Everyone, and welcome to Lexicon's R&D event. Really great to have you here today. In advance of Lexicon's PROGRESS IIb data readout, top-line data readout later this quarter, we're pleased to bring you an R&D event that's going to focus on neuropathic pain, and specifically on diabetic peripheral neuropathic pain, DPNP, for which the PROGRESS trial is currently coming to its conclusion so we've got a great agenda for you here today and what we plan to take you through is, firstly, I'll just set the scene for a few minutes on neuropathic pain and the incredible need that patients suffering from neuropathic pain and DPNP particularly have. Then one of my colleagues, Suma Gopinathan, will take a deep dive into LX9211, our innovative, novel treatment for neuropathic pain.
Then we've got the great pleasure of inviting a couple of external experts who are going to join us for a panel discussion to describe the patient journey, to describe current treatment regimens, and really put into perspective the data and potential data from the PROGRESS trial. I'll sum it up and then look at how neuropathic pain and 9211 fits into Lexicon's overall strategy. And then finally, there's an opportunity for a Q&A at the end. So I think it's going to be a really fun morning with a great agenda. Now, I'm really excited about the upcoming readout of the PROGRESS trial. And really, there's a number of reasons that I'd like to describe over the next few slides. But, you know, firstly, this is by any stretch of the imagination just a horrible disease.
People suffering, as you can imagine, from pain and a range of other symptoms, are really suffering with their day-to-day life and enduring life, if you like. Secondly, patients really have very few options. There's not really been any new therapeutic innovation in a couple of decades, and patients are really reaching out for new therapeutic options to help manage their pain. Third, you know, this is a very prevalent disease. There are many, many millions of patients in the U.S. and outside the U.S. who are really suffering from neuropathic pain and DPNP in particular. And then finally, you know, despite the political and social environment that we are in right now, there's still a ton of use of oral opioid analgesics in this space. It's really going to give potential tailwinds to any commercialization of new innovative therapies in neuropathic pain.
Allow me just quickly to set the scene for neuropathic pain and differentiate it in particular from acute pain, because there are innovative therapies being developed in acute pain currently and in neuropathic pain. Neuropathic pain is clearly very distinct from acute pain, and our panelists will further describe this. Besides the length of the actual pain sensation itself, as the names would suggest, neuropathic pain is very particular to damage or injury to nerves within the peripheral or central nervous system. The pathophysiology is therefore quite different to what you see with acute pain. The signs and symptoms are also very different, and the actual patient experience is very different.
Neuropathic pain is caused by a number of conditions, in particular diabetes, a highly prevalent disease that, as a result of many years of poor glucose management, has an effect on the nerves like it does on a number of other organs within the body. Also, platinum-based chemotherapy regimens can cause neuropathic pain, multiple sclerosis, and other demyelinating diseases. Shingles, for those of you who've suffered from shingles, you know the pain that's associated with that and direct injury to a nerve. Now, the sensations and the symptoms of neuropathic pain are obviously, as the name suggests, a pain, the burning pain, the prickling sensation, the electric shocks that they describe, particularly at night. But it's much more than that. In fact, in the extremities for both the neuropathic pain, starting in the extremities, you also get numbness, pins and needles, and inability to feel one's hands and feet.
And these can have sequelae that are very, very impactful and really make a patient's life day-to-day very difficult to manage. And as you can imagine, in a space where there's been very little innovation over the last couple of decades, patients really rarely get to a state where they have adequate control of their pain. And so this is a space that really is crying out for new innovation. Further to the things that patients suffer with, you know, the idea that your feet are numb, your hands are numb, it creates a whole world of problems that for you and me, we may not even think about. But problems with balance, for example, how you stand, potentially leading to falls and fractures and the consequences of those incidents. You know, it's interesting, patients often can't feel their feet.
Any damage to the feet through things such as stepping on a rock that happens to puncture the skin, et cetera, can really fester and have really dire consequences for the feet, ulceration, and is not a pretty sight for those patients. You know, what I hear a lot from patients is just the activities of daily living. Being able to button up a shirt is nearly impossible. Tie your shoelaces, zip up your trousers, these sorts of things that we take for granted, let alone writing and typing on a computer, are incredibly difficult. As you can imagine, this creates a huge problem for these patients.
And perhaps most importantly, the thing that you hear the most is that these patients just have horrible sleep at night when they're alone and focused on the sensations that they're having and heightened sensitivity and pain in their feet so that sheets can't even touch them. They end up not really getting any quality sleep at all and rather getting up and doing other things. So it's just a very horrible disease that impacts all activities of daily living. Now, looking at the history of drug development in this space, and I really mean history, because we have to go back many decades to when these medicines were developed, you know, whether it's the tricyclic antidepressants, whether it's the serotonin-norepinephrine reuptake inhibitors like duloxetine or the gabapentinoids, these medicines were developed for other reasons and happened to show some efficacy in neuropathic pain.
And so since then, we've had a topical analgesic that's been approved. And of course, we've had opioids. But this is a category that really is in desperate need of new medicines. And it's in desperate need of new medicines because the patient journey is also pretty extreme. You know, folks, when they originally are diagnosed with neuropathic pain, sort of on a potential roller coaster, which is depicted in this slide here, because that's what it feels like to a patient. They start typically on a gabapentinoid, particularly gabapentin, to try and control their symptoms. But oftentimes, that isn't adequate. Either the efficacy for the individual patient is not sufficient or they have side effects. And so you pretty quickly go to a situation where patients will switch therapies to try and find the therapy that's right for them.
It's kind of like switching from acetaminophen to ibuprofen to try and find where that sweet spot is going to be for the patient. And if they don't get an adequate response, which is pretty common, they switch amongst tricyclics, amongst serotonin-norepinephrine reuptake inhibitors, and even opioids. And what surprised me is the incredible use of opioids in this space. In fact, about 20% of patients still receive an oral opioid as first-line therapy, despite the fact that it's actively prohibited in ADA guidelines and from other professional bodies. So there's a huge opportunity for disruptive innovation in this space. Finally, as I mentioned earlier, there are just many, many millions of patients who are suffering from this disease.
And so it behooves Lexicon and the scientists here to really bring this new medicine to patients, because currently, there are about 9 million patients in the U.S. with a diagnosis of DPNP. And given current growth rates, it's expected that that will increase by about 50% over the next decade. And as you can imagine, with increased attention now being brought upon neuropathic pain with focus and innovation, these numbers are probably an underrepresentation of the actual opportunity. So what we have with LX9211 is a new treatment, a novel non-opioid therapy that's already shown clinical and statistical reductions versus placebo in various forms of neuropathic pain. And this is a simple once-daily medicine that patients can use either as a standalone therapy, monotherapy, or on top of standard of care. So we think we've got a great new medicine in our hands.
We have a fantastic person in our team to introduce LX9211 to you, and that is Suma Gopinathan, who is uniquely positioned to describe to you the medicine and the protocols and what we can expect out of the PROGRESS study, because she was part of the original Lexicon team that discovered and developed inhibitors to AAK1. So in just a second, I'll bring Suma on to describe to you LX9211. Thank you.
Thank you, Mike, and thank you to everyone who has joined us today virtually. As Mike mentioned, I have been with this program for a very long time, actually, right from the very start when it was in mouse models and I was a bench scientist to now leading it in late-stage clinical development. Over the next several minutes, I will be walking you through what the mechanism of action is, what the overall preclinical data package looks like for neuropathic pain and beyond, and then take a deeper dive into the proof of concept clinical studies that we have had, and then give you some granularity on the ongoing PROGRESS DPNP study that we are anticipating top-line results in this quarter, so we'll start at the beginning with the target. LX9211 is a potent inhibitor of AAK1.
This target was discovered by Lexicon using a proprietary knockout mouse technology after screening over close to 5,000 plus knockout lines. This target was the most potent for neuropathic pain that we identified. Mice that were deficient in the AAK1 gene were resistant to the development of neuropathic pain. I must emphasize that, you know, with the opioid crisis that we have in a chronic condition like neuropathic pain, AAK1 and LX9211 that inhibits AAK1 does not impact or work via the opioid pathway. What it does is it inhibits the reuptake and the recycling of neurotransmitters that are involved in pain signaling. These inhibitors actually work centrally, which is important because the neurotransmission pathway, the pain signaling pathway in neuropathic pain, is very complex.
Having a centrally acting inhibitor is an important attribute for it to have a potential for a broad variety of neuropathic pain states, as well as an indication like spasticity, which works along several of those similar signaling pathways. So what we have is a novel target that has been validated using a genetic knockout model. We have also tested LX9211 and various other AAK1 inhibitors in validated preclinical models of neuropathic pain and spasticity. In addition to that, we have shown the proof of concept in human clinical trials. So essentially, we have gone from mouse to man using a novel target for neuropathic pain. As you heard from Mike, there is a dire need today for innovative treatment options for patients with neuropathic pain.
So coming to the therapeutic potential for LX9211, we have initially had preclinical models of diabetic peripheral neuropathic pain, DPNP, and postherpetic neuralgia, which is pain secondary to a shingles infection. Those well-established preclinical results translated into proof of concept phase IIa clinical trials, where we saw an effect in humans. In addition to these two peripheral neuropathic pain syndromes, we have also demonstrated preclinical efficacy with LX9211 in chemotherapy-induced neuropathic pain, in lumbosacral radiculopathy, and even in a central neuropathic pain situation like multiple sclerosis pain. In addition to neuropathic pain, LX9211 has been active in well-established models of spasticity, one model in mice with multiple sclerosis and in another in rats with spinal cord injury. So this just shows us the broad therapeutic potential that LX9211 has across various different types of peripheral neuropathies, central neuropathies, and beyond neuropathic pain in the spasticity space.
So with that, I will walk us through the clinical program that we have to date with LX9211. Prior to entering the phase II program with LX9211, we extensively studied it in phase I trials in healthy volunteers, where we established what the profile of the drug looks like in humans and also got a good understanding of the safety and tolerability. One of the things we discovered in our phase I program was that LX9211 has a long half-life of six to seven days. And that will become important as we talk about the dosing regimen and also some of the efficacy results that we see. So the first study that we conducted was called the RELIEF-DPN-1 study. This was a proof of concept study in patients with DPNP.
