Good afternoon, everybody. Thank you once again for joining us for the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the Biotech team. It's really a great pleasure to moderate my first Fireside Chat with Terns Pharmaceuticals. To my left really needs no introduction, Amy Burroughs, CEO. To her left also needs no introduction, Andrew Gengos, Chief Financial Officer. Team, thanks so much for joining us. We appreciate it.
Thank you so much for having us, Yaron.
There's a lot going on in CML. We'll dive into TERN-701. The data really looks super promising and interesting, and it's obviously drawn a lot of attention. Let's maybe just zoom out quickly and kinda talk about CML in general. There's a lot of both innovation going on, not as much innovation going on in the STAMP area, which is specifically what you're going after, but there's a lot of options in frontline. There's the historical first generation Gleevec, there's the second generation compounds as well, obviously more tangible talks. More competition now in terms of Scemblix moving into second line, moving into frontline, and at the same time, physicians are beginning to try to really figure out TFR and at what point do you stop therapy and based on potentially DMR.
Can you talk about the shifting landscape a little bit and the, you know, 'cause that's gonna weave into your data and then how you think about clinical development?
For sure. Thanks again, Yaron, for having us and to the TD Cowen team. I will also say that we will be making forward-looking statements and to refer to our website and our filings for more information. CML is a really interesting area in oncology and different from many other indications. It became a chronic disease with the approval of Gleevec in 2001, and there are multiple approved therapies. There's first generation, second generation, now allosteric, also a third generation active site. In the front line, it's really the first and second generation active site TKIs and asciminib. Despite all of these options, there remains tremendous unmet need, and this is not just in the area of efficacy, but also in the area of safety.
Particularly if you think about a young CML patient perhaps diagnosed in their 20s or 30s, they could be on these TKIs for life. Safety, whether it be rates of arterial occlusive events or pleural effusion, other things that you can see with these TKIs, that's a big concern. One of the big areas of excitement with Allosteric is that they're much more selective, therefore leading to a better safety profile, and we have already shown an even better selectivity and better safety profile than others. I will also say that really the dream in oncology is to offer functional cures, and that's possible in CML. We know that there's data that says that if you drive faster and deeper responses, that you can get higher rates of what they call treatment-free remission.
This means that a patient gets to a deep molecular response, practically undetectable levels of the BCR-ABL fusion protein, and if they stay there for three to five years, they can be taken off of drug, and you see if their transcript levels come back. If they don't come back for about a year, most patients are effectively cured for life, and that would be a dream, and that's a goal, particularly for young patients in the frontline setting. We don't see enough treatment-free remission today, and if a drug that gets faster, deeper responses could do that would again be the holy grail.
Do you have any sense what % of patients these days get to DMR and then are taken off therapy in that setting?
I know that about 15%-20% of patients get to a treatment-free remission. I'm not sure we have the data around how many attempt that.
Once you get to DMR, your then therapy's stopped and you're monitored initially every three months, is it every six months? Is it for about a year and then you go to an annual follow-up? What, what's the latest standard?
I'm not sure actually. If you get to a deep molecular response, you're still monitored for that three to five years. If you go off therapy, I believe you're monitored very closely, and if those levels start to come back, you immediately go back on the therapy that was working for you.
Okay. When physicians are now, asciminib is now moving to frontline, it's got as much as a 15% share, potentially even 20% share now.
About 25.
25. What's driving that option against other kind of older, even generic options?
Yeah. It's really because it's been shown to be a better drug. safety is a huge driver because when we went from imatinib to the second-gen TKIs, you were trading off safety for efficacy. Often, the higher risk younger patients were getting the second-gen TKIs and older patients were getting imatinib. Also just patients who are more cost-sensitive and may not be able to be on the branded therapy. you know, the allosterix and asciminib are really bringing the opportunity to get safer than both and better efficacy than imatinib. you know, they have not been shown to be more effective than second-generation TKIs, and there's more and more data coming out that people believe that efficacy is in the same ballpark.
We believe that they are getting this kind of uptake because you can get the second-gen level of efficacy without, you know, things like a 30% rate of pleural effusion with dasatinib.
How important is it the nice element to the allosteric inhibition that the myristoyl pocket is really shutting down potentially the emergence of resistance? How important is that in frontline, or is it still very much a safety question to your point, and you reserve that activity in a mutant population for a later line?
