this quite well. It blocks the enzymatic activity of the toxin as it turns out there are a couple of surprises with this. One is that there's at least one other binding site on these toxins that the drug binds to and it appears to block the actual attachment of the toxin to the target. And so it gives it a little bit more breadth than we expected in terms of its ability to block the toxin effects. And that means it not only appears to block the enzymatic toxin PLA A two, but there are mutants of PLA A two that are made by snakes that are not enzymatically active, that are also toxic and the drug appears to block that binding site and that's it.

  (00:31:08):
  We've published in collaboration with a group in Brazil, several papers with using x-ray crystallography to demonstrate that the drug is binding to multiple sites. The other surprise is that we saw some in animal studies using venoms with relatively low phospholipase-A2 is that the animals still did better than we expected because there were all these other toxins. And that suggests that the drug is interacting somehow with the host to prevent the response to the venom because a lot of this long-term injury is due to inflammation, fibrosis and other actions of the venom from just the sequelae of tissue destruction that are not directly related to the immediate action of the venom, but maybe the result of inflammation. And so it appears that there a couple of different ways this might be working to give it a little bigger breadth of effect. And again, with this emphasis on the majority of patients don't die, but they have long-term injuries and this may be a mechanism by which the drug can be beneficial.

  Mary Parker (00:32:30):
  The initial formulation of re's drug is an oral tablet and a sprinkle capsule. The benefit of a sprinkle capsule formulation is its flexibility. The capsule can be opened and sprinkled onto food like putting applesauce or yogurt, making it easier to swallow. This is the pediatric formulation and the tablet which offers a higher dosage is the adult formulation. The team is also working on an intravenous or IV formulation that can be administered in the hospital and would be particularly useful if a victim is unable to swallow or is having GI complications. This formulation is currently in a phase two clinical trial. The advantage of an oral treatment is its potential to be administered quickly even before reaching a medical facility. Venom effects start immediately and having an oral treatment on hand could allow the drug to counteract the venom's effects before they become severe. In most cases, this timely intervention could prevent serious harm giving patients a crucial headstart in treatment. Let's hear more on the potential healing effects of this drug. Does the jug have indications for other snake bite symptoms like for example, long-term effects or does it have indications for other species like scorpions?

  Matt Lewin (00:33:46):
  So again, the easy one is other signs of snake bite and venom. Again, if it is directly regulated by this phospholipase-A2, then I think there's a direct path where you can imagine that the long-term outcomes, both the short and long-term outcomes are abrogated. The first clue that the drug was doing something other than just blocking the enzyme was that in test tubes the drug does not effectively block B venom. And B venom has a high concentration of S spla two but is not the same shape as snake venom PLA two and the drug just doesn't appear to be to block the B venom except at extremely high concentrations. And yet when we gave lethal doses of B venom to mice, they survive. So what's going on here? It makes you think there's something about the response to the B venom going on in the animal that is causing the B venom to not be lethal. And so that was actually the first clue that there was this other mechanism in play that has yet to be elucidated. So whether it's scorpion, scorpions don't have a lot of A two in it in, but bees, wasps and ants are loaded with phospholipase-A2.

  (00:35:17):
  But experimentally we've seen this in the B venom experiments and other investigators and Asia have looked at what we call murder hornets in the United States, these large Asian wasps and they see very good effect of the drug, but I don't think it can be explained entirely by inhibition of toxin itself.

  Rebecca Carter (00:35:39):
  I just wanted to just say a quick add here that secretory phospholipase-A2 within snake venoms plays a number of different roles within toxicities and that includes neurotoxicity, hemotoxicity and cardiovascular collapse that you might see with lethality, but it also impacts myo toxicity and necrotizing toxicities that you would see for long-term recoveries. So you ask, well what about kind of long-term recovery? And it's important to think about those aspects of snake bite that impact long-term recovery and those are really focused on local wound and cytotoxicity and there are SPLA two molecules, enzymes in venoms that directly impact that those toxicities and directly inhibits those particular toxins. So hopefully that provides a little more context.