As part of this whole journey, I've had the privilege of going out and meeting with patients and their providers and learning from them firsthand what their journey is like, what the disease does to them, what their hopes for therapy looks like, and what does RELIEF look like for them. We have brought a lot of those back into our clinical trial design and execution. And that has actually paid off in terms of how these studies have enrolled and read out. So coming to the DPNP, RELIEF-DPN-1 clinical trial, this was in patients with type 1 or type 2 diabetes who had moderate to severe neuropathic pain. These patients were allowed to continue on standard of care if they were on it at the time of screening.
Now, this is important because historically, all the studies that you see with pregabalin and duloxetine and other agents, they have all been conducted in patients that were purely either on treatment or on placebo. Patients were not allowed to continue on any background medication in those trials. And that actually continues to today in clinical trials, other clinical trials that are running in this space. So this is one of those patient-centric approaches that we have brought into our clinical trial design. Now, why is it important? It is important for a number of reasons. One is patients are suffering from a chronic pain condition, and it is unrealistic to expect them to wash out of any therapy they are on, even if it is just giving them partial relief. The second part of it is this washout process can often be associated with a rebound pain.
That then elevates the placebo response that comes into the trial and then also is associated then with the quick drop that you see. It adds a lot of variability to that baseline read while you're getting the patients into the study. In this study and in all of our other neuropathic pain trials, we have a two-week run-in period where the patient is actually blinded and on placebo pills. It's a single-blind placebo run-in. This is, again, another key distinguishing factor that we have in our trials. Most trials have about a one-week run-in period. Now, this two-week run-in period is, again, important because it allows us to be able to reduce the variability that comes into what happens when patients enter trials.
Now, one thing everyone knows is that patients who enter neuropathic pain trials, these are patients who have suffered from pain for a long duration of time. Everyone tends to get better. In other words, there is a placebo response in every trial. So trying to minimize that placebo response, trying to reduce the variability, that two-week run-in period is critical. So patients who come in from that two-week run-in period, that is what we use to measure their baseline pain. Once they met the criteria for moderate to severe pain, they were then randomized into three treatment arms: the low-dose LX9211 treatment arm, the high-dose LX9211 treatment arm, and the placebo arm. In this study, we went in with a loading dose on day one. As I had mentioned, LX9211 has a long half-life.
By administering the loading dose on day one, followed by a maintenance dose that was a tenth of the loading dose, we were able to get patients very quickly on day one up to steady state and keep them there for the duration of the double-blind treatment period. As this was our first proof of concept studies, we were exploring this option to see what would happen if we started giving the patient relief very early in the trial, starting from day one onwards. After the double-blind treatment period, we then moved into the safety follow-up, which again was a single-blind safety follow-up. The patients were not aware of the fact that they had switched out of treatment and into placebo.
This allowed us to understand what the safety profile of the drug looked like when the patients came off of it very abruptly at the end of the double-blind treatment period, and also, more importantly, look for signs and symptoms of withdrawal, potential withdrawal, and also rebound pain. As you know, many of the drugs that are standard of care today have to be tapered down very slowly to avoid two of these critical things that these patients face, so let us look at the efficacy results for the study. RELIEF-DPN-1 was a successful trial. We met both clinically meaningful and statistically significant reduction in the average daily pain score in a placebo-controlled trial. In the low-dose arm of LX9211, this was statistically significant, while in the high-dose arm, the effect tapered off and we missed the p-value, marginally missed the p-value.
Now, this is important that we put this data in perspective, right? So the patients in the low-dose arm experienced a drop of about 1.4 units in ADPS compared to 0.7 in the placebo arm. So we are looking at a delta of about 0.7. Now, it is important that we place this in terms of the placebo response. As I mentioned, everybody in a pain trial gets better. So now we are confident when we look at this data that what we are seeing is above and beyond the placebo response. In addition to that, I do need to mention we had allowed patients to come into this trial on background care. So over 50% of the patients in the placebo arm were actually on a background standard of care, mostly gabapentin.
So these are key differentiators between this trial and any other trial that has been reported in this space. There is a key differentiator. We also looked at, you know, whether there was a statistically significant difference based on other subgroups or were similar, including the use of background medication. To further understand whether these results that we are seeing were real, we evaluated our other efficacy endpoints in the study, and we saw the similar significant effects on other parameters, including least pain that the patients experienced, the worst pain that the patients experienced, and even the interference of pain on their sleep. Patients reported improvement in all of these three metrics.
Now, this is important because due to the long half-life of LX9211, patients, even though they are just taking one dose in a day, the therapeutic levels of the drug are maintained at almost a very close to steady state level all through a 24-hour period. So even though the patients take the tablet the first thing in the morning, they are able to see a positive impact on their sleep much later in the evening, and I have to distinguish this. This is not drowsiness associated with daytime sleepiness. This is how their pain interferes with their nighttime sleep and the improvement that they see on that, so altogether, we have a robust efficacy readout from this trial that told us, you know, LX9211 definitely works in the neuropathic pain condition in humans.
Now, looking at the safety profile of patients in the RELIEF-DPN-1 study, we definitely saw an increase in adverse events in the LX9211 treated arms when compared to placebo. These events were mostly mild or moderate. However, we did have these CNS-based effects of dizziness and headache, and especially dizziness had an impact on patients dropping out from the study. So when you look at these numbers here on this slide, you can see that we went from about 15% of the patients reporting dizziness in the low-dose arm to about 27% in the high-dose arm. So we looked at this data much more granularly. You know, this was our first proof of concept study in humans. We are trying our best to understand what that profile looked like.
Here, what we saw was that the incidence of dizziness, as well as the dropouts due to dizziness, happened early in the study during that first week. This was important because we went in with a centrally CNS-acting drug and gave a loading dose on day one. Putting the whole picture together, it is, you know, it was our belief that this could be very easily tied to that loading dose on day one and that to improve that tolerability profile, we would have to seriously consider taking the loading dose off the table. Now I will just briefly go over the second proof of concept study that we had. Now, AAK1, as I mentioned, is a novel target for neuropathic pain. For us, it was important to understand, you know, what the effects of LX9211 could be just beyond diabetic neuropathy.
And we chose postherpetic neuralgia. Now, this study was very similar to the RELIEF-DPN-1 study, as you can see. Patients came into the trial with a diagnosis of postherpetic neuralgia secondary to a shingles infection. They had moderate to severe pain. And similar to the first trial, they were allowed to continue on background medication. This trial also had a two-week run-in period. Now, we had two key differences. I forgot to mention on the previous study that it was a large study, that RELIEF-DPN-1 was a large study with around 106 patients per arm. In this study, we had about 40 patients per arm, 38 in the LX9211 treatment arm and 41 in the placebo arm. In addition to this, we did not test the low-dose arm in this study, which was the arm that actually met statistical significance in the prior study.
So let us review the efficacy results from the study. You know, we saw a drop of 2.4 units from baseline in the LX9211 treated arm compared to 1.6 in the placebo arm. The delta was definitely similar. The delta difference between placebo-treated and LX9211 treated, that delta was very similar to what we achieved with the RELIEF-DPN-1 study. However, we did not achieve the primary endpoint of the study with the study missing the p-value that was pre-specified. Now, this was possibly attributed to the lower number of patients we had in the treatment arm, the high dropout rate that we saw, and perhaps the absence of the low-dose arm in this study. But overall, what we understood here was that we were able to see a reduction in ADPS from baseline in these patients.
We were also able to understand what the safety and tolerability profile looked like in patients with PHN. It was very similar to what we saw in patients with DPNP, with dizziness, headache, and nausea being the leading AEs and dizziness being the leading cause of discontinuation in this study. So that brings us now to the current ongoing PROGRESS study in DPNP. So we have achieved proof of concept twice using a novel target in the clinic. But we did understand that there is room for improvement, room for improving the tolerability profile of this drug. So we moved into a phase IIb study. And this study, like our previous two studies, is designed to be patient-centric. We are meeting the patients where they are in their standard of care. You saw on the slide that Mike presented where patients have a really roller coaster journey with treatments.
They come on treatment, they go off treatment, they come back on treatment, they combine treatments, and they go off of it again, and then the whole cycle repeats itself while their diabetic neuropathy and the underlying pain continues to progress. So this study, like our previous two studies, is designed to meet the patient wherever they are in that patient journey. So it's a patient-centric trial. It's an innovative design. Our patient population remains very much the same as we had in the RELIEF-DPN-1 study. Patients with type one and type two diabetes, whether they are on standard of care or they are off of it, they were eligible to enroll as long as they met the other inclusion and exclusion criteria. In this study, like in our previous studies, we have a very robust patient selection criteria.
These patients are diagnosed using the MNSI tool, which is a validated tool for diagnosis of diabetic neuropathy, and patients were diagnosed also on their pain score. They had to have a moderate to severe pain score to be eligible to move into the study. The key design elements that we employed in our previous two successful trials, we brought that forward into this trial. We have the same two-week run-in period, and it is placebo-controlled. You know, we have not decided to just run multiple LX9211 arms and compare them with themselves. We have again a placebo-controlled trial because it is very important to be able to interpret the results from any neuropathic pain trial to have that placebo arm in place to understand what the true efficacy effect of the drug is. Now, learning from our past two trials, we have removed the loading dose in the study.
We have also invested in training patients on pain reporting. Both the sites and patients randomized into the trial are trained on pain reporting. Let us take a quick look at the schema. This is the study schema that we are truly unveiling for the first time in its entirety. As you can see, it is very similar to our RELIEF-DPN-1 study. The patient population remains the same. They are allowed to continue on standard of care. They then move into a two-week placebo run-in, which from where they are then, if they meet the cutoff for pain severity, they are then randomized into one of four study arms. They are either on placebo, an LX9211 10 milligram arm, an LX9211 20 milligram arm, or they are on 20 milligrams for the first week and then switched over to a 10 milligram arm.
After this eight-week treatment period, the double-blind treatment period, they then move into a four-week safety follow-up period. So this study was actually scheduled to complete enrollment and top-line results released in Q2 of this year. Due to the increased interest in this study, we were actually able to complete enrollment in November of 2024, a full quarter ahead of schedule. Not only did we pull the timelines in, we actually exceeded our enrollment target by approximately 20%. Now, this is very important. Many of you know that neuropathic pain trials are very difficult to enroll. Now, the interest that sites and patients had in us, we believe, is due to two critical reasons. One is the patient-centric innovative design that meets patients wherever they are on their journey in the treatment paradigm.