I think it's that in CML, resistance mutations are not the biggest driver of, patients becoming refractory to their therapy. We don't really have data across, you know, active sites versus asciminib and emergence of mutations, but mutations are not the big driver in CML and the big unmet need for patients. We know in the frontline, say for myristoyl pocket mutations, that's about 4%-7% in the frontline over a three to four years period.
It's a slow emergence.
Yeah. You know, our ability, and we've already shown, in an asciminib resistance mutation F317L, we've shown a patient that was resistant to asciminib and responded to TERN-701, and we think, you know, a different molecule with higher target coverage could. We've seen preclinically too, more potency on some of these mutations.
By the way, for the audience, if you have any questions at any point, feel free to raise your hands and happy to take them. Let's maybe talk about a little bit about your CARDINAL data in Phase I. It was a dose-finding regimen. At this point, you're expanding at 320 and 500. I think you went 160, 320, 400 and 500.
Correct.
I think we saw about 63 patients, right, at ASH. The data looked really good, including to your point, you had data obviously in prior first line, sorry, first generation, second generation failures, and even in patients who had asciminib. They failed either for tolerability or for efficacy, including you said some data now in the mutations. It looked really good and achieved MMR was 75%. The achieved DMR was 36% at the expansion cohorts. MR2 actually looked very, very good at 62% as well. I think you said at ASH that you had 85 patients or so enrolled.
Yes
Or more, or at least 85 patients.
As of early December, we had 85.
As of early December. As you think about the stage in development that you are now with 701, and maybe what we should see this year in terms of data, maybe kind of walk us through your thinking?
Sure. Based on those 85 patients that we had enrolled in December, we knew that we would have the data to submit to the FDA and speak to them in the middle of the year about our dose. To pick a dose, we need to look at exposure-safety and exposure-efficacy. We've already seen that safety looks pretty good, and we don't see an issue with the higher doses in the ASH data that you saw. Assuming that holds, what we'll really be looking for is do we see a benefit on efficacy at the higher dose. We also wanna see at least 20 patients at each of the 320 and 500 for six months. We were able to, you know, calculate that, and that's how we're able to guide to meeting with the FDA mid-year.
We will talk to the FDA about our pivotal trial designs and plans. We hope to gain their alignment to move directly into a second line plus pivotal. We do not need to finish everything in the CARDINAL 1/2, Phase I/II to do that. We're also going to talk to them about our first line pivotal and how quickly we can move to first line.
Okay. I think the data, and I'm just going through memory, of the 63 patients at ASH, I think 10 were at the 160-
Mm-hmm
Essentially 53 were higher, and 320 was already like 21 patients, and I can do the math to get how many of 500. If you need 20 at six months, I mean, you're getting there pretty quickly while you're continuing to enroll.
Correct.
You should be in pretty good shape. What drives the decision as to which dose to take forward? Is it MMR? Is it DMR? What's more important to you?
It's really about looking at the different subgroups, normalizing across different covariates, and really looking at what kind of efficacy response we see in terms of categorical shifts. It's not so much. You know, MMR is more about the regulatory endpoint, and we're really looking at categorical shifts in transcripts, and do we see something different at 500 than we see at 320?
In parallel, you're now doing the study in the 20 patients, or at least 20 patients are gonna be, who are mutants, and for that, you're actually using the 500.
Yes.
Two questions on that. Is that potentially down the line label enabling, or is that sort of work? 'Cause asciminib did the same, roughly, you know, patient numbers. Secondly, you're choosing 500, so it sounds like you're fairly comfortable with the safety. Why not even decide if things look good to take the 500 forward to a pivotal?
For all patients?
For all patients, yeah.
Yeah, if we see that, if we see that efficacy response at 500, we would like to go to 500 and have that dose for all patients. You were asking about the mutation cohort, whether that's label enabling. The 20 patients we're looking at really is signal seeking. These are rare patients. We're not sure how long it will take us to enroll. We think, you know, every patient will actually be informative, like the F317L patient that you saw to date in the escalation, and we'll take that and expand it. asciminib got their label with 45 patients, and so we'll expand the cohort from there based on what we see initially to enable putting that into the label.
At that point, that goes into the clinical section of the label.
I believe so, yes. I don't think it will be at first approval.
Okay. That's something that you-
Yeah
do in parallel. It sounds like based on the initial 20 patients, you then potentially decide to expand?
Yes.
You have a few years to continue to do that in parallel.
Yes. Can't guide the timing on that. We can say that would not expect to see data from that cohort this year, just based on it will enroll fairly slowly. These patients are difficult to find.
