Hey, everyone. Welcome to our next session with Alima Pharmaceuticals. My name is Lee Wasek, a biotech analyst here at Cantor, and it's my great pleasure to have Sean here with us today for the fireside chat. I think it's great timing just given the fireside news this week. So I think, first off, we can maybe just hand it over to Sean to give us some quick intro remarks.
Yeah. Thank Thank you, Lee, for having us. Thanks, everyone, for attending. So just to remind everybody, Olima is a breast cancer focused company, particularly ER positive, HER2 negative breast cancer, so the majority, seventy percent of breast cancer, most common cancer diagnosis in women in the world, second most common cause of cancer death. We have two clinical stage assets.
Our lead asset is a complete oestrogen receptor antagonist called palisestrant. Palisestrant in one phase three clinical trial ongoing, and a second to initiate before the end of this month. Ongoing trial is called OPRA-one, it says a monotherapy in the second third line, advanced for metastatic setting that's post CDK foursix plus an AI, and then you progress. That trial will read out in the second half of next year, and it's enrolling quite well. The second trial, and I should add, that's a 2 to $5,000,000,000 market opportunity.
We've shown data, compelling data in the ESR1 mutant setting, where others have had some success, but also data in the wild type setting, which would be a very meaningful differentiator. Those are both being tested in that trial. The other pivotal trial is called Opera two. It's a combination with ribociclib in the first line setting, and that trial will initiate before the end of this month. We will update on that combination data in a few weeks.
We'll do it at ESMO in October in Berlin. So a pretty news flow rich period for us. And what we're going to show there is more mature PFS data. We have previously shown over a year median PFS. This is in the post CDK four six progression setting.
We're going to have more mature data in that setting. But then also we're going to do something I think will be interesting to people. We're going to break out the wild type and the mutant subsets here. Majority of the patients in that data set were wild type, And I think there's a lot of belief that there's activity, extraordinary activity in the mutants, but not so much conviction around the wild type. And we're going to get a chance to address that.
I think it'll be interesting for people. Our other clinical stage asset is a cat six inhibitor called OP-three thousand one hundred thirty six. That's in phase one, phase one b. It's continuing monotherapy dose escalation. We just started the fulvestrant combo dosing, and in the near term we will start alisestrant combo dosing.
So these two assets work very well with each other. Preclinical data says so any targeted agent is combined with an endocrine agent. Our preclinical data says certainly that fulvestrant enhances the activity, but palisestrant is much more powerful. So we're very interested in seeing what happens with that combination. Data will be presented from the mono and combo, first half of next year, for the cat six.
Yeah. I think I think that's that's enough for now.
Yeah. Great. So, I guess before we dive into posastron and the clinical trials, do want to get your thoughts on the evolving landscape of breast cancer just given we're seeing some recent data sets ASCO we've seen some and I think recently Cell Cudi presented some data there as well. So I guess in the context of second line ER positive breast cancer, guess what is your view on the landscape, the opportunity, and where can you fit in?
Yeah. So, I'm going to answer it a little differently from the standpoint of each of the assets. Yeah. Because they're a little different.
Yes.
So, I think it's important to sit back and think about what is the objective of therapy when women, mostly women, one percent men, is diagnosed with ER positive HER2 negative metastatic breast cancer. The objective, obviously, is to extend life and ribociclib Kisqali is winning in the first line precisely because of that. But but also, you know, extend progression time, freedom from progression, with quality. Right? Quality of life is a big deal here.
So part of that is to put off chemotherapy as long as possible. So what you want to do is improve the targeted therapies and get new targeted therapies that you can sequence to achieve that objective. So, from it's important to remember that from the standpoint of the targeted therapies, they all are combined with an endocrine agent. The fundamental driver of this cancer is the estrogen receptor. So what happens biologically is that, as cancer does, the ER plus HER2 negative cancer cell co opts a normal growth and proliferation signal.
Estrogen receptor, we see its effects as human beings all the time. A young woman goes into puberty, the ovaries start producing estrogen, a variety of tumors respond to that, but one is the breast tissue, that's normal. Breast growth and development, this gets recycled throughout life, it gets recycled in pregnancy and lactation. The tumor hijacks it, and grows inappropriately. So you want to turn that off.
