Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome Steve Brady, the CEO, and also Sam Whiting, the CMO of Tempest Therapeutics. Steve's gonna do an intro with some slides, and then we'll switch over to fireside chat, so sort of a hybrid format. But thanks so much for joining us today, Steve, Steve and Sam.
Thank you, Maury, and thanks to the Jefferies team for inviting us to speak this year. We appreciate it. As Maury mentioned, my name is Steve Brady. I'm the CEO of Tempest Therapeutics, and to get rid of the legal piece first, we will be making forward-looking statements, so please refer to our filings with the SEC. So Tempest Therapeutics is an oncology-focused company. We are development stage with a truly classic diversified portfolio of programs ranging from early-stage research, novel programs that to our knowledge, no one else is working on, all the way up to, a randomized phase II data set and a phase II that is poised to move into a pivotal phase III in first-line liver cancer. So a great time to be talking to you about the company 'cause it's an exciting transition point to us.
One thing to note about this portfolio is that each of these programs, the reason I said it's traditionally, could be described as, diversified, is they really do stand on their own two feet. There isn't a single guiding hypothesis or requirement for these programs other than that they're novel, and that we believe they're gonna move the needle for cancer patients in a significant way. We have two clinical programs, TPST-1120, now known as amezalpat, hot off the presses, and then a second clinical program, TPST-1495, TPST- 1120 or amezalpat is a PPARα antagonist, and we're gonna go into a little bit more detail about that today, and we don't have enough time to talk about the second program, TPST-1495, but that is in the prostaglandin pathway, and it is a dual EP2 and EP4 antagonist.
To our knowledge, both TPST-1120, amezalpat, and TPST-1495 are the leaders in their respective target classes in clinical development right now. And then finally, it is worth noting that we are a wet company. We have labs. We have a research group. All of the programs that we're gonna be discussing today were invented at the company by our own scientists. There was some news a couple of years ago where we in-licensed a program from Cal that's working within the fibroblast. But again, the hypothesis behind all these programs is that the targets are amenable to intervention to make a significant difference in areas of unmet need. So we're gonna focus on TPST-1120 today, and as Maury noted, he's asked for a hybrid fireside chat presentation model, so we're gonna move quickly through these slides.
Happy to follow up with anyone after the fact. So TPST-1120, amezalpat, we will update these slides. We literally just got the name approved. It is a PPARα antagonist. You're probably familiar with the pathway because there are multiple agonist programs and approved drugs. This is the other side of the field. This is targeting PPARα for cancer, and one of the beautiful things about this program is that in the beginning, at its inception, we had a hypothesis that this was gonna be a dual MOA, and by that I mean it was going to act directly on tumor cells, and that it was also gonna have an immune-mediated function.
The exciting data that we showed in fall, in October, that caused all the news, the randomized phase II data, really validated that early, early hypothesis from years ago, which is always exciting because when you don't, you know, sometimes those stories don't come full circle, and things don't work the way you thought they were going to do. So this not only did from an MOA perspective, but this lead indication in first-line liver cancer was our number one choice when we founded the program as well because of the target expression profile. So how does a PPARα antagonist work, and does what you combine it with matter? For the first question, it is expressed directly on tumor cells. So HCC being number one, RCC, cholangiocarcinoma, multiple types of tumors express PPARα .
Interestingly, those top three that I mentioned, HCC, RCC, and CCA, are where all of our data are emerging right now. We had really interesting RCC data at an oral presentation at ASCO a few years ago, and as I just mentioned, we just announced exciting randomized first-line liver cancer data. The other piece, and the reason I mentioned the dual MOA, is that PPARα is also expressed on immune suppressive cell populations. So the theory was that we can work both against the tumor and shut those suppressive cells down, enable the immune system to do its job. That is bearing out in the data as we continue to move this program forward. And then that's also relevant to what should you combine with? Will it make a difference?
Yes, it was one of the hypotheses to combining with PD/PD-L1 axis antibodies, which we are doing in first-line liver cancer, and there's also genetic evidence that the target is relevant in anti-angiogenesis, so combining with bev also, or TKI, also made sense, and that we're doing that in first-line liver cancer as well. This is what I was referring to. This was some of the earliest work we did around expression profile of the target, and as you can see on the far right, or maybe you can't see it because it's too small, but liver cancer is all the way on the far right.