Yeah. The data, I think typically you release data at medical meetings, right?
Yes
... the natural ones are probably ASCO, EHA, and probably ASH. You know, as you think about different subgroups that we might see data from, sort of what comes to mind and what's important?
Subgroups of patients in terms of... It's really similar to what we showed you. You know, the things that affect how a patient. What kind of response rates you expect to see. Baseline transcripts is big, and you see that even from the asciminib data, how much lower they saw in the 10% plus baseline transcripts. Whether or not they've already seen drugs like asciminib and ponatinib is a big deal. What treatment line they're in. Well, it will be similar to what you have seen to date and what you saw at ASH.
Maybe before we talk about the phase II trial design and second line and then potentially front line, can you maybe zoom out for us and think or help us understand differentiation of TERN-701 relative to asciminib on maybe coverage of the STAMP site, maybe potentially how the exposure relates to then potential you coverage of mutants.
Mm-hmm
and on overall tolerability.
Yeah. For that, you can look at the data that we presented at EHA last year, where we looked at potency on these mutations in preclinical assays. We also talked about this, we had a webinar in September, which I think people still find informative. It was really an educational webinar on how to interpret Phase I to CML data, where we talked about the preclinical data supporting higher target coverage for TERN-701. I think it's important to note too, the reason that we're able to get that higher target coverage is not just, you know, the different drug. Even at the same exposures, we see higher target coverage. It's also the fact that we see such good safety.
Yeah
... that enables us to go up to 500 and get much higher target coverage. The other piece that we talk to people about is, you know, there could be a different way it's binding to the pocket, and other things that make it a different drug.
From a pharmaceutical properties for the drug, can you talk about, asciminib does have a food effect, and I believe at this point you don't?
Correct
... and you're not expecting it. Can you maybe discuss that in the PK and what you've seen on the PK of the drug?
We're confident that we don't have a food effect. We are dosing in this trial without regard to food. People have asked, you know, "Why does that have that with asciminib?" I'm told they got unlucky.
At this point, you don't need to do a food effect study. That's not your expectations.
No. We've done our food effect study.
Okay. As you, Any questions from the audience by any chance? For Renee.
If the CML resistant mutant is not driven primarily by mutations, then what was the primary driver?
Yeah. The question was just for people who may be listening, if resistance mutations are not the primary driver, what is the driver of patients being refractory for efficacy? We think that it could be target coverage, but we don't know for sure what it is.
I mean, is it also, is there any data on time and therapy in relating to, tolerability? If you're not really getting to the right dose and you, or you've got a dose reduce and you're on therapy for a short period of time, efficacy is probably-
Oh, yeah.
not optimal.
There is a huge, you know, our CMO, Emma, will tell you. I'm sorry you could not be here today. Our CMO, Emma, will tell you that there's a big relationship here between tolerability, safety, and efficacy. If you can't get to the right dose, then you won't have the same level of efficacy. We think that the 80 milligrams of asciminib is kind of at the bottom range of where they need to be in terms of target coverage, and we are multiple folds higher.
One of the questions that I think is out there and that we've started getting is the Phase I CARDINAL data that we've seen, again, has been really strong. It's still early in development of the drug, and there's been some questions about as you continue to enroll, your level of confidence that that level of efficacy will continue to hold up and really show differentiation, obviously against asciminib, but obviously also against some of the other competitors versus expecting some decrement. Any thoughts about that?
Yeah, absolutely. We've talked a lot about confidence intervals. You know, I, sitting here today, do not know what that, you know, that magic sort of top-line number is gonna be the next time we release data and we ultimately get to the end of the trial. We are incredibly confident based on the robustness of the data that we showed you at ASH, that it'll be within that confidence interval, which is meaningfully superior to asciminib and everything else out there.
I think you've said specifically, even given your, maybe just give us a little bit more thinking, and your views on the confident intervals of the data you've seen and what that, it relates to even asciminib's higher end of their confidence interval. I think I believe.
Yeah, there's no, there's no overlap. I think we have a great slide in there, whether you're looking at all doses or, you know, what you really care about is the dose we're going forward with. We're showing now 320 and above because it's going to be 320 or 500. Ultimately, you know, when we release data, you're gonna be interested in, you know, if you're going forward at 500, if you're going forward at 320, what does the efficacy look like there? You know, so far 320 and above there's no overlap in the confidence interval. Do you wanna add anything to that, Andrew?
