Jefferies Global Healthcare Conference

Good evening, everybody. Welcome to the Jeffrey's Healthcare Conference. My name is Dennis Thing, a SMICAP biotech analyst here. I have the great pleasure of having Sean Bowen, CEO of Volima Pharmaceuticals, here. Welcome. Thank you, Dennis. What a time to, you know, to be alive in breast cancer, right? It's exciting. In terms of all the, you know, the progress made in the space and all the different mechanisms and just coming out of ASCO as well. So, you know, before Before we get to Persevera and just some of your thoughts, I'd love to talk a little bit more about CAT-6. I think it deserves a lot more air time. So maybe just remind us of what you guys presented at ASCO for CAT-6 and the path forward there.

Yeah. Thank you. And thanks for the opportunity to share that. So we had a poster on Saturday, a very well-attended poster on our phase one single agent DOS-ASCO for OP3136. This molecule inhibits CAT6A, B, and also CAT7 at the exposures that we are achieving. And what we saw, I think, quite encouragingly, was single-agent activity in ER-positive, HER2-negative breast cancer, heavily pretreated patients at multiple-dose levels. In addition, and differentiating from an efficacy standpoint, we saw clear monotherapy activity in castration-resistant prostate cancer. And that obviously presents a significant therapeutic opportunity, but there's another differentiation opportunity, which is tolerability. And in particular, the cytopenias that are caused by some in the class, the lead molecule from Pfizer, at their 5 milligram dose, which is in phase 3, has 50% of patients dose reducing because of cytopenias. And what we saw was a considerably lower rate and also lower grade of cytopenias in breast cancer. We saw 22% grade 3. We saw no grade 4 toxicity of any kind, no DLT. We don't have an MTD yet, up through 60 milligrams daily. And that's about half of the grade 3, 4 toxicity that Pfizer saw, in addition, without any grade 4 toxicity. And so what that presents, potentially, is an opportunity to expand from the doublets, which are ongoing with bilvestrin, and palazestrin into triplets, so to add in a CDK inhibition into the endocrine therapy and the CAT6, which would be unique and really an opportunity to possibly stop three mechanisms of the advancement of the cancer. We also, the week before, announced a collaboration agreement and a clinical trial supply in collaboration with Bayer for Nubeca their androgen receptor inhibitor to be combined with OP3136 in prostate cancer and so that will start in the not too

distant future perfect and to be clear you know this is dose escalation from two milligrams to 45 milligrams you saw promising activity in breast cancer but also what's differentiating here is prostate cancer as well which I believe Pfizer does not have any responses there but also on safety and I think the nuance there is that even though when you compare the safety tables side by side with Pfizer your levels were numerically higher but maybe that's because of prostate cancer right so like when you back that out they aren't for

neutropenia for neutropenia they're lower ours is 33 and there's 44 it is true though that when you back out breast cancer you go down to 22 and we think there are a few reasons for that one is the prior treatment so prostate cancer patients tend to get a taxing docetaxel about 70% of the patients that had prior chemotherapy there's also a treatment modality that gets used in prostate cancer that just isn't used in breast cancer and that's radio immunotherapy Plavicto which which targets the tumors primarily in the bone prostate cancer and so obviously you're not targeting a radioisotope to the bone which which has merrill effects and so those patients are probably more

predisposed to Cytopenias. Got it okay and then in terms of you know the PK data that you guys presented yeah you know it doesn't seem like you guys have you know hit any dose limiting talks we have not yet continue dose escalate so I guess you know how high do you think you'll need to go to be how will you make that determination whether it's PK or PD data let me talk a little bit about that and and when you think you'll be able to make that decision yeah that's a great