And so one of the things that we were talking to investors about today when we got our data in fall, we were thrilled, because it sets us up, obviously, to move into a pivotal study, but we shouldn't have been surprised because it is in liver cancer, and it is also going, combined with atezo and bev, as I just mentioned. Preclinical data there, we don't have time to go through today. There's a broad set of preclinical data that predict the activity we're seeing right now. But, one of the strongest preclinical signals we saw was actually in, HCC models combined with a checkpoint inhibitor. It's the red line at the bottom. It literally crushes the tumors, and they don't come back. There is a target of interest right now that some companies are targeting directly, beta-catenin.
You're gonna hear us talk about beta-catenin in this 1120 program. We are not targeting beta-catenin, but it is relevant. When patients with HCC are beta-catenin mutants, it up regulates PPARα , and so there's an increased reliance on the target, which we thought when, again, at the inception of the program, we should look better in beta-catenin mutant patients in HCC. That's bearing out in the data as well. So this was a classic randomized phase II . We did it in collaboration with Roche. 70 patients, 40 patients in the TPST-1120 arm added to atezo and bev versus atezo and bev, and it was run in about 26 countries. It's a global study run very well by Roche.
We announced in fall, I believe it was in October, a primary data cut that, as any of you who are stock watchers saw, sent the stock into the stratosphere. I think we went up almost 4,000% on the first day. One thing to get out right out of the way is these arms are balanced, right? Roche agrees with it, we agree with it. The reason this slide has any color coding on it is 'cause when we went into demographics and baseline characteristics, we actually noticed that some of the characteristics go against the TPST-1120 arm, and we still saw the data we did. This is available on our website, by the way, if you want a higher res image of the slide. A summary of the data that we presented.
So now this was the phase II, so this was primarily an ORR-driven study. OS is actually the regulatory endpoint worldwide for first-line liver cancer, but when Roche first did their IMbrave study, ORR was relevant, and statistically significant towards OS benefit. So we were very interested, as was Roche, in what the ORR would look like. And as you can see here, the TPST-1120 arm did incredibly well. It was 30% confirmed objective response rate. This is at about, let's just say 9.5 months median follow-up for each arm, versus 13% in the atezo- bev arm. We very quickly wanted to know what was happening with overall survival.
The control arm had reached a median OS at that point of 15 months, and we had not reached the median OS in the TPST-1120 arm , which thrilled us, because we had a 0.59 hazard ratio. Obviously, as you know, that is incredibly important as we go into designing the phase III. When I said in the very beginning that we were happy when the data came in because it confirmed the hypothesis, as you can see here in the final two rows, in the PD-L1-negative patients, which is an enormous percentage of liver cancer patients, our hypothesis is that TPST-1120 should be indifferent to PD-L1 status and to the nature of the tumor, whether it's inflamed or not. That was, in fact, the case here. Our ORR largely didn't change.
It went from 30%-27%, and the PD-L1 and the atezo-b ev control arm dropped down to 7%. In the beta-catenin mutant population, which is, you know, 20%-30%, depending on the papers you read, we were, I think 26%. Our ORR went up to 43%, and we had a 100% disease control rate. So again, that story hypothesis from the beginning coming all the way back. So what are we doing now, Maury? I'm just gonna pause on this slide because it's the, it's the summary of the data from fall. So what is everyone asking for bios right now? What are we excited about and what comes next? It's what is the OS? What do we have as a median OS?
We are planning to start our phase III, if not by the end of the year, in the first quarter of next year, so we're gonna be talking to FDA this summer. And we are looking forward to taking this program forward because, again, it's not just the clinical data, it's all the biomarker data. Everything comes together to make us excited about moving this program forward. We don't have time to go into the phase 1 data. I mentioned there's interesting RCC data. Please take a look at it if you have a chance. We held an investor event at ASCO a couple of years ago, and RCC KOLs were not surprised at all that we were seeing that activity. There's an opportunity there as well, capital permitting, to do what we did here.