  Matt Lewin (00:36:42):
  I want to build on that a little bit. I think that's a good point. I think one thing we have not really discussed and maybe should have come up earlier is that phosphatase A two is a multifunctional family of enzymes. Some destroy muscle, some destroy tissue, some destroy neurons, and they all work by the same basic chemical mechanism, but they have additions to them that cause them to target certain tissues. And so it's a very versatile weapon for snakes because if your strategy is to paralyze, you just have to change one end of the molecule without changing the business end of the molecule and it's neurotoxic. You take that same machinery, you add a different peptide to it and now it goes to the muscle. And so that's why this weapon has been used over and over and over for tens of millions of years because snakes in North America use it, snakes in Africa use it, snakes in Asia use it, snakes in Australia use it, everybody's using it, bees are using it, and even plants use fossil lipase A two as part of their innate defense. This is a very ancient family of enzymes that tell you it's been both very successful and likely to be an important and desirable target for this purpose.

  Mary Parker (00:38:01):
  Do you think that people might benefit from taking the drug even if say they did get the antivenom quickly, would they still maybe benefit from taking it?

  Matt Lewin (00:38:10):
  One of the right, the fantasy is that you could come up with something, I'm going to just replace this older technology and that's not a realistic expectation at this point, but I think that what we have found and others have found quite consistently is that when you combine the drug with the anti-venom, they work better than either one would work alone, right? Each has attributes that are very useful. Varespladib is very versatile. You can take it in the field. It's extremely potent for this toxin that anti-venoms tend not to be very effective against, but anti-venoms have a long half life and block other toxins that cause damage. And so the overall effect is that there's a synergy between these two approaches. And so I think that what you'll find, what I predict, we don't have clinical data. We have a lot of animal data and a lot of laboratory data, but what I predict is that you'll find that this combination strategy will prove quite effective for a long time until technology advances where you could potentially have a completely synthetic anti-venom. But for the time being, I think this is a really big step.

  Mary Parker (00:39:20):
  Can you walk us through the manufacturing process for this drug?

  Rebecca Carter (00:39:25):
  Sure. I'd be happy to give you a little information because Varespladib is a synthetic molecule. It follows a very traditional manufacturing path and we have a significant advantage in this over anti-venoms that require snake colony to be maintained and milked or you have to actually go out and capture wild snakes and milk the wild snakes, which is very dangerous not just for the handlers but also for the snakes themselves.

  (00:39:56):
  Many of these snakes are endangered species and the very nature of trying to capture wild snakes and milk them, it puts them at risk. Following that, of course, the venom needs to be injected in small amounts in large animals like horses or even camels and allow the antibodies to build over time. And then of course blood is collected and the antibodies are isolated, thus creating the anti-venom. And our process, because it is a synthetic, is a much simpler process. It's standard chemistries and we're able to produce drug product in just a few weeks versus a much longer period of time and a much more complicated process that is required for anti-venoms.

  Mary Parker (00:40:49):
  So Ophirex is currently running the Broad spectrum Rapid Antidote, Varespladib, Oral, or BRAVO (which is much easier to say) study, for which it received full enrollment. Can you share more about this study?

  Rebecca Carter (00:41:02):
  Sure. I'm going to start and then turn over to Matt. So Bravo was the first of its kind study looking at snake bite envenoming across multiple countries. This was a phase two clinical study. We enrolled 95 patients from hospitals in the United States and India that had come in for treatment from snake bite envenoming. We did not require any kind of specific speciation - that is, we didn't require certain snake bites to be enrolled only that they exhibited certain symptoms of envenoming. And the trial itself, of course, it was not ethical for us to withhold treatment. We couldn't withhold anti-venom. So the trial evaluated Varespladib plus anti-venom in comparison to anti-venom plus a placebo. Our primary endpoint in the trial looked at the clinical improvement in multiple body systems from baseline, which is when patients originally were enrolled in the study to a very short period, which is nine hours post first administration of Varespladib. And unfortunately, we didn't hit our endpoint, but we saw really exciting positive signals both in ultimate recovery as well as in patients that received the study drug within five hours a bite. And I think Matt has more details that he can provide.