So one thing is that any targeted therapy, CDK4six, CDK4 selective, PI3 kinase, AT6, AKT, you have to combine it with an endocrine therapy. So for palisestrant, we believe we have the potential to be the best endocrine therapy, the endocrine therapy of preference. So you talked about Celcuity. We love new targeted therapies. It's just something else to combine with.
Combinability, however, is not easy. And so what we have found with palazestrant is that we are able to combine very well at full doses with other agents. This has been a tripping point for all of the others in the class. So we combine with ribo, we combine with palbo, we combine with abalicib, we combine with everolimus, we're going to start atoramaciclib, I'm sure we'll get to that. So if another comes along like Celcuity, we just say, oh, they're going to need to combine with palazastrate.
The other aspect of this is we need more targeted therapies. Right? So that's where cat six comes in. This is another opportunity to give an oral remember, the cell acuity molecule's IV. That's not what patients really like.
It's combined with fulvestrant, that's large volume injections. What we are object what we are shooting for is oral therapies that allow patients to put off the chemotherapy. So for us, that's the overall context.
Okay. And then maybe diving into this second line monotherapy opportunity, Just given what we're seeing from Lilly's molecule and Arvina's very tech too, I think to your point Sean earlier, investors are understandably skeptical that this is going to work in the wild type patients. Obviously, you guys are enrolling the Phase III trial right now looking at all comers.
We don't look at all comers actually. Okay. We look only at mutant or
wild The mutant and wild type. That's just put this way. So, you still have confidence know, will be different and will show something in wild type patients as well. I guess there is, you know, a question, do you think the wild type patients in second line is still sensitive, to an ER agent? I mean, what is your take on that?
I think most of them are. Some of them most definitely are not. Right? So if we think about how this disease evolves, right? Biology here is fascinating.
When the first line therapy, everybody knows what it is right now, right? It's a CDK four six plus an AI. Really, it's Kisqali because of their survival benefit, and that's the direction things are going in. Unless you have a contraindication, which is a small minority of patients, but it's Kisqali. What's interesting is, when you then progress, by far the dominant resistance mutation is an activating mutation of ESR1, the gene encoding estrogen receptor.
These mutations occur in the ligand binding domain, and they turn the estrogen receptor from a ligand regulated transcription factor to a constitutively active transcription factor. So two things are and that's forty to fifty percent of the patients. It's a high prevalence. Two things that you learn from patients who progress with that mutation: one, they're using the estrogen receptor, right? It's still a driver.
The other is AIs, fulvestrant aren't going to do anything there. So the SERMs, like veptigestrant, like elacestrant, weak agonists, weak antagonists, have shown some activity in that population. Now, patients, the other fifty-sixty percent, progress without the mutation. So that means they're mutating other pathways. Now some of those mutations are going to bypass the estrogen receptor.
We have strong conviction that palazestrin is the best endocrine therapy. If the estrogen receptor isn't driving the tumor, it won't matter. They're truly endocrine resistant. But we know that a lot of those patients are still using the estrogen receptor. We believe the hypothesis of how much activity can you get in those patients hasn't even been tested yet, except by us in phase two.
So what did that data show? Post CDK foursix, plus AI, plus or minus chemo, the Emerald eligible population. We saw seven point three months median PFS in ESR1 mutant. So an opportunity to differentiate there by having better efficacy in ESR1 mutant, but we saw five point five months in the wild type. And so, in that context, that's better than what others have seen in the SR1 mutant.
So we think there is a real opportunity, it is tested in OPRA01, as you say, to differentiate in one or both of these ways.
Okay. And then in terms of the Phase III trial, obviously you have the mutant and the wild type. What do you think the PFS bar would be from a regulatory perspective? And just given in the mutant patients, have approved agent already, probably we're going to be getting two more relatively soon. How are you thinking about the bar?
Yeah. The bar doesn't change, actually. The bar is a minimum of two months.
Mhmm.
That that so the the current gold standard, and admittedly, I think you're right. This is gonna this isn't isn't gonna be alone Mhmm. For much longer. But everybody's done the same thing. Right?
Two months. One scan cycle of eight weeks, which is which is what regulators need to see, and they did it only in the mutant. So so that's the bar. We think we can exceed that in the mutant. As I said, if you get seven months, that that's more like doubling it.
The bar in the wild type is the exact same. It's two months. It just hasn't been achieved yet by anybody. And so that's the opportunity that we're looking for there.