RCC, as you know, is moving towards a triplet first line as well, just like HCC, and we would be interested in doing that as well. There's also the TPST-1495 program that we expect to start a phase II, in FAP, this year. It is being funded by the NCI, and we've received significant investigator interest to do other non-Tempest funded approaches with the TPST-1495 as well, and we're open to all of those. We are transitioning into the fireside portion. We're being joined by Sam Whiting, our Chief Medical Officer, in addition to Maury.
Thanks, everyone, and thanks, Steve. I think that was a great intro and overview of the company. You mentioned that you've got this, overall survival, data update coming soon. A lot of interest in that. Maybe talk about overall survival, what you need to show that would be viewed as meaningful.
Yep.
In the phase II data, and also eventually in a phase III study as well.
Yeah, absolutely. I'll start, and then, Sam, feel free to jump in. It's a great question 'cause we just got back from ASCO, where we were meeting with KOLs and PIs from all around the world, discussing our phase III, and there's a general view that anything which is clinically significant, which is three or more months of improvement over the control arm, would be meaningful to all of the prescribing physicians. And so, you know, that would, if that translates to the commercial opportunity, obviously. So that would be our floor. I mean, we'd want to be three or higher.
Yeah, I agree. Long-term treating physician myself, three months in OS is what we would like to see from a new drug. And the thing we're excited about with these data is that the hazard ratio that we're working from at the top line, 0.59, would be well above that three-month increment, and so we're optimistic about where things are gonna go with the next data update.
Got it. And is there anything more you can say on timing? You mentioned that, I think you're going to meet with FDA in August, and so, is there any more granularity on timing?
We actually said we were gonna meet with the FDA this summer.
Oh.
But we would expect to give the market feedback before the end of the summer.
Got it.
We can tell you our philosophy around the phase III. I mean, one of the things that Sam and I agreed upon early on as this program started to show activity, was that if we were fortunate enough to move into a pivotal study, we did not want to make some of the same mistakes that folks have made, where they have a winning randomized phase II, and then they change a bunch of variables. So we are not going to do that. If we—you know, Sam, I'll hand it over to you. We're looking at a conservative approach because we want to win in this phase III.
Yeah. So, to the question of when is the data, when we expect the next OS update, what we're saying is second half of the year, but which is coming soon, obviously. And as you know, we're going to be talking to the FDA this summer, which also says something about when we'll have data. The study design, to Steve's point, is what we think of as a very appropriate conservative study. It would be an OS primary endpoint, powered for a good performance of the atezo-bev control arm. It's a good regimen.
Historically, it's had better and worse results in, you know, different studies and in real world data sets, but we're choosing the higher end of its performance for the study design to power for statistical significance, with a clinically meaningful benefit against the best that atezo-bev has done. We're confident that we're going to see that based upon our data. And we also see this really as a manageable timeline and cost, given the size of HCC as a first-line indication. Globally, 250,000 treated patients a year. And so we're excited about basically the timeline and the course we're going to take.
Got it. And, what would the size of the study look like, and any more on logistics that you can comment on for that?
Generally speaking, the study will be similar in size to other pivotal studies in the 700-patient range. Actually, in terms of how we're designing and how we're looking at for enrollment, it's a global study. It will be in all the key countries that other pivotal studies are in. There's a large number of patients in Asia. China and Japan are important areas to develop. We're deep into discussions in terms of patient access and regulatory strategies in APAC and China and Japan. And we're, yeah, we feel like we're well on our way to Steve's point of initiating the study late in the year or first quarter of next year.
And Maury, I would add logistically, because of this, we think this is going to be a visible study, to our knowledge, we're going to be one of the only randomized phase IIIs going against standard of care, coming up at least. So the inbound interest, sort of unsolicited, that we've had from the big CROs has been helpful because they're throwing in and being really aggressive on the bids, even the biggest ones. And so what the lens that we're using, you mentioned APAC, is, you know, we're looking at folks that can operationalize, have a long history of operationalizing in APAC, with and in HCC.
Got it. And it's interesting with the CROs. Maybe talk a little bit about the process and when you could make that decision on picking a CRO.
