Hi, everyone. My name is Liisa Bayko. I'm one of the biotech analysts here at Evercore ISI, and we're gonna be talking to Terns today. I just wanna start out by saying, you know, I'm really sorry to hear about Senthil, and he was someone I really liked a lot.
Yeah.
I got to know him at Intercept and, of course, as CEO of Terns, and he died very prematurely, so he could have done a lot. So he'll be very much missed.
Yeah.
Great person.
Yeah. Thanks, Liisa.
Thanks for the kind words.
Thanks for the words. He made a huge impact, not just at Terns, but across the industry. So-
Yeah.
... you know, I appreciate you recognizing that here.
I'm glad he did all the work he did for the field of cancer, too.
Yeah.
So-
Absolutely, his foundation-
One of his legacies.
Yeah.
Anyway, okay, with that, Mark and I have known each other. Actually, Mark used to be an analyst. He knows the pain.
Certainly of conference time. I don't envy your position now, but yeah, we've known each other for a long time. So thank you for having us at the conference. It's great to be here.
Right. And Erin is kind of in Senthil's shadow, I guess, but now coming up as CEO, so congratulations, Erin, on that.
Yeah. President and Head of R&D of the company.
Yeah.
Yeah. Yeah.
So, tell us, I guess, just get everyone on the same page a little bit more about Terns.
Sure. So Terns is a development-stage company. We are focused on serious oncology and metabolic diseases, with a focus in CML, and then also on obesity, and recently, we had a phase II read on MASH as well. So yeah, headquartered in California. Mark sits in New York, so we're a little bit bicoastal, which we think is a great advantage, and we're really happy to be here today.
So where... You know, you started off obviously kind of more on the kind of MASH side of things, and then you kind of have sort of evolved into CML, and like, where are you getting the most traction, would you say, these days? 'Cause it's been, it's been kinda oscillating, right, between, like, what's been important.
I think we've seen a nice evolution of the pipeline. When we IPO'd the company, certainly there was a focus on liver disease, and we had a portfolio of assets to target steatohepatitis. I still haven't gotten used to saying MASH yet.
Yeah.
So I'll just say steatohepatitis. And there was always parts of our portfolio that had a potential to add diversity. We had originally kicked off discovery efforts with the GLP-1 as a steatohepatitis drug, and we're fortunate to do that at the time when small molecule discovery was not in vogue at large pharmas. And we had a lot of expertise, as proven by our success across other areas in small molecule discovery. So very fortunate to kick it off when we did, and we've now seen that molecule move into the clinic for obesity. And at the time of the IPO, we also had TERN-701, was our CML asset. Very fortunate to partner that with a great partner in China of a large company called Hansoh.
They were able to do all of the necessary work to get that molecule ready to go into the clinic. And as we saw other parts of the portfolio mature, either come to the forefront or maybe not justify continued capital investment, we had other assets that we could look to move forward, and TERN-701 and CML was one of those assets. So, you know, we see nice diversity to the pipeline now with TERN-601, our GLP-1, with TERN-701, our asset for CML, and then as Erin said, we had a readout on TERN-501, our THR-β. So some nice diversity across the pipeline in both that oncology and metabolic side of the house.
Well, let's focus on, like, MASH first 'cause it's a little bit more my expertise, and I'm sort of curious, how are you thinking about this unfolding? 'Cause I know at one point you had kind of like, you know, THR-β, and you had FXR, and now you have GLP-1 as well. You know, what's your plan for how you're gonna move these forward and... Yeah.
Well, first, maybe I can just talk about, you know, just a brief summary of the top-line data, you know, for TERN-501.
Mm-hmm.
... which is our in-house discovered THR-β agonist, which is highly selective for THR-β. We showed liver fat content reduction as good as any, you know, THR-β has shown and with just a remarkably clean safety and tolerability profile in our 12-week trial. So, in that study, we did combine it with another asset in our pipeline. So we were the first to do a THR-β-based combination. In this case, it was with an FXR agonist, which I think was successful 'cause it showed that TERN-501 can be used in combination, which we think is critical for most of the things in our pipeline, actually. And that there wasn't any safety drawback.
