Good morning, everyone. Thank you for joining us for the 41st JP Morgan Healthcare Conference. We're thrilled to have you here, and we're thrilled to have Rain Oncology. We've got Avanish Vellanki here who's gonna President and CEO of Rain, who's gonna kick us off.
Thanks, James. Thanks, everyone. It's a pleasure to be here. We wanna thank the conference organizers and our friends at JP Morgan for allowing us to share our story today. My name is Avanish Vellanki, Co-Founder and CEO of Rain Oncology. Before we get started, on a more lighthearted note, and given the weather that we're having in San Francisco, I think it's forced upon us to explain the name Rain. Let me tell you the story. In 2017, when I incorporated the company, California was in the midst of a drought, and as far as the eye could see, it was just different shades of brown. Everything was dying, and patches of dirt where the grass used to be. It's really dawned on me how much of a need there was for renewal, rebirth, that rejuvenation of life, all of those concepts.
California was in desperate need of rain. It also struck me that the human species kind of depends on it, and that's where Rain came from. When we talk about patients, when we hope to give patients that are struggling with difficult cancers and cancers with very few treatment options, we hope to offer them hope. We hope to offer them new solutions, and in a way, we hope to bring the rain, and that is the impetus for Rain Oncology. On with the show. Here's an exciting slide for you. I just wanna remind everyone, we'll be making forward-looking statements throughout the course of the presentation. We've built a team led by myself. I'm joined here today by our co-founder, president, CSO, Dr.
Robert Doebele, best known for his work in the NTRK field, first identifying the molecule called ARRY-470, better known as larotrectinib, in his work in the NTRK field. Also, as a global lead for the STARTRK-2 study with Ignyta for entrectinib. We're also joined by our Chief Medical Officer who leads our clinical team, who led the late-stage clinical development through the commercial launch of neratinib at Puma. By several others, just under 70 people at Rain Oncology today, primarily focused here in the Bay Area, all for whom precision oncology is their religion. The story we're gonna tell you today is about a small molecule oral inhibitor of the P53-MDM2 complex. It's not necessarily appropriate to call ourselves an MDM2 inhibitor company. It is appropriate to call ourselves a P53 reactivation company.
Why we're so excited about this opportunity, why we're so excited about this mechanism, it could be the most important mechanism in all of cancer because P53's role, fundamental role, is to protect us from the onset of cancer, to guard the genome, the guardian of the genome. Up to 50% of cancers, half of all cancers may be addressable by addressing ways to reactivate P53 in those cancers that are wild type P53 and that's why big pharma was so interested. That's why Roche, Novartis, Amgen all stepped in a very big way with the first generation programs. What they may have failed to anticipate is the exquisite control in blood cells that there needs to be for MDM2 and P53.
Slight disturbances of that balance in our hematopoietic cells leads to P53 reactivation, ablation, cell death, loss of platelets, loss of neutrophils, thrombocytopenia, neutropenia, anemia are the primary AEs of concern for this class of drugs. Instead of starting over the 1st-generation programs, those companies moved on. Because this opportunity is so immense, which is why we're so excited by it, the 2nd-generation companies, 3rd-generation companies of which we are a part, we've taken a fresh look. One of the ways to solve this problem of those on target adverse events is to look at dosing these molecules more like a chemotherapy rather than a TKI, attain a very high Cmax, high blood concentration, induce cancer cell killing apoptosis, but then back off. Back off and allow the bone marrow to recover.
Every company in this space is doing exactly that. Every molecule in this space has a different schedule to address their own PK properties, potency, half-life to find an optimal schedule. Our biggest advantage with milademetan is that we were the first to take a novel dose schedule into the clinic, identify clinical profile, and move it to a pivotal study. That's why we're excited. A quick word on the mechanism for those of you that aren't familiar with the MDM2 P53 mechanism. On the left-hand side, this is a play on P53. MDM2 is only partially the focus. The real objective here is to reactivate this all-important factor of P53. P53 acts to bind DNA, induce the transcription of several genes that are meant to protect the cell from cancer, induce cell senescence, induce apoptosis. MDM2 is a natural regulator.
