Good morning, everyone. My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler, and thank you for joining us this year. This is the company's 36th, but my 21st, or no, 20th, we skipped one year, Healthcare Conference, so pleased to have you all here for this momentous occasion. Before I begin, I am required to point out certain disclosures regarding the relationship between Piper and Tempest, our next presenting company, which I posted at the back of the room and also at the registration desk, so Tempest is developing amezalpat for first-line liver cancer, and the company shared some really impressive data in combination with Tecentriq and Avastin, and we'll obviously focus much of our presentation on that today. I'm pleased to be joined by my good friend, Steve Brady, CEO, and also Sam Whiting, PhD, Chief Medical Officer, so thanks, guys, for being with us today.
Thank you for having us.
Amezalpat, or what used to be TPST-1120, targets PPAR-alpha. Maybe you guys can start off by describing the biology around this target and how it's working.
Yeah, I can take that. So PPAR-alpha, the target of the drug, is a transcription factor that is involved in regulating the metabolism of fats as a source of energy. The cells in the body use a variety of sources of materials for energy, glucose being a classic one. Fats are interesting because, in the setting of cancer, our starting hypothesis was that the metabolism of fats is important to some tumors as a source of energy to grow, proliferate, and metastasize in the body. So part of their dangerous biology of cancer involves metabolism of fats. And then secondarily, or actually not really secondarily, equally important, there's a component of the immune system, what are called immune suppressor cells, that also preferentially metabolize fats as a source of energy. And that's in contrast to immune effector cells, the killer immune cells, which are metabolizing glucose.
The idea behind amezalpat is to inhibit this fundamental pathway of fat metabolism and then basically simultaneously inhibit the proliferation of tumor cells that are fat dependent and immune cells that are fat dependent. And the immune cells are the ones we want to inhibit because they're immune suppressor cells. That plays out in the preclinical setting where we can show the combination activity of amezalpat with, for example, immune therapy. And then ultimately, clinically, in our trial in liver cancer, which is a cancer that is now very well approached by immune therapy but needs still better treatments.
Yeah, and Sam, I apologize. I downplayed your four years of med school. I didn't include that, Dr. Whiting. I apologize. Sam's an MD, PhD. I apologize. So Sam, you just started to kind of touch on that. Walk us through standard of care first-line HCC today. And what did adding amezalpat show in the MORPHEUS-Liver study?
Standard of care in first-line metastatic, unresectable liver cancer is systemic therapy. There are two regimens that are right now, I think, considered to be kind of the biggest regimens. One of them is a combination of Avastin. These are both Roche drugs, Avastin or bevacizumab, and atezolizumab, which is their checkpoint inhibitor anti-PD-L1. There's another immune regimen that combines two different immune therapies without the anti-angiogenesis component of Avastin, durvalumab and tremelimumab. And then there's two small molecule oral therapies that target receptor kinases that are ultimately in the kind of history of liver cancer treatment. This is an older pathway that doesn't have an immune component and is less active. So those are the big four. There are other trials that are either ongoing or have read out recently. BMS's trial of ipilimumab and nivolumab read out.
And we think in the field that eventually that should lead to a label, although it will arguably not be the most popular regimen because of the side effects. But that's what people choose from. We went into this program in the clinical collaboration with Roche, knowing that Roche's doublet of Avastin and Tecentriq was well over half of the prescriptions written for first-line liver cancer because of its activity and how well understood and easy to use it is by doctors. And so we were excited, really, for the collaboration because we were going from our Phase I program into a randomized head-to-head against best available standard of care in a first-line patient population, is kind of everything we had dreamed of for where we would aim to go in our clinical development.
What was shown in the study, which was so exciting to us, is that in this randomized comparison where we had a standard of care arm and then that same regimen plus our drug, really all of the efficacy endpoints were improved by the addition of amezalpat, the Tempest drug. It made sense with the biology because we combined with an IO therapy and an angiogenesis therapy, and we have a mechanism that interacts preclinically and mechanistically with both of those. The confirmed objective response rate got meaningfully better from just under 15% to 30%. The progression-free survival got better. Most meaningful from our development path forward, the overall survival got better. And that included both a really favorable hazard ratio for survival of 0.65 at the latest update, which is pretty mature, but also an improvement in the median overall survival of six months.