Okay. And then in terms of the the commercial opportunity, obviously, you guys are going to have your top line readout next year, fingers crossed. Maybe you'll show benefits in UL type patients. Obviously, that's going to be a home situation for you guys. It would be.
Right? But in the case that you did not see the things you want to see in the wild type patients, but you did hit wild type, How are you thinking about the opportunity there, just given we mentioned there are several agents that could be on the market by then? And do you still have the conviction maybe to go ahead and launch this product?
We do. So so first of all, I think it's important to look at the market size. Right? The market is 2 to 5,000,000,000, we believe. That that that's a big range.
Right? So why 2 to 5? Well, it's exactly what you said. Forty to fifty percent are the mutant that gets you the two. If you're able to get the wild type, five.
If you don't have to do the test and you can treat everybody, you you are I think I agree with your thesis that you're very much differentiated. Now what happens if it's only mutant, or the PTS is definitely higher? I think there are a couple of things that go on. One is there's still an opportunity to do better efficacy wise in a meaningful fashion, and that is differentiating. $2,000,000,000 market for a company with a market cap around 500,000,000 is a big, big opportunity.
Now, if it's mutant only, it is busy, which is something that you point out. But there's another motivation for us which is different than the other molecules, which is we have a life cycle. Mhmm. Because we have APRA o two with ribo coming behind. So getting a first approval, getting out there and having physicians comfortable with and learning about using palazestrin, is extremely valuable in setting up for that Opera O2 first line ribociclib readout.
Now that is different than the other molecules. None of them have a first line opportunity. So I think that it does create a different context for palcestrant and Aleema.
Okay. And then you picked the ninety mgrenz, the phase three monotherapy dose, so between ninety and one hundred and twenty, how are you guys deciding on which dose to go? Exposure, clinical activity?
Yeah. So the exposure is the same.
Okay.
So so which means that, to be perfectly honest, we didn't have strong conviction either way. We would have just done 90. But there's project optimists, and you have to do these things. I it is true that 90 was picked. I wouldn't say we picked.
Right? So what happens is there's an unblinding of the part one of OPRO one. Mhmm. Our IDMC gets to see that data, safety and efficacy, and made a recommendation. Again, the exposure is the same.
We have seen the exposure data unblinded. The FDA then looks at the data and IDMC's recommendation and agreed, and so we move forward with 90. Again, for us, it really is of no consequence. If there were significantly lower exposure, I think that that would make us worry, but it's the same.
Okay. And then, you know, going back to the the phase three frontline, combo trial with RIBO, I think what you're doing is pretty unique combining with RIBO. I guess, what are some of the gating steps before you can start that trial?
There are no gating steps.
There's no gating steps. Okay.
Yeah. We will initiate the trial by the end of this month. Okay. All the regulatory interactions are done. There was a big gating step late last year, which was raising money and getting a lot of ribo, but that has also passed.
So not a remaining gating step through through our collaboration with Novartis and the and the pipe the that we were able to do in November. So we commenced, there's very high investigator enthusiasm for it. We have the sites, and like I said, the regulatory interactions are done. It is really a major focus of most of Olima is execution.
Okay. Now, in terms of execution, it's going to be a pretty big trial it's great that you guys got this collaboration ongoing with with Novartis. So is there any sort of operational assistance that Novartis will, you know, provide for the frontline trial or
I mean, they're an active collaborator. Don't have a formal agreement for assistance. It's really we're the sponsor. We lead it. They have a lot of visibility.
There is major operational assistance coming from them in terms of supply. That won't surprise you. This isn't a I think just to give everybody everything you said is right. It's a thousand patient trial. The control arm is Ribociclib plus Letrozole, the experimental arm is Ribociclib plus Palisestrant, it's a blinded, placebo controlled trial.
So obviously that's a thousand patients all getting Ribociclib. And that ribociclib supply comes from Novartis. So there is a lot of supply distribution logistical support. The operational execution is us, but again, they have high visibility. They have a lot of experience.
So so we do get input suggestions from them which are valuable to us.
Okay. And then, in terms of frontline trial, can you talk about patient selection, the criteria that you guys use? And I think there's some arguments in terms of the biology in the second line may not be the same for the patients in frontline. What is your take on that?