MDM2 binds P53 as a control mechanism, exports it from the nucleus, marks it for proteasomal degradation. That's its job. If there's too much MDM2, you lose P53, you lose the ability to control cellular pro-proliferation. There's various ways to get to a heightened MDM2 state. We at Rain are looking closely at those tumors that are not only P53 wild type, but are MDM2 dependent. There is a reason, whatever the reason may be, that leads to elevated MDM2 levels. You may obtain MDM2 dependence either through greater copies of the MDM2 gene amplification. You may achieve it because of protein overexpression. There are viruses that help produce more MDM2. You may lead to MDM2 dependence because you've lost a regulator of the MDM2 control mechanism. These all represent the specific tumor types that we're pursuing.
We are not pursuing those initial tumor types pursued by many big pharmas, such as acute myeloid leukemia and others, that while they're P53 wild type, there's no sign of MDM2 dependence. We are trying to stay true to the precision oncology name and focus on those tumors that represent the greatest chance of success. On the right-hand side, the green molecule symbolizes milademetan, Mila for short. All it does, not to oversimplify, is just bind MDM2 at the site that it interacts and binds with P53. There is no inhibition of anything else that it does for MDM2. MDM2 still possesses its ligase capability. It just prevents that complex formation. By inhibiting that complex, we reactivate and restore P53, and P53 is free to go on to protect the cell, and that is the mechanism for this entire class of programs.
We have identified three tumor types that are the preliminary focus for our strategy, starting with liposarcoma, specifically in liposarcoma, the subtypes that are MDM2 gene amplified. No companion diagnostic is needed for these tumor types because all patients have it with a specific subtype. Liposarcoma, the dedifferentiated subtype of liposarcoma is in an ongoing phase III study called the MANTRA study. It targets about 1,400 patients annually in the US, and we expect to read out top-line data this quarter. The second trial is a basket study looking at all solid tumors that exhibit a certain degree of MDM2 gene amplification. Now beyond liposarcoma, other tumors that exhibit this MDM2 dependence through gene amplifications have been enrolled. We announced preliminary interim data last quarter, this targets a patient population of around 8,000 patients annually in the US.
That study is currently enrolling as well. The third study, called the MANTRA-4 study, is our second basket study. Two basket studies after our initial liposarcoma trial. The third study is looking at a new gene biomarker called CDKN2A. Loss of CDKN2A loses a regulator of MDM2 and also creates a highly dependent situation. In this circumstance, this targets 45,000 patients per year in the U.S., so a sufficiently large patient population. We are certainly excited by that. This trial, the MANTRA-4 study, also represents our first combination study, and we'll be working with Roche's PD-L1 checkpoint inhibitor, atezolizumab, in a combination setting. That study is planned to start this quarter.
We have just under $150 million pro forma cash post a follow-on offering that we did in November, which provides a runway well into 2025 and certainly allows us well to complete all the studies on this slide. A little bit of detail of each of these three trial designs. Starting with the top, the MANTRA study, the phase III registrational, global registrational study in dedifferentiated liposarcoma. This is a 175 patient study controlled with the standard of care called trabectedin, IV therapeutic, randomizedone to one This is a progression-free survival primary endpoint. Notably, liposarcomas don't respond to nearly any agent, so responses are not the preferred endpoint.
We completed enrollment well ahead of schedule, five months ahead of schedule in July of last year. We expect the analysis of the PFS events to be triggered upon hitting 105 events. Again, top-line data is expected this quarter. Our second study, the MANTRA-2 study, is actively enrolling. It's a single-arm study in 65 patients here in the U.S., looking at patients that exhibit gene copies of MDM2 of eight or greater. That is the line in the sand that we drew to identify a level of MDM2 dependence. Copy number eight and greater, as well as wild type P53. All of these studies are using the identified dose and schedule of milademetan of 260 milligrams on a schedule of three days on, 11 days off. That's days one, two, and three of every two-week period.
