Good morning, and thank you all for joining the Tempest Therapeutics conference call. At this time, all participants are in listen-only mode. As a reminder, today's conference call is being recorded. Following management's remarks, we will hold a question-and-answer session, and at that time, the lines will be open. I would now like to turn the call over to Aljanae Reynolds. Please go ahead.
Thank you, operator, and good morning, everyone. Thank you for joining our call to discuss the new positive data from the global randomized trial of TPST-1120 and first-line liver cancer. For your reference, a press release covering the news is available on the company's website at tempesttx.com. Joining me on the call today are Steve Brady, President and Chief Executive Officer, and Dr. Sam Whiting, Chief Medical Officer and Head of Research and Development. Turning to Slide 2, during this call, we will be making forward-looking statements that are subject to risks and uncertainties. Our actual results may differ materially from those described. We encourage you to review our Risk Factors and our most recent SEC reports on forms 10-K and 10-Q, which can be found on our website at tempesttx.com.
While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so, even if our views change. With that, let me pass the call over to Steve.
Thank you, Aljanae. Good morning, and thanks to everyone for joining our call to discuss these exciting new data from Tempest TPST-1120 program in first-line liver cancer, also known as HCC. As you may remember, we released early interim data back in April, where TPST-1120, when combined with atezolizumab and bevacizumab, which is the standard of care therapy for first-line liver patients, was compared to atezolizumab and bevacizumab alone. That first look at the data was positive for the 1120 arm over the control arm on multiple fronts, including a better objective response rate and importantly, more patients still on study and on treatment.
The fact that almost half of the 1120 patients were still on treatment at that time, as compared to about 23% for the standard of care control arm, led us to believe that the full per-protocol data cut, scheduled to come in this part of the year, could reveal an even better performance for the 1120 arm, both in numerical and relative superiority to the control arm. In addition, we've been looking forward to this data cut because it contains new biomarker data that could support the hypothesis that TPST-1120 might make a difference for certain patient populations, namely those with mutations in what's known as the beta-catenin pathway and/or those with tumors the immune system doesn't recognize, also known as cold tumors.
We're excited to be sharing these new data with you because not only have they improved substantially, so back in April, but a profile of 1120 has emerged that shows a novel molecule that appears to be providing benefits to patients in the manner it was intended when it was designed, as you can see on Slides 5 through 7. That is, to target cancers like HCC that are known to express, express its target, PPAR alpha, as well as to help patients with immune systems that are not adequately fighting the cancer. So a dual mechanism of action. As depicted on Slide 8, because of these data, we believe the next step for TPST-1120 is a pivotal study. And whether it ends up being direct on-tumor activity or the ability to activate the immune system or a combination of both, these new data are exciting.
I'll pass the call on to Sam Whiting, our CMO and Head of R&D, to dive into the results. Sam?
Thank you, Steve. I'm excited to dive deeper into these updated trial data. As a reminder, this is an ongoing global randomized p hase Ib/II study, operationalized by Roche in the MORPHEUS program. It's being conducted in patients with unresectable or metastatic HCC being treated in the first-line setting. Eligible patients are randomized to receive either TPST-1120 plus atezolizumab and bevacizumab, which we'll refer to as atezo plus bev from here on, or to the atezo plus bev standard of care control arm. Roche enrolled patients at 26 sites in 7 countries in the U.S., Asia, and Europe. Study eligibility criteria match with Roche's IMbrave150 approval study for atezo and bev in the first-line HCC setting.
Per protocol, 40 patients were randomized to TPST-1120 arm, and 30 patients randomized to the atezo plus bev control arm, with the primary efficacy endpoint of objective response rate and key secondary efficacy endpoints of progression-free survival and overall survival, and exploratory analyses performed in biomarker-specific populations. An important aspect of this randomized design is that it models in a phase II study the key design attributes and selection criteria of a pivotal registrational study. As such, this design and the study results could serve to inform the operational and statistical design of a larger approval study. As you can see on Slide 10, data from this updated per-protocol readout shows superiority for the TPST-1120 arm in every category compared to the atezo plus bev arm.
