#409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients | Lloyd Klickstein, M.D., Ph.D.

“He later held leadership roles at several biotechnology companies, including Versanis Bio, where he led the development of Bima before the company was acquired by Eli Lilly.”

“Okay. So how did you guys discover Bima? How did you create it? So again, the earliest biology was done by Chris Liu's team in the Pathways group at Novartis Institutes.”

“Yeah. Yeah. So let's get back. You get Bima into the primates. Yes. And how does it how does it perform? Well, in order to do toxicology studies, you have to know how much to give them and how long it's going to last and what it's doing.”

“In the case of Bima, because we were thinking older adults, these were older healthy volunteers and people in whom we would be able to measure some of the effects of Bima, we hoped.”

“So there's some things you always do, like a set of standard blood tests. But in the case of Bima, we were assessing people's muscle mass and strength. This is almost archaeology at this point, thinking of what we measured, but we would have measured muscle mass.”

“and so forth. Did you see any adverse effects in the phase one? Yes. So the three adverse effects that are evident with Bima that we think are on target and that were assessed in that study were muscle spasms or cramps.”

“Probably. Like, here's a great example, right? Yeah. Like Bima could have been more of a hit if maybe, and maybe not, but a drug like that could have been a hit had it been appreciated that, oh, by the way, like you actually have to kind of do something to reap the benefits.”

“Remember, there's four combination arms. Yep. Right? There's low dose Bima, high-dose Bima, low-dose SEMA, high-dose SEMA, four combinations, and then placebo. And we saw the dose effects in all the arms. So that was good.”

“Well, Lloyd, this has been great. This has been kind of a wonderful education on drug discovery using, I think, a very interesting drug in Bima as a case study for the complexity and the nuance of the process.”

“And then everything changed when Novo's data came out with semaglutide, which was amazing. It was the first really effective obesity medical therapeutic.”

“when you took Bimagrumab with Semaglutide or Tirzepatide or Liraglutide. It did them all. And the efficacy was sort of unprecedented, never seen. For both fat loss and obviously for preservation of lean mass.”

“Tide is peptide. But were they forced into liraglutide, semaglutide, tirzepatide? The tide is the same. It's going to be for that class, but there are other peptides that end in tide.”

“do a bigger study. We're going to do it in combination with semaglutide. And this was during the pandemic. So there was a lot of complexity and supply chain disruptions. And remember, with semaglutide, it was a proprietary drug of Novo.”

“We couldn't make a placebo for that. So the study design included semaglutide as open label, but we did placebo-controlled bimagrumab because we had control of that.”

“We ended up doing something called a full factorial design. So we did all possible combinations of low-dose semaglutide, high-dose semaglutide, low-dose Bimagrumab, high-dose Bimagrumab in placebo. So it's a nine-arm study.”

“Technically, actually, and we had to do this because we weren't using the semaglutide in its intended population. I think it wasn't registered yet, I guess, was the issue.”

“And we know what happens when you withdraw semaglutide, right? Everything goes back towards where it was, doesn't quite get there. And we're going to find out with Bimagrumab. I expect some things are going to reverse.”

“When you buy a, with the exception of saying, buying a bottle of Tirzepatide from Eli Lilly, but typically when you buy a drug from somebody, the drug's substance, the chemical, is manufactured by one company, and then it is formulated or put into a mixture that makes it predictably absorbed or administered, is done by another company”

“when you took Bimagrumab with Semaglutide or Tirzepatide or Liraglutide. It did them all. And the efficacy was sort of unprecedented, never seen. For both fat loss and obviously for preservation of lean mass.”

“Okay. But you got to ask them. I see. So publicly, the only thing we know is they're still doing something with it, presumably testing it with Tirzepatide, I'm guessing, or Retatrutide. The study that's in clinicaltrials.gov is a complex combination study with Tirzepatide.”

“what they do are almost non-existent. I've been reading in the popular literature about this one that's, I think it's called BP197. BPC 157.157, yeah. All of the data for that peptide come from one investigator who's the only person published on it.”

“There's a lot of grift in the health and wellness industry. You're not insulting me. But that's my point. Despite how much grift there is in the health and wellness industry, I'm putting BPC 157 on the podium, at least. I would too. Yeah. I would too. Okay, so we've made Bimagrumab and it's made it through all of the IND enabling study activities and we're ready to give it to people.”