  Matt Lewin (00:42:35):
  I think. Well, I agree with Becky. This is a very novel study. It was a pretty typical phase two study. We got insights about what went well, what went wrong, and in our ongoing study we've learned the lessons of BRAVO and have focused our endpoints to highlight those signals that we believe are the most important, which of course are time to recovery and improvement. Even with the background of anti-venom, that was a big challenge because of course you have the treatment that's being given and now you need to find a signal over and above that. And Becky alluded to, we found those signals in this first phase two trial and this ongoing trial is honing in on those signals so that we can get the signal we need to show the efficacy. And what we saw, which was really the most exciting, and which again is the focus of the ongoing study, is that when patients got the drug early, so the closer to the bite that the patients got the drug, the bigger the signal.

  (00:43:45):
  So in the first trial we took all comers, maybe they got bit an hour ago, maybe 10 hours ago, and it was a little bit noisy in the signal when you looked at this group that got treated within five hours or four hours or three hours, they just did better and better and better. So in this study, we're focusing on that early group because this is the closest proxy we can get to a field treatment while still doing this in the hospital. And I think the outcome from that I think will highlight the potential of the drug much better than we did on the first try. As Becky said, it's a rough sport and so it would be nice to get it perfectly on the first try, but I think on this one we're going to nail it. That's my prediction optimistically.

  Mary Parker (00:44:32):
  I hope your prediction comes true. So even under normal circumstances, the drug repurposing journey is not always very straightforward. So being a small public benefit health biotech company, how do you manage your collaborations and partnerships to make it all work when you're working with for-profit companies?

  Rebecca Carter (00:44:52):
  This is in my mind one of the most important questions that we can answer as a company. Ophirex is a small business. We are public benefit, but we are very small. We have about 20 members. Actually, we just hired our 22nd member and he'll be starting in a couple of weeks, which so we're happy about that. We're celebrating, but that means that we don't have many hands. Drug development is a very complex, it requires a lot of expertise and a lot of hands, and we rely heavily on our collaborators and partners. I think Matt mentioned at the outset that one of the things that he was really proud of was our ability to create a team around this issue and that team to us extends to our collaborators and partners. One of the key partners that we have relied on over time, frankly has been the United States military, particularly US Special Operations Command and the US Defense Health Agency.

  (00:45:59):
  Their interest at a high level is to provide an important capability for service members who may be bitten by snake and they need to preserve life and limb. That is their stated purpose, but they also recognize that there is a significant global need and the support that they give us is really representative of some of the work that the military does in general to overall support requirements for the military that are extended into civilian sectors and play a big role in our ability to support health of community at large as well as global health for neglected tropical diseases. This is a role that they played over and over again and they are a critical partner for us. Specifically of course, they provide generous funding through the Defense Health Agency's small business innovative research program and we're supported by the US Army's Medical Material Development activity.

  (00:47:12):
  And they have worked strongly with us not just to provide funding, but also regular guidance and thought partnerships. They collaborate with us. They consider how to help us move through potential barriers, and those partnerships have been just essential. We also have received funding from the Welcome Trust, which is a large granting organization within the UK, and they have seen snakebite as a global health need and have reached out to us and helped us, and we're just very, very grateful for our funding partners in this space. One of the other areas that I want to extend partnerships in is our contract research organizations. So CROs like Charles River are frequently removed from development. You might come in and do a project and then leave, and that is not how we view our CROs as a small business. One of our really critical steps has been selecting partners and we consider our CROs as our partners every day we talk to them, we talk to them about our strategies, we talk to them about our specific methods and how we're going to resolve problems. They help us break through barriers. They help us consider appropriate techniques and ways forward, and these partnerships are the foundation of how we are approaching drug development and how we will, I believe, eventually succeed in providing a solution to the field. We have really to Matt's point, built a community around this mission and it's that community which includes people like the US military and the Welcome Trust and Charles River and many, many other partners that are focused on this mission and committed to making this happen.