That is the schedule moving forward with all planned studies. The third study, again, the population that have lost CDKN2A aimed at being a 30-patient study, with the purpose of confirming the safety profile of a combination with a checkpoint inhibitor, in this case, atezolizumab. This is a novel de-escalation trial design. Both agents will be started at the full dose and only step-down in the milademetan dose if needed. However, based on precedence with other MDM2 targeted companies, complex inhibitors in this space that have combined with checkpoint inhibitors, at least on paper, there's no overlapping toxicities, and we don't expect meaningful change in the dose, and we do expect this to rapidly progress into a 30-patient signal finding study.
Let's talk a little bit more about the data and liposarcoma specifically that got us excited about this phase III trial. Liposarcoma, the tumor of the fat cells. It's an adipocytic tumor. It affects about 3,500 patients per year in the U.S. When we look at the two subtypes that are MDM2 gene amplified, those are called well-differentiated and dedifferentiated liposarcoma tumors. Together, they represent about 2/3 of the liposarcoma market or 2,300 patients. When we look at the patient population that's addressable systemically on an annual basis, we peg that market size to about 1,400 patients per year. Again, they are all MDM2 gene amplified. Genetically, they represent the perfect population to pursue with an inhibitor of that P53 MDM2 complex. That's the genetic reason to target those patients. The more practical reason is on the bottom half of the slide.
Unfortunately for patients, the standards of care have not met their needs. There's 2 approved therapies. One from J&J, one from Eisai. They're both chemotherapeutic cytotoxic agents. When looking at the efficacy, specifically in this MDM2 amplified population, PFS is around 2 months. We need to offer patients something better. Let's start with the safety data that was generated in a very large phase II study called the U-101 study. Let's address the elephant in the room based on what I previously said about the AEs being the biggest concern for this class. Let's talk about safety first. When dose finding and dose schedule determination was pursued on the left-hand side, there was various schedules tried, starting with every day, 21 days out of 28 days, 28 days out of 28 days.
Ultimately, the level of toxicities in that continuous dose schedule was not too dissimilar from the historical MDM2 class. We saw high grades of thrombocytopenia and grade 3/4, high levels of anemia and neutropenia. It was not possible to escalate to a meaningfully high dose. It was a very narrow therapeutic index. However, when we backed off and took a fresh look at the rates of platelet neutrophil recovery after short-term dosing, it was mapped out and modeled that a pulse dosing scheme would be effective. It was determined that a three days on, 11 days off schedule could be effective. That is the Schedule D that we refer to for all of our trials.
On the right-hand side, it was possible to escalate to the highest dose achieved with the program at 260 milligrams on that three days on, 11 days off schedule. Even with a much higher dose, the toxicities came way down. Thrombocytopenia grade 3/4 rates fell from 35% - 15%. Anemia went from 18%- 0%. Still modest neutropenia from 10%- 5%. That profile you see on the right-hand side of this slide, in our view, was the best AE profile ever observed for an MDM2-P53 complex inhibitor. That's why we got excited, because we believe this safety profile should be transferable across tumor type. Liposarcoma represented the first strategy to get to market. The prior data in 53 patients with dedifferentiated liposarcoma demonstrated a range of 6.3- 7.4 months median PFS.
Together, across all 53 patients, 7.2 months median PFS. Reminder, just a moment ago, we talked about the standard of care at 2 to 2.2 months. At the optimized dosing schedule, Schedule D, 260 milligrams, was 7.4 months, a tripling to quadrupling of what we see historically from the standards of care. That excited us. Liposarcoma seemed to represent the most rapid path to market, upon which is a very powerful perch to sit to expand indications. Liposarcoma represents the first indication to pursue. Moving on to our second study, the MANTRA-2 study. We spoke a moment ago about how we wanted to take this concept of MDM2 amplification a bit further to other solid tumors that exhibited gene amplification.