question so so far at least the the old school way of dose selection right which is you dose up until toxicity that's intolerable and then you know the dose below which is the maximum tolerated dose that doesn't seem to be working and We do have exposure targets that we've set based on the hardest to treat xenograft models in animals, and we're far exceeding that. We really exceed it starting at 6 milligrams, so with the 60 milligram dose data was not presented, but that's enrolled, we're tenfold above that. We see, I think, pretty compelling activity. We see activity at all dose levels, but at 20, we see pretty compelling activity. So I think there are several factors that will come in. First of all, with Project Optimus, you're going to expand at two dose levels. That's part of it. So we have to choose those, probably 20 and something above. The other thing we want to factor in is combination activity. We have fulvestrin and palzestrin. So in breast cancer, you don't give these targeted therapies as monotherapies. You always give them in combination with an endocrine agent. our preclinical data suggests that palzestrin should be much more potent in combination than uh than full vestrin not only with 3136 but we also tested the pfizer compound and it had the same effect there so that's ongoing in the clinic with full vestrin we're just a little bit behind the 45 milligram cohort is enrolling now we're because it's a novel novel combination a little bit further behind with palazestrin but ideally we'll be incorporating that data plus expansion at doses. I would guess it'll be next year before we're really certain of what dose we're going to move forward. We do have the opportunity, I think, potentially as soon as the end of this year to present the first combination data with the endocrine therapies. If not, certainly in the first half of next year we would share that.

Okay. And again, for CAT6, the eventual profile of this product is not as monotherapy. It's It's going to be in combination, right?

Yeah, I mean, none of the targeted therapies that are used in breast cancer are given as monotherapy. If you think about CDK4-6s, PI3 kinase inhibitors, AKT, mTOR, all of it, you always have a backbone therapy, which is an endocrine therapy. And in the second, third-line setting right now, that's a pretty poor one, which is full vesperin. So the opportunity here is to improve the targeted therapy by using a novel mechanism with a better age, a differentiated age, but then also to incorporate a superior endocrine therapy in the combination.

Got it. And then for those combo studies, what are we looking for or what are you looking for as you dose escalate? What's considered promising to you?

So it is a place where, in combination, you can use response rate, which is interesting in this disease because the mechanism of these particular targets is primarily not cytotoxic. It's cytostatic. You slow the growth and proliferation of the tumor. What we know from the Pfizer program is, well, they had a modest response rate as a monotherapy when they combined with Fulvestra and the second line study, it went into the 30% range, high 30% range. And so that gives us an indication that as we start to advance dose and expansion of the combinations with 3136, we should be able to use response rate. The responses don't all come right away. They do take time to follow the patients for a little while to really get a good estimate of it. And so I think, but that is a useful marker.

Okay. And presumably that's in combo with filvestrin, but what about for palazestrin?

Yeah, I think we would use the exact same thing and hopefully see some differentiation there. Remember, palazestrin is able to differentiate from filvestrin really in two very significant ways. One is if the preclinical data is recapitulated in people, there should be superior efficacy. But beyond that, patients don't want too large volume intramuscular injections every 28 days. They're painful. They don't provide a whole lot of exposure to the agent in fulvestrin. And so if you are able to advance CAT6 plus palazestrin, you have two daily oral pills, which is much preferred from a quality of life standpoint.

So that's, you know, that program continues to move forward. Maybe we'll get updates, additional updates in the phase one through, you know, the second half of the year, and then combo, maybe, you know, first half of 27. But then we'd love to talk about Palo Zestrant and, you know, obviously, you know, Persevera. We saw that data at ASCO. We'd love to hear your initial thoughts and, you know, how, you know, why it matters for Olima and Opera 2.