No, that's right. That's exactly right. If you, if you have a situation where the lower bound of your confidence interval exceeds the upper bound of the comparator, that's a good place to be. Yeah. We actually went and we did an analysis where we could, 'cause some drugs have kinda lumped all their phase I data together across doses. Sometimes it's a little harder to tease everything out. On Scemblix, from the early data to the late data, they actually had a gain. Obviously, number one, we know from the data, right, that the longer you're on therapy, the better you do. Two, Scemblix actually stepped up from phase I to phase III. The response rate went up incrementally.
Bosulif was flattish, Iclusig is the only one that actually had a decrement from the Phase I that they had to ultimately the Phase II, you know, 10 years ago or so. At least we have two cases out of three where the data was the same or even got better. Now, that's not within the same protocol. That's moving from one protocol to another.
Yeah. I can't speak so much to the ponatinib data, but the asciminib data actually is relatively consistent. The Phase I data is 24%, the Phase III data is 25%. We actually think that it's a comparable patient population with the same endpoint, or almost the same endpoint. It's at 24 weeks, and we can calculate that towards the end of our trial, we think it will translate very well.
For the examples in the past. Now moving to the Phase III trial design. Give us maybe your latest thoughts on second-line, and do you need to have asciminib as a control, given that they've never actually done a second-line study? They've done third line and front line. What that means for the front-line strategy.
I'm actually gonna start with the last part of the question, which is based on the data we've seen, we think we should have confidence to compare ourselves to asciminib and win. We think the best place to do that is the front line. The front line is frankly the majority of the market, and the way that the ASC4FIRST trial was done with asciminib, they had stratifications of second-gen TKIs and imatinib. Our thesis today, we haven't decided, we're not guiding specifically to it, but we're leaning into having asciminib in that control arm of standard of care. For the Second Line Plus trial, we're still considering it. From a regulatory standpoint, we don't think either trial will require asciminib being in the control arm.
In the Second Line Plus, we'll definitely have patients who've been refractory to asciminib, and we think that's important, especially given how many patients are being put on front-line asciminib today. That's an important proxy, not only for being then used in the second line, but also for efficacy. There could be reasons not to put asciminib in that trial in terms of speed and cost and getting to market. We're still considering it, and we'll let you know later this year after we talk to the FDA.
You know, as you think about Scemblix's frontline studies, to your point, it was an all comers, and then they did the primary also against either first generation or second generation. To your point, what drove the win in the overall population was really the activity against Gleevec. They didn't beat the second-gen drugs. If you also then add Scemblix to your first-line study, and maybe it's too premature to even discuss it, is there gonna be head-to-head, sort of an all comers and then looking at each subtype? Excuse me.
There would likely be a primary endpoint similar to theirs, where it was a blend of the two. As more data has come out, you know, in their ASC4FIRST trial, they did see a trend in better efficacy. There's a trial called ASC4START, where they see very similar efficacy and closer to 60% or high 50s for asciminib. We're not sure there's a big difference between second gen TKIs and asciminib, and we're pretty confident the fact that we're seeing frontline type of MMR achievement and DMR achievement in these incredibly difficult to treat patients gives us confidence for winning in the front line.
Okay. Any questions on that?
Yeah. Have you thought about combining with an active site molecule?
Yeah. Just to repeat so people can hear it, have you thought about combining with an active site molecule? Based on the responses that we're seeing, we don't see a huge need to do that and add, frankly, the cost and the toxicity of an active site. There could be a small group of patients who have particularly poor prognosis where that could be done in the future, whether it be in combination with TERN-701 or with asciminib. In terms of us getting to market, and particularly before we're approved, That's not a priority for us at this point.
On the, when you guys give your update, let's say it's, on the two doses, is this just the same 85 patients that we saw from ASH, or are you gonna have incrementally more data?
We have not guided to EHA. In fact, we've said that, you know, dose selection's going to be done sort of midsummer, with the FDA, so we will not be talking about that until we speak to the FDA about it. We had 85 patients in December. We're continue to enroll rapidly, and we will use all of those patients as we look at the exposure efficacy and exposure safety. As I was saying before, it's not just six months MMR, it's really looking at categorical shifts, so it should be more than 85 patients included in that analysis.
Right. It's almost we should think about it as almost like two sets of data, sort of the ASH update and 63 patients, and then another opportunity is to update us on the bigger N.