Yeah. So one of the things to note about the speed of this program, when we presented our phase I data at ASCO, at the oral presentation, that was20 21, and then we had,
2022.
Actually, sorry, 2022. Thanks for that, makes it better. It was 2022, and then we had randomized phase II data 12 months later because the phase II was ongoing while we were doing the phase I. So the team has been in overdrive, getting ready for everything you have to do to start a phase III in the first quarter of next year. So the CRO process has not been rate limiting at all. It's really just the regulatory requirements to go in. But from a practical perspective, it has been a classic, "We're interested in doing this.
This could be good for both of us." And they've been coming in and doing bid defenses with enormous teams flying in from all around the world, which is funny because, you know, we're just a little Tempest, and some of these guys are these enormous, you know, multinationals themselves. But it's been wonderful. People are throwing in, they're doing work at risk. We're getting information on reimbursement in different parts of the world. Some have already started, or actually, several have already started feasibility analyses. So we have all this valuable information already, and we haven't picked a CRO yet.
Got it.
It's been great.
Interesting. You've also talked in the past about whether you would run this study on your own./
Yeah.
At Tempest or whether you would partner? I guess, what are, what are your latest thoughts on that?
Yeah, no. So Sam has already run a randomized, a global randomized phase III as is our head of ClinO ps. So last year, if you had asked us this question, and the world was a very dark place, and we were sort of in Dante's Inferno, we would have said we need to partner. The capital markets weren't there, and we, you know, didn't have the data that we have now, and so our view is different now. The length of the trial is not that long. If the OS data are as positive as we hope, our base case is to go finance, which, as you know, if you look at our market cap, would be a painful financing.
But if you do the math on a positive phase III and first-line liver cancer launching into this market, which is one of the more uncrowded multibillion-dollar markets, we will be okay with the fact that we did this financing. So that is, you know, a base case for us. We were just meeting with partners, potential partners at ASCO as well. You know, could a deal happen? Sure. But, you know, I'm an ex-M&A guy, and you just- you run your company to, you know, the base case, not to someone else's deal, and so that is our base case. And the board fully supports it, because again, the math is the math, right?
Got it. And so a lot of moving parts, second half of this year.
Mm-hmm.
For making that decision on which CRO you're gonna go with. Is that everything hanging on the overall survival data that you get? I guess, would that determine partnership, whether you do it on your own, and then whether which CRO you pick as well?
I don't think it's gonna change. The CRO is based on their capabilities in the regions we care about and the nature of the terms we can negotiate with the CROs, right? These are not just traditional, "We're gonna pay you for doing this," they're success-based opportunities to negotiate with the big CROs. We're looking for somebody. I mean, we're gonna be all in on this with them, right? So there's a personality fit, too. But the OS data will be a direct, it'll determine how much we can leverage the capital markets. Absolutely. Yeah.
Got it.
It could catalyze a partnership, whether that's the right path for the company or not.
Got it.
Right.
During your presentation, you mentioned the relationship between overall response rate and survival. Could you sort of bookend the scenarios for how you would expect overall survival to play out based on the response rate that you're seeing?
Well, we expect to win based on this, based on the p-value, based on the difference in confirmed ORR. We expect to beat the control arm, absolutely. The question for us is, is it, you know, is it a number we're gonna be excited about or not, right?
Got it.
You all will be excited about.
Right. Right, and so for that, I guess the upper end of that is something that you have projected, and is there anything you could say on that or?
We have not projected that publicly.
Okay.
Yeah.
Okay. Got it. And then let's see. And so with this clinical study, you were partnered with Roche, and we just talked about partnering potential. I guess, what's the latest with Roche? Is that something you can comment on?
Yeah, so we just, f or those who don't know, it was a classic clinical collaboration where we provided TPST-1120 amezalpat to Roche. They ran the study, and they don't have any rights to TPST-1120. So again, our base case is we're gonna move forward independently. We have a right to use all the data, and so we're moving forward independently. If something interesting happens there, and it's good for the company and for stockholders, we'll be open to it. But, you know, again, base case is move forward.
