It is Michael Schmidt, Senior Biotech Analyst with Guggenheim. I'm very pleased to welcome our next presenting company, Rain Oncology. With us we have CEO Avanish Vellanki. Avanish welcome and thanks for joining us.
Thanks for having us Michael.
All right. As always, we'll go right to the Q&A. Your lead program is an MDM2 inhibitor that you originally in-licensed from Daiichi Sankyo. Can you help us understand the scientific rationale of your clinical development strategy, I think, which is slightly differentiated from what companies have done historically?
No, that's absolutely right. It is very different from what companies have done with this mechanism. Historically, companies and really the big pharmas have stepped aggressively into the hematologic malignancy space with acute myeloid leukemia being a critical focus. One of the aspects of our clinical development strategy has been to focus in on MDM2-dependent cancers. What does that mean? MDM2-dependence we'll certainly define as, of course, being wild-type p53, but also having some mechanism that elevates MDM2 levels. If there is elevated MDM2 levels and you have wild-type p53, it seems to suggest that you would be susceptible or sensitive to an MDM2 inhibitor. However, that contrasts to the prior strategies from different companies where they didn't look for MDM2-dependent, they just looked for wild-type p53 markets. That is why we believe we're being a little bit more diligent in picking the right cancers for development.
You know, again, this is not the first MDM2 inhibitor in development. There are a few others, but yours could potentially be a best-in-class agent. Perhaps talk about, you know, what differentiates your, you know, milademetan from potential other MDM2 inhibitors?
Yeah, t hat's absolutely true that MDM2 inhibition has been around before without a whole lot of success. Well, just to back up a bit, the reason for the interest in this mechanism is because half of all cancers are wild-type p53. That certainly does open up a substantial market with a successful program. Now, the initial players in the space, we believe, didn't anticipate a set of on-target toxicities that stymied the landscape, that's why things fell apart a bit. MDM2, p53, the balance between the two, is critically important, specifically in bone marrow and in various blood cells, therefore, small disturbances of that balance can lead to cell death. What the primary on-target toxicities you see from this mechanism is loss of platelets, loss of neutrophils, hence thrombocytopenia and neutropenia anemia.
When the initial set of companies developing this mechanism saw those issues, they didn't go back to the drawing board. All the new generation companies that are focused on this mechanism have a different approach to it. Our approach, which is not too dissimilar from other approaches, but I'll tell you what differentiates us. Our approach, and call it version 2.0 or version 3.0 with the technology, is dose this more like a chemotherapy. Short periods of time of pulse dosing, hit the tumor hard, high Cmax, induce apoptosis, but then back off. Let the platelets come back, let the neutrophils come back to recover. All current companies focused on this MDM2, p53 interaction inhibition are doing the same type of thing.
That specific schedule, that on and off window, is gonna be dependent on the properties of the molecule, the half-life, the potency, tissue accumulation properties, et c.. What makes us different, just getting back to your original question, is that we licensed this molecule from Daiichi Sankyo, as you mentioned, and they did a lot of initial modeling work to identify the specific schedule that would offset these on-target toxicities. They put it in the clinic, and we have data on that. What we saw is what we felt to be a very compelling tolerability profile. A very low grade 3, 4 thrombocytopenia rate, which if tolerability is improved, and this could be a long-term therapeutic solution, for the first time the hope is to be able to reactivate p53 in a multitude of tumors t hat's what excites us.
We're also the most advanced company in the space, and we hope if our phase III is supportive, we could be the first filed NDA in the U.S..
You know, you obviously taking advantage of this mechanism in sort of three different contexts. You're seeing three different studies m aybe just highlight to us, you know, those different opportunities and as they sort of unfold?
Yeah, absolutely. The three studies have been outlined. The first two are based on MDM2 amplification, so gene amplification of the MDM2 gene. The first trial, the pivotal study, is in liposarcoma, and specifically a subtype of liposarcoma, where all patients are documented of having gene amplification. There's no need for a companion diagnostic because all patients have it t hat is the pivotal study in LPS. The second study is also MDM2 gene amplification, but now outside of LPS and all advanced solid tumors that exhibit a certain degree of MDM2 gene amplification. We are leveraging a diagnostic partner to assess the copy number level of those solid tumors. Like the first study, they're both based upon gene amplification, and that's how they get to MDM2 dependence. Both, of course, are wild-type p53.
The third indication, which is a trial called the MANTRA-4 study, which is slated to start mid-year this year, is based upon getting to MDM2 dependence by losing a regulator of MDM2. MDM2, just like so many other proteins, have its own built-in regulatory mechanisms, and one of those regulatory mechanisms of MDM2 is a protein called p14ARF, encoded by the gene CDKN2A. In patients that have lost CDKN2A have lost that natural regulatory mechanism of MDM2, and then they become dependent as well. Again, going back to the central concept of identifying where MDM2 dependence occurs as a developmental strategy.
Right. Let's maybe start out talking about the MANTRA study in LPS, which is your, again, your first pivotal study that's fully enrolled. You did announce this morning that the study, the data will now read out in the second quarter as opposed to the first, which is what you've guided to before. Can you just remind us of what happened here and what changed your, you know, your guidance?