And the second is the fact that there is a high unmet need in this patient population, and the need for new therapies is extremely important. So, as Mike mentioned, you know, we are anticipating, and I personally am extremely excited about the top-line results we will be releasing later this quarter. So, what are we looking for here, right? Personally, this is just another major milestone in my long journey of, you know, close to 15 plus years with this program. So, in this study, we are looking at our goals are to achieve a similar or better efficacy in patients on LX9211 treatment. One of our goals coming into the study was to improve tolerability by removing the loading dose.
I can tell you this, and I know it has already been previously publicly disclosed, that looking at the blinded data in its entirety, we have definitely improved the tolerability profile. Now, from the three different LX9211 treatment arms that we have, we are looking at identifying a single dose to take into placebo-controlled phase III studies. We are using the same study design, making minor tweaks along the way to accommodate, you know, removing the loading dose. We want to reaffirm our pragmatic patient-centric study design. With that, you know, in anticipation of hopefully seeing positive results in the top line that we release, we will be looking at moving very quickly into end of phase II conversations with the FDA and targeting starting of phase III studies in 2025.
So, with that, I thank you for your time today here, and I hope, you know, you will continue to stay with us as we move into the next stage of our agenda. We have our panel discussion on it. You know, we will have Dr. Busui, who is actually the lead PI on the PROGRESS study, and also Dr. Edelman. And our this panel will be moderated by our Chief Medical Officer, Dr. Granowitz. We are going to just pause here very briefly while we bring on our panelists, and we'll be right back. Thank you.
Welcome back to all, and looking forward to our upcoming panel discussion. I'm Craig Granowitz. I'm the Chief Medical Officer at Lexicon, and so thrilled to be here today. I want to introduce our two panelists that are joining us by Zoom. I'll introduce them in order they can introduce themselves, Dr. Rodica Busui and Dr. Steven Edelman. So, Rodica, could you introduce yourself, please?
Sure. Good morning, and thank you so much for having me here. My name is Rodica Busui, and I'm a professor of endocrinology and diabetes and the director of the Harold Schnitzer Diabetes Center at Oregon Health & Science University in Portland and the division chief of endocrinology and diabetes. I am a physician scientist, and I have dedicated my career to trying to find new medications, new therapies for people with diabetes and complications. One of those is diabetic neuropathy. It is arguably the complication that it's behind regarding finding disease-modifying therapies and has tremendous consequences on patients' lives, as you have already learned.
Therefore, I'm so excited to be part of this program that identified a new viable pain medication that can help our patients, given that treating neuropathic pain in people with diabetes, it's very, very difficult and very challenging.
Thank you, Rodica. Steve, could you please introduce yourself as well?
Yes. Yeah. Hi, Craig. Basically, I'm a long-term clinical trialist. I work at the VA and UCSD, but I also see lots of patients in our VA Diabetes Clinic, UCSD Clinic, and I run a not-for-profit organization that really has a wide reach now post-COVID, where we turned virtual, and we have an open forum, blogs, and I can tell you that in my clinical experience, it really is true that diabetic peripheral neuropathy pain is one of the true unmet needs in therapy, and we're still looking for something that could really be effective.
As Mike said so eloquently, you know, it's hard. It's a tough disease, and there's no one single bullet out there that seems to be the best therapy. So I welcome this new molecule, and it looked very promising either alone or in combination with other drugs that we use now on the market.
Thank you, Steve and Rodica. Again, we're just so fortunate to have them and also Suma back to join this panel as well. You know, one of the things I really find so wonderful about working with both Steve and Rodica first is they're both on the West Coast, so they got up very, very early this morning to participate in this panel. I think that demonstrates their commitment to the patients that we're collectively serving and their commitment to this study as well. So I wanted to thank them.
Also, they're very humble in their self-introductions. Rodica is a recent president of the ADA for science and medicine. Rodica was also instrumental in developing the Michigan test for making the diagnosis of neuropathic pain, the MNSI, and perhaps we can touch on that a little bit later as one of the additional defining characteristics that make us feel so confident in the homogeneity of the populations we've been studying, both the RELIEF study that Suma covered and the PROGRESS study that's running right now. Similarly, Steve is really, I think, probably unique in the world or nearly so in that he wears all the major hats of every stakeholder involved in the management of diabetes and neuropathic pain. Steve, as he's mentioned previously, so I hope I'm not sharing any personal information. Steve has had long-standing type 1 diabetes.
As Steve mentioned, he founded and is the head of TCOYD, taking care of your diabetes as a patient group really focused on education. Steve's also a highly experienced, like Rodica, clinical trialist with a large number of both registrational and other trials to his name and his experience. So we're really fortunate in having our two panelists today, as well as our head of clinical research in Suma on this program. What I wanted to do is cover briefly before going into the specific questions our objectives for this panel today.
And one of the things that's become clear to me as I've been working in the neuropathic pain space over the last three or four years is the lack of information and good understanding of pain as a concept and the differences between neuropathic pain and acute pain, the importance of placebo effect, and a number of criteria that are really fundamental for understanding the treatment results. So with those goals in mind, what we wanted to specifically cover briefly at the beginning is educating a bit on neuropathic pain and specifically DPNP from the perspective of the clinical trialist, the patient, and really an expert who has really characterized what neuropathic pain is. And along with that is understanding a bit more of the patient journey and the burden of disease.
But we really wanted to spend the majority of the time talking about the current treatment landscape, some of the similarities and differences of the clinical trial that Suma shared with you that make us feel so confident in the robustness of both the population we're studying and the results that we've seen, and then talk specifically about the PROGRESS trial that, as Suma mentioned, has now been patient enrollment is completed. That's why for the first time, as Suma was going through the schema, we actually this is the first time we're sharing today that there was also a two-week placebo run-in because now all the patients have finished the active dosing phase of the trial. So with that, I thought we would start with living with DPNP.
And Steve, perhaps you can comment on that, really wearing your multiple hats as both a patient and an educator in that regard.
Yes. Well, first of all, let me just say, and I'll try to make my comments brief. I know we have limited time, but, you know, it's one of the most common complications we see in clinic. And once again, there's treatments are really part of an unmet need. Diabetic peripheral neuropathy, as Rodica knows well, you know, it's a stocking-glove distribution. So primarily the lower extremities, bilateral. Occasionally, it affects the hands, and that's serious as the neuropathy progresses. And I think the thing that I wanted to mention is that the symptoms change over time. We all know the early symptoms: tingling, burning sensations, pins and needles, numbness in the feet, and mild pain. But then they progress to sharp, stabbing, shooting pains.
This is so difficult for the patient. That's where opioids, marijuana, alcohol are brought in by the patient when they're so frustrated when nothing they've been given or they haven't been given works. You can get increased sensitivity, loss of sensation, and that's extremely dangerous because one thing that hasn't been mentioned yet that peripheral neuropathy is probably one of the most common causes of amputation in adults with diabetes. That's a serious issue. Once you don't feel anything, obviously, as Mike said, you can step on a rock, you can step on a nail through your shoe. We have patients who throw their car keys in their shoes, and then they forget, they put on their feet, and then they get necrosis throughout the day besides not finding the keys to their car because they don't feel it.
So, you know, and then when the nerves innervate the muscles, you get weakness and muscle loss, balance problems, and, you know, ulcerations and wounds. And then there's a condition called Charcot foot where, without any trauma, you get breakdown in the bony architecture of the ankles, leading to collapse of the bony structure, severe disability with very few treatments other than wearing a big boot or having a complicated surgery. So patients are desperate. They are willing to do anything to get a physician that knows about neuropathy and find a doctor that can prescribe a medication that's covered by their insurance. And as mentioned earlier by Mike, you know, people go up and down. Sometimes a drug will work, sometimes it won't. Sometimes medications are added to it, and it does affect all their activities of daily living 24/7.
And sometimes it's even so bad at night because they have increased sensitivity. They have metal bars at the bottom of their bed to keep the sheets off their feet. And of course, if they're working, the absenteeism is high, presenteeism isn't good. And I would say that of all the complications that I treat of diabetes, I'd say this one causes the most aggravation not only for the patient, but effects on their loved ones around them, whether that's their spouse or their kids or their friends. So it's a serious condition. We don't have good therapies for it. And I'm excited about the Lexicon product.
Wow, Steve, that was really comprehensive. I'm sure, Rodica, if you want to add something.
And there was also, I think, a comment because I know we have a number of patients and patient groups. This issue around tight glucose control in neuropathy and even patients with tight control can still develop neuropathy. I think that's an important component to mention as well. Thank you, Steve. But Rodica, I don't know if you want to have any other perspective from your standpoint to add to what Steve has already said.
Yeah. So definitely, Steve has made a very, very comprehensive, you know, overview. But I like to highlight that when we say that diabetic peripheral neuropathy and diabetic neuropathies are the most prevalent complication of diabetes, those are supported by very strong facts. And I think that it's important to put things in perspective as well about the numbers.
As we speak now, in the U.S. only, we have more than 39 million people with diabetes diagnosed and approximately 90 million people with prediabetes. We know now because we had the opportunity, and I was very fortunate to be part of most of these large cohorts, that indeed neuropathy will affect more than 50% of people with prediabetes, even prediabetes, that it's true, and diabetes, and that has been shown here in the U.S. and in Europe across the entire spectrum in more than 60,000 of people that we had the opportunity to study directly, so these are facts. In addition, we know that even in people who are relatively good control, the presence and the development of neuropathy, particularly neuropathic pain, happens. We understand now that there are other factors among which obesity, this metabolic syndrome, are important contributors.
This is important because, unfortunately, we see a change in how even our people with type 1 diabetes are presenting today with overweight, obesity, that, you know, it's a component of their clinical presentation. We also know that neuropathic pain, as Steve mentioned, is indeed extremely challenging. And it is actually very different in diabetes compared even with other neuropathic pains. It's just because this milieu of diabetes, you know, this environment that there is this constant chronic inflammation further fuels all these changes in the neurons and in the receptors that are making pain such a challenge.