We are pursuing a 65-patient study, single arm, looking at patients that exhibit copy number 8 or greater that also possess wild type P53. In November, we presented the first 10 patients of data from that initial study. What we saw is we enrolled a tremendous diversity of tumor types. In fact, of those 10 evaluable patients, every patient had a different tumor type. Tremendous heterogeneity and the presence of multiple co-drivers and co-alterations genetically in the other presence of other oncogenes. Starting with the right-hand side of the slide, we see that we have two PRs and two near PRs. The pancreatic cancer patient that had received six prior therapies received milademetan as the seventh line therapy and achieved a 34% tumor reduction upon the first scan.
The lung cancer patient with a concomitant EGFR and KRAS G12D mutation saw a 30% reduction on that patient's first scan. Unfortunately, that patient passed away shortly after the first scan due to COVID-19. There's two other near PRs, including a breast cancer patient that had six prior therapies, that achieved a 27% tumor reduction upon the first scan. In our view, in this novel strategy of looking at MDM2 amplification as a manner to enroll patients, clear signs of monotherapy activity in a very difficult to treat patient population. That excited us. Notably, this is independent confirmation of the opportunity of the MANTRA liposarcoma study as both trials are looking at patients with MDM2 gene amplification. This trial is progressing nicely, and we're continuing to enroll across 11 centers in the United States.
At the time of the data cutoff back in late October, multitude of patients remained on therapy, with the longest patient being a biliary tract patient that was on therapy for more than nine months. Safety was almost in fact, exactly in line with the prior data set from the RXDX-101 study. No surprises in terms of the rates of cytopenias or GI toxicities. That's the MANTRA-2 study. Finally, we'll touch upon the MANTRA-4 study, the patient population that we're looking at to evaluate loss of the gene CDKN2A and possess wild type P53. Again, the rationale here on the left-hand side of the slide is that CDKN2A encodes for a protein called p14 that acts as a natural inhibitor of MDM2.
A loss of p14 through gene loss of CDKN2A leads to the same MDM2 hyperactive status and dependence that could make inhibition of that complex effective. On the right-hand side, we see that in over 200 cell lines that exhibit loss of CDKN2A, when separated by status of P53, there's almost a perfect explanation of sensitivity to an MDM2 P53 complex inhibitor based upon P53 status. Mutant P53 and CDKN2A loss samples are almost nearly unanimously resistant to an MDM2 inhibitor, whereas P53 wild type of CDKN2A loss are nearly uniformly sensitive to an MDM2 P53 complex inhibitor, and therefore providing some of the initial rationale to select for patients with P53 wild type and CDKN2A loss. Again, targeting a patient population of approximately 45,000 patients in the U.S.
The two pieces of public guidance that we have provided thus far is that we expect to have pivotal data from the MANTRA study this quarter, top-line data, as well as starting the MANTRA-4 study in patients that have lost CDKN2A. With that, the takeaways from our story, as one of the leaders in the space to reactivate P53, as an inhibitor of the MDM2 P53 complex, led by a liposarcoma study, where the prior data favors strongly in our view versus the standard of care, 7.4-month median progression-free survival versus a 2.2-month for the standard of care. We're much more excited about where this program could go in the future as a pipeline in a program. Up to 50% of cancers to be addressed, either as a monotherapy or in a combination setting with milademetan.
We're excited by MANTRA-2, the preliminary activity that we see with a couple of PRs and a couple of near PRs, very much on mechanism as expected with this mechanism of action. It's the schedule of milademetan that's the secret sauce. That schedule has been the first to be diligently evaluated in the clinic and could represent the first NDA filing for this class of drug. With that, we thank you for your interest in the Rain Oncology story. Happy to take questions.
Thank you. If you'd like to ask a question, please raise your hand. We'll have the microphone brought over.
To kick it off, Avanish, maybe one question, and Bob and Richard, you're welcome to join up here as well if you'd like.
