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spk00: Greetings and welcome to the RAIN Therapeutics Third Quarter Earnings Conference Call. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dan Ferry with LifeSci Advisors. Please go ahead.
spk08: Thank you, Operator. and good afternoon. With me today on the phone are Avinish Valanki, Chief Executive Officer of RAIN Therapeutics, Robert Doble, Chief Scientific Officer, Richard Bryce, Chief Medical Officer, and Nelson Cabotuan, SVP of Finance. During today's call, Avinish will provide an overall business update. Bob will review the interim Mantra 2 data. Richard will provide an update on RAIN's clinical programs. and Nelson will review the financials. Before we begin, I would like to remind you that statements made during this conference call that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based upon RAIN's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties as described in RAIN's annual report on Form 10-K for the year ended December 31st, 2021 and subsequent filings with the Securities and Exchange Commission. All forward-looking statements made during this conference call are based on management's assumptions and estimates as of today, November 10th, 2022. RAIN undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after today. except as required by law. With that, I'd like to turn the call over to Avinash Valanki, CEO of RAIN Therapeutics. Avinash?
spk04: Thank you, Dan, and thanks to everyone for joining us for our third quarter earnings update. The team at RAIN continues to drive forward our lead late-stage clinical program, meledimetan, our oral small molecule inhibitor of the P53 MDM2 complex. Again, you may hear us refer to meledimetan as MILA to be brief. We were excited to release the early data for MILA from our second study called the Mantra 2 study last week, and we look forward to sharing a few additional insights from that trial on today's call. We will also share updates on our other ongoing and planned MILA trials, including some notable changes to our guidance initially discussed as part of our revised corporate presentation and 8K filing last week. We also remind you that we announced a $50 million registered offering last week, concurrent with the release of the early Mantra 2 data. With this additional capital, RAIN's cash position is even stronger, now providing a cash runway well into 2025. We're excited to welcome several new large healthcare-focused funds to RAIN as part of that financing. Let me start with our revised corporate guidance before turning to Mantra 2. First and foremost, we're getting closer to the release of results from our pivotal mantra trial, the registrational phase three study of Mila in patients with specific subtypes of liposarcoma. We completed enrollment with 175 patients in July of this year, and we can now refine our guidance for top line data to the first quarter of 2023 or next quarter from the prior guidance of the first half of 2023. Second, we previously stated our interest to pursue Merkel cell carcinoma as an indication with meledimetan, and we're aiming to start a new study there called the Mantra 3 study. However, while we continue to remain convinced of the opportunity for MDM2 inhibition in Merkel cell, we now intend to prioritize other larger market opportunities in our ongoing efforts to be very prudent with cash and personnel management, and therefore we do not intend to pursue the Mantra 3 study. Our priority is to ensure operational execution and the highest ROI indications for the milodimetan franchise. In light of those priorities, the Mantra 4 trial is certainly a priority for RAIN, and we expect to start that trial next quarter. The size of the Mantra 4 target patient population is materially large, and we're very excited about the science there. Therefore, you'll notice that after RAIN's initial indication for mila and liposarcoma tumors, which exhibit genetic uniformity and driven by where the initial data existed at the time of licensing the program, both of our other near-term priority indications represent large market tumor agnostic basket trials, the MDM2 amplified Mantra 2 study and the CDKN2A loss Mantra 4 study. This is very much consistent with our focus on a precision strategy at RAINN. Finally, I want to come back to the preliminary insights from the MONTRA2 phase two tumor agnostic trial released last week. Bob will comment in more detail shortly, but let me first provide our high level views. We noted clear monotherapy activity with two early unconfirmed partial responses and two other patients with early tumor regressions nearing the PR threshold in a study that was the first to evaluate MDM2 amplification as a patient selection strategy. There have already been several observations from this study, including, first, safety has thus far been consistent with the prior phase one study. And recall, a major reason for our licensing of this program was because we felt MeLa possessed an optimized dosing schedule that may meaningfully improve its therapeutic index to enable its use as a single agent and in future combinations with various other agents. This is how we intend to grow the value of this franchise. There were no surprise findings to us from the early Mantra 2 safety set. Second, we are starting to receive some early insight on tumor kinetics with the MDM2 protein-protein interaction inhibitors that was more unclear before. We anticipated responses might be more gradual with the PPI versus what we've historically seen for the TKI class. Time will tell if we can identify a pattern between early responders versus patients that may take a longer time to achieve a response. And lastly, MDM2 inhibition with milodimetan appeared to show initial activity both in patients with other genetic co-alterations and in patients with a significant number of prior therapies. These were all very encouraging early observations from Mantra 2. At RAINN, we remain very excited about the continued progress of our milodimetan program and are looking forward to the Phase III pivotal data for myelin liposarcoma next quarter. With that, I'd like to turn it over to our President and Chief Scientific Officer, Dr. Bob Doble. Bob?
