speaker-0: Hi, my name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denat. In this episode, you'll hear from Lance Alstock, Chairman and CEO at Biorestorative Therapies, and Paul Meal, Chief Business Officer at South Rampart Pharma. We explore why pain has remained such a difficult therapeutic area to tackle and one of the biggest unmet needs today, and how non-opioid mechanisms to regenerative therapies could reshape. The future of treatment. Paul, thank you so much for joining this episode of Denatured where we're gonna be discussing the pain space. So if you can introduce yourselves, that would be great. Lance, why don't we start with you?

speaker-1: Sure, Aaron Lance Allsen. I'm CEO of Biorestorative Therapies, a NASDAQ listed regenerative medicine company developing cell based therapies for chronic degenerative diseases. Our lead program, ERTX 100, is an FDA fast track designated therapy for chronic lumbar disc disease, and we complement our clinical pipeline with a growing commercial biologics business and an in house G C and D manufacturing. ⁓ capabilities.

speaker-0: Perfect. All right. Why don't we go ahead with you, Paul?

speaker-2: ⁓ thank you, Jennifer. I'm Paul Meal. ⁓ I'm the Chief Business Officer for South Rampart Pharma. We're focused on non-opioid pain therapies, specifically our lead asset, SRP001, is a is an orally available as well as intravenously administered ⁓ non-opioid small molecule.

speaker-0: Perfect. Well, thank you so much, both of you for joining me. So we know that pain has been one of the hardest therapeutic areas because it is so subjective and trial results have often disappointed. So what do you think has been the main reason why so many pain programs have failed?

speaker-2: I'm not sure that that pain trials have failed on a higher proportion than than other CNS indications, which are also subjective endpoints, things like depression. The nature of the subjective endpoints of pain are that there has been a propensity over the years to try and compensate for the variability ⁓ by doing much larger trials. And When those trials don't succeed, they're very high profile failures because of the size of the trials, especially at the later stages. More disciplined approaches, and if we use Lily as an example, manage drug development in pain the same way as other areas. ⁓ Lily's been very active in the pain space over the last several years. They've done multiple collaborations, they've done multiple acquisitions. They did a billion-dollar acquisition of site one last May to a Obtain a nav inhibitor or a sodium channel inhibitor. In the second half of the year, they discontinued two earlier stage programs. So they're being disciplined about what's working and what's not. They announced another acquisition of a company called 4E Therapeutics, another novel mechanism to target non-opioid-based pain therapeutics. And so you see there, they're looking to to rotate out programs which don't seem to be working as effectively before you get to the big late stage failures, but continuing to to be proactive with novel mechanisms, again, trying to achieve the the industry goal of trying to replace or minimize the use of opioids in pain management.

speaker-1: I guess from the lens of where we sit from a cell therapy company, I think s one of the biggest challenges in pain drug development is that many programs have focused on reducing symptoms without adequately addressing the underlying biological driver of the pain. And pain is h inherently subjective and often highly heterogeneous, particularly in chronic conditions where there's structural damage and inflammation and neurological signaling, all those can contribute differently from patient to patient. ⁓ I think the challenge is also patient selection, broadly enrolling diverse pain populations can make it really difficult to identify treatment effects, especially when the underlying causes of pain vary significantly. And we're seeing the field evolve towards more targeted approaches. I know we've taken that approach by having better patient stratification, better focus on our protocols for specific indications and therapies that are designed to address specific biological mechanisms rather than treating pain as a single disease category. I mean ultimately I believe success in pain management will require therapies that that not only reduce pain scores, but also improve function Durability of response, quality of life. Standard diagnostics for pain must also improve, such that we have the ability to provide a more objective response versus the standards today, which are primarily driven by subjective and quite inconsistent scales of measurement.

speaker-0: Yeah, that does make a lot of sense. So right now the field looks like it's goes between opioid based treatments, opioid sparing strategies, and true non-opioid approaches. So how do you think the biggest unmet need sits today? Lance, it sounded like you had said there's various areas to address beside pain as well, quality of life and kind of various other areas. So is that also part of the big unmet need that we have today?

speaker-1: ⁓ I think the the the greatest unmet need is in therapies that provide meaningful and durable pain relief without the risk associated with chronic opioid use. While opioids remain important in certain acute and severe pain settings, I think long term reliance creates very well documented challenges around tolerance and dependence and and safety related issues. I think some of the opioid sparing strategies have been an important step forward. ⁓ but many still focus primarily on symptom control. I think what the field continues to need are are non-opioid approaches that offer confirmable eff efficacy while maintaining a favorable safety profile and minimizing sort of that long-term treatment burden. ⁓ for chronic conditions in particular, there's also growing interest in therapies that move beyond pain suppression altogether and and address the underlying pathology. contributing to pain. I think that represents an important frontier within the field.