You know, and there may have been a little bit of additional efficacy with the FXR, although probably not enough to really invest heavily in the combination moving forward. So we feel like we have the best-in-class THR-β, based on the totality of the data that we should-
What makes it best-in-class? What different-- Because there's a couple others besides obviously resmetirom.
Right. High degree of liver fat content reduction, very uniform responses, the highest increases in sex hormone binding globulin that have been seen at 12 weeks. That's a marker specific for THR-β and shows target engagement in the liver. It's gonna be a really nice biomarker to follow in the clinic, a really simple blood test as opposed to fancy imaging. And then the safety and tolerability profile was so clean, so no difference from placebo in anything, whether that be GI-related AEs, which we've seen with some other THR-βs. No cardiovascular AE signal, which is a concern, you know, with the mechanism overall and speaks to its beta specificity. And then, even with the thyroid hormones, everything was similar to placebo, so no concern about central thyroid axis perturbation overall, which is also a theoretical con-...
concern for the class. So that's really, really makes it best in class overall.
Okay, great. Let's turn to your GLP-1 and kind of that asset. I know. Walk us through the GLP-1 field. You're working on oral?
That's right.
There's different scaffolds within oral, and there seem to be, like, a couple of different camps. Maybe walk us through that dynamic and kinda where you sit within that, and then, and what your plan is to move that one forward.
So TERN-601 is an oral small molecule GLP-1 receptor agonist. To even take it higher level than that, Liisa, there is one marketed oral GLP-1, and that's oral semaglutide. Semaglutide is a peptide mimicker of the actual GLP-1 peptide, if you will, and then it's been put into a formulation to make it somewhat orally bioavailable, but it's really not very well absorbed at all. The small molecules are totally different than that. They're not peptides. These are small molecules that are meant to be given orally in the first place, and they just engage the GLP-1 receptor because we know the hot spots where you need to design a molecule to activate that G protein receptor. Within that, there's further separation between partially biased agonists and fully biased agonists.
And where there are examples of both that are in late phase development, there are examples of both that are in early phase development. The idea being a fully biased agonist biases away from beta arrestin recruitment, which theoretically can cause the receptor to not be expressed anymore. So the premise is that there may be more activity with full agonism away from beta arrestin. At Terns, we feel that that may be the case, and we understand the biology behind that, but we have not seen that play out in any of the clinical trials, that it's had an advantage either on weight loss or on tolerability. So TERN-601-
Is that what Pfizer's doing with the...?
Pfizer is a partially biased-
Okay.
... agonist in danuglipron, which is their asset that's in phase II development. Any day, we're expecting to see some results from a phase II-B weight loss trial with that drug.
Okay. And structure?
Structure, as I understand it, follows the fully biased approach.
Okay.
... which Eli Lilly has done with their orforglipron molecule. TERN-601 is a partially,
Okay.
... biased agonist that we designed to engage the, a GLP-1 receptor, as danuglipron, Pfizer's molecule has done because that was one of the first publications, and that's really what's allowed us to become, come into the clinic as one of the first biotechs in the clinic with an oral GLP-1.
What's your development plan now for TERN-501?
For TERN-501 or TERN-601?
Uh, TERN-601.
So TERN-601 is currently in a phase I single and multiple ascending dose study. We're going into patients who have elevated BMI, healthy volunteers who have elevated BMI and are otherwise healthy. There will be single-dose escalations, and then we'll move into 28-day dosing in patients who are obese or overweight and otherwise normal, otherwise healthy. And so in the second half of the year, we'll be looking for 28-day weight loss with TERN-601.