spk07: Thanks, Avinash. Let's continue the discussion of the MONTRA-2 data. The MONTRA-2 study continues to enroll patients with MDM2-amplified P53 wild-type solid tumors with 10 active sites in the U.S. currently. We anticipate enrolling a total of approximately 65 patients across a range of solid tumors using the same dosing regimen as in the registrational mantra trial, that is, with milidimethan dosed at 260 milligrams in the 3 out of 14-day schedule. Regarding patient selection by tumor MDM2 copy number, the protocol allows enrollment and dosing of patients with MDM2 copy number 12 or greater based on local NGF. and then retroactive central testing using the Tempus platform. As was anticipated and built into the protocol and analysis plan, there are modest discrepancies between local and central MGS testing with regard to MDM2 resulting in a small number of patients enrolling with tumors that had MDM2 copy number of less than 12 when centrally tested. We observed preliminary activity in tumors with less than copy number 12 and greater than copy number eight. For efficacy assessment at this interim analysis, RAINN only included patients defined as MDM2 amplified using the TEMPEST criteria of copy number greater than or equal to eight and excluded patients with copy number less than eight. Going forward, patients will be enrolled based on local MDM2 copy number eight versus 12. As of the cutoff date of October 26, 2022, the Montreux 2-basket study of milodimetan and MDM2-amplified patients has enrolled a total of 17 patients. Of those enrolled, 15 patients have started treatment with milodimetan, and these 15 patients comprise the current safety cohort. Of the 15 patients dosed, 10 have MDM2 copy number of 8 or greater and are considered available for efficacy. Of the five patients not available, one patient had not yet reached the first scan but is currently continuing on therapy, two patients withdrew for reasons unrelated to study drug, and two patients were deemed not eligible by central testing criteria. As of the data cutoff, there are eight patients continuing on therapy, including three who have not reached their first scan. Of the 10 efficacy-available patients, tumor types included but were not limited to lung, breast, biliary, and pancreatic cancers. Notably, every resist-available patient had a different tumor histology, and nearly every patient had evidence of a coexisting oncogenic driver or tumor suppressor mutation. As a reminder, the benchmark we set out to test was a 30% objective response rate. we are pleased to report that we observed two unconfirmed partial responses and two near-partial responses. A patient with pancreatic cancer and a KRAS mutation achieved a partial response at their first scan and is awaiting their second scan. A lung adenocarcinoma patient with an AGFR exon 19 deletion, as well as a KRAS mutation, also achieved a PR at their first scan, but sadly died after this initial assessment due to COVID-19. In addition to these responses, we observed tumor regressions of 29% in a patient with cholangiocarcinoma and an IDH2 mutation, and a 27% reduction in a patient with breast cancer harboring a PI3 kinase mutation. All the patients with a PR or near PR, with the exception of the patient deceased due to COVID, are continuing on therapy. Of the eight patients still ongoing therapy, the longest patient continues on study for over nine months. Safety was reported in 15 evaluable patients, those who received at least one dose of milodimetan, and is consistent with what was reported in the prior Phase I study of milodimetan. The 260-milligram dose of milodimetan administered three out of every 14 days was chosen from the Phase I study based both on the ability to achieve a higher dose and thus higher C-max, as well as reduced toxicity, especially with respect to the on-target hematologic toxicities such as thrombocytopenia. No new safety signals were observed, and the toxicity profile and frequencies are completely consistent with prior experience at this dose and schedule. Notably, patients in the safety evaluable set experienced four median prior lines of therapy with a range of 1 to 11 prior therapies. The pancreatic patient responder had four prior therapies, the lung cancer responder six prior therapies, and the breast cancer patient with a near response five prior therapies. To reiterate Avinash's point made above, we view these early data as encouraging with respect to both anti-tumor activity and safety, particularly in this histologically and genetically diverse set of patients. At this point, I will hand it over to our Chief Medical Officer, Richard Bryce, to discuss additional updates around RAINN's clinical trial pipeline. Richard?