Yeah, so first of all, I'm going to split it into two, which is one the criteria, the second is the biology. Both good points. So criteria in the front line are pretty straightforward. Actually, OPRO-one is a little more complicated than OPRO-two. What you do in the front line is you take patients who are newly diagnosed with advanced or metastatic disease.
Now, most of those patients have already been diagnosed with breast cancer. They were diagnosed with limited stage cancer. They got surgery and or radiation, they got adjuvant treatment. They will have completed their adjuvant treatment, been treatment free for at least a year, and then when they progress, that's first line advanced for metastatic. It's a standard of care there, very straightforward.
CDK foursix plus an AI. RIBO is the preference, that's the direction everyone's moving in because of the survival benefit, the NCCN category one, etc. So that part's pretty simple. So they'll be randomized, palzestrant, or letrozole all plus ribo. The biology part is interesting.
These patients are almost all ESR1 wild type. The mutation frequency arises in the context of the selective pressure of the CDK foursix plus the AI, that's why you see it in the second third line setting. But these are not, these wild type patients are not the same as the second third line wild type patients, because they are endocrine sensitive, all of them. Right? They not displayed resistance to an endocrine mechanism.
So what you are going to see us present in ESMO is, I think, compelling evidence that halosestrant plus riboye's activity in the wild type, even post CDK foursix, when the resistance mechanisms occur. And then obviously in the mutant, that's important because the forty to fifty percent of patients who develop the mutation in the letrozole arm, those clones are just going to grow. AI doesn't do anything. But in the palisestrant arm, we're going be able to suppress them. Now eventually, they'll find their way through, but that gives us the potential for PFS benefit.
I think what we're gonna show in October is the other 50 to 60% also have an opportunity to benefit in that wild type setting. So, think that's what's going to be exciting. It's not just me.
Yeah. And I think what's also exciting for the oral search space is the Roche's frontline data. Yes. I think that's going to be very informative in terms of, you know, frontline use. And, obviously, if that trial is positive, it's it's going to be phenomenal you news for for you guys.
Correct. Now, the other hand, if it's disappointing, how does that impact your thinking around the front line strategy?
Yeah. So I I think, again, I'm gonna separate it in two things. One, sentiment, which I think you described Yeah. Perfectly. And and then and then actually our conviction.
Sentiment wise so so let me give background here a little bit. So the trial that Lee is referring to is PERSONAERA. Yeah. It is a a frontline trial. From the standpoint of patient selection execution endpoints, it's a lot like Opera O2, or I guess you could say Opera O2 is a lot like Persuvera, it came first.
There is a major difference, two major differences. One is that CDK four six is different, so Perseverance, palbociclib. And that's a historical thing, right? Ibrance ruled the world until the survival data came out, and that's how and that's how Roche chose their design. So we're the only first line with ribociclib, the stand the current standard of care.
There's a palbociclib. And then they're using their CRAN. It is a complete antagonist, Gerodestrin. And we're using Palzestrin. We are very hopeful that that trial will be positive as you described.
I think sentiment wise, people will say this is proof of concept Mhmm. That the AI can be beat with a CDK four six, and that will read through very positively to us because as you'll see in October, the data will create, I think, conviction Mhmm. Around the ribo, palisestrant combination. I do think there's an intermediate where they trend but don't hit.
Yeah.
And I think that that will probably be viewed largely positively Yeah. For us as well because our data is so strong. Now, then there's another situation you described. Yeah. It just doesn't show anything.
Yeah. I think that's harder sentiment wise. It doesn't change the data we're generating. Mhmm. Right?
Mhmm. And and I don't think it changes our conviction that palzestrant is different. What's the difference here, really? The difference is combinability and exposure. Jiradestrant is a potent, complete antagonist, molecularly a very good molecule.
It has a challenge. When it combined with palbociclib at its original recommended phase two dose, one hundred milligrams a day, where their exposure is very comparable to ours at ninety and one hundred twenty, they have bradycardia. So what they decided to do is dose reduce. They dose reduced to thirty, so a three fold dose reduction. Their exposure is still better than anybody other than us.
So I am optimistic. I want them to succeed. It is the the competitor in this space is a bad disease. And so if they can give a good treatment to a bad disease, I think that's great, I think it'll help sentiment, and I think we have an opportunity to do better with the CDK four six of preference. So I'm optimistic, actually.