Do you have any ideas to maybe combine your THR-β with, like, 501, basically, with-
Absolutely. We are very interested in the potential for a TERN-601 plus 501 combination, a THR-β plus a GLP-1. We see that combo is having a lot of different advantages. The THR-β doesn't cause weight loss in and of itself, so that's what you're really missing with the THR-β for metabolic disease. Otherwise, it can reduce liver fat content, it can reduce liver inflammation, and probably fibrosis as well, as we've seen from Madrigal's compound. And then, it also has wonderful effects on lipids, decreasing LDL cholesterol, increasing HDL cholesterol, and really having a significant decrease in apolipoprotein B, which is a, which is a high-risk lipid. It's what traffics, cholesterol into plaque, you know, in arteries. So a decrease in apolipoprotein B is pretty, pretty meaningful decrease. It just doesn't...
THR-βs don't cause changes in glycemic control, nor do they cause weight loss. That's where the GLP-1s come in, right? You know, where you can have the weight loss, you can have the improvement in insulin resistance, and then the THR-β can add to, for example, fibrosis reduction, better lipid control, and we have some really interesting preclinical data that when you dose the two together, there may actually be enhanced weight loss, when the-
Mm.
... THR-β is added to the GLP-1.
Interesting.
Pretty exciting. So we're pretty excited about-
When will you start to combine those then? Will it be after this initial data that you're looking for?
601 needs to catch up, right?
Okay.
You know, so 501's been in phase II, so the first important step is what we've done right now, which is to advance 601 into the clinic.
Okay. And then I see you've got GIPR. Is that correct?
That's right.
Yeah.
The TERN-800
Tell us about that.
... what we call the TERN-800 series, so those are the GIPR modulators. We say modulators because our 800 series is actually two discovery programs. One is looking at... we're looking to design a agonist of GIPR. That's what, like, one part of the tirzepatide or Mounjaro Lilly's molecule is, is a GIPR agonist. Amgen's AMG 133, which is earlier in development, is a combination of a GLP-1 plus a GIPR antagonist. So we also have a small molecule antagonist development program, so we're going at it from both angles.
Hmm, interesting. Okay. And what is the? Are these oral, first of all?
These will all be oral-
Okay.
... small molecules-
Okay.
... with the idea that we can build combinations in-house if necessary. You know, on top of TERN-601 and GLP-1, we could go the THR-β direction. We could also add in GIPRs and come up with an oral version of, of Mounjaro, right, of tirzepatide.
And so as you think about this portfolio, is it more towards obesity, is it more towards MASH, or sort of that intersection?
... Yeah, I mean, there's clearly diversity across the portfolio in terms of the scope of indications and development paths as we look forward, not just from a length of time, but also from a capital need. MASH sits on one side of those. It's long and fairly costly at this point. There's simultaneous phase III trials that some companies are needing to run to get to approval. And then on the obesity side, also large trials. Where we sit on metabolic is we believe that establishing proof of concept is important. And, you know, we think strategically about the next steps would be and whether those are in the hands of Terns for additional steps or in the hands of partners.
I think we're opportunistic with regards to moving them forward, just with the idea that we're in the business of getting drugs to patients. And if a partner is able to accelerate that goal, I think we're obligated to consider that. On the other side is CML. We haven't had a chance to talk about TERN-701 yet, but this is an indication and a regulatory and clinical development path that is well within the purview of a company of our size and scope, up to and including commercialization.
So I think that could live longer within our portfolio, but again, we're in the business of getting drugs to patients, and if there's a way in which we can do that in-house quickly, that's great, and if bringing in a partner will help us accelerate that, that's something that we would consider.
So this is an allosteric inhibitor in development for BCR-ABL in development for CML. Tell us the dynamic. We were talking about this a little while ago when you first told me about the program, but the dynamic is very interesting, interesting in CML. It's like people kind of seem to rotate through these different products, and that's really the opportunity. Can you maybe expand on that a little bit more?
Sure. So, prior to Terns, I was at Gilead and did a lot of work in HIV, and chronic myeloid leukemia reminds me a lot of HIV, right? It's a deadly disease that now becomes a chronic disease if you can take your medicine every day, right? So that's CML. It's unlike many other cancers because patients are living for decades. In fact, patients who achieve a major molecular response on treatment have a normal lifespan. So it's really a matter of finding drugs that work for patients, not just for controlling their tumor, but also that is safe and tolerable for them to take, and easy to take in their lifestyle.