Got it. And for running this phase III, maybe you talk about the investigator interest, and how that's going to work as well.
So, I can take that, Steve. So we've been meeting with investigators, both via Zoom and directly face-to-face at ASCO. Some of that facilitated by the CROs that are, again, the experts in Asia. They've got KOL doctors in Taiwan and Hong Kong and China. And it's been really amazing, the enthusiasm, A, for the data, for the results of the study, and B, for the desire to participate in the study, and the enthusiasm for how they think the study will go, the interest from their patients, how that will influence our enrollment rate. Everything that we're hearing, I've told Steve, it's basically been 100% positive, enthusiastic response from the investigators that we've had conversation with so far.
Got it. Okay. And, Steve, you also mentioned beta-catenin and PD-L1 status, which are important prognostic factors in HCC, but does this matter for your phase III study? I guess, how will this be factored in.
Right.
To the design?
So, we are not. We view these data as supporting a win in the overall population. We are not going to be looking at subpopulations other than, you know, retrospectively. This is. I mean, again, we're taking the phase II. As Sam said, we're expanding it. It is first-line HCC patients, period. Now, we do think that the beta-catenin and PD-L1 status are relevant because PD-L1 negative patients, as I mentioned, it's such a high percentage of the population. The fact that adding TPST-1120 in, again, mechanistically makes sense that you are not pulled down by those patients, that's number one. The beta-catenin mutation status, smaller population, but a built-in lift, right, to the ability to improve patient outcomes. So we're not targeting, but it's relevant.
Got it. And you mentioned that the study was run against standard of care. With adding TPST-1120 , essentially, you'd be changing standard of care.
Yeah.
Then. H ow do you think about just positioning with this, this combo and with other competitors in the space? Maybe talk about that.
Yeah, I'll start, and then Sam, please jump in as the guy who was, you know, treating patients for 15 years. From a commercial perspective, right, this still remains one of the less crowded, enormous markets, right? And I understand that liver has been a different histology to make inroads, and we are pleased but not surprised at what we're seeing, given everything we've talked about earlier. So one of the slides that I didn't go through, again, available on the website, is the safety profile. TPST-1120 safety profile has consistently been, I would say, w hat's a good word that doesn't get us in trouble? It's been a positive safety profile that I think is gonna make a difference when competing with other molecules. So we have really kind of Grade 2, y ou know, we don't have significant toxin when you add this on.
The slide, if you go to the safety slide from this, these phase 2 data, you'll see that the drug intensity, the dosing intensity of standard of care when administered when you add 1120, it actually goes up a little bit. We think that's a function of the patients doing better. So, you know, we just saw data right at ASCO yesterday with ipi and nivo, sorry, in first-line liver cancer, and we do think that tox is going to become a differentiating commercial aspect. But, doctor?
Yeah, I don't have a lot to add on to that. I do think that there is a commercial advantage to having an oral therapy versus IV therapy. And I do think that fundamentally important to doctors and patients is the tolerability of a regimen. When it comes to head-to-head, I've got multiple choices, you know, how am I gonna talk to patients? How am I gonna describe the downsides of therapy? And how am I gonna. And so, how are we gonna, you know, as a team, the doctor and patient strategize? I think that we will have an advantage there.
I would also just come back to the fact that right now, 70% of the market is atezo-bev, and that's the regimen we're going up against, and we anticipate that we'll beat. Two of the four approved regimens in first-line liver cancer right now are single-agent TKIs. They don't get a lot of use. One of them, sorafenib, gets almost no use. There's just a lot of space there for active regimens to fill in, and we wanna be one of those.
Got it. And so we are out of time. Maybe to close out, if you just wanna highlight the key public disclosures you're gonna make over the next couple of months with all these updates happening.
Yeah, sure. So in the TPST-1120 amezalpat program, there's two main that we expect to be disclosing. One is the OS data, when it's ready for prime time. Secondly is FDA feedback, once we have our minutes back from the FDA. And then in the 1495 program, we're gonna—we're planning to start a phase II in FAP before the end of the year, funded by the NCI.
Great. Steve, Sam, thanks for joining us.
Thank you.