So based on our, not only the mouse study I mentioned, but an additional mouse study where we used a mouse model of accelerated aging that we think, we and others think also can be a model of sporadic AD because these mice, as they go through the accelerated aging, they develop a number of cognitive problems that are similar to what the AD mice develop and also changes consistent with early-stage Alzheimer’s disease in their brains...
So based on our, not only the mouse study I mentioned, but an additional mouse study where we used a mouse model of accelerated aging that we think, we and others think also can be a model of sporadic AD because these mice, as they go through the accelerated aging, they develop a number of cognitive problems that are similar to what the AD mice develop and also changes consistent with early-stage Alzheimer’s disease in their brains. And we found in that study as well that CMS121 was able to, in that case, prevent the development of cognitive problems and also improve overall brain metabolism and particularly mitochondrial function. So yeah, based on this, as well as a variety of toxicology studies that we did in order to get IND approval, we decided to do a Phase I clinical trial in order to move CMS121 forward. And in this study, it was a four-part study. So it was, we did a single ascending dose study, a multiple, based on those data, we did a multiple ascending dose study at four doses. We also had a small elderly cohort and we also did a food effects study. And so in the single ascending dose study, we tested a very wide range of concentrations ranging from 50 milligrams to 1800 milligrams. And in all cases, it was well-tolerated and there were no significant adverse events. And based on those data and from our mouse studies where we knew what we thought the effective concentration of CMS121 should be, we then did a multiple ascending dose study where we used 150, 300, 600, and 900 milligrams a day for seven days. Oh, I didn’t mention that CMS121 is orally bioavailable. So this is also something that was always very important to us. And we’ve used oral administration throughout our mouse studies, because we felt that something that had to be injected or delivered by infusion or anything else was really not going to be useful in the long-term for patients with Alzheimer’s disease or even earlier stage, say, with mild cognitive impairment. So in the multiple ascending dose study, again, the pharmacokinetics looked good. There was a dose-proportional increase in the levels of the CMS121 in the blood. There were minimal adverse events, nothing serious. There were some at the higher doses, some gastrointestinal problems, but everybody completed the trial fine. And we then did this small elderly cohort, which we chose a single dose, 600 milligrams. And again, it was very well tolerated. And we also, I forgot to mention, we also did a variety of obviously other clinical tests, and there were no indications of any problems with the heart, the liver, the kidneys, anything like that. And the blood work was always fine on all of the subjects that were treated. So in the elderly subjects, this is one of the interesting findings from our Phase I study. We found that the pharmacokinetics were quite different, that the levels that were achieved with the same dose as compared to the young healthy subjects were very much higher, and that CMS121 persisted for quite a bit longer. So this suggested to us that we need to do more exploration on the pharmacokinetics in the target population, which is obviously elderly subjects. And in the food effects study, what we found, which was we did this because in our mouse studies, we actually put CMS121 into the diets of the mice. And so we thought that that likely helped its uptake into the mice and into the brain. And so we wanted to see if that was indeed the case in humans as well, particularly because a lot of times, as you probably know, drugs are often, people are told to take drugs in the absence of food or before they eat breakfast or something like that. So we wanted to know if actually food would help with the uptake of CMS121. So we had 12 subjects that were either given, fasted before they were given CMS121 or were given CMS121 with a light meal. And it turned out that indeed food helped the absorption of CMS121. The levels were about 50% higher in the blood given with the food and CMS121 persisted quite a bit longer in the blood of the patients.
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