Yeah. I mean, I think Really the bigger N is what you're gonna care about, and you're also gonna care about, as we said, the go-forward dose and what the efficacy looks like there. We're gonna have a lot more than the 63 patients as we go through time, with, yeah, a valuable for efficacy.
Yeah. You said data, I believe, in the second half, you said that you'll update?
We said by the second half, so we haven't guided specifically.
Okay. Yeah, EHA is straddling FDA communication and decision and update. When you're thinking about, there's two other active site competitors. One's approved in China moving into Phase III, another one is the Enliven compound as well. I think they're planning on potentially starting their pivotal sometime later on this year, second half or so. When you're thinking about differentiation and overall profile, sort of what comes to mind?
Well, when we think about overall profile, particularly in the front line, they're looking at efficacy and safety, primarily. We think on the safety front that an allosteric has been shown to be much more selective and will generally be preferred over an active site for safety. The efficacy, the physicians don't think of it so much as sort of what class you're in, but really about what does the data support and what can I expect. The data that we saw at ASH and that we expect to continue to evolve is really in a different tier from what we're seeing from other therapies in development. We think those are good therapies and important to have additional options for patients.
We see TERN-701 really being used primarily in the first and second line, where we're gonna be competing with the generics in the front line, and potentially with asciminib.
Maybe just remind us in terms of tolerability, what was your most common AE?
The most common AE was hematologic AEs. They were significantly lower than you see with other therapies, we did not have, in terms of non-hematologic AEs, we didn't have any particular signal or high degree of AEs. We only in this data set lost one patient due to an adverse event, and it was joint pain and fatigue.
Which dose was that in?
I'm not sure.
Yeah.
I don't think we said.
No, we didn't say.
Okay.
If you look at the safety, we don't see a dose relationship.
Yeah. In terms of, you know, preclinically, your activity, are there any mutations where the drug is shown to be kind of have better activity or is it, you know, equal across all mutations?
Yes, particularly some of the mutations where you see non-myristoyl pocket mutations and resistance to asciminib, like the F317L that we talked about.
That one you see, you see good activity, you see good coverage.
Well, we see good coverage preclinically and now we've seen a response in a highly refractory patient. That patient failed asciminib despite going to double the dose of asciminib and also failed Enliven and responded to TERN-701.
Maybe just to the remaining one and a half minutes or so, when we been speaking to a lot of clinicians, and some of them, even big KOLs have expressed a little surprise how well asciminib has been doing. 'Cause some of them, you know, in academic centers sometimes they wanna start with the older drugs and do a kind of typical escalation, keep the best drug for last. The community though has obviously gotten on board in using the drug, you know, fairly routinely. What do you think really explains that?
It's funny. As a commercial person, I find some of this market research in CML to be challenging. You know, it took Novartis quite a while to start their frontline trial, I think because some of what they were saying but yet what they've done are different. I think there's also a lot of patients. I think most people in this room, if you got CML, and needed a frontline therapy, you'd wanna pick the best therapy. I think that there actually is a lot more. Even in the time that I've been in CML, I've seen the KOLs and the academics really change their perspective as they get more experience with asciminib, and I expect the trajectory with asciminib to continue to go up and frankly for them to prepare the market for us for an even better therapy.
To your point, I mean, if it's not so much a resistance issue, but it's tolerability in the frontline, but that also leads to better efficacy. Ponatinib is a great drug, but the tolerability is a real issue, right?
Correct.
Wouldn't you also get to much higher DMR rates if you start with a better drug and then you have a better chance of TFR?
I mean, we're seeing DMR rates in the 3rd line plus comparable to what anybody's seen in the frontline. We definitely think that will translate to faster, deeper responses in the frontline which, as we started out with, could lead to higher rates of functional cure.
Any maybe final last quick question? Maybe just timeline to some of the earlier pipeline, some of it you're potentially looking for a partnership. Any update on that?
Yeah. For our metabolic portfolio we've really chosen to focus in oncology, so we're looking to license TERN-501, THR-β and TERN-801, our GIPR antagonist preclinical development candidate, and we are working actively on discovery for oncology small molecule targets.
Is that oncology broadly or hematology more?
We are interested in hematology but we're looking more broadly.
Okay. I assume you haven't given any timelines on potentially partnering some of those early assets.
No.
Okay. Well, great. Team, thank you so much. Good to see you. We appreciate it.
Thank you guys all for being here.
Great.
Nice to see you.
Thanks, everybody. Thank you.
Thanks for asking.