And that's actually also a nice target to sit on. And then finally, there was a safety profile from the triplet that was consistent with our Phase I data, our own safety characterization, which is that inhibiting fatty acid metabolism does not have a lot of significant toxicity. It's manageable, usually without even altering any dosing of the drug. And that played out in the randomized comparison where the two arms looked pretty similar for adverse events. So everything we wanted to see that would allow us to design a pivotal study to basically replicate this study, this Phase II study, now in a Phase III setting.
So added efficacy without a lot on the safety side. That sounds like a good scenario.
Yeah.
One of the aspects that you didn't touch on that I was very impressed by was the activity seen both in PD-L1 negative as well as beta-catenin immune patients. So maybe you can describe those patient populations and why that's important.
Do you want to do that?
I can do that. I mean, one of the things that was exciting for us about this program was we all start development programs with hypotheses about the way it should work, both in the histology and then in certain patient populations. And even when drugs work, they don't necessarily, the story doesn't necessarily play out the way you think it's going to. One of the really special things about the amezalpat program is what we've seen now to date on the randomized P hase II data, everything is playing out, quote unquote, "as it should." Right? So not only from a histology, first-line liver cancer, high expressor of the target, we expected to see activity there. But in these two subpopulations as well, we thought that adding amezalpat to the standard of care should be significant. And the reason Sam already touched on why, right?
The target is expressed on both the tumor and on a suppressive immune population. So PD-L1 negative patients, a huge percentage of first-line liver cancer patients. So if you have only an immune therapy, obviously you're going to be at a disadvantage in those patients. I think in the literature it's north of 60%, sometimes over 70% looking at the patient population. So adding something like amezalpat to a heavy immune-focused therapy should have added a significant benefit. And in the Phase II, in PD-L1 negative patients, we had no difference effectively in our activity. It basically took the standard of care and kept its level of activity. The beta-catenin patients were also really interesting for not only a biology perspective, but also a strategic perspective. So beta-catenin is a drug target, right? There are companies going after beta-catenin. We are not.
Beta-catenin is relevant in first-line liver cancer because in patients with the mutation, the target, our target of amezalpat is upregulated. So we thought these patients should do better. They did. Our confirmed ORR popped up to 43%, and our disease control rate went to 100%. So everyone, of course, asked, well, are you going to do a companion diagnostic? Are you going to narrow your patient population? And the answer to that is absolutely not. When you look at the data that we've published, we have activity across mutation status. So the wild-type patients look great. The beta-catenin mutated patients look great. We would be leaving patients who could otherwise benefit, aside from the whole headache of having to do a companion diagnostic and pay for it. So those two subpopulations, it was wonderful to see those data.
So we'll get to the Phase III trial design in just one second. But maybe to put you guys on the spot a little bit, is there the potential then for amezalpat to actually expand the patient population for Roche's standard of care? So do you think they would actually be able to use Tecentriq in these PD-L1 low patients or the triplet in these PD-L1 patients? I mean, that would be a.
Yeah, based on our data, yes. I mean, you would not be concerned about patients being PD-L1 negative. And one thing we haven't said yet, it's an oral therapy, and it's easy to take. If you talk to our clinicians on the Phase II, they said it's very easy to give in the clinic. And you already talked about the safety profile. So there's that aspect as well.
This is actually true for many IO therapies today. They're used in all patients, and then they don't work as well in the immunocompromised patients. And so what's seen with the Roche regimen is that its label includes all patients, including PD-L1 negative patients. But the performance of the drugs, the survival of patients, the response is not as good in the PD-L1 negative. We do think that that's an advantage because ultimately, those patients are going to be built into the clinical trial that we run. A large number of patients are going to be PD-L1 negative. And then secondarily, we hope to see a recapitulation of the same data where in the pivotal study there's a clear signal there that would drive patients and doctors who wanted to have the best outcomes to selecting this regimen in those patients.
Yeah, great. So you guys did recently receive a study may proceed letter from the FDA. I'm sure that's framed somewhere important at the company because it's a lot of work to get to this point. Roche is supplying Tecentriq for the phase three trial. Tell us about the phase three trial design as it's planned and what still needs to be done before we kick that off.
Let's start.
So yeah.
So the most fundamental point about the Phase III study design is it looks just like the Phase II study, right? So the point of the Phase II study in development is to prove to yourself as much as you can, almost always without statistical significance, the activity of your regimen, and it's warranted to go on to a large pivotal approval study. So that obviously happened. Then the next, in my opinion, as a clinical developer, the next thing is to not screw that up and not change variables or patient selection or the things that companies oftentimes do because they get new ideas basically in between Phase II and Phase III. We don't need new ideas. This Phase II, which was by Roche, is this super well-designed study, the right patient population, the right regions of the world, the right patients selected, all of that.
