ASH 2025 | Phase III STArT trial results: sickle cell disease treatment with arginine therapy

We presented the results of our Phase 3 trial, and STArT stands for Sickle Cell Disease Treatment with Arginine Therapy. And it was a randomized controlled trial, Phase 3, that looked at the use of IV arginine to treat acute pain in children and young adults with sickle cell disease, aged 3 to 21 years who presented to an acute care setting for treatment of their pain requiring parenteral opioids. So we recently analyzed the results, and the primary outcome measure was something called time-to-crisis resolution. And it’s very similar to your length of hospital stay, but it’s defined as the time of the first dose of the drug, the study drug that we’re giving, to the last dose of IV opioids. And patients with pain and sickle cell disease are usually admitted so that they can receive aggressive pain management through intravenous analgesics. So once they no longer need IV opioids, they’re usually ready to be managed at home with oral medications. It doesn’t mean that their pain is completely gone, but it means that they can be managed outside the hospital. So that was our primary outcome. And unfortunately, the study was ended early by the Data Safety Monitoring Board for failure to meet that outcome. We randomized 274 patients and we gave study drug to 271 individuals, which is actually a really large, one of the largest pediatric studies. And in fact, we were nearly a year ahead of schedule for our enrollment. So we were doing well on that end. But since the study concluded, we’ve been analyzing the data. And as we know, there’s no difference in time to crisis resolution. But this study has really highlighted a challenge with that clinical endpoint, not just for my study, but for every study. So, you know, we joined the ranks of every single phase three trial for acute pain and sickle cell disease that failed to meet its primary outcome. And, you know, which is unfortunate because as an emergency medicine physician, I see firsthand the suffering that these patients are experiencing when they come into the ED. And I have nothing to offer them except opioids, right? And of course, it’s critical that we get them out of pain, but we need to do better. So, you know, the concept of arginine is based on nearly 30 years of preclinical and clinical data and multiple phase two trials in the United States, in Nigeria, and in Egypt that showed promise from decreasing time to crisis resolution, but also decreasing pain scores, decreasing opioid use. And in our recent study that we published, our phase two trial out of Children’s Healthcare of Atlanta, we found significant improvement in mitochondrial function and oxidative stress. And so those aren’t necessarily biomarkers that are accepted as clinical endpoints now, but some of the experts like Shruti Shiva, who ran the mitochondrial function from University of Pittsburgh, was one of our speakers at our workshop on Friday, where we talked about the importance of finding novel surrogate biomarkers for our clinical trials. So people will ask me, well, what’s wrong with time to crisis resolution, right? We want to be able to shorten their pain. And I think, one, because it’s very subjective. But we also learned that it is more likely to be a reflection of the hospital that you’re admitted to and the practice at that hospital than your individual pain. And there’s so much variation in practice. So we did a deeper dive on our clinical trial looking specifically at the placebo arm. So that means that’s standard of care across all the sites. And this paper was just recently published in American Journal of Hematology talking about the variations in this outcome. When I first got into the field, you know, as a young investigator, patients were admitted to the hospital for about six to seven days. And we powered our studies to actually see a significant decrease by 17 to 24 hours. But as the time went on in the last 20 years, the amount of time that patients spend in the emergency, spend in the hospital has shortened. So, and right now it’s less than 72 hours. And the, you know, for patients who did not have acute chest syndrome in our STArT trial, it was actually less than 60 hours. So it becomes difficult for any intervention to actually have an impact. So that is important for clinical trials design because it means that we’re spending tens of millions of dollars on these clinical trials with an endpoint that is flawed. So one of the silver linings, though, from our study is that we found a subgroup, the patients who had acute chest syndrome, either they had it at presentation or they developed it, who had not a statistically significant because they were a smaller number of our larger patient. There were 54 patients who had acute chest syndrome. But they had a 75-hour reduction in time to crisis resolution favoring the arginine arm. So the question I ask is, is there really something different about acute chest syndrome? Or are these patients just remaining in the hospital long enough because the mean length of stay for a patient with acute chest syndrome is about five to seven days? So those are questions that remain to be answered. But I’m also thinking that in the sense of a novel drug is not going to treat everybody. And it becomes really important for us to find the subgroup who’s going to benefit from that novel drug and try and get it to the patients who are going to have the greatest benefit. One of the discoveries from my phase two trial is we reanalyzed our data and looked specifically at patients who came in with an arginine deficiency. And we saw a statistically significant difference in total opioid use in that group. And that makes sense, right? So if you are arginine deficient, you are going to respond best to arginine therapy because arginine is actually a nutritional supplement. You know, it’s an amino acid that’s found in our diet and our body uses it to make proteins. So although it’s considered a drug by the FDA because we’re treating a disease like sickle cell disease, really it’s a nutritional supplement. And it’s part of what we need in our diet, but it’s not possible to get enough arginine just from your diet to have the kind of impact to reverse the arginine deficiency we see in sickle cell disease. And what we’ve also learned over the years is that this deficiency is driven by the process of hemolysis. So again, it’s a component of the disease that the consequence of hemolysis, you end up with an arginine deficiency. And we know that if you have a nutritional deficiency, you need to replenish it because there are clinical consequences of those deficiencies.

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