spk06: Thank you, Bob, and good afternoon, everyone. Moving on to our pivotal Phase III mantra study, we previously announced that we had completed enrollment of 175 patients at the end of July, five months ahead of our prior year-end 2022 guidance. In fact, the trial began at the first clinical site in July 2021, and therefore enrolled in about 12 months. We believe the accelerated enrollment completion speaks to the tremendous unmet need in patients with de-differentiated liposarcoma for which milidimetan offers a targeted therapeutic strategy relative to standard cytotoxic options. We now anticipate top-line data in the first quarter of 2023, towards the early half of the previous guidance of the first half of 2023. As a reminder, we met with the FDA and EMA prior to the start of the MANTRA study. And therefore, we anticipate that if the MANTRA data are supportive, we will submit an NDA for melidemotan, indeed differentiated liposaccoma in the United States, with similar submissions in Europe and possibly other regions as well. We expect shortly to start our second tumor agnostic basket study, MANTRA4, which will be a Phase I-II trial designed to enroll 30 patients with wild-type P53 advanced solid tumors that also exhibit loss of the CDK N2A gene. This trial will be our first combination regimen with milidimetan using a checkpoint inhibitor, roshistocentric, or a tesolizumab. As a reminder, loss of the gene CDKM2A and its protein product, P14R, leads to increased MDM2 levels. P14R is a natural regulator of MDM2 and helps to maintain P53 function in cancer cells. There are a significant number of patients with wild-type p53 solid tumors with advanced disease that exhibit loss of CDKN2A. In fact, this is the second most common tumor suppressor aberration after p53 mutation, occurring in as many as 6% to 7% or more of all solid tumors, representing over 45,000 patients per year in the United States. The Mantra 4 study is anticipated to start next quarter. And finally, as Avinish mentioned, we have decided to deprioritize Merkel cell carcinoma as an indication for milidimethan, and therefore have discontinued planning for the Mantra 3 trial. As a small and lean biotechnology organization, we are electing to focus our financial resources and the time of our clinical team on indications that represent a greater value to the overall Milodermatan franchise, as well as allowing us the ability to ensure timely and successful execution of our clinical strategy. With multiple clinical strategies for Milodermatan underway, we are excited by all the emerging and potential new clinical data and the associated potential commercialization opportunities and benefits for patients while providing a best-in-class MDM2 inhibitor for patients across multiple tumor types. With that, let me now turn it over to Nelson to review our financial results. Nelson.
spk05: Thank you, Richard, and good afternoon, everyone. I am pleased to provide an update to our financial results for our third quarter and the September 30, 2022. I would also like to invite you to review your Form 10-Q file today for more details. For the third quarter of 2022, we reported a net loss of $18 million compared to a net loss of $18.4 million in the third quarter of 2021. Research and development expenses of $14.5 million in the third quarter of 2022 were slightly lower as compared to $15.3 million in the third quarter of 2021. The decrease was primarily due to the milestone fee to the HECNCO of $5.5 million incurred in the third quarter of 2021, partially offset by higher external R&D costs for melidematon, as well as higher payroll-related costs for R&D personnel. General and mercantile expenses of $3.9 million in the third quarter of 2022 were slightly higher as compared to $3.2 million in the same quarter of 2021. The increase was primarily due to higher payroll-related costs for our G&A personnel, outside consulting, legal costs, and various third-party G&A costs. As of September 30, 2022, RAINN continues to have a strong balance sheet with $90.7 million in cash, cash equivalents, and short-term investments. As announced last week, we completed a $50 million registered offering of common stock which increases our pro forma cash balance to over $140 million and provides additional runway well into 2025. With that, I'll now turn the call back over to Avinash.
spk04: Thanks, Nelson. We'll now be happy to answer any questions. Operator?
spk00: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Your first question comes from Michael Schmidt with Guggenheim. Please go ahead.
spk03: Hey, guys. Thanks for taking my questions. I just had a couple follow-ups on Mantra 2. One question maybe for Bob was if you could talk a bit more about the MDM2 amplification cutoff. And I think you said you have seen activity below 12 copy number. And maybe if you could talk about which patients in the study did have activity with the lower cutoff. I should think about the overall market size perhaps going forward with the aid cutoff.