  Matt Lewin (00:49:20):
  I was just going to say we're nice, but I suppose I think that exactly what Becky's saying, I think that one of the things is that this is a very small field. There are a few dozen labs on the planet that think about this problem and are bringing it forward, whether it's using antibody-based technologies or small molecules like we're doing, and we have good friendships with all these groups. I think, again, I think one of our achievements as a group is that we're very collaborative and that extends both in the academic direction as well as in the development direction. And I think that's something that I would agree with, Becky, that we can be legitimately proud of above and beyond the technical success if it turns out to work as well as we hope.

  Mary Parker (00:50:11):
  So when you're considering the impact of what this drug might have, when you're thinking about a first responder network on a global scale, how can you educate people and distribute this snake by treatment for use in the field, especially when you only have 22 people?

  Matt Lewin (00:50:28):
  I think that the best advertisement for a drug is if it works. So if it works, hopefully that will become apparent to the community that has the stakeholders. And there are other ways that the word gets out through the World Health Organization, through advocacy groups, but I think something like this will be adopted fairly quickly if it realizes its potential.

  Mary Parker (00:51:02):
  Like local health centers, getting it put into pre-made hiking kits for people or getting them put into national parks, visitor centers, things like that would seem like a way to go.

  Matt Lewin (00:51:15):
  You could also imagine if it works for animals, people's livestock, their pets are very important to them. And so I think that how this pans out again, will be dependent upon if the drug works, which would be, like I said, the perfect way to get the word out. But I think over time, once it shows what it can do, what its limitations are, I think people will adopt it fairly quickly.

  Rebecca Carter (00:51:49):
  Absolutely. I guess I would like to add onto what Matt offered here and say that one of our big goals that we are working on right now and that we'll be working on in the future is not just development, but it is global access. And that is a very short phrase for an awful lot of work. It's one thing to get the drug into backpacks and hands here in the United States or in other development countries, something entirely different to move the drug into remote settings where people need it. And Ophirex is very focused on global access. Our board is very focused on global access, and as a matter of fact, Sally who is not interviewed today, sadly, is leading the charge in global access for us. And her entire role is thinking about how do we get the drug into the hands of the people who need it, and that also will require a community of partners, and we're currently working on those partnerships and looking for good partners in this area.

  Mary Parker (00:52:59):
  Yeah, that makes perfect sense. I mean, why reinvent the wheel? There's so many international relief organizations and companies with specific purposes to distribute things in developing countries, piggybacking on their work by just handing them a crate of these tablets would be just as effective as trying to come up with something all on your own. So partnerships are key in that area.

  Rebecca Carter (00:53:23):
  Yes, absolutely.

  Mary Parker (00:53:26):
  So speaking of the future, what does the future hold in terms of lifesaving antidotes for snake bike victims?

  Rebecca Carter (00:53:33):
  So I guess I'll start here and say we've had excellent communications with the FDA. That's one partner that I haven't said, and I want to say for us, they have been really collaborative, very helpful with designation of our drug as fast track. They formally recognize the unmet medical need for a drug like ours. They work with us and help us in thinking about our strategy and how do we best approach development to get the drug across the line and eventually have it approved and available for use in the United States. We think that we have a path that will get the drug available in the next few years. We're working hard to make that happen. Matt really mentioned a lot of the other work that's ongoing outside of X in other areas, like looking at other potential molecules or looking at other monoclonal antibodies and other work that will support victims of snake bite in the future

  Matt Lewin (00:54:41):
  Future. Yeah, I think up till now we've been quite focused on this space, which I think is quite unique where biologicals are not likely to be effective or have the ability to be used. We're always looking for the next thing to add to this, that we will improve what we've started, and I think we're making good progress on that. We do have some funding to continue this work, extend it, improve it, and continue to contribute to the field.

  Mary Parker (00:55:14):
  Do you think and hope that the work you're doing to help pave the way for future innovation could improve outcomes for snake bite victims?