We know because we also have been very fortunate to have a very large cohort of people with type 1 diabetes in this country that has been studied for more than 40 years called Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications, where we were fortunate to have the opportunity to look at neuropathy natural history as well as most recently, like we published last year, neuropathic pain. How many people develop neuropathic pain and when does it happen in the course of the disease? And we've learned that, in fact, sometimes it may happen later in the course of the disease. Sometimes it can happen very early. And while glucose control is important definitely to prevent, there are many people who do develop neuropathy and neuropathic pain despite having very good glucose control. So, as Steve mentioned, there is a huge unmet need.
This exaggerated neuropathic pain that he alluded to called hyperalgesia, when people actually feel pain at the touch of socks, for instance, or bedsheets, it's extremely difficult to live with. It does affect the life of our patients. It does affect their sleep. We have very strong evidence now, again, from large phenotype people with diabetes that it is one of the most important risk factors for psychological complication, anxiety, depression, lack of sleep, and then, of course, need for polypharmacy, given the fact that as we speak, we do not have an effective pain medication that can be taken safely by our patients. When we talk about diabetes, we also have to remember that people with diabetes have to take a very large number of medications just because they need to treat their glucose, they need to treat their blood pressure, their heart risk, their kidney risk.
In that context, taking some of the available pain medication prohibits their use as effective doses because of the risk of side effects and interaction with other agents. This is just to sum up the absolute need that we are facing these days and the reality supported by facts.
Thank you. Really comprehensive. I think that it's also a great lead-in, Rodica. Maybe, Steve, you can comment on how neuropathic pain is being treated today or, frankly, minimized in some of the provider interactions because they don't have effective therapies for all the reasons you've talked about. If you could briefly sort of take us through that journey of, as Mike laid out in a high level, of the cycling of the patients and the cyclicality of the disease, but sort of this downward progression of more morbidity and ultimate mortality related to it.
Yes. I wanted to mention, too, that we haven't highlighted is that when you look in the differential diagnosis of a patient with peripheral neuropathy, there's probably no other condition that has more abnormalities that could cause peripheral neuropathy. We have lots of different things like, you know, chemotherapy, vitamin deficiencies, vitamin overdose. You know, there's many issues that could make it worse. And that person with diabetes could have some of those issues as well. And a lot of people without diabetes do have peripheral neuropathy. So it's extremely common. And it also relates to why it's difficult to study. And we'll get into that a little bit later. Most healthcare professionals, really, for lack of a better word, do not have a clue. It's a complicated area. There's multiple different drugs with different mechanisms of action.
As Mike mentioned, these drugs that we use today weren't really developed for treating peripheral neuropathy, and you know, what most physicians do is give something to the patient for pain, depending on their symptoms, and then you can get to physicians who may have a little bit more knowledge, like a podiatrist who deals with peripheral neuropathy and a neurologist, and they might take the patient's symptom and match it to one of the drugs that we have. So basically, you know, the drugs we have are we have the antidepressants. They've been mentioned several times, like Cymbalta, amitriptyline. That's kind of the for milder symptoms. People take it at night. It helps them sleep. They might do a little bit better on those therapies. Then, of course, pregabalin, gabapentin are sort of the workhorses, as I see it, out in the community.
And then they, you know, trying to get the right dose, increasing it to the dose that relieves pain. And most of the time, they end up with some side effects, especially being drowsy and tired during the day. So your dose that you can use is limited. Then there's opioids. And then, of course, a good alternative to an opioid is like a pain medication like tramadol that's finally generic now, but it's only marginally effective. And then, of course, we have topical treatments like capsaicin cream. Some people try lidocaine patches. But I hope you can get from this long laundry list of medications and creams that we try; it's very frustrating. And I can't even remember a patient that came back and said, "Oh, yeah, my pain is gone.
Thank you for, you know, the gabapentin." And access to physicians these days has never been worse, especially if you want to see someone that knows anything about peripheral neuropathy. And medications are expensive, especially some of the non-generic ones. So access to physicians that are knowledgeable, access to medications is extremely difficult. So it makes therapy this up and down situation. And that's the best-case scenario. The worst-case scenario, patients don't have access to medical care. And I think neuropathy, at least according to our statistics, is underdiagnosed because patients, some patients give up and they don't even complain to their physician about it because they hardly ever see their physician. So I hate to sound so negative, but we're in a tough situation with diagnosing and properly treating and addressing neuropathy with the drugs we have. So we need more.
Thank you, Steve. And I think you've raised and Rodica have raised a couple of really important points. And I just wanted to go one step before talking specifically about AAK1 and LX9211. But Rodica, since you're really so instrumental in making the definitive diagnosis of DPNP as a medical condition, perhaps you could talk a bit about the MNSI just briefly. And then, Suma, maybe you could talk about how we incorporate it into the trial and what we saw when we screened patients with the MNSI. If you could, Rodica, just give a brief sort of synopsis of how is DPNP diagnosed or actually not diagnosed in the real world today.
Yes. Thank you for the question. That further highlights that, you know, neuropathy is indeed a very complex disease.
It's because the anatomy of the nervous system is so complicated with multiple types of nerve fibers that have distinct role and functions, and each of them being responsible by different sensations. Like large fibers are responsible for, you know, balance, light touch, vibration. Smallest fibers are responsible for pain, temperature discrimination, and other sensations, and there is indeed this progressive damage and loss of these various nerve fibers, so in order to identify, you know, their damage and loss and to be confident that what we see in a patient who presents with neuropathic pain or any other type of pain is truly due to neuropathy, we need first to confirm that the person has diabetic neuropathy.
As Steve mentioned, you know, the care of diabetes and, in general, healthcare delivery, it's actually so burdensome these days that most physicians do not have the time and do not have the knowledge of how to identify that, and that can be done actually even in the office. We have developed the Michigan Neuropathy Screening Instrument. In fact, my dear friend, Dr. Eva Feldman, had described it back more than 30 years ago, and then we had the opportunity to validate indeed the sensitivity and specificity of this instrument in the large cohort of more than 1,400 people in DCCT, comparing with the entire battery of nerve conduction studies and quantitative sensory testing.
We know that it is pretty sensitive and specific, that assesses a couple of, you know, physical examinations like vibration with a tuning fork at the grade two, ankle reflexes, look at foot deformities, and also has a patient-reported questionnaire that has two critical questions regarding neuropathic pain. Do you feel a burning pain at night? And also, the pain, it's so intense that you cannot tolerate the sheets. Most recently, working with our colleagues at the University of Oxford and UK Biobank, we were actually able to validate these two questions that are being extremely specific and sensitive, specifically for diabetic neuropathic pain. That is why when we designed the RELIEF study and PROGRESS, we wanted to make sure that the people that we enroll in these trials truly have diabetic neuropathic pain. It's very important because we cannot compare apples and oranges.
Again, to be confident that a drug is effective for the disease state that is, you know, supposed to be, we want to make sure that the people who are enrolled in clinical trials are truly relevant for the disease, and that's important that can explain why prior therapeutic interventions have failed to be effective at the point of care. Because if we do not enroll relevant participants in a clinical trial, then we cannot be surprised that these drugs may not be effective, and, you know, the list of poorly designed trials that led to, you know, unexpected results, it's very long, and I can go on forever, so that is why this instrument that has been validated and now used in all these cohorts of people with both type one, type two diabetes, prediabetes, including adolescents, and that's something else that we forgot to mention.
It is sad to see, but the reality is that youth who have type 2 diabetes and are also obese do develop neuropathy and neuropathic pain. And we have that now, the evidence from two large cohorts in SEARCH and in TODAY, that unfortunately, now these complications happen even at very young ages, that therefore, the need is even higher.
So, Rodica, thank you for that. And I guess before turning over to Suma talking about the actual enrollment and screening, but Rodica, just from a pain pathway standpoint, would you get a positive result from, let's say, acute pain or post-surgical pain with the MNSI?
No. I mean, first of all, depending on the acute pain, right? So most of the acute pain trials that I am aware of are evaluating very different patient populations.
Let's say after a surgical procedure like abdominal surgery or after a surgical procedure on their feet, like bunions that are pretty common in the large population. So that is a very different patient population. It's a surgical procedure, short-term treatment. This cannot be actually even, you know, labeled as neuropathic pain. So that's one. And therefore, yeah, there is a possibility that among these patients, some people may have also diabetes and neuropathy. But that acute pain reduction is targeting a completely different mechanism and a completely different patient population.
Perfect. Thank you. Steve, you had a comment?
Well, I was just going to say that, you know, there's no comparison between acute pain, which is usually an injury or a surgery or infection or some other medical condition. The duration is short, and the mechanism is quite different than with long-term neuropathic pain.
And the treatment for acute pain is usually just analgesics, things like that. But neuropathic pain, especially DPNP, it takes time. It develops over an extended period of time. It changes, you know, character as time goes on. And it's quite different than acute pain. I mean, I don't think it'd be very. They're very distinct. And I think it's important that the test that Rodica developed clearly differentiates that as well.
Well, very good. Thank you. And Suma, maybe you could comment on the screening that we saw in certainly the RELIEF trial that we've already published on and just some insights, if you have any, on the PROGRESS trial in terms of the use of the MNSI and what we found.
Absolutely. You know, as Rodica and Steve have both mentioned, these patients, patients with DPNP, they come into the study with a number of comorbidities, you know, a number of many conditions that leave them in pain. And when they are patients suffering from chronic pain of various kinds, it is very hard for these patients to distinguish whether or not they have neuropathic pain versus pain secondary to, say, a back pain or a pulled muscle or something else along those lines. So having Rodica actually work with us and help us truly identify a homogeneous patient population to get into our trial has been very important.
What we saw from the RELIEF-DPN-1 study and also from screening in the PROGRESS study is that we have a very high screen fail rate because the patients do not accurately get diagnosed with diabetic neuropathy to meet the criteria to actually enter the trial. So this is very critical for us to get the right population. As Rodica mentioned, we need to make sure that the study has the right population to make sure that, you know, what we are measuring in terms of an efficacy readout is actually in the intended patient population.
Thank you, Suma. I guess that sort of leads into because I would call that in the clinical trial jargon, sort of de-risking of the study that you know the population that you're studying.