Right. So, I mean, I think Persevera was interesting for palazestrin. I think it's important to recognize that palazestrin's data to date based on phase two, both as monotherapy and in combination with CDK4-6, particularly Qiskali, ribocyclic, which is what we're using in phase three, which is what the standard of care is today in the first-line setting, superior to what has been seen with any other estrogen receptor agent. And that's probably because palzestrin is a complete estrogen receptor antagonist. It has an eight-day half-life with daily dosing, leads to a higher exposure than any of the other agents. And in addition, one important differentiator is that its combinability is superior. We do not have the dose reduce, either palazestrin or a combination agent, and we have tried a lot. We've combined with palbociclib, ribociclib, alpalisib, everolimus. We're combining with atormaciclib, the Pfizer CDK4 selective now, obviously OP3136 is ongoing. I'm sure we'll do more things in the future. And so our confidence in palazestrin, both in OPERO1 and OPERO2, is primarily based on data with palazestrin. That said, Persevera, which is a study with Roche's SIRD, gerodeskrin, combined with palbociclib, IBRAMS, which is an older standard of care, I think the data is encouraging. They did not have a positive trial. They didn't meet statistical significance with a hazard ratio of 0.89. However, if you look at their median delta in PFS, it was about five months, 4.9. And we think that that is very much indicative of a couple of things. One, as we had all suspected, as their Ladera trial and adjuvant showed, aromatase inhibitors are inadequately suppressing the growth and proliferation signal from the estrogen receptor. And we are leaving some efficacy on the table. We think that gerodespirant partly addresses that, but because of its inferior exposure is limited in its ability to do so. And I think that what they showed us is that they're getting close to what would be needed to have a positive trial and change the standard of care. I think with our superior data, with the better CDK4-6 choice in Qiskali, I think it bodes very, very well for the OPERA-02 study. There are some implications beyond that probability of success boost from Persevera, and that is there are aspects of Persevera that we're going to look at to see if we might want to make changes to the OPERA-02 trial. In particular, the control arm in Persevera modestly outperformed the historical control. The historical control, Paloma II, was 24.8 months. They got a little over 28 months of median PFS, and so we may want to revise the design of the OPERA-02 trial, in particular the number of patients enrolled. So we'll look at that now. We also may wait for Serena IV, which is the AstraZeneca Phase III trial, very similar design, but larger than Persevera, and that is, AstraZeneca has communicated that will be out in the second half of the year, and if they stay to that timeline, we could use that too.

Yeah. Okay. So, you know, the study was encouraging, even though it didn't hit statistical significance, in that there was a numerical benefit on PFS, that PFS was clinically meaningful. Yes. And, you know, like you argued that, you know, gerodestrant may not get the proper exposure, PABO may not be the best CDK4-6, and those are areas where, you know, you feel like you have an edge on top of, you know, what Roche has done.

Yeah, I think that's exactly right. You make a good point, which is that five months is clinically meaningful if you get something statistically significant that you can file. We, six months is kind of the slam dunk extension of PFS, and obviously they weren't that far Actually, off of it, if you talk to breast cancer doctors, if you talk to patients, patient advocates, they say at six months, you change the standard of care. At five months, they'd say definitely that's meaningful to us and we would use it. Four probably also, you get below that, then it starts to get more complicated, the tolerability profile becomes a more important consideration. So we think with superior activity in phase two, five months, making it that modest increase to six is well within striking distance. I think it's also important to remind people that, you know, breast cancer is the most common malignancy in women, the second most common cause of cancer, death. These are big market opportunities, the first-line setting is $10 billion plus annually. The second, third line is $5 billion if you get both immune and wild type, and that's also applicable to the CAT6 program in breast cancer, not really accounting for prostate

cancer at all. What do you make of the baseline characteristics in Persevera, right, in terms of, you know, there were a few things that looked interesting in terms of visceral disease, it seemed a little bit higher. De novo diagnosis is seen a little bit lower. Like, how does some of that data and some of that subgroup data inform your approach to OPERO2? Yeah, I mean, there are some

properties that you look at that are a little different than historical trials. It is true. Visceral disease at 60% is a little higher. Why is that important? Visceral disease is a generally poor prognostic factor. Just to remind everybody, ER positive, HER2 negative breast cancer, also true of prostate cancer, these endocrine driven tumors have a propensity to go to the bone when they metastasize. And in some patients, you get disease only in the bone, in the metastatic setting. And so that tends to be the majority of patients that don't have visceral disease, They just have bone-only disease. Those patients do better pretty much with all therapies. They progress more slowly. So when you have more visceral disease patients, you probably have a more difficult-to-treat patient population. The other thing that they had is 20% de novo patients. This is usually more like 30% to 40%. So why did they have so much less? Well, they capped it. That's why. And it's not clear to us why you would do that. To explain the difference between the de novo and the endocrine experience, when patients are diagnosed with metastatic breast cancer, they really come to that through two pathways. One is their first diagnosis of breast cancer, they are found to have metastatic disease. And that's de novo. And so obviously what that means is that they've never received any prior treatment. They never had a diagnosis of breast cancer. So when you were giving them their initial CDK46 plus endocrine therapy, they're naive to prior treatment. The other way, the somewhat more common way to reach diagnosis is you got diagnosed with early breast cancer, you got adjuvant therapy, you finished it, you had at least a year off, and then you were diagnosed with metastatic disease subsequently. So you're endocrine-sensitive by that treatment history, but you are not endocrine-naive because you've had prior therapy. Okay.