speaker-2: Agree with Lance, the the holy grail in pain as as well as many other conditions like hypertension is to treat the underlying cause. The pain therapeutics, when we think about opioids, NSAIDs, the nav inhibitors, these are really about pain management, as Lance said, managing the symptoms. And for acute settings where you have a minor surgery or a minor injury, you have a Bigger tolerance for side effects because it's a short-term management of the symptoms for an underlying cause that will self-resolve as you recover from that minor surgery or injury. For longer-term chronic conditions, whether that's rheumatoid arthritis, neuropathic pain, chronic management of those pain symptoms when the underlying cause cannot be resolved is a challenge. And that's been a lot of the push to move away from opioids. Because even in acute setting, they cause respiratory depression, disruption of the GI system, and of course the addiction potential. And so that's been the push. The challenge is that all of the pain drugs have their own side effects, ⁓ whether they be on the kidneys, the liver, the GI system, on coagulation. And so the approach has been multimodal to to blend different non-opioids together and in some cases even the opioids themselves to reduce the amount of opioid. And I think most of us who who've had children with a fever have been given the advice to alternate between acetaminophen and ibuprofen to minimize the side effects while still managing the fever. The same approach applies to pain management. And the pain doctors that we've spoken to now that the the nav inhibitors, systemically administered nav inhibitors are available, they've acknowledged the limitations. They're they're mild analgesics, similar to NSAIDs and acetaminophen, but they do appreciate that they're a new addition to the armamentarium that they can offer their patients because even on an individual basis, certain patients will react differently to ibuprofen at the same dose. And so they need alternatives. And that's going to continue to be the approach going forward.

speaker-0: When you talk about the nav inhibitors, the newer entries here, what what are some of the liabilities? I think we know quite well at this point, know with some of the NSAIDs and acid aminofin, but where does nav inhibitors fall into that case of liabilities?

speaker-2: ⁓ well on the efficacy side, the nav inhibitors have the limitation that at least the the currently available ones like Jernavax are are only peripherally acting. And so that limits the number of pain indications that they're applicable for. ⁓ for example, they they don't enter the CNS, so they'll never be applicable to migraine and and indications like that. ⁓ they do bring their own risks and they are a new class. The nav inhibitors are really. A more selective version of broad sodium channel inhibitors, such as lidocaine. And the reason lidocaine is only administered locally is because its inhibition of sodium channels inhibits conduction in the heart, and that that can cause conduction irregularities and arrhythmias. The new nav inhibitors are more selective, and the trade-off is they are therefore less potent on sodium channel inhibitors. ⁓ but it does remain to be seen now that they're in the general population and being used more broadly, chronically, and at higher doses, what that may manifest as in terms of side effects. We saw something similar with what were called the COX-2 inhibitors, Celebrex and Viox, which were next generation effectively ibuprofen type drugs, and they targeted the same target and they were effective in clinical trials, but once they were out in the broad public. they did exhibit cardiac toxicity and ultimately Viox was taken off the market and Celebrex is still around, but it's it's used on a much more limited basis.

speaker-0: That does make sense. Now to flip to now your individual pipelines, Lance, let's talk about the BRTX one hundreds. How do you think about the opportunity for this biologic or biologics in general in chronic spine pain?

speaker-1: ⁓ so chronic discogenic back pain is an area where the limits of traditional pain management are particularly evident. Most existing treatments focus on you know managing the symptoms through medications and ultimately surgical intervention, but they generally don't repair the damaged disc itself within the spine. And that creates a very significant opportunity for biologic and regenerative approaches. The goal is not simply to reduce pain temporarily, but to address the underlying structural and biological changes that are contributing to the condition. So if regenerative therapies can help restore tissue function and create durable clinical benefit, they have the potential to fundamentally change how chronic spine disorders are treated. That biorestorative, our focus with your TX one hundred is aligned with that vision. We're also evaluating whether a patient's own stem cells can be used to support repair and regeneration within the damaged disc with a long-term objective of improving both pain and function and really solving the problem as opposed to temporarily managing those symptoms, treating this as a transactional-based form of medication. We really want to solve the problem such that. we bring that patient back on prior to the occurrence of that injury or the onset of that degenerative behavior within the disk. From a commercial perspective, we think the opportunity is tremendous. I think what we've discussed in the past is always that ⁓ it's not a matter of if but when you experience some form of degenerative behavior within your musculoskeletal system, albeit whether that's the spine or the hips, the knees, the shoulders, it's it's just a matter of time. And in the spine specifically for discogenic pain that represents tens of millions of patients here in the US and triple that the rest of the world. So we think that there's a really interesting and ⁓ relevant, unmet need here for this type of biological response.