The addition of TPST-1120 to atezo plus bev improved the confirmed objective response rate to 30%, compared to 13.3% for atezo plus bev alone. Looking back to our first interim analysis, compared to 17.5% for the TPST-1120 arm when we reported back in April. It's important to note that confirmed objective response rate also has been shown to correlate with overall survival in the first-line HCC setting, which we'll touch on in a few more slides. The key endpoint in a registrational first-line study would be survival, and the survival endpoints are maturing and currently favor the TPST-1120 arm. We are pleased that the progression-free survival hazard ratio, or HR, is 0.7, corresponding to a 30% reduction in the risk of disease progression or death on the TPST-1120 arm compared to the control arm.
The median PFS values are 7 months for TPST-1120 plus atezo-bev, the confidence interval extending from 5.6 to 13.8 months, versus 4.27 months for the atezo plus bev control, the confidence interval extending from 2.8 to 7.3 months. The overall survival hazard ratio is 0.59, favoring the TPST-1120 arm, corresponding to a 41% reduction in the risk of death compared to the control arm, but remains immature at this cut, with only 25% of subjects having died on the TPST-1120 arm. In addition, as Steve noted, another reason we've been waiting for this data cut is that two biomarker-specific populations were analyzed as relevant to the TPST-1120 mechanism of action. First, beta-catenin mutation in tumors is associated with a decreased dependency on FAO and with an increased expression of PPARα.
In this population, the TPST-1120 arm confirmed ORR went up to 43, and the disease control rate went up to 100%. While we do not have beta-catenin data for the control arm in this study, in the pivotal IMbrave150 study, atezo plus bev performed similarly in beta-catenin mutated versus non-mutated tumors. So this appears to be a TPST-1120 effect that is consistent with its mechanism. Because the preclinical TPST-1120 mechanism of action data showed both direct on-tumor activity and reversion of immune suppressive cell populations, we have been interested to see the activity of the TPST-1120 arm in patients with immune-cold tumors. We are pleased to report that in further support of the mechanism, there is a notable benefit for the TPST-1120 arm in tumors that stained as PD-L1 negative at baseline.
The confirmed ORR remained essentially unchanged at 27%, compared to 7% for the atezo plus bev control arm. The safety profile for TPST-1120 has been seen to be well tolerated as monotherapy and in combination with nivolumab in our phase I study. That tolerability continues through both data cuts from the MORPHEUS study, and we will review some of those key safety data today. The study patient disposition table is shown on Slide 11, and the numbers really speak for themselves. With a median duration of follow-up of greater than 9 months, the TPST-1120 arm is favored for patients on study, 72.5% of the 1120 patients, compared to 46.7% of the control arm patients. Still, also, patients still receiving treatment, 40% for the 1120 arm, compared to 16.7% for the control arm.
Finally, for patients alive at this data cut, 75% for the TPST-1120 arm versus 53.3% for the atezo plus bev control arm. Turning to Slide 12, you see the Kaplan-Meier survival curve for progression-free survival, or PFS, which has hit the median in both arms. The curves separate early, at less than 3 months of time, and remain well separated through to 15 months, when the at-risk population drops to low single digits. The hazard ratio of 0.7 and the medians and ranges all favor the TPST-1120 arm. The overall survival data remain immature at this cut. However, the HR trends in the direction of TPST-1120 was at 0.59 for overall survival.
Slide 13 shows waterfall plots for the 2 study arms, clearly highlighting the greater number and proportion of patients in green columns, those with confirmed responses by RECIST 1.1 criteria, and the disease control population of both green and blue subjects. Also notable is a greater proportion of two patients with any tumor shrinkage from baseline in the TPST-1120 arm compared to the atezo plus bev control arm. Slide 14 and 15 show the same waterfall plots, but this time with the addition of the new biomarker data, which is really exciting.
Specifically, they show confirmed best objective response rate by patients overlaid on the pre-study biopsy PD-L1 expression status, which ranges from negative in gray to greater than 10% staining in dark red, and the tumor immune cell infiltration status, which ranges from immune cell inflamed in red to immune cell excluded in orange and immune cell desert in blue. Consistent with the data for many immune therapies, the atezo plus bev control arm responses are associated with PD-L1 positive and/or inflamed tumors. On Slide 14, this shows the green responding patients over the red immune-active tumors. In contrast, the TPST-1120 responses are seen across the board in PD-L1 negative and immune-excluded and immune desert tumors. See Slide 15 for green responder patients over gray, blue, and orange immune-compromised tumors.