Suma, you touched on a couple of the elements of the trial design, both in relief and either further refined in PROGRESS. Rodica, from your perspective as the principal investigator and coming to the investigator meetings, if you could comment a bit on what I would call these issues around de-risking of the phase III trial to minimize some of the variants and either both the false negatives, particularly false negative trials, and also false positive studies, I think that would be very helpful to share.
Yeah, no, absolutely. That is why we, first of all, wanted to make sure that we are enrolling the right patient population. Including a homogeneity in the patient population will increase our confidence that the results that we are, you know, observing are true.
We know that pain, it's a subjective, obviously, symptom, that the, you know, perception of pain can vary from one patient to another. There are so many factors, including expectations, including cultural beliefs, including tolerance to pain. Definitely having this uniformity in our patient population, first, making sure that the cause of the pain, it's most likely diabetic neuropathy. We have, you know, ironed that out by having a very, you know, sensitive, specific instrument that can be administered in a standardized fashion. We have also demonstrated through all these large cohorts that I mentioned that it is very feasible to educate the clinical coordinators at the given site to perform this instrument very, you know, uniformly. We do have, you know, a validation and procedures in their training, and that minimizes the inter-rater variability in grading this instrument.
These are some of the approaches that we have further included in our trial besides using a standardized instrument, using the training procedures of the investigator who are administering. We are confident that the data, you know, variability is minimized as much as possible. We have also had very clear criteria regarding the pain level that was required to enter the trial. We know very well the placebo effect. Even by participating in a clinical trial, patient expectations are that they will get better. Plus, the level of attention that they receive definitely will lead to a better outcome. And so therefore, having these additional steps in place to minimize initial expectations with participating in the trial and continuing to have a uniform pain threshold when we are actually, you know, starting the trial are additional components that we have been very careful to plan.
Well, thank you, Rodica. And one of the elements that I think we need to perhaps reinforce a bit more is allowing the patients to maintain therapy on an underlying DPNP medication. And I just wanted to highlight before asking Rodica and Steve and Suma for their perspective, this is not, in a sense, a true placebo because the patients are continuing on effective therapy. They might still have residual pain. But as Suma had mentioned in passing during her comments, these patients are not on a true placebo because a third of them in the ongoing trial and almost half in the prior trial in some of the arms were on a medication that was considered effective. Suma, you might just want to comment a bit on that before turning it over to Dr. Busui.
Yes, definitely. You know, as we had mentioned during my presentation, that we allowed the patients to continue on standard of care, and in the first trial, we did not stratify the patients based on baseline use of DPNP medication, so we ended up with actually about 55% of the patients in the placebo arm were on underlying treatment, and this was predominantly gabapentin. So, you know, in a true essence, patients were already on some medication for pain, and we were comparing ourselves either on top of standard of care or in the absence of it against that particular group, so this is actually very critical from our perspective with our interactions, you know, with physicians like Rodica and Steve and also with the patient community, is meeting the patients wherever they are on their journey, on their treatment journey.
To be able to work as a standalone treatment, it is important. And also to, if they need it as an add-on to their underlying medications, to be able to show that effect is also important. So from a clinical trial perspective, that actually made execution of the trial a lot more smoother because that patient interest in coming into the studies, the interest of sites in participating in our trial with us has been very high. And one of the key reasons they keep mentioning is that we have had this patient-centric protocol that they could work with.
Thank you, Suma. And Rodica, from your standpoint, is that common that you see in neuropathic pain trials that they're allowed to continue on their underlying medication?
Well, so of course, the field of designing clinical trials in neuropathic pain has evolved as well.
And I see that that was really remarkable and relevant to the patients that we really see. It's to make sure that we enroll people as we see them in our clinic. Withdrawing medications for someone who had been requiring medications for a number of months, and I want to clarify that we had enrolled people who had been on a stable medication regimen would also not be ethical. I mean, people have pain. And therefore, and again, you want to have a trial that it's relevant to the patient population that we currently see in clinic. So continuing their current stable pain medication and obtaining pain reduction, it's even more relevant than taking people out of their medications for a while.
I think that that's another very strong, you know, characteristic of the design that we have pursued to test the efficacy of this new molecule as a potential viable and effective medication to treat neuropathic pain because this is the reality. People are being treated. Of course, we also had the novel populations who are more recent new development of neuropathic pain who were not necessarily on a pain medication, allowing us to compare both groups.
Thank you, Rodica. Steve, you had a comment as well?
Yeah, quick comment. I don't think there's any condition more difficult to study than DPNP because of the many variables that are also subjective. I'm impressed, Rodica, with your leadership in organizing this study to make it as less variable as possible. But there still are issues in terms of doing the vibratory sense and, you know, reflexes.
Even, as you mentioned, the patient's mood when they take their pain score. So I think you've controlled as best you can. I like to call this study a real-world randomized clinical trial because patients are on a current medication that might be working a little bit, and to take them off would just create confusion in analyzing the results. Lastly, I do think it emphasizes the point where you just cannot compare clinical trials like this that are done well with other clinical trials in the field addressing diabetic peripheral neuropathy pain. Very difficult to compare.
Thank you, Steve. I wanted to move on really to one more design element that I think is important, is the importance of the placebo effect in neuropathic pain.
Rodica, maybe you could comment on that first, and then I'd like to get Steve's perspective and Suma's perspective on the importance of having a placebo, particularly in this indication. Rodica, from a historical standpoint, if you could comment first.
No, absolutely. I mean, and I think that both of us, Steve and I, have alluded to that before. Placebo, it's a very well-described and real effect that happens not only in pain trials, happen basically in most of the trials, but it's particularly relevant in pain. So what is the patient expectations when they enter a trial that, you know, it's testing a new molecule for pain reduction? It's definitely that they are going to experience pain reduction. And that has been demonstrated over and over again, particularly in the diabetic neuropathy field.
I think that one of the reasons that we have failed disease-modifying treatments over time, which means, you know, agents that have tried to reverse the nerve damage, was because the placebo effect was not correctly estimated and the placebo effect was larger, and therefore, the difference at the end of the day was no longer significant. So therefore, not having a placebo arm and not correctly, you know, analyzing the pain reduction in the placebo will not give us a real image of what is the effectiveness of that particular drug because then in real life, the expectations of pain reduction will be not real. So having a placebo arm, it's essential.
Studying the placebo effect in pain reduction and then, you know, estimating the actual active drug in comparison to placebo are critical components to have a viable agent that is effective when we treat our patients in the clinic.
Thank you, Rodica. And Steve, I know you and I talked about this comment. I know we're getting close to the end of our panel time here. But the difference between the patient experience on a therapy and then the placebo-adjusted benefit of an experimental therapy compared to that placebo, maybe I think you're so far so much more eloquent than I am if you could simply explain that to our listeners because I think there's a big confusion because many of the trials, their primary endpoint is to the patient's baseline, not subtracting out the placebo effect.
As Rodica said, in every trial that's been done with pain, the placebo effect is statistically, highly statistically significant in and of itself. So maybe you could just comment on that briefly.
Yeah, Craig, I'll be very brief. I cannot, I could never evaluate a study unless they had a placebo group because we know placebo could have strong effects on the patient's symptoms. And even in other studies where we're looking at oral agents or injectables, GLP-1s, SGLT2s, to me, it's incredible that someone would do a study and not have a placebo-controlled evaluation of the results. It just doesn't make any sense because placebo is placebo. And for some of the studies I've seen, they should just double the dose of placebo. It would be better than their actual active drug. So to me, it's a silly argument, to be honest, especially with diabetic peripheral neuropathy pain.
So that's all I'll say. I cannot believe people would actually do an evaluation without subtracting placebo. It just doesn't make any sense. I can't believe the FDA would accept anything like that as well.
No, thank you, Steve. And Suma, you might want to comment because I know you've done a lot of research on pregabalin, for example, where they've really published nearly all of their trials that were used as part of large placebo-controlled trials and what the results were from those and what percentage of those trials actually separated from placebo.
Yes. So, you know, as part of our question to going into the space and developing clinical trial protocols today to meet the patient where they are, it was very important for us to understand all the little nuances that go into treating, as, you know, both of our esteemed panelists have told us, a very, very difficult disease condition. So part of that was a deep dive into the placebo response that we see in this patient population. And what we saw looking at reported data for pregabalin was that in almost every study, they have a statistically significant effect change from baseline in the placebo pain score. And these values range anywhere from 0.9 to over 2.5 unit reduction in their average daily pain score.
So for us, it absolutely was critical that when we go into studying a novel therapy, a novel target, that we actually compare the effect versus placebo to get a real true measure of how LX9211 works. And so we ran all of our trials as placebo-controlled studies. Now, we have, yes, pregabalin is an approved therapy, but even in that scenario, there have been trials with pregabalin that have failed because of lack of separation from that particular placebo arm in that particular study. So it is very critical to understand the success of a trial to have a placebo arm, especially in a neuropathic pain condition like DPNP.
Thank you, Suma. And again, just as a reminder, a third to a half of the patients in our clinical program were not just on placebo. They were on an underlying active medication, generally gabapentin.
About 90% of the patients in the RELIEF study who were on an underlying DPNP-allowed DPNP medication was gabapentin. Onto our last question, I guess, Rodica, I'll start with you, is if the results of the ongoing PROGRESS study achieve their endpoint, I mean, what would be your takeaway from that, you know, in terms of confidence of the result, excitement about moving into phase III, and potential value of this as another alternative if confirmed in phase III studies?
Yeah, thank you, Craig. I'd just like to highlight a few points. One, definitely the need is there, and we have highlighted that. Second, the fact that we enroll ahead of the schedule, it's extremely relevant because it means that further reinforces the need, and second, that it is well-tolerated medication. Third, it's a simple dosing regimen once a day.
This is also very important because most of the other available pain agents require more than once a day dosing. And we know very well that even in people who are motivated by pain, compliance with more than once a day dosing, it's always much lower. Therefore, further hampering efficacy of a given agent. The fact that we see, you know, this high tolerability after refining our study design and applying the lessons that we've learned from RELIEF into PROGRESS, it's extremely relevant. And the bottom line is this: we need pain medications that are effective and they are safe. And we also need to be cognizant of the fact that because of the complexity of neuropathic pain associated with diabetic neuropathy and the complexity of diabetes state by itself, it is unlikely that a patient will be able to be treated with one single agent.