A bsolutely, t aking a step back to review the trial design of MANTRA in dedifferentiated liposarcoma, it's a 175 patient study, randomized 1-to-1 versus the standard of care drug called trabectedin or Yondelis. The required number of events to trigger the primary PFS analysis is 105 events. Upon hitting 105 events, the PFS analysis will kick off. We expected, after completing enrollment back in July of last year, that we would hit those number of events by late December, possibly early January. We did not hit those number of events by late December. By late January 30th, which was last week, we still did not hit the number of events. Therefore, when we look at the most reasonable timeline to present top-line data, it's unlikely to be in the first quarter.
Right. I guess, is there a chance that timelines could slip further? I'm sure you are keeping close tabs on the event rate, and also maybe talk about what could be explanations for that?
Yeah. It's, it is an event-driven trial, w e have to largely sit on our hands until we see the events triggered, so it is completely out of our control. It is possible that it could slip. However, we believe it's unlikely based upon what we know about the rates today, which we are not disclosing. We believe the most likely timeline is gonna be the second quarter. We can't speculate on what the reasons are and we certainly don't want to go there, despite, I think, significant questioning throughout the day around that exact issue. We will stay with the timeline of the second quarter, and we're as eager as you are Michael, for the data.
Will you announce when you have reached the number of required events, or will you just, you know, disclose the data once you have it in hand?
We'll just disclose the data.
Got you.
We have no intention—
Right
to disclose when we hit the number of events.
You know, if we maybe step back then, you mentioned it's a randomized study compared to Yondelis, which, is a sort of a drug that's been on market for a while. Just as we step back, you know, how should we think about probability of success in context of the data that's available in the public domain?
Yeah, that's a great question. When we first set out with this trial, we looked at the standards of care in this space. dedifferentiated liposarcoma, actually liposarcoma is not a homogenous group of patients, and there's four subtypes. Two of the subtypes are MDM2 gene amplified, and the other two are not. When we look at specifically the activity of Yondelis, we're very specific about the activity in the MDM2-amplified population that we're enrolling. The published data from the Yondelis pivotal study shows a median PFS of 2.2 months. That's the best data that we have to benchmark what the control arm could do. Now, having said that, we actually improved it for our assumptions, our median PFS assumptions in our pivotal study. We assumed three months. You know?
We thought perhaps there's been an optimization of therapy over the years. Perhaps physicians are more adept at using the drug, maybe a 50% improvement from the published data could be applicable. We assumed a three-month median PFS in our assumptions. Going back to why we believe why we like our chances, in the prior Daiichi phase I study across all 53 patients enrolled with dedifferentiated liposarcoma across all doses, all schedules, most of which were suboptimal dosing, suboptimal schedules from a safety perspective, median PFS was 7.2 months across 53 patients. When it was identified that this specific dose schedule of three days on, 11 days off was identified, it was a 7.4-month median PFS. Tolerability improved dramatically.
Thrombocytopenia rates came down meaningfully in our view, with no loss of efficacy. That's a tripling to quadrupling of what the published trabectedin levels were. That's why we're optimistic in terms of, the outcome of the study.
Right. I think there are also responses, right? I'm not sure if Yondelis has any sort of, you know, RECIST responses.
Responses were modest across the board. This interestingly is a tumor type in liposarcoma that doesn't suggest responses to nearly any agent. Whether it's an MDM2-p53 interaction inhibitor or otherwise, liposarcomas do not shrink—
Right.
no matter what you tend to throw at it.
Right, t hen as we step back, just help us understand the market potential in liposarcoma for the drug in the U.S. and, you know, I know there are some unique features in your trial enrollment criteria that could perhaps justify first-line use as well, if you maybe include that.
Sure. In terms of market opportunity, when we look at what the drug could potentially do in terms of peak revenue, we look at a patient population of about 1,400 patients per year in the U.S. Liposarcoma comprised of four subtypes, about 3,500 patients per year. As you whittle this down to the dedifferentiated liposarcoma population, we're focused on about 1,400 patients per year. This is comprised of not just newly diagnosed advanced dedifferentiated liposarcoma. That's typically the number that based on SEER we come up with, and that's about 500 patients a year, just advanced d-diff alone. Then you factor in patients with a resectable advanced disease, unresectable early-stage disease, and patients that have previously diagnosed well-differentiated disease that progressed to DDLPS, it's about 1,400 patients per year.
A 1,400 patients per year, and then assuming typical pricing that we would expect, based upon other comps in the sarcoma space of between $30,000-$40,000 per month price point, an average treatment time, on therapy of around 10 months. We believe that this overall market size is just sub $500 million.
Yeah. Some people point to just as a potential analog market. Is this a fair comparison in your opinion?
Yeah.
Yeah.
Absolutely.
All right. Let's talk about some of the other opportunities. MANTRA-2 is your basket study. We've seen some early data last year and yeah, just update us on how that study's been progressing since and how we should think about that opportunity.