The TPST-1120 data are consistent with two potential mechanisms of action of TPST-1120 that were demonstrated in our preclinical studies, including direct on-tumor activity due to inhibition of fatty acid oxidation... and also de-repression of the immune microenvironment through alteration of the immune milieu of the immune infiltrate. Or said differently, TPST-1120 may be turning the immune cold tumors hot. Also shown on Slide 15 is the relationship of tumor beta-catenin mutation status to confirmed ORR. In this population, 7 of 33 subjects were evaluable for beta-catenin status, that's 21%, were mutated. This proportion corresponds to the medical literature that 15%-40% of HCC is beta-catenin mutated. Of these patients, 43% responded to the TPST-1120 regimen, and 100% showed disease control. That is objective response plus stable disease.
While small numbers in this phase II study, the fact that 20%-40% of HCC is predicted to be mutated, we believe predicts for an advantage of a TPST-1120-containing arm over an atezo plus bev control arm in a larger study, such as a pivotal study. Slide 16 shows key safety data comparing the atezo plus bev control arm to the TPST-1120 arm. Across the categories, including fatal adverse events, high grade, Grade 3 and 4 adverse events, adverse events leading to treatment discontinuation, modification, or interruption, related serious adverse events, and immune-mediated adverse events, all are comparable to favorable for the TPST-1120 arm. This slide also shows drug dose intensity for the atezo plus bev drugs when delivered as a standard doublet or in the triplet combination with TPST-1120. That is, the proportion of drug actually taken by the patients compared to the amount of drug prescribed.
The maintenance or even slight improvement in dose intensity further confirms that the addition of TPST-1120 to atezolizumab plus bevacizumab does not impact the safety and tolerability of the control drugs. Finally, turning to Slide 17, the patient demographic and baseline characteristic data highlight a patient population that is generally balanced between the two arms, including some factors that are typically advantageous, favoring the control arm. For example, patient age, ECOG performance status, extrahepatic spread, and macrovascular invasion of cancer, baseline neutrophil to lymphocyte ratio, and baseline PD-L1 negativity, and some characteristics that are typically advantageous favoring the TPST-1120 arm, baseline alpha-fetoprotein level and region of patient enrollment. This general balance between arms supports the conclusion that TPST-1120 is the critical factor driving the difference in outcome between these two study arms.
With that dive into these exciting results, I will turn the call back to Steve for concluding remarks.
Thank you, Sam. That should not be a surprise. The team here at Tempest is excited about these new data and the potential of the 1120 program. It's satisfying to see a novel approach produce key data in the cancer types and with the companion therapeutic that makes sense, given its mechanism of action. In this case, three of the top cancer targets since inception of the program have been HCC, RCC, and cholangiocarcinoma. In addition to today's data in HCC, in an oral presentation at ASCO last year, we presented very interesting data in both RCC and cholangio. Moving to Slide 18, we're pleased that these data position 1120 as pivotal study ready, and there's a significant opportunity to improve the lives of patients here.
HCC is an aggressive cancer with high mortality rates, and we're enthusiastic about the potential to move TPST-1120 forward, either with atezo-bev or with other combination partners, such as a PD-1 plus VEGF TKI combination, towards the ultimate goal of helping patients live longer with TPST-1120 without compromising safety. We have thought through multiple approval strategies and look forward to advancing our discussions with potential partners who share the vision for TPST-1120. This concludes our prepared remarks, and we're happy to open the call for Q&A. Operator?
Thank you. To ask a question, please press Star one one on your telephone and wait for your name to be announced. To withdraw your question, please press Star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Matthew Phipps with William Blair. Your line is now open.
Hello, good morning. Thanks. Thanks, guys. Thanks for my questions, and congrats on really confirming what we saw earlier this year in a nice data set. You know, I guess-
Thanks, Matt.
Can, yeah. Moving forward, maybe can you just—you gave a couple of examples of pivotal paths. At a high level, maybe how much would something like that cost, and how much do you feel like you need a partner to move this forward?