And therefore, having, you know, choices that we can use in combination safely, it's another very important point. So the need, the safety, the ease for prescription, it's non-opioid. And that I cannot, you know, highlight how important it is. With the American Diabetes Association, we have published guidelines for treating diabetic peripheral neuropathy pain that we have revised more recently. Again, seeing the evidence of the very large use of opioids, unfortunately, still as we speak. Despite that, in fact, if we look critically at the trials that even led to some of their approval, tapentadol particularly, their design is very poor with more than 40% of people that actually did not finish the trial. So questionable efficacy for diabetic neuropathic pain and yet very large use leading to all these complications of addiction and severe complications.
So, I cannot highlight the importance of having new agents that are effective, safe, easy to take, easy to prescribe.
And 9211 and the PROGRESS study would reaffirm and really tick all those boxes. Very good.
Absolutely.
Thank you. So, I wanted to advance on to Mike Exton now. He's going to make a few key takeaway comments, and then I think we're going to turn it over to questions from our investors and then also to keep Steve and Rodica, have them come back for the question and answer period. Mike?
Yeah, look, thanks so much. What a fascinating and informative session. I'm going to really skip through my section pretty quick and get to Q&A to take advantage of our two external panelists.
But really, the most important thing to inform everyone is that as we now move from clinical into potentially a commercial asset, we can reveal to you the generic name of LX9211 as pilivapadin. They've even spelt it phonetically there in case you don't understand my Australian accent. And so hopefully that will become part of our vernacular in the very near future. So without any further ado, let me move forward now into question and answer session. We have Dr. Busui for about another 20 minutes, I think, because she's off to do grand rounds, and we want to make sure that she can get there. So before I turn it to the operator to line you up for questions, if those people asking questions could prioritize questions for Dr. Busui, that would be fantastic so that we can take advantage of her precious time.
So operator, right over to you.
At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. You may remove yourself from the queue at any time by lowering your hand. When it is your turn, you will hear your name called and receive a message on your screen asking to be promoted to a panelist. Please accept, wait a moment, and once you have been promoted, you may unmute your video and audio and ask your question. We will wait one moment to allow the queue to form. Thank you. Our first question comes from Yasmin Rahimi with Piper Sandler. You may now unmute your video and audio and ask your question. Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Wonderful. Good morning, team, and thank you so much for the very thoughtful and very helpful discussion. I would love to ask Dr. Busui and Dr. Edelman a question that we get from clients very often, which is, what is considered a clinically meaningful change in the pain score in the study about to read out? And then I think we also really understood today the heterogeneity of a complex disease beyond pain. So if you could help us also understand what are other endpoints you would be looking for in the study as we're awaiting data. And then for the management team, if there is an extent you can talk about, if you powered for additional endpoints beyond pain that could establish really this key differentiation of this asset for this very complex disease, that would be very helpful. And thank you again for a great discussion.
I'm happy to go back to my mute.
Great. Thanks, Yasmin. Rodica, I'll hand that over to you for, you know, what is clinically meaningful in terms of the reduction of pain score versus placebo.
Yes, thank you so much, Yasmin, for this very thoughtful question. That is very important, again, to understand from patient perspective. And in fact, we have done studies in which we have done exactly that. And I'm just going to highlight one that we have used also when we published the guidelines from the American Diabetes Association. We asked approximately 2,600 patients with diabetic neuropathic pain, what is a clinically meaningful reduction in pain? And people responded that a 50% reduction in pain, it's super clinically relevant, but 30%, it's also very, very important, and that's how they responded.
So this is a strong piece of evidence that came from patients living with a disease from various backgrounds, and that allowed us to also evaluate the evidence from the perspective of how many are meeting those guidelines. The reality is also that, you know, we need to look at the baseline. But we have also incorporated in RELIEF and in PROGRESS additional important endpoints. So the pain, of course, the pain score is one of the primary ones. But we have looked at patient-reported outcomes exactly for that reason. The patient global impression of change, which is now incorporated in many of the pain trials that FDA mandates, the sleep interference, you know, and many other scores, ability of, you know, carry on your daily function, this is also very important.
Of course, in our published trial, we have detailed all these outcomes, and we will continue to do so because pain has so many aspects in a patient's life, not capturing this additional, you know, secondary outcome like we call them. It's also a limitation which we wanted to avoid.
Rodica, maybe I could just ask for you to provide a bit, and maybe Steve, you could comment too, is that those numbers that you were talking about, Rodica, those are patients compared to their own baseline. Again, there's a difference from a regulatory approval standpoint where it's placebo-adjusted, but patients are going from their own starting point. Maybe you could comment a bit more on that.
Yeah, that's exactly, yeah, let's compare with their baseline where they started, and that was their patient response.
But how pain also affects other functions, their daily living, also contributes to the clinical relevance of the pain reduction. So then when we looked at the data, you know, like the point average from baseline that we described from a regulatory perspective, and we linked that to patient global impression of change, that we were able to do so, the sleep interference, anxiety, and daily function is also an important way to evaluate, you know, the patient perspective on pain reduction.
I'll make a quick comment because taking it out of the clinical research setting, when you give a patient a medication for painful diabetic neuropathy, when they come back, you talk to them and hopefully their caregiver, their spouse, someone that they live with, and right away, it's called talking to your patients.
And right away, they'll tell you, "I'm feeling better," or, "This medication really had no effect." And sometimes talking to the caregiver really helps you quantify and qualify, you know, if that's true and how much is going on because we could tell as clinicians when we use neuropathy drugs. So when a drug works, we as providers are extremely happy, and we may continue that therapy, we may change the dose. And if it's not quite satisfactory for the patient, we would add another medication. Because I do think because of neuropathy being so difficult to treat, using different drugs with different mechanisms of action might be the way to go for certain patients. And Rodica, I think your comments on the clinical trial and what the issues are now with the unmet need, having a single drug with reduced side effects was so key.
I think I'd like to tape record that and play it in my lectures.
Suma, maybe you could comment a bit on the statistics and the powering, particularly with the nearly 80 additional patients above and beyond the target that we had in the study.
Yes. Yes. And thank you, Yasmin, for that question. You know, we have powered this study for its primary endpoint. And the actual goal of the study, as mentioned during my presentation, was to understand what the impact of the loading dose was on tolerability and identify that one dose arm to take into phase III studies. So the simple answer is it is powered for the primary endpoint. And as we over-enrolled, as we exceeded our enrollment goals by about approximately 80 patients in the study, where we are in terms of power actually increased for the primary endpoint.
We also have, as Rodica mentioned, we have the secondary endpoints on efficacy built into the trial as well, and we will be looking at that results with great interest. Thanks.
Thank you very much.
Our next question comes from Andrew Tsai with Jefferies. You may now unmute your video and audio and ask your question. Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Yes. Hi. Thanks for hosting this. Really appreciate it. I guess to follow up on another Yasmin's question, maybe asked another way, you know, there are three drug arms in the study being compared to placebo. So do you essentially have three shots on goal here? Is a study sufficiently powered to show that? And maybe for the management team, what is the minimum, I guess, efficacy delta you would want to see for you to continue on into phase III?
What's the go-no-go threshold? And then maybe for the doctors, if the original phase II data is replicated in PROGRESS, this phase IIb, and then also replicated in your subsequent phase III studies, what percentage of your patients would you be prescribing LX9211 and why? Thank you. Great.
Thanks, Andrew. Let's start with the last question first, Rodica and Steve. Based on the placebo-adjusted reduction in pain score, do you see that as a compelling profile for your patients?
I'll just say quickly that we're looking
—go ahead.
We're looking. I'll just say in very short, we're looking for more therapies for quite some time, and the current therapies are just not adequate. So if I had to give a percent, I would say it would have to be well above 50% because I don't—it's been very unsatisfactory right now with the drugs that we have.
Adding them on might be an option in addition to using them as first-line therapy in a patient that I might see for the first time.
Completely agree with Steve.
Wow, that was short. I love it. Maybe I'll move on to the statistical analysis plan, Suma. You're probably best positioned to answer that because you've been so involved with our statisticians and the FDA in terms of powering the study and the methodologies used and the approaches taken.
Yes, absolutely. Our study, Andrew, this is powered for our primary endpoint, and we have three treatment arms here. Each of these three treatment arms will be compared versus placebo. What we are looking for is identifying that one treatment arm that stands out to take into phase III. Now, of course, one of the leads there will be the efficacy component.
But from our historical data in the RELIEF-DPN-1 and the RELIEF-PHN-1 study, we also will put a lot of weight in what we see in terms of tolerability with the patients. So ultimately, the goal for us is to find one arm that we take into the phase III trial.
And Suma, a number of people have asked me about splitting the alpha or otherwise with multiple comparisons. I think that was kind of what Andrew was hinting at. You might want to clarify that because I think that was another topic we thought long and hard about.
Yes. And so this study, unlike our RELIEF-DPN-1 and RELIEF-PHN-1 study, where we were actually looking for, you know, a proof of concept design, this is more identifying one arm to take into the phase III study.
So in this study, per our SAP, our statistical analysis plan, we are not splitting the alpha across the three treatment arms. They are individually being compared versus placebo. And then we will be comparing each of these three arms using a procedure, statistical procedure called MCP-Mod, to identify the appropriate arm to take into phase III.
And there's not an absolute number we're looking for here in the size of the reduction versus placebo, Andrew. I think, as Suma mentioned, we're looking for a single dose to take through into phase III . And when we're confident that we have that, then we will proceed.
Thanks so much.
Thanks, Andrew.
Our next question comes from Roanna Ruiz with Leerink. You may now unmute your video and audio and ask your question. Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Great. Morning, everyone.
A question for the KOLs first. So thinking about the PROGRESS trial results coming up, what would be exciting for you on the efficacy side that from a prescriber perspective might motivate you to use 9211 earlier than other current agents in the DPNP space? And second question, given the polypharmacy in the sector, what do you think about 9211 fitting in your overall treatment sequence when managing different types of patients as well?
Go ahead, Rodica.
So first of all, seeing the same pain efficacy, the safety data, as well as effectiveness and additional outcomes that we've mentioned, which are patient-driven outcomes, would be extremely compelling.