Beyond liposarcoma, we're intending to pursue two basket trials, two tumor-agnostic strategies. MANTRA-2 is based on MDM2 amp, MANTRA-4 is based on CDKN2A loss. MANTRA-2 is progressing nicely. The enrollment has picked up since the release of the initial 10 patient data. When we started the trial, this was a novel concept enrolling based upon MDM2 gene amplification. We were the first to start a study like this. As you know from the data that were presented, some patients with significant number of prior therapies, a tremendous diversity and heterogeneity of tumor type, effectively every patient had a different cancer. It is true basket trial. You'll recall that we saw clear signs of monotherapy activity.
Monotherapy study all at the 260 mg dose, all at the three days on, 11 days off schedule. We saw some interesting signs of activity, i t is still early. We have not provided guidance on when we will update that data. What we have said is the most rational time to update the street is when it tells us something, when it tells us whether a tumor-agnostic strategy is viable, and we wanna take the next step, whether we wanna do some tissue-specific expansions because the data are pointing in that direction, or in a downside case, if we need to look at combination therapy because we're not getting there as a monotherapy by itself. When we know which direction the data moves us, that's the right time to update the street.
Right. I think you saw two out of nine responses, two near responses. I guess what, you know, what efficacy signal, you know, do you think is supportive of a perhaps a single agent strategy versus a combination strategy?
Yeah, f or a monotherapy strategy, we've always thought that the line in the sand was gonna be around 30%. A 30% with a duration of response of five months or better, that's gonna be the hurdle for success with the agency. You know, that's, that is, not based on FDA feedback to be clear, but that is our expectation looking at, looking at the landscape.
MDM2 amplification, are there certain tumor types that are more prevalent with that? Are there certain concentrations, you know?
Absolutely.
In the cancer landscape that you could pursue in terms of tissue-specific indications, or is it evenly distributed across the board?
The top three are lung, breast, and bladder. Of the 8,000 patients per year that exhibit copy number of eight or greater, 6,000 per year are in lung, breast, and bladder cancer. There are certainly based on the overall frequency is a disproportionate level of those patients.
Right. All right, I think you're also planning the MANTRA-4 study, where you did announce a collaboration with Roche last year as well. Maybe just help us understand again sort of the mechanism, or the concept for this trial and then how you're thinking about, you know, the phase I study.
This is an exciting one. CDKN2A loss is not very well understood. This is CDKN2A, not CDK. Important to get those two right. CDKN2A loss is a gene that is responsible for two products. One is p14, one is p16, p14 is the one that matters for us. p14ARF. If p14ARF is lost because of CDKN2A loss, again, this goes back to what creates more MDM2? What elevates MDM2 to create an MDM2-dependent situation? This is exciting for multiple reasons. Perhaps a big one is that there are 45,000 patients per year with CDKN2A loss cancers. Going back to overall clinical development strategy, we're starting small with liposarcoma, but we are most certainly not a liposarcoma company. We are a p53 reactivation company.
That's exciting because with CDKN2A loss and the non-clinical data that we have published on suggests tremendous sensitivity of cell lines when there are p53 wild-type and a lost CDKN2A. We're combining with Roche's atezolizumab, their PD-L1 checkpoint inhibitor, in patients that have previously relapsed from a checkpoint inhibitor. This is not a situation where these results are not gonna be interpretable. These are patients who have stopped responding to another immune checkpoint inhibitor. We hope that'll provide some clear signs of what our drug is contributing in that combination.
Great. again, CDKN2A loss, are there, you know, particular tumor types that are particularly, you know, affected by this?
Yeah. In this situation, it's lung, bladder, and melanoma.
Grea, s ome big indications there.
Yeah.
All right. I think, I mean, that's all I had in terms of questions. I know you are not just focusing on MDM2 long term. This is, you know, you're looking at other, you know, product opportunities as well down the road. Maybe just update us where you are in terms of sort of the rest of the pipeline and sort of building that out over time.
Most certainly. We, expanding the pipeline is certainly gonna be a priority for us. We're not able to talk about anything that we're planning on or are currently doing until it is publicly available. I would like to make one point, though, that the reason for the enthusiasm around milademetan, again, beyond liposarcoma, is in this landscape of oncology that all of us are focused on. As we all know, there are multiple things happening in cancers, in cancer cells. What we think about p53 reactivation is it has to be part of the component of therapy. Today, there is no avenue to address p53 reactivation as part of a commercial strategy or part of a commercial product.
What excites us is we have a program that if we show it's well-tolerated, if we show that it successfully reactivates p53 to a beneficial outcome, we like the opportunity about it being the backbone of a multitude of regimens across a variety of cancers. That's the bigger vision here. It's not, it's not liposarcoma, it's not some of these initial indications. We do believe that liposarcoma, hopefully with the MANTRA data, helps de-risk this program and instills confidence that p53 reactivation is a legitimate strategy.
Perfect , great. Thank you Avanish. I think with that, we can wrap up. Really appreciate it.
Thank you Michael.