Yes, absolutely. And then Sam, feel free to jump in. So this steps up... Yeah, it immediately connects with the partnering strategy question. So if Tempest were to do this 100% alone, pay for everything, including companion drugs, you're looking at north of $100 million to do this study. But that drops dramatically in a partnership for a couple of reasons. One, there's opportunities, depending on who we partner with, that all of the drug costs, you know, the companion drug costs would be covered. So that's a significant savings for us. And then we would most likely in the deal structure, be sharing costs doing this global study. And so it... you know, it could drop what we would need to raise to under $50 million to be able to do the full phase III.
And with respect to a partnering strategy, given how quickly we want to move, given this data cut, there's nothing that, you know, we believe should stop us from moving into a pivotal study as quickly as possible. So doing this with a partner who has pre-existing infrastructure outside the U.S., which Tempest does not yet have, makes a lot of sense. So it's both, you know, a money-saving piece. It is an infrastructure and expertise piece with your partner, and it's also not being as reliant on the capital markets, which, as everybody knows, haven't been very friendly for some time.
I'll just, just chip in and add that, that because of the aggressiveness of HCC and the unfortunate bad outcomes, that are still expected, it's really not that large of a trial number, compared to a number of other indications. So we would be looking at, an overall survival-powered trial, that would be in the 600 or more patient size. That's the kind of the average size of pivotal HCC studies. And it's a very, very large patient population globally, that are available and, ready to enroll on trials.
Thanks, Sam. And follow up, you had some real nice biomarker data here showing the, you know, activity across some subgroups of HCC. I know we haven't seen kind of as much detail from the other MORPHEUS liver arm with tiragolumab, but I guess, is there any areas where you particularly feel 1120 would likely be differentiated from another, you know, triplet regimen such as the tiragolumab regimen as far as patient subgroups?
So yeah, actually, potentially both biomarkers. Certainly from the beta-catenin perspective, although we don't have data from the MORPHEUS program, we know that in the more than 600 patients IMbrave150 approval study, the activity of atezo plus bev and beta-catenin mutated cancers was really the same, irrespective of beta-catenin status. We think that it's always gonna be improved by the addition of 1120, and that would be a built-in advantage for the 1120 arm, even against a TIGIT, for example, which does not have the metabolic profile and the FAO targeting ability of TPST-1120. The immune therapy in immune cold tumor is an interesting issue. I mean, we do know that the pure immune therapy regimens typically have a reduced response rate in PDL negative disease.
It's not really a controversial statement, even across indications. In the TIGIT presentation at ASCO, the response rate of the triplet did drop pretty significantly in the PD-L1 negative patients compared to the PD-L1 positive patients. Again, something that may favor 1120.
Great. Thanks, Sam. One last question for me. You know, seeing this data and kind of confirming the activity of 1120, I know focus is clearly on moving this to first-line, randomized phase III, but do you go—do you—can you have plans now to look at cholangio and RCC a little more based on some of the early activity you saw?
Yeah, absolutely. We've had interest, Matt, from KOLs in starting an RCC study definitely, as well as cholangio. It's really just gonna be a function of resources. We've even had one of the renal KOL say: Why don't you do this, what you just did in liver cancer, why don't you go do it in first-line kidney? I mean, we would get behind that. So yeah, there's one of the reasons we refer to this as a potential franchise is, as we mentioned in the prepared remarks, when we set out and designed this program, we were interested in HCC, RCC, and CCA, and this molecule is behaving exactly like it was predicted, and so we would love to be able to go beyond HCC.
Great. Okay, thanks, guys. Congrats.
Thanks, Matt.
Thank you. Our next question comes from the line of Ted Tenthoff with Piper Sandler. Your line is now open.
Great, thank you. Can you guys hear me okay?
Hey, Ted. Yes, good morning.
Congratulations. Really fantastic result and great result for kidney cancer patients. The efficacy is obvious and pronounced, but I was really impressed by the safety profile. It seemed to me that the triplet actually improved safety across a number of parameters, which is pretty incredible, considering you know, the efficacy benefit. What do you think is driving that, and how big of an issue is that going to be for a potential partner?
So, thanks, Ted. The key point is that, as shown also in our study, you know, dose intensity data, adding 1120 to the standard care doesn't appear to increase the toxicity or the difficulty of that regimen at all. In that context, we think probably the simplest answer is that patients on the 1120 arm are having better control of cancer, better, you know, progression-free survival, better overall survival, and that ultimately leads to fewer adverse events and fewer serious adverse events, which tend to accumulate in patients as cancer progresses towards death, frankly.