Given that has been mentioned already, given the available medications and their spectrum of efficacy, which is definitely not even close to be optimal, the LX9211 would have a role as soon as possible in our prescription, as well as the ease of prescribing the non-opioid mechanism, which is so important. So having another non-opioid agent available that is easy to take and it's safe, it's extremely compelling in addition to obviously the pain reduction and effectiveness and other patient-reported outcomes. And I will have to leave now. I was really very happy to be part of this panel, and I will leave you in very good hands with Steve and our Lexicon colleagues. Thank you so much.
Thanks.
Thanks, Rodica.
Thank you, Rodica. Steve, you want to add on to what Rodica said around, you know, where would this place and the cycling, etc.?
Yeah, I think Rodica said it very nicely, but I would just say this, that if the results of the PROGRESS study and other studies with this compound bear that it's effective with minimal side effects because it directly affects some of the causes of neuropathy, the mechanism of action, I would feel very comfortable starting it as first-line therapy because nothing else I've used as first-line therapy typically works very well. And saying that, I might have to add something else depending on how the patient's doing. But once again, treating neuropathy is really difficult because you don't know where they are in that natural history. So I think it will add it to the trial and error, but I would have no issues.
In fact, I'm eager to get this drug available so I could use it as first-line therapy and then get a real feel for how that works early in the course. If you got it.
Let me add a little bit of color to this first-line, second-line therapy add-ons, etc., because in neuropathic pain and DPNP, it's a bit different to what you see in other disease states. This cycling is incredibly rapid. In fact, if you look at claims data, the time on first-line therapy is on average four months. And so it actually doesn't matter really where it fits in the treatment paradigm, whether it's a first-line or an add-on or a switch.
You know, this potential for innovative therapies in this area is highly likely to be used both on the comments from Steve and Rodica and just what we see in this rapid cycling of medicines because of all the reasons that Steve and everyone has talked about.
And just Mike, I think it's an important clarifying point is that these drugs in general take two to four weeks or more to reach steady state to minimize some of the CNS-related side effects. So when you think about a four-month course of therapy, it's frankly not four months because it's taking a month for them to even achieve steady state with the current regimens.
Yep. That makes sense. And a question for management as well.
I think you mentioned before that over 50% of patients in the placebo arm of the prior DPNP study were on background standard of care, mostly gabapentin, I think. So could you just explain to us how does that correlate or compare to the proportion of patients on background standard of care in the different arms of the PROGRESS trial that's going on today, if you're able to share?
Yeah. So yes. And thank you, Roanna. In the RELIEF-DPN-1 study, we allowed patients, you know, as you know, to continue on standard of care. However, at that time, we did not stratify patients based on that characteristic prior to them getting randomized to treatment groups. So we had a higher percentage of patients in the placebo arm, about 55%, on background of care compared to the LX9211 treatment arms.
In the PROGRESS study, you know, learning lessons learned from the RELIEF-DPN-1 study, we actually implemented stratification across the four arms in this study. And so overall, what we have had is approximately about 30% of the patients who came into the PROGRESS study have been on background therapy.
Got it. Appreciate the help.
All right. Thanks, Roanna.
Our next question is from Yigal Nochomovitz with Citi. You may now unmute your video and audio and ask your question. Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Hi. Okay. Thank you very much. Question, please, regarding the definition of this additional training on pain reporting. Could you just go into a little bit more detail on what exactly you mean by that in terms of, I assume, suppressing variability? What exactly is being instructed to the patients there?
Yes. Thank you for that question.
So this was something that we implemented in our RELIEF-DPN-1 study and as well as our PROGRESS study. It is called accurate pain reporting. It is a well-established, well-published process whereby the patients, you know, as you have heard both of our expert panelists mention, neuropathy is such a complicated disease and pain perception varies from person to person. So my pain score of five may be someone else's pain score of eight. It just depends on how we perceive pain. And what we were trying to do was essentially make patients understand what their pain score is. So for every patient, they are grounded at what a zero is, a complete absence of pain, and what a 10 is, which is the maximum worst pain that they have ever experienced.
And then, understanding that what they are reporting on their daily pain diary is pain secondary to DPNP alone. You know, they could have a really bad migraine one day or could have back pain the next day. That shouldn't cloud their perception of what they are reporting as the DPNP-related pain. So it is a training where patients usually come in and they say, you know, I don't know. I don't know how to report my pain. You're just giving me a pain scale of zero to 10. How do I do it? So this grounds them. So it is not that we are taking everyone and standardizing them to a four or a five. It is meeting the patient where they are, grounding them on what absence of pain is. That is a zero. What the worst pain is, it is a 10.
And then every day, what you're going to report is only pain related to diabetic neuropathy.
Right. And if I could just clarify a couple of things, Suma maybe ask you to clarify a bit more. It really is the variability of that patient from day to day. We're not forcing all the patients into a certain pain bucket.
Correct. That is absolutely correct. And there have been publications, you know, on this that have shown that this reduces that daily variability, the within-patient variability that you see that often results in a large placebo response.
And I think, Suma, also that if you could comment on the duration of the two-week placebo run and how those two sort of relate to each other.
Yes. So this training is actually given prior to the start of the placebo run-in period.
And then the patients enter that two-week run-in period where, you know, once patients just enter into a study, there's a lot of variability that comes into it. They are given a lot of attention all of a sudden. They are on new medication. There is that expectation that they're going to get better. So training them and adding a two-week long period, bringing them into that double-blind treatment period kind of gives us that better stability in understanding what their true baseline score is prior to entering the double-blind treatment period.
Okay. That's super helpful. And then kind of getting back to the shots on goal question, I was just curious maybe if Dr. Edelman can comment as well as the company, you know, the three arms, the 10, the 20, and then there's the 20 going down to 10 after, I believe, just one week.
I'm just curious, you know, what are your thoughts on the necessity or the value of that 20 mg titrating down to 10, given they'll spend most of their time on 10 anyway? Do you think that's a valuable addition to the study? Or I'm just curious your thoughts on that.
Yeah. Well, I'm not intimately involved in designing the protocol, but just seeing the data, you know, it looks like it's a way to see if they could reduce the pain a little quicker by not giving a total loading dose in the beginning that led to some side effects, presumably. But it's kind of a softer, gentler way to get to that steady state on the 10, get off to a little jump start. So that's just my thought, Suma and Craig.
So you nailed it. That's pretty right. Suma?
Yes, Steve.
And you know, you got it absolutely right. So we did a lot of modeling work, exposure response modeling work based on the RELIEF-DPN-1 study. And so we know that patients have to get to a certain, you know, exposure threshold for them to start seeing relief. And in the RELIEF-DPN-1 study, that loading dose on day one allowed us to get there. So when we take that loading dose off the table and we are dosing, you know, a drug with a half-life of six to seven days, but we are dosing it every day, this allows the patients to get up to a steady state level in about two weeks-ish. So our goal, and then we knew that, you know, the tolerability was a problem in the 200 milligram, the high-dose arm in the previous study.
So what we are trying to do here is group these patients, you know, you have the 10-mg arm that takes them around a two-week period to get to steady state, which will be similar to our low-dose arm. Then we have the 20-mg arm, which should mimic again the high-dose arm over a two-week period. We have the other intermediate arm to allow patients to get up to that steady state level somewhere much closer to five days to seven days. They should get to that therapeutic level that we saw in the low-dose arm and then allow them to stay on that longer. So if these patients needed efficacy earlier on, you know, that would allow them to start getting that pain benefit earlier on in treatment. So Steve, you're absolutely right.
It was, you know, that essentially built modeled on the PK of the drug and just to start seeing that efficacy kick in a bit earlier.
You know, just want to add a quick comment to your first question, which was excellent. You know, these studies will have PROs, and these questionnaires should pick up some of the improvements in patients' daily life. And that should go in parallel with their pain scores. And that's one way to sort of corroborate the effectiveness of the drug, how it affects their total life. And then, of course, there's the very objective as you can, the MNSI, too.
Yeah. Steve, I just wanted to echo that point.
In the RELIEF trial, the phase II pilot study, all of those metrics moved in the same direction, including, and we didn't get a chance to talk about this because we covered so much, the use of what this rescue protocol was for patients that had pain that was just not tolerable. There was the option in both the RELIEF trial and the ongoing trial that clinicians could use up to two grams a day of a certain nonsteroidal to manage that pain. The use of that rescue protocol was far greater in the placebo group than the drug treatment group. It's yet another metric that validates that the drug is actually having a clinically important and meaningful effect to the patient.
Yeah. That is important, Craig, for sure.
Very quickly, the last one, and this one is certainly, I believe, for Dr.
Edelman, it's a clinical question. You know, you mentioned the patients having difficulty even with things such as having the blankets or the sheets over them at night causing pain. I mean, just a very basic question, what do you do about, you know, clothing and things like that? Do they have to wear very loose-fitting clothing? Like, how does that seem like a hell of a problem?
Yeah. I mean, I can't even describe how bad it is because if they do have a partner, there's no way they could even sleep in the same room because sometimes patients will moan out loud. And as I mentioned, they sell these metal bars that clamp onto the bottom of the bed that keep the sheets off. So they wear shorts. And even things like socks can be irritating.
As I mentioned, to stocking-glove distribution, most of the time it's lower extremities. Rarely, or I say infrequently, does neuropathy travel up and affect the hands because neuropathy is a function of the distance from the spinal cord, which is why the lower extremities are affected first. So when someone has their hands affected, they have pretty bad neuropathy. Then they have gait problems. But to answer your question, it's pretty miserable. And we have to use heavy-duty pain medications if it causes pain as well. This pain is intense. The allodynia, just the touch. So these people are pretty much confined to their homes. They really can't go out. And so it's, yeah, it's hard to describe what these patients go through.
Gotcha. Thank you.
Thanks, Yigal.
As a reminder, to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. Our next question comes from Joe Pantginis with H.C. Wainwright. You may now unmute your video and audio and ask your question. Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Hey, everybody. Thanks for taking the questions and appreciate all the details. So one question about PROGRESS and one broader question for Dr. Edelman and management team regarding overall perspective for DPNP and pain. So with regard to PROGRESS , what are or are there any demographics, one or more, that you consider higher risk with regard to attaining a more homogeneous population?
Any heterogeneous populations that might pose a risk to the trial, gender differences or ethnic differences, et cetera?
