Good afternoon. So instead of showing you the interim results, I'll show you the full results of the Phase II study, or RBT1, and possibly, of course, inpatient with elective CABG and or valve surgery on cardiopulmonary bypass. My name is Andrei Lamy. I'm a cardiac surgeon. I have no disclosure. I'm a local investigator of the study, the START study, and I'm presenting on behalf of my colleague investigators. So the learning objectives. And so the preconditioning for organ protection. So it's an old concept, but it involves priming a stress response to elicit protection against subsequent injury. So it started about 100 years ago, and you've seen in the last 10, 20 years a fair amount of trials where they use a sphingal manometer on the arm or leg to induce ischemia. It didn't work very well, so what I want to show you today is the pharmacological preconditioning. So we're using a drug. It's called RBT1. It's a stannic protoporphine with iron sucrose, and it does induce a small inflammation in the patients, and then it produces, within 24 hours, three, not many biomarkers, but three biomarkers of importance. The HO1, hemoxygenase 1, which is an antioxidant, interleukin-10, which is an anti-inflammatory, and ferritin, which is an iron scavenger. And all these three biomarkers will go everywhere in the body and protect all the organs, but I will talk mostly about heart and lungs and kidneys today. So it's a phase 2 study, randomized, double-blind, placebo-controlled, and we have two doses with 45 milligram and 90 milligram of stannous protoporphine, and the primary objective is to generate a preconditioning response by generating the three biomarkers that I mentioned. And there's also case-study outcomes, which are days on ventilator, days in ICU, days in hospital, and make 30, AKI, respiratization, and safety. So very important to understand that the population of these patients is not enriched, contrary to most trials that you've seen. We took them coming to cardiac surgery as they were, and also we randomized at the site level to avoid any discrepancy between the standard of care in each hospital. And we have 135 patients who received the drugs, and only 121 went for surgery because the timing of the drug and the surgery has to be precise. It has to be more than 24 hours but less than 48 hours due to the pharmacokinetics of these biomarkers. So I will present my results on the 121 patients and this modified intention to treat. Age is 65 years. There's no difference in gender or ethnicity, and the placebo patients are slightly less, or slender, I would say. The reviewer score, the means vary quite a lot, but the median is basically about the same between placebo, 1.47, and we combined both low-dose and high-dose together for statistical purposes, and it's easier to present. There's a little bit more low-risk patient with the placebo group, but if you look at its type of surgery, the CABG and VALV are a little bit more frequent in the placebo group than the RBT1 group. Interestingly, the time of surgery and the time on pump are identical on the groups. So the primary endpoint has been met, so it's a statistically significant increase in these biomarkers with both those RBT1s. So for the first one, HO1, ferritin, and interleukin-10, you can see the low-dose in orange and the high-dose in green. Now, if you look at the time in ICU, we combined both those together. It's easier to demonstrate. If you look at ICU time, there's a statistically significant reduction in ICU from six to 3.3 days, and we see the same effect, if you prefer, in the ventilator days and the length of stay in the hospital. Another way of showing the results, the patient seems to get out, seems to be extubated faster, get out of the ICU faster and go home faster. Also, we look at troponins, so there's a 60% reduction in the total troponins between the RBT1 and the placebo, 24 hours. But if you're a cardiac surgeon, you're interested in troponins. And also, there's a significant reduction in the 30 days cardiopulmonary readmission, with 17% in placebo and 5% in combined RBT1. And this readmission was due to volume overload, so CHF, congestive heart failure, worsening pulmonary hypertension, pleural diffusion, pericardial diffusion, post-cardiotomy syndrome, and respiratory failures. The rate of AKI and MAKE, it's about just a 10% reduction. This group is not enriched to demonstrate a reduction in MAKE-30. In terms of the clinical events reported by the investigators, three are more important. There's atrial fibrillation, that went down from 41.5 to 26.3% in the RBT1. And the rate of anemia has been decreased by half, and hypervolemia has decreased by two-thirds. Time for atrial fibrillation, so with the placebo, AFib arrives quicker. And for these two curves, we have the log-rank that is at 0.06. So RBT1 improved the possibility of outcomes in patients. It's a significant reduction for ICU time and readmission. And there's the same important results, or meaningful results, as seen for ventilator days, hospital days, and atrial fibrillation. So as we're planning a phase three trial, we will use a win ratio in the phase three trial. Win ratio is basically, each patient is compared to the other patients in the other group. So 41 times 80 patients, you get 3,280 pairs. So each pair is tested with the various outcome, and it's hierarchical, so we're starting with the worst outcome death, and we go down all these six outcomes. What's very interesting is, virtually all patients in the trial contribute to the p-value. Contrary to the Cox regression that we see, cardiology trial, the death, MI, and stroke, where only a fraction of the patient contribute to the results. And you can see here, the win ratio, 1.6 with a p-value of 0.017. If you use only two outcomes, the most frequent one, of course, it's even better. And it's very significant. Again, this is a post-hoc analysis. If we look at the adverse events, there's a lot of adverse events in these phase two trials. We collect everything. But in the middle there, you see the serious adverse event, and they're basically similar. And the death on the study, there's three deaths for each group. Again, these are the most frequent adverse events. The atrial fibrillation is the most frequent complication we see in cardiac surgery. And they're quite balanced, except, of course, anemia and hypervolemia that I mentioned previously. Photosensitivity, so that's probably, it is the only side effect of this drug. It's a porphyrin, after all. So it goes in the tissues, and if you're exposed to UV rays, you will react. And some patients have described a reaction to sun exposure, and they had some sunburns that are pretty mild, but they're preventable with sunscreen, regular sunscreen that you can buy. But it's there, and it's dose-related. So in summary, there's a statistically significant increase in the biomarkers, a reduction in ICU and readmissions, and clinically meaningful reduction in eventual time, hospital length of stay, and atrial fibrillation and troponin levels. And as a postdoc analysis, we have a statistically significant benefit using a composite outcome with win ratio analysis. Thank you. And we're starting the phase three soon, so if you're in the United States, in Canada, or in Australia, and you're interested in participating in the phase three, you can contact me or Boopender Singh at Rainibus. Thank you.

cardiac surgery

RBT1

pharmacological preconditioning agent

biomarkers

Phase III trials