“Haven't seen a lot of new data on that. Well, there was that study somewhat recently suggesting that rapamycin impaired, I don't know if it was impairing MPS or some other metric of physical performance or something.”

“And then we can test the biology. And do you think that just intermittent dosing of Everolimus or serolimus gets that? Maybe. Again, it's hard to tell in healthy people because, you know, in cancer, when you study mTOR inhibitors, the cancers have a highly upregulated pathway, and it's easy to see the biology.”

“And you can buy online peptides that may be the same as Retatrutide. They might not. You have no way of knowing. Yeah, and in many ways, that's the premium you're paying when you're buying the drug from Novonordisk or Eli Lilly or Novartis or whatever is.”

“Okay. But you got to ask them. I see. So publicly, the only thing we know is they're still doing something with it, presumably testing it with Tirzepatide, I'm guessing, or Retatrutide. The study that's in clinicaltrials.gov is a complex combination study with terzepatide.”

“All the parents out there are going to remember the grape and the cherry-flavored Tylenol or Advil or grape, etc. Was a particular favorite of mine when I was giving my kids drugs. Yeah, so that's one example.”

“And these were the first antibodies used in people. And of course, the other foreign antibodies that are still used are antivenoms. Most of them are horse serum. As you can imagine, you only want to get bitten by a snake once and need that because when you need it the second time, you have kind of a ferocious serum sickness response.”

“And there have been great examples of that. Think Atorvastatin and Rosuvastatin in a Mevacor, Zocor world. And those have been enormous commercial successes, and there's a strong bias throughout the drug development infrastructure to do those kinds of things because they're relatively low risk and there's not so much uncertainty.”

“Some people might also be aware of the idea that not everything has to be patented. So for example, the classic example is Coca-Cola. Had they patented the formula for Coca-Cola hundreds of years ago, I guess I don't remember when Coke started, but call it 150 years ago or something like that, we wouldn't be drinking the same thing today.”

“And then we can test the biology. And do you think that just intermittent dosing of Everolimus or serolimus gets that? Maybe. Again, it's hard to tell in healthy people because, you know, in cancer, when you study mTOR inhibitors, the cancers have a highly upregulated pathway, and it's easy to see the biology.”

“And what was the, what was the GLP-1 before liraglutide? Um, there's, there's exenatide, exenatide, right? So the TIDE became the thing that everybody had to link to going forward. TIDE is peptide. There's. So any.”

“probably testing this in parallel with the newer generation GLP-1 agonists. As best I can tell, that's what they're doing. And it's not now just Eli Lilly because many other companies who have seen the believe data, because we've been presenting it at national meetings and international meetings, for that matter.”

“You'll never figure out how to make it. So both of those things happen depending on the drug. Exactly. So one good example would be, let's say, AbV and Humira. They patented every single little thing around that drug that they could. It was a huge winner for them, and they wanted to keep it protected as long as they possibly could.”

“So if you're using an. So, yeah, you were using Ozempic, not Wegovy. You were still using... We used them both, actually. We did. Whatever we could get. Remember, they were in short supply. And to the regulator's credit, they recognized all of this and were willing to allow us to substitute interchangeably Ozempic for Wegovy.”

“Remember, the SARMs were extensively studied, is that you can make muscles larger. They don't get stronger in the absence of resistance training. So it's not unique to the active and receptor antagonist pathway.”

“The first person who I ever read articulating this was Steve Rosenberg. Wrote one of my favorite books about science called The Transformed Cell. This book is over 30 years old. I probably read it cover to cover 10 times during the course of my life.”

“All the parents out there are going to remember the grape and the cherry-flavored Tylenol or Advil or grape, etc. Was a particular favorite of mine when I was giving my kids drugs. Yeah, so that's one example.”

“So if you're using an. So, yeah, you were using Ozempic, not Wegovy. You were still using... We used them both, actually. We did. Whatever we could get. Remember, they were in short supply. And to the regulator's credit, they recognized all of this and were willing to allow us to substitute interchangeably Ozempic for Wegovy.”