  Matt Lewin (00:55:25):
  Why do it if it's not going to do that? I think that's a lot of us have had our lives completely altered in terms of plans and careers to pursue this mission, and you wouldn't do it if you didn't think it had a chance of success.

  Mary Parker (00:55:41):
  So what does the year ahead look like for ovex?

  Rebecca Carter (00:55:46):
  Busy? We are in the middle of a phase two clinical trial and we hope to complete enrollment of that trial this year. We are also working on continuing the development of our oral program, our oral drug, and are hoping to move that closer towards an eventual FDA submission. And as we mentioned, one of the big items we're looking at this year is global access and moving forward with regulatory interactions globally outside of the United States.

  Matt Lewin (00:56:28):
  Well, I think that I say we work sort of in parallel lanes. I'll be in the laboratory trying to fix up the next iteration of this approach. Finding ways. I think for me in particular, finding ways to not use animals has become a really important mission for me. You can't casually use animals, and I think the longer I do it, the more motivated to find ways to advance the science far enough so that the minimum use of animals is the end result. And so that's been the focus of my laboratory work and is the current focus of it is to find ways that we can find surrogates that can be modeled by Becky's team and avoid unnecessary use of animals.

  Mary Parker (00:57:22):
  We do like the reduction and the replacement of the three Rs. Those are good ones. What do you hope Fr X's legacy will be, Matt?

  Matt Lewin (00:57:32):
  I think that for me, that we may have successfully changed the way people think about an important problem and that whether it's this drug or another drug, that this will have changed the way people look at it and people will benefit from it. That's why you go into a field like this. It's a rare opportunity.

  Mary Parker (00:57:54):
  Absolutely. How about you, Becky?

  Rebecca Carter (00:57:57):
  Well, Matt knows I am very numbers driven and goal oriented, and so what I would say is a little more specific. We started our interview today and talked about the unmet medical need. We talked about those people that just an incredible number of people die before they can ever reach medical care. 150,000 people a year die annually. That's well more than other neglected tropical diseases and my legacy that I want to leave for opex, I want to change that number. I want to see that number change. I want to see that number significantly lower. I want us to be successful with a drug that will change people's lives.

  Mary Parker (00:58:56):
  What's the one thing that you want our listeners to know about your company and about your research?

  Matt Lewin (00:59:03):
  The one thing that I think that we are collaborative, I think that we are able to advance a sustainable commercial program and still be great partners for the field, and I do think we've done a good job at that.

  Rebecca Carter (00:59:22):
  Yeah. I'd say in snake bite time to treatment matters, and we're very focused on that particular aspect. Time to treatment and drug development is hard. I know I've said that a few times and it takes time and it takes a community of partners, and I'd like people to know that there's a dedicated community of people that are committed to make this change and to bring help to those in need around the globe.

  Matt Lewin (00:59:59):
  I wanted to actually add one thought to that because in light of terms of the collaborative attitude, I would say that one thing I would like people to know is how grateful I we are to all the other laboratories around the world that have taken the drug and done things that we couldn't do to address its potential and limitations. Things that we could not do ourselves have contributed a huge amount to the field and given us confidence and is well given us the sobriety to know that we can keep doing better.

  Mary Parker (01:00:37):
  Absolutely. Well, thank you both so much for joining me. It's been an absolutely fascinating conversation. I'm so glad you could both be here. Thank you. Thank you for having us. It's been great. Dr. Matt Lewin is the president and chief scientific officer, and Dr. Rebecca Carter is the Chief Development Officer at Urex. Did you know that Charles River has a sister podcast, Eureka's Sounds of science. Hi, I'm Mary Parker, the voice of Sounds of Science. Moving forward, Vital Science will fold into Sounds of Science, forming a unified podcast. We look forward to sharing more scientific, patient and advocacy perspectives on trending issues in drug discovery and development. You can subscribe to Sounds of Science on Apple Podcasts, Spotify, Stitcher, or wherever you get your podcasts. Until then, thanks for listening.