A simple answer is that what we're seeing in the comparison of the safety is not that atezo-bev is improved safety-wise, but that the treatment of cancer is improved by TPST-1120 addition.
Ted, on the partnering front, it's a benefit, right? Because when we talk to folks who are not Roche, they look at these data as, "Oh, if you're gonna combine with my PD-1 and my TKI, something like that, you know, this bodes well.
Yeah.
Yeah. Completely, completely agree with that. And from a development standpoint, it's exciting really, to be able to develop a drug that could partner with multiple-
Yeah
... different mechanisms of action in a tolerable way.
... Yeah, and I'm excited to see what it does in kidney and cholangiocarcinoma, too. So congratulations on the data.
Thank you. Thanks, Ted.
Thank you. Our next question comes from the line of Joe Pantginis with H.C. Wainwright. Your line is now open.
Hey, guys. Good morning. Thanks for taking the question. Congratulations as well. Really nice data. So,
Thanks, Joe.
Thanks. A little bit more of, you know, looking forward questions as well. I guess, you know, obviously, BD is a priority or something that you're certainly considering. I wouldn't expect to ask you about timelines or the such, but I guess I would ask, you know, can you sort of describe the maturity levels of your discussions or the continuum that you have right now? You know, the fact that it seems like you might have a lot of options, and I'll sort of link that to, you know, the demographics where it even talked about region of enrollment impacting TPST-1120 better, you know, how does that impact your potential choices for BD as well? Would you, like, mix it up potentially?
Yeah, that's a great question. So thank you for being psychic and knowing that we're not gonna go into detail on who we're talking to and how deep they are. But we are comfortable saying that it's a good group, and it ranges from those who are just coming on board, as well as those who are doing serious work. And the nature of the... or the demographics around where this disease presents is really key to how we think about partnering, right? Most of the time throughout my career, when I'm trying to do a BD oncology deal, you're fighting to keep any meaningful role in North America. And in these conversations, they're different, right? Because HCC is massively an Asian disease.
I mean, it's obviously important in the United States and Europe, but it does open up flexibility around if Tempest remains independent, retaining a meaningful North American presence to, you know, retain strategic premium in our, in our stock for, for our shareholders. You could also see splitting between two partners, you know, not our first choice, but you could see an Asia-only partner and a European regional. We've had conversations like that. So it really is... You nailed it. There's a lot of flexibility for us that at least I haven't had working in other histologies.
No, I appreciate that. That's a lot more detail than I was hoping for, so thanks for that. So I guess, you know, maybe we could just talk a little bit about the data and the real-world implications here, because, and I want to talk specifically about the responses in the control arm that are obviously quite lower than, say, what was seen in the IMbrave study. I guess the fact that this is randomized, you know, is a good discussion point here. Hopefully, you could give a little more color.
Yeah, I'll address that, Joe. Fundamentally, the point to start with is that this is a randomized controlled study, and without question, the best comparator arm for any of the experimental arms on the MORPHEUS program is the contemporaneous control arm. To that point, and to the fact that the control arm performed less well in this study compared to the pivotal study a few years ago, the control arm of the TIGIT data that were reported at ASCO was actually slightly below the response rate of the 1120 arm that we're reporting now. A little over 11%, I think, was the control arm response rate for that in the TIGIT comparison.
That said, fundamentally, what we should just acknowledge is that, each individual patient is different, and each trial is a combination of a number of individual patients, and it's very difficult to extrapolate, how patients should do in a trial based upon some historical data points or some other, trial that was performed in a different context. And that's precisely why randomization and randomized controlled studies are the gold standard for evaluating regimen, because you can really never look at a treatment outcome and compare it to some other outcome and make a reliable conclusion, about the data.
Fantastic. Really appreciate the color, guys. Very nice again. Thanks.
Thank you, Joe.
Thank you.
Thanks, Joe.
I'm currently showing no further questions at this time. I'd like to hand the call back over to Steve Brady for closing remarks.
Thank you, operator, and thank you everyone for joining today's call. We look forward to keeping you apprised on the company's progress. With that, operator, please close the call.
This concludes today's conference call. Thank you for participating. You may now disconnect.