So, thank you, Joe, for that question. You know, we looked into our RELIEF-DPN-1 study, and we did a lot of subgroup analyses. You know, we split the data in every different demographic, you know, baseline characteristic way that we could, you know, be it age, the sex of the patient, the race of the patient. We have looked at that data, use of baseline DPNP medication. Irrespective of whichever way we cut the data, you know, LX9211 had a similar effect on the pain score. So we don't have a risk group, so to speak, where LX9211 does not work. Right? So it has been, the effect has been uniform across the patient demographics that we have studied before. The study, of course, the PROGRESS study is still blinded.
You know, these are things that we will be looking to understand it better before we move into phase III. At this time, based off of the RELIEF data, we don't have any subgroups of concern here.
No, that's helpful. Thank you. Yep. Sorry. Go ahead.
I was just going to say that once again, it's a very difficult condition to study with all the different variables. You know, as someone that looks at clinical trial data all the time, you know, we look at the type of subjects, how long they've had diabetes. I would say how long have these patients suffered from neuropathy. You wouldn't want patients who are like fresh off the boat and just developed it in the last month. You may or may not, depending on the MNSI score.
But you don't want people that are totally insensate that they do have pain occasionally, but they're already past the point. I hate to say it like this, past the point of no return because nerve damage is hard to repair. Is there the similar degree of control? What's the A1C? Has it been under control for an extended period of time? What other medical problems? What medications are on? So I'm trying to give you a feel for these studies are difficult. And I do think the folks at Lexicon with Rodica's, you know, guidance have done about as best a job as you can to control all the variables that may affect the results of this study.
No, I appreciate that. And my broader perspective question is, you know, when you look at the field itself, and Dr. Edelman, you treat patients here, there are different pain scales.
So right now, Lexicon's using the ADPS or the average daily pain score, and others are using numeric pain rating scales. So I guess, you know, how would you view the differences for these, how they impact different studies, and, you know, and how you look at these when you treat patients in the clinical setting, and how you really apply this to a regulatory path?
Yeah. Well, I'll just tell you from someone that sees patients, you know, we see a lot of veterans with neuropathy, those poor guys, some of them just don't have access to the best care, even though they're veterans. And a lot of people at the university and, of course, the people we talk to as part of our not-for-profit organization, you know, we don't use pain scores. We don't use any of these measures in clinic. We ask patients, how are you feeling?
Are you feeling better? And if they are, they're very adherent with these medications, and they're very appreciative. And we either continue or think about adding something else. So as a clinician, you know, these scores that are used in clinical trials, they're there for clinical trial's sake and for the FDA because you want to make things as objective as possible. But in the clinic, it just doesn't. We don't have patients fill out forms because they don't really mean anything to us in reality. We talk, we see if the patient's quality of life is better if their pain is down.
Perhaps you want to comment on the ADPS and the selection of that versus other pain scores for the trials.
Absolutely. And, you know, Steve, you said it beautifully that these pain scales that we use are all meant for the clinical trial setting, right?
We have to be able to quantify in some way the patient's pain, and we depend on this patient-reported outcome. So, you know, Joe, irrespective of whichever scale is being used, all the scales that are being used are very well-validated instruments, right? So the scale that we are using in our trial is a very well-validated instrument, and we have even got FDA feedback on the utility of it in registrational trials. So what we are using today in our studies will be what we use in our phase III program as well because it is acceptable to a regulatory agency. But, you know, going to the more broader question of comparing one trial versus the other, we have heard about the complexity of the disease, the complexity of the trial design, the different protocols that come into place.
This is just another one of those reasons why, you know, no two clinical trials should be compared head-to-head in the space. We all have our different formats and protocols that we use that are essentially created for the patient population that we are bringing into that trial. So for us, you know, from our perspective, this is a regulatory requirement for us, and it is definitely a means of measuring the efficacy of a novel therapy. So we are using a validated instrument that has worked for us in the past that is, you know, accepted by the FDA, and it is what we will be using going into our future studies.
Thank you very much.
Great. Thanks, Joe.
Our final question comes from Joseph Stringer from Needham. You may now unmute your video and audio and ask your question.
Please begin speaking when you see the Lexicon Pharmaceuticals leadership on your screen.
Great. Well, thanks so much for taking our questions. First question is for Lexicon and to Dr. Edelman. Just given some of the prior LX9211 phase II data in DPNP, and in particular on the dose response, what are your expectations for a potential dose response on the ADPS endpoint at week eight between the three arms and the PROGRESS trial? Would you need to see a dose response there to increase your confidence in the overall phase IIb results and subsequent dose selection for phase III?
Okay. Do you mind?
Oh, did they want Steve to answer first? Pardon? Steve, I think the question was directed to you.
I think, and Joe, I don't want to overstate your question, but it sounds like how important is a dose response in your confidence in the validity of the results? Joe, I hope I didn't misstate that.
That's correct. Yep.
Well, no, once again, I wasn't involved in the study design, but just based on reviewing the prior studies, I think it's a good design. And I think it's what I was impressed was, and I'm not involved in these studies, just to let you know, is that I was impressed on their learnings from the earlier studies to improve the protocol design. So I think it's a good design. I think it's a good way to go to the next step. I think they've done things very methodically, and they have adjusted based on the learnings from the high loading dose of the first study.
And I think it'll be really interesting to me to see the data on patients who were not on any other therapy like gabapentin versus the ones that were. Because I think when I look at the data, if you take the drop in the pain score, subtracting placebo, even though many of these patients were on gabapentin, that puts the results. It tells me the results could even be better, just hypothesizing in patients who are not already on a drug because almost any drug we treat in medicine, one drug plus one drug, you don't add their benefits together. So you're testing the Lexicon drug on top of gabapentin, and that puts the data at a disadvantage. So whatever you're seeing, I'm hypothesizing that it could be better when you use LX9211 in patients who are not already on another drug. So we'll see.
So I think the study design is good, and I'm anxious to see the results.
Suma, your thoughts around the necessity to see a dose response?
So, Joe, I mean, I'll answer this, you know, in two different ways. I think, you know, we are not looking to see a dose response. You know, that is not the intent of this study. What we were looking at is to improve the tolerability profile and identify one arm to move into the phase III program. However, you know, when we looked at the data from our RELIEF-DPN-1 study, we had a lot of dropouts in the high-dose arm compared to the low-dose arm. And that, you know, when you have a statistical analysis plan and you look at the overall picture of everyone on the intent-to-treat population, that does actually flatten out the curve.
Now, when we separate that out and just do an exposure-response modeling, so patients who stayed in the 200 milligram arm and had higher levels of the drug in circulation, their pain score was definitely better. So with increase in exposure, there was an increase in the pain response. Now, I don't think for our purposes and intents for the PROGRESS study, we are not looking to see a dose-response. If we see one, it would be great. But our goal for this is to identify one arm to take into our phase III program.
Right. And thank you, Suma. And, Joe, just I think to put it in context, we're looking at, as both Dr. Busui and Suma said, we're not just looking at the efficacy. We're looking at the tolerability.
For example, if there's no dose adjustments required with the lower dose, that's going to simplify dosing. That would certainly play an important role. I think, as you also know, with centrally acting drugs in neurology, there's not sharp dose responses. And I think what drove us to the 20 and 10 is that exposure responsiveness and also getting very deep in the weeds of statistics without going there, having three arms in the modeling exercise, as Suma said, to pick a final dose is a very important component of that modeling, statistical modeling work to pick a single dose.
Got it. That's very helpful. And for the phase IIb PROGRESS trial, you mentioned the, I guess, can you outline the high-level stats plan for handling potential dropouts? And is FDA on board with your analysis plan there?
So I'll take this question. And the short answer is yes.
We submitted our protocol to the FDA prior to initiating the trial, and we definitely got their feedback on it. What we are looking at is a classical dose response scenario in the study. It is called the MCP-Mod method. It is very well accepted by regulatory agencies for this kind of a study where we are looking at selecting one arm to go into, you know, further clinical development. So that is definitely there. On the other hand, we do have the primary endpoint, which is the change in the ADPS score over the double-blind treatment period. And that will be very similar to our RELIEF-DPN-1 study where we use the MMRM method to handle missing data.
And so both of those, Joey, are being discussed and are widely accepted by the FDA.
Around the missingness of data, because this question has come up before, and I know we've answered it in Q&A sessions at other places, is that in addition to the MMRM model for dropouts, there are a number of other sensitivity tests that are done around that model to make sure that that methodology is robust to take into account those patients that drop out of how do you carry that data forward to the end of the trial. So we feel quite confident, and in the primary publication that was discussed in some length in the notes related to that, and again, it was published in a high-tier journal, so there was a thorough review of our statistics as well as the FDA, that the modeling work that is done with the primary endpoint and the dropouts, we feel quite confident that that is a true result.
Got it. Thank you. And then just lastly for Dr. Edelman, I guess this question has been asked a couple of times already, but maybe I'll just ask it slightly differently. So if the approximately 0.7 placebo-adjusted improvement in ADPS that was seen in the prior phase II trial, if that was replicated in the phase IIb PROGRESS trial, would you consider that a clinically meaningful result or an improvement, or do you think the majority of treating physicians would maybe want to see something higher than this or greater than this?
No, it's a good question, and it deserves to be asked a few times. The answer is absolutely yes. I base that response on the fact that we really don't have any good therapies out there now, and it's just trial and error, on and off.
So we're looking for anything that shows statistically significant improvement in the patient's pain. And that's, of course, documented in a clinical trial that's done as well as possible for this very complicated condition. So the answer is easy. Yes. And I think, as I mentioned earlier, I could see myself using this quite a bit, and especially in the beginning, we want to see how it works as monotherapy or in addition to other therapies. But yes, that data is all I would need to prescribe this medication.
Great. Thank you very much.
Great. Thanks, Joe.
Thank you. There are no further questions at this time. I will now turn the call over to the Lexicon Pharmaceuticals leadership for closing remarks.
Well, thanks very much. Firstly, thank you to Steve and Rodica, our two expert panelists, for their time and their insights.
Really fabulous to have them on board and share their thoughts as we move towards the top-line readout of PROGRESS phase IIb later this quarter. We're incredibly excited for this opportunity, not only for Lexicon, but clearly this thought that we can potentially bring a new novel therapy to patients, so many patients who desperately need it, is truly inspiring and motivating. So thank you very much all for your time, and have a great rest of the week.