Okay. And then in terms of some of the data that they've shown in Western Europe, which seemed really strange, I believe the hazard ratio was like 1.29 or something like that. That was a quarter of the study, right? So it didn't seem like Roche had a great explanation for that. curious you know if you have any sort of hypotheses yeah I don't have an

explanation for it you know it is a subset it's 25% of the study so you do have to be careful you get large error bars around that but it does trend in a different direction than the the other geographies interestingly North America and Asia were look pretty positive right there in the mid point seven range for hazard ratio the thing that we look at when we see that is we sort of say, well, why is this? And there are two ways you can get a hazard ratio like that. You can see an underperformance of one of the arms so that patients did less well in one of the arms than elsewhere in the world. That isn't what happened here. What happened here is it looks like the control arm did quite well, better than it did in the other populations. It is really unclear to us why Paoba plus AI would do better in Europe than it would in the rest of the world. So I think one thing that would be useful to know, and I don't know if we'll ever get it, is are the demographics, these attributes we were talking about, are they distributed unequally geographically? And that's hard to tease out.

Yeah. Okay. So, then, going back to OPRO2, I mean, you mentioned that, you know, you're going to, you know, Persevera will obviously inform how you enrolled the trial in terms of, like, the powering and things like that, right? But then Serena 4 supposedly is supposed to come out in the second half, and that could be another data point. Maybe just talk about, like, the differences in patient populations between Persevera and Serena 4. Maybe Serena IV might be a little bit sicker, a little bit more endocrine sensitive. Do you share that view?

Yeah, I mean, I think it's a much larger trial is, I think, the biggest difference. Persevera is just below 1,000 patients. OPERO2 was 1,000 patients, so very similar to that. Serena IV is just under 1,400, so it's quite a bit larger trial. The other thing that happened in Persevera, which is a bit strange, is that at the beginning of the trial, they allowed a group of patients where if they had progressed within one year of their adjuvant therapy on tamoxifen, they could go on the trial. And that was about 10% of patients. We don't allow that. Actually, none of the other trials in the first-line setting, Paloma II, Mona Lisa III, can go through, also true of Serena IV and OPERO2, allow progression within one year of completion of adjuvant therapy. And they then, the discussant, or the speaker reminded us, they amended the trial to exclude that. So afterwards, it was, that was out. And those patients didn't look to do particularly well on the trial. Again, a small subset. Serena 4 has none of those patients, and so it's all endocrine-sensitive. The concern with Serena 4 is camazestrin, because of its inferior tolerability profile, has the lowest exposure of all of the agents. And then because of the time, the era when they were started, both Persevera and Serena 4 are being conducted with an old standard of care CDK4-6, that is iBrands. The standard of care has moved to Gizcali because of the survival benefit that that molecule confers. And so we, by virtue of the time that we started OPERO2, were able to adapt to that newer standard of care. The interesting part, however, is the PFS is the same amongst the different CDK4-6 agents. So we think that this is interesting and informative of information, and it would just be great to have two data sets rather than one to help us understand.

Yeah. And then you're going to make some, I guess, penning some of the data, you will make some adjustments because, you know, it's very important in that you don't want the drug to fail the trial. I think the drug works, but you don't want the trial to fail the drug.

This is, yeah, this is very important, and just to, people may be asking, hey, 20 35 months, historically, now it's 28. What happened there? What happened in Persevera Wheat? You know, the truth is we can't be 100% sure, but what we know is that in oncology and cancer treatment, it is very common over time for a given regimen to perform better. And that's probably a combination of oncologists becoming more comfortable, maintaining dose intensity, managing the AEs more effectively, and ancillary care improving over time. But we have seen this in other types of cancer with other regimens that if you look at that same regimen over time, it actually does improve. So I think that this was not unexpected.

Okay. Do you have an expectation in terms of what the control arm would show in Serena 4?