We're basically taking that design, making it larger to treat more patients to get statistical significance. And then importantly, again, this is from a clinical kind of a PTS standpoint. The outcome of the Phase II study was actually better than we would need for an approval study in first-line liver cancer. The hazard ratio is better than is needed, and the median improvement in median survival is better. And so this study is powered and sized for statistical significance with outcomes that are really not as good as the Phase II, but are still clinically meaningful, meaningful to doctors, meaningful to patients. And so we think that that is another way of improving the probability of success of the pivotal study in terms of the design.
In a nutshell, in terms of the key characteristics, it's obviously randomized against the Tecentriq and Avastin in first-line liver cancer per the label of the drug. It's global. It's in Asia, Europe, the U.S. The stratification of patients at randomization are the same as Roche's pivotal study design. We've got built into it something we're excited about, again, clinically, and that is an early look at efficacy. You can read out a study at the time of the primary endpoint, and you can, with conversations with the regulatory authorities, look early if it makes sense. Some people look early in more of a Hail Mary strategy where they don't know what's going to happen. Our early look at efficacy is actually with an endpoint that's not as good as the Phase II study.
So we think that there's another real probability of benefit and success even at the early look at the data. So it looks like the Phase II. It's bigger. It's designed with a regulatory eye for approval of the drug globally, is the way we look at it.
Yeah, that was strategically important. When Sam and I first started working together, we didn't want to make the same mistakes that we see where you have something great happens and then you change three variables. Right, and then the Phase III doesn't go the way you want. We absolutely did not do that here.
And when do you expect to start the study? And do you have any early ideas about how long it might take to enroll when we could get data?
So yeah, we expect. We've been guiding to the end of the first quarter. Obviously, there's two people working on this study. So if it slips into April, that's not going to make a material difference. When I say two people, obviously, Roche is supplying and working with us on this study. So we've said 24 months to enroll, 12 months to primary data from LPI. We expect to beat that for multiple reasons. One, when your CRO comes in and says, "We can beat that and we'll put money on it," obviously, that always changes things. But we've had phenomenal conversations with KOLs and PIs around the world, HCC docs, all of whom I don't think I've ever worked on a study before where you have batting averages perfect and everybody wants to be on it.
And because we're going against standard of care, they believe it'll aggressively enroll as well because of the Phase II data. And so we think it'll enroll faster. And then after that, obviously, it's all biology. Right? As Sam said, there's a potential early efficacy analysis at 70% of events that it could shorten the study by up to eight months. That's on top of us beating the enrollment criteria. One thing we didn't talk about yet is we have conservatively designed the Phase III that the control arm would behave like it did in its pivotal trial. If you follow HCC, you'll know that the standard of care was a sea change, and it was awesome for patients. But there are a lot of real-world studies that show that it does not perform in the real world like it did. We have some theories on why.
It was a different time, different practice of medicine back then. That could also shorten the study, so it could very well be under three years, and then there's a futility analysis as well.
And that's separate from the.
Early efficacy analysis. Yep.
Yeah, yeah. Okay, good. Now you guys ended the third quarter with cash around $22 million. I think you took down some additional funds from the ATM. So it's more like $40 plus, $42, something like that. How long will this fund the company? And how do you guys envision paying for the Phase III?
We have an updated guidance since we took down that money. Obviously, we can start or we could start the Phase III, obviously, with that. We're not finishing it on those dollars. Tempest owns 100% of the amezalpat. One of the beautiful things about the, actually, now the two deals we've done with Roche, when Sam said they ran the Phase III, we supplied them drug, they did run it operationally. They didn't get any rights to the molecule and then when we did the supply deal with them, they still don't have any rights to the molecule. The optionality on the table for us on financing the Phase III is all capital markets, combination of capital markets and BD. But we've even talked to royalty finance guys because some of them are coming earlier now and want to do things, as you know, pre-Phase III.
I think all three of those are on the table.
And we'll see sort of what path you take. But Sam, you mentioned the big opportunity for hepatocellular in Asia. So maybe a regional deal does make a lot of sense. It's certainly on the table here, I think, for this indication, maybe even more than some.
Yeah, it's huge. I mean, in the U.S. alone, first-line HCC is around myeloma size. I mean, so it's still a significant market, right? But Asia is huge. It's over 200,000 new patients a year, I think, in China alone.
