Obicetrapib

“And with Obicetrapib, he is now at the center of one of the most important open questions in cardiology, whether C-TEP inhibition can finally deliver meaningful reductions in LDL, APOB, LP-little A, and ultimately cardiovascular risk.”

“The history of C-TEP inhibitors, why earlier drugs failed, and what makes Obicetrapib different. Obicetrapib's effect on LDL cholesterol, APOB, LDL particle number, LP-little A, diabetes risk, and cardiovascular outcomes.”

“I mean, how many more trials do you need to show that LDL, no matter how you lower it, results in a clinical benefit? I think we'll talk about Obicetrapib. That might be the last mechanism. And once that study prevails, the PREVAIL trial, we have a 10th different mechanism of action of LDL lowering and benefit.”

“Let's talk a little bit about Obicetrapib. Your colleague, John Kaserlin, was a guest on this podcast. Gosh, I want to say three, maybe four years ago. Certainly one of the more enjoyable discussions I've had because I tend to really enjoy talking about these things.”

“I think it was eight. Okay. About Obicetrapib. Yeah. It could have been 2006. I feel like it was the fall of 06, but anyway. You're right. It was definitely Christmas, December, got the call somewhere in that range. Yeah. So it's- All right. So first this was Pfizer combining this with Atorvastatin in a clinical trial. Okay.”

“It was stopped for futility when it should have kept going. That was for us a big issue for our drug, Obicetrapib. That was the hardest one to explain. And what were the features of the Lilly drug in terms of HDLC and LDLC kinetics?”

“So, with all of that as background, now let's talk about Obicetrapib, the work that you and John and the team, of course, but let's just talk about how you decided it was worth going after this for a fifth time.”

“And that study is actually coming out this year. It's called the Zeus trial. It's a big, big study coming out. I had sold Corvidia, and John said, let's get Obicetrapib back from Amgen. Amgen had put it on the shelf because Repatha had struggled on its launch.”

“Right. They kept Obie on the shelf for five years? I think they bought it in 2017. They bought it in 2017. Interesting. They actually did a lot of great work on the manufacturing, the process. They worked on it, made it much more cost-effective manufacture, but they didn't do any clinical trials. They just kept it on the shelf.”

“Yeah. Can you remind me and the listeners what that study looked at? So it showed that 45% LDL lowering. Okay. So what was different about OB? It's a much more potent. So it's only, the other CT inhibitors are all in the 100 milligram plus range and they lowered LDL, as I mentioned.”

Our IdentificationSaid as “OB”. We believe this refers to Obicetrapib.

“The reasons to believe, we still have hope that Obicetrapib's HDL-raising benefit can result in a cardiovascular benefit, but we're also focusing primarily on what the other HDL benefits could be, like we're still talking about later, like diabetes prevention and Alzheimer's.”

“Obicetrapib lowered it by an additional 40%. So lowered it from 100 to 60 milligrams per deciliter. Approximately. That was, I think, those approximate numbers. About 40% was the reduction at the end of 12 months versus placebo.”

“It's all over the world, yeah. China, Japan, everywhere. It's 400-plus sites. And it's a global study. And the outcome of that study, should it be positive, would be approval in Europe and North America for Obicetrapib in secondary prevention? We actually don't need it for approval in Europe.”

“And we hope Obicetrapib can be part of that treatment paradigm. From a purely cardiovascular standpoint, how do you see Obicetrapib being used? Should the outcome trial end in the fashion that you would expect.”

“It lowers mostly the non-small particles. What does Obicetrapib do well? It lowers the risk of diabetes based on our Broadway trial data, as well as other CTV inhibitors. It lowers LPLA in that 50% range in that moderate band.”

“It lowers LPLA in that 50% range in that moderate band. And it lowers the risk of diabetes, lowers LPLA, and lowers the small particles by 90%. And so it would be a great companion drug to statins.”

“And if you need even more potent, you can add the azetamib combo pill. So we believe that with OB alone and OB with azetamide, 90% of patients are done with their lipid treatment. And so that's how we think for primary care doctors, that's what they're looking for.”

“So that's the background about APOE4, and it's a lipid gene. And what is important about Obicetrapib is that we had that genomic data, we had the animal data, and then we know that HDL is the one lipoprotein that does interface with the brain.”

“the biomarkers improved. 181, amyloid 4240, GFAP, neurofilament light, all got better with Obicetrapib. And that's what we published in our paper. So we felt that this data really confirmed that Obicetrapib was in fact active in potentially preventing Alzheimer's disease.”

“And so they gave us, we got a great drug. We got a great drug to work with. It's going to be very hard to match the profile that obicetrapib has from a pharmacokinetic perspective. And to give folks, again, just a sense of what does it take to develop a drug. So if you look at the money you paid to acquire the drug, what you had to raise through the clinical trials,”

“I was incredibly excited about Obicetrapib when we spoke about it the first time with John. And everything you've updated us on today only makes that, look, we just can't wait to get this drug into the hands of people.”

“So I'm pulling for Clotho, I'm pulling for Obicetrapib. And then, of course, if they're successful, what that's going to do is open up the door for more things. But what I love about the two of them is potentially they're working by a different mechanism.”

“And it's clear we're going to need multiple therapies. That's the thing. Obicetrapib alone could be a preventive strategy. You're going to need more. I need something else as well to make a difference. Well, Michael, thank you for the amazing work you're doing. And thanks for taking the time to come out here today.”

“And one of the first things that stood out to me looking at the Broadway and Brooklyn trials, which were the phase three trials of Obicetrapib, were that the reductions in LDLP and LDLC were greater than the reductions in APOB, if memory serves correctly. What do you think is happening there?”

“I know you and I have spoken about Obicetrapib and the profound impact it's having, at least in a pilot study, when you look at the biomarkers.”

“So that's the quick story with Obicetrapib. Yay for its ApoB ability. We're all going to certainly be using for that. That'll be its FDA indication.”

“There are emerging therapeutic strategies, such as obicetrapib , which we've also covered on this podcast, being studied that specifically show promise in ApoE4 carriers”