Anand Patel, MD, CPI, chief medical officer at Conquest Research, discussed a phase 2 study that investigated the efficacy and safety of LX9211, an oral medication targeting neuropathic pain.
Postherpetic neuralgia (PHN) is a consistent pain condition experienced by patients after an acute herpes zoster vesicular eruption has healed. The pain associated with the condition can severely affect a patient's quality of life, quality of sleep, and ability to participate in activities of daily living.1 Some of the treatments that are available do not provide effective pain relief and are associated with adverse events such as somnolence and peripheral edema. LX9211 (Lexicon), a small molecule inhibitor of adaptor-associated protein kinase 1 (AAK1), is currently being investigated as a nonopioid target for the treatment of neuropathic pain.2
Results from a recent multicenter, phase 2 study evaluating the efficacy and safety of LX9211 showed that the treatment had a consistent reduction in Average Daily Pain Score compared with placebo throughout a 6-week dosing period. These findings were presented as an abstract poster by lead investigator Anand Patel, MD, CPI, at the 2023 American Academy of Neurology (AAN) Annual Meeting, April 22-27, in Boston, Massachusetts.
Patel, chief medical officer at Conquest Research, sat down with NeurologyLive® after the meeting to discuss how LX9211 performed in the phase 2 study, as well as the different factors that may have influenced the study's results and the interpretation of the data. In addition, Patel talked about the implications of the findings for future research and the development of LX9211 as a neuropathic pain treatment.
NeurologyLive®: Could you provide an overview of the abstract that was presented at AAN 2023?
Anand Patel, MD, CPI: LX9211, an oral once daily, small molecule medication is being positioned as a potential treatment option for neuropathic pain. Recently, Lexicon published the results of a phase 2 study for diabetic painful neuropathy and the results were quite positive for that study. That study also had a sister study, a phase 2 study known as RELIEF-PHN1, that focused on the efficacy and safety of LX9211 in the treatment of post herpetic neuralgia pain. It was a double blind, randomized placebo-controlled study that we were participating in.
What was your objective for conducting this study and the methods?
As I mentioned, it was a phase 2 study, the goal was to test the efficacy and safety of LX9211 in the treatment of patients who suffer from postherpetic neuralgia (PHN). The drug itself works by inhibiting an enzyme called AAK1, which is intimately involved in a mechanism called clathrin-mediated endocytosis. Through a pretty robust preclinical science program, Lexicon has identified LX9211 as a very potent oral medication that inhibits the activity of AAK1 and clinically that translates to potentially reducing neuropathic pain. Patients that were potentially eligible for the study were put through a 2-week screening period. In that screening period, once consent was obtained, patients had various inclusion and exclusion criteria vetted. They had to be male or female and above the age of 18, had to have a diagnosis of PHN at screening, and had to have symptoms present for at least 3 months.
They were not allowed to be on opioids in the 2 months prior to screening, and could not utilize [non-steroidal anti-inflammatory drugs] NSAIDs, specifically for their PHN pain 2 weeks prior to screening. But it's important to note that they were allowed to take 1 concomitant neuropathic pain medication while being in the study. Patients who were deemed eligible through screening were then enrolled in a 2-week period called a single blind placebo run-in. The goal here was to collect some important information. They were asked to keep a diary where they documented their average daily pain score, and also documented interference with sleep.
I should note they were allowed to use acetaminophen 3gs for rescue medication if deemed appropriate by the principal investigator. The goal of the diary was not only to identify patients that had adequate pain to qualify for the study—they had to have an average daily pain score of greater than 5 to be eligible—but it was also designed to ensure diary and medication compliance, and to also minimize the enrollment of placebo responders enough so that it would be appropriate for this particular study.
What did you observe in the findings and the implications of those results for this patient population?
The primary endpoint for the study was to determine if the treatment arm had a clinically significant reduction in their average daily pain score after 6 weeks. For this particular study, the primary endpoint was not met. The treatment group had a pain reduction score of 2.42 while the placebo arm had a pain reduction of 1.62. While it did not meet its primary endpoint, there's a couple of important things to identify as potential reasons why.
There was a fairly high dropout rate in the treatment arm which likely skewed the results. That's probably one part of it. The other interesting thing is that in the placebo arm, especially during the week 6 period, which was a very critical time to measure their average daily pain score, there was a very high amount of variability in pain scoring. It appears that the placebo response was higher than expected in the placebo arm and that likely the skewed the data.
I think when you look at the data post hoc analysis, when you graph out how the 2 groups scored over the 6-week period, it was pretty evident that there was a drug signal that occurred fairly quickly. We believe that's because there was a loading dose that's utilized in the treatment arm of 200 mg, which was designed to create a fairly quick therapeutic effect. But that may have actually led to some increased patient withdrawal because of adverse events. The other thing is, when you look at the head-to-head comparisons of the 2 groups on average daily pain score, at week 1, 2, 3, 4, and 5, the separation of the 2 groups was statistically significant. When you look at the average pain scoring across those 6 weeks, and not just the 6-week number alone, that typical significant difference between the 2 groups is also evident. Something about that week 6 data point, the variability in the placebo responders and the diminished volume of patients that remained in the treatment group may have skewed the results away from being significant.
What else do you think should be further investigated in future research with this treatment?
I think Lexicon is certainly rethinking the loading dose. It may not be necessary to implement a loading dose at the beginning, as I think the goal was to achieve a fairly rapid drug signal. While that may have occurred, it may have also potentially led to the onset of adverse events. The optimal way of dosing in further studies is something that’s been revisted. But also, when you take these results, which certainly are open to interpretation, and you couple that with meeting the primary endpoint in the sister study for diabetic peripheral neuropathy, there's certainly compelling evidence that the drug does have potential benefit in treating neuropathic pain. I think for the next study that they design, the goal will be to find out the optimal dosing, and to try to make the best efforts possible to avoid enrollment of placebo responders.
What do you think should be talked about more in the field?
The treatment options that are available for neuropathic pain now have been around for a while. They certainly are recognized as having shortcomings in terms of therapeutic efficacy and the balance of efficacy versus adverse event profile. The space is lacking sorely in terms of having effective treatment options. It's certainly welcome to have a novel molecule enter the space and I think it's very exciting. Specific to this drug, I think it shows tremendous potential. In the previous sister study for diabetic painful neuropathy, not only was the drug tolerated well, but there were no withdrawal effects when the drug was stopped.
When patients entered the single blind placebo washout period, the drug’s signal predictably diminished, indicating that the drug clearly had a benefit. There were no reported adverse events that occurred when the drug was stopped. You're looking at a drug that has potential efficacy. I think if they work out the proper way to dose the drug and find that harmony between efficacy and tolerability that this adverse event profile that was noted in this study, you're talking about a medication that could be positioned as either a first line agent, or potentially as a common medication with other drugs in the space, and really provide value add in terms of treatment options.
The takeaway message is that this is a drug with certainly a lot of potential, although there are kinks [that need to be] worked out. It certainly supports the idea of inhibition of AAK1 as a viable new mechanism of action for treating not just these 2 neuropathic pain conditions, but also other medical conditions that are neuropathic in origin. Thinking chemotherapy induced pain, post-op spasticity related pain after a stroke. There's lots of potential runway for the drug, and most certainly supports further exploration of LX 9211. Personally, I'm very excited about the next tier of studies that are coming out that Lexicon has in plans to further vet the drug for positioning as a viable option.
Transcript edited for clarity.
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Editor’s Note: Patel disclosed that he serves as a consultant and is on a Scientific Advisory or Data Safety Monitoring board for Lexicon Pharmaceuticals.