Yep, great. And just with such a primary mechanism in terms of how tumor cells survive, are you considering development in other cancers? Would a potential partner consider development in other cancers? How are you thinking about that side?
What doesn't get a lot of attention is we had an oral presentation at ASCO. The Phase I and the Phase II were running at the same time. I've actually never had that happen in my career. So it accelerated the program by years. And so at our oral presentation at ASCO, we almost had no HCC patients because we were enrolling during the pandemic. Academic sites are the greatest source for HCC patients. They were not doing this type of a study. But we had really interesting signals in renal cell carcinoma and in cholangiocarcinoma. And as I said earlier, this molecule is behaving like it should. Those are two of the other top two expressors of the target. And so that oral presentation had data from that in there as well.
Long-winded way of saying we would love to do what we just did in first-line liver and first-line renal.
Yeah. But again, eye on the prize. Focus on liver cancer for now. So I'm just going to pause and see if there's any questions from the audience on amezalpat or the Phase III or financing. Now, I wanted to save a minute or two just for 1495. Two questions on this. Firstly, you guys are developing in an endometrial cancer and I believe have a cohort that's enrolling. Is that still ongoing? What's the latest there?
So yes, we do have that study ongoing. As you said, we're eyeing the prize in terms of the company focus on liver cancer. But we're excited about this second drug. We expect to report data from basically an expansion cohort of our Phase I with TPST-1495 this coming year. And then I think, well, it's not so much luck because it's based upon the biology of the drug. But we have a collaboration going with the NCI, the Cancer Prevention Network of the NCI, to take TPST-1495 into a Phase II study in patients with something called FAP syndrome or familial adenomatous polyposis syndrome. It's a mouthful, I know, but it's essentially an inherited germline mutation and a tumor suppressor that leads to really prolific development of adenomas in humans who have it and then development of typically colon cancer.
Right now, it's very difficult to manage without just cutting pieces of the body out, removing the entire colon, surveying the small bowel because you can't resect the small bowel and removing polyps. It's a bad disease. There are no good medical therapies for it. The biology of 1495 fits there really nicely. We have preclinical data. We were actually approached by doctors who treat this disease asking about testing the drug. Ultimately, this became an NCI-funded Phase II study that we're able to give drug. We're excited about it. In my past, I was a GI cancer oncologist, and so I'm very excited about it. We're focusing on liver cancer and then using our collaborators to advance that program.
We have a minute. Tell us about the funding in a little bit more detail and what that Phase II could look like because it's kind of a nice way to sort of get non-dilutive funding to run a second study here.
Yeah. Well, being approached was wonderful, obviously, because we're a very, as you know, very lean organization. So we weren't out canvassing the world to take 1495 into other indications. And we will not be paying for the study. We will not be running the study. So in a similar way that Roche ran the Phase II with amezalpat, this group of doctors and then the NCI are going to be funding it. And from a study design perspective.
Yeah, it's actually very straightforward, and how to do a study in FAP is well understood at this point. The patient population is people who they've been diagnosed with FAP syndrome. In the natural history of the disease in patients, invariably people undergo a colectomy early in life, sometimes in their teen years, sometimes in their early 20s. Ideally, it's as late as possible for the kind of psychosocial issues of it, but early enough to head off the development of colon cancer. Those patients are then they have to be surveyed aggressively for the rest of their lives to try to detect cancer as early as possible when it occurs, so that's the point to intervene in this disease right now is in the patients who've had their colectomy and undergoing surveillance. Patients in the Phase II study will be getting our drug.
They'll be getting endoscopy procedures before they start to look for and count basically and measure adenomas that are already existing in the small intestine, in the rectum, or the ileal pouch that they have after surgery. Then they'll be treated for six months. And at the end of that, they'll have another scope, another counting procedure, well-established how it's done. And then this we would see as kind of similar to the HCC study, a proof of concept. If it looks good, then we're off to the races. And actually, we would take the program back into talking to the FDA about a pivotal study because again, a medical therapy in these patients would be really meaningful on top of all the surgery.
Especially if you could even ultimately move it pre-colectomy. That would be too exciting.
That's exactly the longer-term goal.
Great. Well, excellent. Well, guys, thank you so much. Always a pleasure. Great way for me to start my conference, so thank you very much, and good luck with the upcoming trial. We're excited to hear more.
Thank you. Appreciate it.