I should add for everybody, their guidance is that Persevera top line will read out by the end of this year.
Yeah. So that's definitely going to be a key event, you know, for the for the space. Now other than, you know, Rebel, you guys, I think this week, announced you're going to do some collaboration work with with Pfizer's terminal. That's the CDK four. I think that's the next exciting thing that could be Yeah.
You know, replacing CDK four six. Right. So I guess, number one, what you guys hope to to show from from that initial combination, and what would be the bar for you to move into maybe a a phase three frontline trial?
Yeah. So, agree with you about a term of ciclib. Again, I'll provide a little context, right? CDK foursix is this current standard of care. The dose limiting toxicity for Ibrance and for ribociclib really, dominant CDK foursix's over this past period, is neutropenia, and it's very clear that the main driver of neutropenia is not CDK four, it's CDK six inhibition.
So, the hypothesis that Pfizer is pursuing with atoramisiclib is, if we dial out the CDK6, we'll decrease that neutropenia, and we'll be able to hit CDK4 harder. I think they've demonstrated pretty compellingly the first part, which is that they can dial out the neutropenia. The second part takes a phase three trial. Their first phase three is ongoing, it's called four late three, and that's atorvastatin versus CDK foursix of physician preference, both with an AI. And that will test if you hit four harder, are you able to get better efficacy, get better PFS.
At the same time, Pfizer has been consistent in the belief that the endocrine therapy space is going to continue to evolve. So previously, they had placed a big bet on that. That was their collaboration with our Venus around Vepigestrant. As has been announced over the past few months, they're not proceeding with palbociclib or atoramaciclib with that collaboration. So that then led to the opportunity for them to collaborate with us
Mhmm.
And combine atoramaciclib with palazestrate. We will start that very quickly. We have an ongoing trial where we've done Ribo, Alpulisib, Everlimis, all at full doses, all combining without enhanced toxicity, and now we get to test atormaciclib. This is going to be up to thirty five patients. I think we'll be able to look at it quickly.
It doesn't take very long to look at tolerability and PK in there, because those come in the first one or two cycles. It'll take a bit longer to get efficacy Mhmm. Because because that that that progression free is is a longer endpoint. But I but I think with PK and tolerability, there is the opportunity to ask what is the next step. Mhmm.
And I think that we first have to generate that data, and then we can talk together about how do we wanna proceed.
Okay. Maybe touch on the CAT six, obviously. That's one of the hottest targets right now in breast cancer. Sure. Guys have actually in a great position that you have a CAT six and you have telesterence, so you can do some interesting combinations.
So, maybe just talk a little bit about where you think Casix can fit in, and with palisestrant combo, I think that's very interesting things that you guys can do with this.
Yeah, so as mentioned at the beginning, the objective here is to continue to have targeted therapies. What's nice about CAT6 is that it's an oral daily molecule, right? So, obviously, you get that's an important quality of life thing. We think our cat six is more potent in vitro. It's more potent than the than the Pfizer one.
It's a bit more selective. It dials out cat five and eight. And and we'll have to see in the clinic how that plays out tolerability wise. Pfizer's Cat six has definitely validated this target. Mhmm.
And as is always the case with the targeted therapy, when they combine with endocrine, fulvestrant in that case, it enhanced the activity. So that is actually ongoing, right? We're continuing the dose escalation with the monotherapy. Interestingly, that monotherapy isn't just breast cancer. It's got castration resistant prostate cancer and non small cell lung cancer.
So we think there's potential opportunistic life cycle there. We've started the fulvestrant combo. That's breast cancer only, obviously. And soon we will start the palazestrant combo. To your point, what's interesting here is our preclinical data says if you take Cat six with Fulvestrant, it enhances the activity, if you do it with Palisestrant, it enhances it much more.
So we're very excited about doing that. We're the only people who can do it right now, right? Because we're the only ones with Palisestrant. So that's a really exciting additional opportunity, and a very good fit between the two molecules. We will have data, combination, and monotherapy, probably second quarter of next year, before mid year next year, that we will be able to share with people on Cat six.
Are absolutely right about the interest in it. The investigators love it. This trial enrolls very quickly, So it is exciting to be able to progress that molecule.
Okay. Great. Really looking forward to that. I think that's all the time we have. Thank you so much, Sean.
Yeah. Thank you.