So we see the CML field evolving more and more towards these regimens that are efficacious in controlling the tumor, but that also are satisfying a need for safety, for convenience, right? You know, for patients who are seeking something else in their, in their, in their treatment journey. So you're right. CML itself is an orphan disease, but the prevalence is going to triple by 2040 because patients are living longer. And they do tend to cycle across therapies. They may, they may change because they don't achieve that major molecular response, and so they start with something like generic imatinib Gleevec, which transformed the field 20 years ago.
Right.
And now they need to move on to something that has a higher efficacy profile, which to date has been the second generation active site TKIs, which, yes, they can be more efficacious, but because they bind to the pocket more tightly, they also have more off-target kinase activity, so it also leads to more safety issues, right? With the onset now or the arrival of the allosteric inhibitors, which bind a different part of the pocket and don't have as much off-target kinase activity, doctors now have the option with asciminib, and hopefully in the future, with TERN-701 being likely second to market, of a class that is not only better than active site TKIs in terms of efficacy, but is also much safer and better tolerated.
The labels are very different, you know, with fewer discontinuations and fewer adverse and GI side effects overall.
Where will you position this drug in terms of, like, which line of therapy do you see? I mean, with the profile you're talking about, it seems like it could move up. At the same time, you have generic imatinib out there, so...
We agree that we think it would move up in lines of therapy, so we're actually quite interested in second line and see that as a-
Okay.
... as an important option-
Okay.
... for patients moving forward for the reasons we talked about. Patients who get started on a drug, and they're either tolerating side effects or they're failing, right? And so we think that especially with second-generation active site TKIs becoming generic over the next couple of years, more patients will be started on those drugs. When they fail, they can't go backwards to imatinib. They're gonna really need to just go to an allosteric inhibitor. So we see a lot of, a lot of opportunity and a lot of ability to help patients with a second-line indication.
So you're looking. There's some data coming next year. Tell us about, sort of briefly, about that trial and what you're hoping to see in that, in that data.
Yeah, absolutely. So we've made a lot of progress in the TERN-701 program, and we recently announced in October that FDA has cleared our IND, and we talked a little bit about the study design for the Cardinal trial. So Cardinal is a open-label dose escalation, dose expansion, two-part phase I study in patients with chronic CML. The first part is a dose escalation phase. We're starting at a dose of 140, sorry, 160 milligrams, which is a win. Our partner in China brought it first-in-human last year. So this is not a first-in-human study. This is a second-in-human study, and we were able to leverage Hansoh's data to start at 4 times higher starting dose, first of all.
We're excited about that because that will probably help the enrollment dynamics. If patients know that they're starting at a higher dose, that could be potentially efficacious, and because of the data that we've seen from Hansoh, we think it could actually be in the efficacious range. The other key win we had from FDA is that we can include second-line patients in the study. So we're not just limited to third-line patients. They agreed that this drug could hold promise for second-line patients. So that's, again, we think, a very positive sign that we could pursue a pivotal trial, a phase III trial, following this phase I in an earlier line of treatment.
Okay. I guess who, who else is working on allosteric inhibitors that you kind of got your eye on?
Enliven is another biotech company that's working in the CML space. They have an active site tyrosine kinase-
Okay.
... inhibitor, though, that they feel could be safer than some of the available options. So we see them as complementary rather than as a competitor in that space.
Great. I'm gonna turn it to Mark, just to kind of wrap up. Talk to us about kind of your cash runway and kind of where do you get through the catalyst coming up, particularly in 2024?
Yeah, everything we've talked about today is covered with cash on hand. We just reported our earnings a few weeks ago, just under $270 million in cash. It lasts us into 2026, so we're well-funded. Includes readouts across the two programs that we talked about. TERN-601, we've guided for the proof of concept MAD data that Erin talked about in the second half of next year, and then initial data will start to flow from the CML program as well in the second half of this year. So a lot of exciting stuff coming in, in 2024.
Excellent. Well, thank you.
Thanks so much for having us, Liisa.
Yeah.