speaker-0: Brilliant, thank you. And I I we when we first talked, I could commiserate as someone who did suffer from terrible spine pain and the spine issues. So it was thinking, ⁓ gosh, the thought that there could something that could address this in the future would be amaz

speaker-1: It's really amazing that given where we are today and landing rockets on the moon and everything else, we just don't have a a number of very good acceptable solutions for spine pain. And perhaps it's a design flaw of the human body, but that's a whole separate podcast.

speaker-0: Yes, it is. Indeed. We can talk about that another time. Paul, let's switch over to you to talk about South Ramport SRP zero zero one. You know, have this analgesic without liver toxicity of acetaminophyn. So why is that mechanism compelling and what problem does it solve that existing drugs do not?

speaker-2: Sure. Well, acetaminiphen is actually a very effective analgesic. It's been around for quite a long time. It's effective both acutely and high doses, where it's used and administered intravenously in the post-surgery setting, again, as a first step to try and reduce the amount of opioids. The challenge is that really that high dose can only be administered once because of the liver toxicity. In the outpatient setting on a lower dose. more chronic and acute setting, it's still the same problem that the acetamenshin is effective, but you can only take so much of it. And even if you're taking a lower dose, the liver toxicity is cumulative. And so on a chronic basis, you will have an increased impairment of the liver over time. And so you will need to rotate to other analgesics. Ironically, if acetaminophen were going through the FDA today, it it probably would not be approved because of its its liver toxicity. There are actually drugs on the market specifically to treat acetaminophen overdose in the outpatient setting. So what South Rampart has done, and and somewhat analogous to what was done with the COX-2 inhibitors. They looked to improve on the NSAID model of ibuprofen and the proxin, which inhibit an enzyme called cycloxygenase. The COX-2 inhibitors were more selective. They had less of the gastrointestinal bleeding. And that was really their claim to fame. In today's world, the new nav inhibitors can really be thought of as more selective lidocaine. They're the same mechanism working on sodium channels. Again, they're more selective, trying to minimize the toxic side effects and enable them to be administered systemically. The third leg of the stool in the non-opioid class is acetaminophin, which acts via something called AM404. Acetaminifin is really, it can be thought of as a prodrug. It's metabolized first by the liver, and the byproduct is what causes the liver toxicity. The active analgesic agent is actually formed up in the brain in the CNS system, and that's what actually generates the pain relief. So, what SouthRampart has done has generated a new molecule based on AM404, which also is metabolized as a first step in the liver, but the byproduct here is a non-toxic metabolite. And so we get all the benefit of the pain relief. without the liabilities of the toxicity. And what we've seen, some other benefits of the modification are that SRP001 has a faster onset of action, which is important in pain relief. It has a longer duration of action, which again is helpful in pain relief to reduce repeated dosing. We don't see any of the toxicity in the liver, the kidneys, coagulation, gastrointestinal, and Because we don't have the toxicity, we're actually able to dose higher. And what we think the end goal here is, is that SRP001, as opposed to to some of the other milder analgesics, can really start to treat that moderate to severe pain and limit the opioids potentially to really being a rescue medication for breakthrough severe pain. And In the preclinical models, we have plenty of data showing efficacy across pressure pain, heat pain, and neuro importantly neuropathic pain, even compared to the standard of care gabapentin. We show very strong efficacy without the liabilities of the toxic side effects of gabapentin as well. So that's what we think is is very encouraging and and offers a centrally acting pain reliever, which covers the entire range. of acute pain, chronic pain, neuropathic pain, as well as migraine, which is something the nav inhibitors don't do and the NSAIDs have limited efficacy in a lot of those indications.

speaker-0: Understood. Well, we've come to the end of our episode. ⁓ time flies when you're discussing a really interesting topic. So thank you so much, Lance, and thank you so much, Paul, for joining this episode of Denatured. If you'd like to listen to more episodes, please turn to biospace.com. Thank you so much.