My guess is it's probably pretty close to what you see in Persevera. You pointed out, I don't know how much 10% of the patients would affect, but, you know, it may be a little marginally better because they don't, they didn't have these patients that have progressed within a year of their adjuvant. That's not allowed in Serena 4 or OPRO 2. To us, the bigger thing is just having two data sets is, you know, just increases your confidence if you are going to go out and make changes to a trial.

Okay. So in the last five minutes, maybe we can talk a little bit about OPERA-01. I think that's one of the more near-term catalysts in the fall. So talk a little bit about that, your prior Phase II data and what gives you so much confidence, you know, going to that readout.

Right, so OPERA-01 is a trial in the second-third line setting. It's a monotherapy trial with the control arm being fulvestrin or eczemestane. It'll be 70-80% fulvestrin, actually. And when you go into that setting, there's a prevalence of the ESR-1 activating mutation as a resistance mechanism. And so the way that OPERA-01 is designed is it's almost like two trials in one. And the analysis plan allows us to analyze the mutant and wild type populations separately. What we saw, now there's precedent, right, for having activity as monotherapy in the mutant population in this setting, the first of these was elicestrin, or surdu and emerald showed a modest benefit, a two-month increase in PFS, and it has led to its approval and success commercially, we saw seven months, over 7.3 is what we actually saw in an emerald-like population in Phase II, as opposed to IV. So we're hopeful that not only can we be active in that ESR1 mutant population, but we can give a greater benefit, and that will be tested in Opera 01. The interesting thing is that in that same Phase II population, if you were ESR1 wild type, we saw 5.5 months median PFS, which again is better than our SIRDU saw in the mutant population. They had two months, actually no effect at all in the wild type. So we are hopeful that we can generate data that says we can treat this whole population. In the ESR1 wild type population, no one has been successful to date. So that remains a significant unmet need. It's 50 to 60% of the patients. So it is a large opportunity. As you said, enrollment is going very, very well. And that trial will have its primary readout in the fall of this year.

If you hit on wild type in opera 01, wouldn't that give you more confidence in opera 02?

You know, there are different populations. I think, first of all, having more activity always gives you more confidence in the subsequent trials. So simply put, yes. But at the same time, remember, as I described, and we talked about this in terms of differences between Persevera and Serena 4 and Opro 2, the population in the first line is almost all wild type, but it's endocrine-sensitive wild type. The population in the second, third line is biologically different it's endocrine resistant because they've all progressed it is required to enter the trial that you have progressed on a cdk4-6 plus an ai we even allow them to have a second endocrine therapy and then they would have had to progress on that so it is a biologically uh different population for instance um in this in the second line setting gerodespirant had you know very little activity but as we discussed it it came close and certainly showed some evidence of activity in the Persevera setting so I think we it's important

to recognize those are biologically different yeah maybe in the last minute or two just you know opero two is in the first line opera one is in second and third line but you know obviously with what they are at they're moving into adjuvant so talk about how important is moving into adjuvant for you guys and and talk about what are some of the gating factors. Capital, I think, is one of them. But just talk about how much of a priority is that for Olimar over the next few years. Yeah, capital's the big one.

So the first thing is, remember, we're a company with a market cap of about a billion dollars, enterprise value of about 500 million. I would argue we're undervalued just for OB3136. Yeah. You can kind of get Palo's Estrin, that's a cumulative $15 billion market opportunity kind of as a bonus. So in that respect, Adjuvant is a really large market opportunity. It's a large unmet need. It's a great option for us. At the same time, I'm not particularly worried about it in terms of delivering shareholder value and value for patients. On the other hand, I think in a partnering discussion as we seek a collaborator, it's a really important topic because it is an opportunity we would like to access. The current problem is really that you can't do a trial like Ladera, again, monotherapy head-to-head. You have to incorporate a CDK4-6 because that's the adjuvant standard of care now. And when you do that with the size of the trial, the length of the treatment, it becomes in excess of $1 billion to do that trial. And we don't have that. We're in a great cash position with half a billion dollars on the balance sheet at the end of Q1 runway in the second half of 2028. but that does not include putting in a billion dollar budget.

Yeah, for sure. All right. Well, thank you so much, Sean, for hanging out with us and for this great discussion, and hope you have a great conference. Great. Thank you, Dennis. Thank you.