One question on the MANTRA-2 study. As you think about enrollment, you mentioned you've got 11 centers open. Can you talk about the momentum there and any challenges to enrollment you could foresee?
Sure. I'll kick this off and have Richard and Robert Doebele chime in. As this was a novel strategy to begin with, as an MDM2 amplified strategy, we were the first to start an MDM2 basket trial. Enrollment was slow to start, and hence we enrolled patients that were highly refractory patients. Post this data set, which excited, in our view, a tremendous number of investigators, there has been an acceleration. Since that, of course, we have many more patients on study than that data point. But it's certainly an acceleration of enrollment post that data cut.
Yeah, I can just add that, you know, I think, a lot of this is education around a new target and a new pathway. We are identifying a lot of patients, both at our local sites who are doing local testing and also through our partners, Caris and Tempus, who are identifying patients. There are a number of patients out there. A lot of this is just educating investigators who may not be aware of, the MDM2 inhibitor, strategy.
Excellent. A follow-up, you mentioned, product in a pipeline, and clearly you've had multiple paths, MDM2 amplified tumors, CDKN2A loss. Are there other paths you're considering or thinking about? As you mentioned, potential monotherapy or combination options? Any comment there?
There are, some of which we've published, some of which we haven't. What we have published beyond the three trials we are pursuing, we have talked about combinations with, atezolizumab, checkpoint inhibitors. IO represents a rational place to look for combinations because of, the opportunity across tumor types. Recently, we also presented data in combination with MEK inhibitors, and Bob could speak more to that, based on potential strategies pursued refractory tumors.
Just to follow on that question, we recently presented preclinical data, of course, across a number of different models, ranging from MDM2 amplified, CDKN2A loss, and those tumors that just have P53 wild type and saw similar activity of the combination across that wide breadth of tumor models, multiple different tumor types and multiple different genetic co-alterations. That's exciting preclinical data, and we'll see how we develop that later on.
P53 has been undruggable for decades. You reawakened the field. Can you tell us a little bit about what may be happening in terms of competitive and scientific reevaluation of this target and what kind of timelines you might have?
Absolutely. This is gonna be, we expect, a busy year for this space of P53 reactivation. Based upon the competitive landscape starting middle of last year, we've seen multiple companies enter this field. Again, going back to the topic of up to half of all cancers that could be looking at a P53 wild type route. There are new players, not to mention competitor names overtly, that are looking at P53 mutant strategies to ensure that that mutant structure looks like wild type P53. There is gonna be a bolus of news flow in the P53 reactivation landscape throughout 2023, as we would expect. We've seen other large pharmas enter this field of the MDM2 P53 complex inhibition. This will be the only competitor I mentioned.
Boehringer Ingelheim is one competitor that is moving aggressively in the space, effectively mirroring our strategy in liposarcoma as well as MDM2 amplified tumors. There are several others that are looking at not only solid tumors but in the heme space. Myelofibrosis is a major push in this with this mechanism of action, where we could see some additional data. Several other players are also trying to identify the right dosing schedule for their specific molecule's properties. We would expect to see, given the importance of P53, and to the point, it is a remarkably important player and contributor to cancer, that for the first time there seems to be some understanding of how to address some of the historical limitations. I didn't wanna name specific competitors.
What does the timeline look like for this? What does the timeline look like for this year?
The timeline for Rain Therapeutics, assuming positive potential supportive data from the MANTRA study, we would assume that that data would be submit-able to the regulatory authorities in the U.S. and Europe. We do not expect another study if the data are supportive. We did meet with the agencies prior to the commencement of the phase III study to understand what their needs were from a trial design perspective. And again, supporting that we could be the first player with this mechanism to be on the market. We can take any other questions from the audience.
If nothing further, I can pass it back to you, Avanish, for closing remarks.
I'd just like to thank everyone for their interest. Again, we think this is going to be an exciting year for the P53 reactivation space. We often talk internally about there being no more important factor in all of cancer than this target. It's exciting that the industry is able to move science forward, the ball forward, to address this historical limitation. Thank you.