spk07: Thanks for the question, Michael. Bob? Yeah, thanks for the question. Maybe I'll start with the last part first. So we're anticipating that the market size is approximately 8,000 patients per year. As you said, we messaged that we've dropped the copy number from 12 to 8 based on activity that we've seen in that range. We haven't released details on individual patients and what their copy number was, but obviously we're seeing activity at copy numbers lower than the initial threshold, which has prompted a reanalysis on many levels and the decision to drop that copy number. You know, we've always said that we don't think that there'll be a significant relationship between very high copy number and sensitivity versus lower copy number. We think that there will be a threshold effect. And I think this adjustment to the protocol going forward reflects what we're seeing in real time with the study.
spk03: Okay, great. And a follow-up question on the data. Obviously, that Mantra 2 so far enrolled a broad diversity of cancer types in the study, but I thought it was interesting that there were a fair amount of co-mutations occurring, including KRAS. I was just wondering if you could share your thoughts on whether the drug is perhaps more active in certain types of cancers and how you think about the impact of these potential co-mutations.
spk07: Yeah, thanks for that question. You know, we've obviously been very interested in this question of co-mutations. We've previously published a co-mutation status with oncogenic drivers at AECR earlier this year, so we have some data on that. We expect that roughly somewhere between 15% and 20% of all patients with MDM2 have amplification will have a co-mutation. Our belief has always been that these are independent pathways and may not significantly impact the effect of milidimetan, which obviously is affecting the MDM2P53 pathway, you know, rather than, for example, RAS, which is in the RTK-RAS-RAS-MAP kinase pathway. You know, we obviously, if you think about kind of the reverse situation, patients with oncogenic drivers such as EGFR about half the time have a p53 mutation and while there are some long-term prognostic impacts of that we obviously still give those targeted therapies for the EGFR alterations despite there being p53 alterations you can kind of think of this as the the reverse or inverse situation. But we are obviously continuing to look at this. We're getting next-generation sequencing, comprehensive next-generation sequencing on all of our patients, so this allows us to, again, look in real time at these relationships and try to better understand whether there might be future impacts that we have not yet anticipated.
spk03: Great. Well, thank you, and congrats on the data.
spk04: Thanks, Michael.
spk00: Next question comes from with Citi. Please go ahead.
spk02: Yeah. Hi, Avinash and Bob and team. Thanks for taking the question. Just a few for me. With respect to the decision to stop the Mantra 3, can you just say approximately what the cost savings will be on that decision? And then with respect to the choice to lower the cutoff to copy number, Does that make a meaningful difference to the long-term market opportunity for the drug? Thank you.
spk04: Thanks for the question. I'll take the first question and I'll ask Bob to address the second question in terms of what the copy number change does to the market opportunity. In terms of the Mantra 3 study, in terms of the cost savings, we can assume it's slightly less than a quarter's worth of cash in terms of our historical burn rate. So hopefully that provides you some sort of read-through in terms of the extension that that gives us by itself.
spk07: And, you know, for the second part of the question, the anticipated increase in market is a little above 40% increase in the market size by dropping the copy number.
spk02: Okay, great. And then just one follow-up, which is more strategic in nature and long-term. But obviously, you guys are aware that Barringer is starting a phase three and first line de-differentiated liposucoma soon. Obviously, you guys are doing second line, but to what extent have you thought about the potential to do a first line trial down the road yet?
spk04: Yeah, I can take that one, Yigal. Thanks for that. So, I think it's important here to be specific in terms of what first line means as it's distinguished from treatment-naive patients. So, what we think happens in the treatment landscape and as part of standard protocol for liposarcoma patients with de-differentiated subtypes is We do expect some patients to receive anthracyclines around the time of surgery as adjuvant or neoadjuvant care. So we'd like to remind everybody that in the Mantra trial design, patients may receive meledimetin as the first-line metastatic therapy if those patients previously received an anthracycline around the time of surgery. So we would anticipate that if our trial is successful, that we would achieve a label possibly in line with the trial design of the mantra trial. So in first line and beyond metastatic patients. So I just wanted to clarify that as we talked about first-line versus treatment-naive. In terms of subsequent strategies for liposarcoma, if the MONTRA study is successful, I think there's quite a few opportunities to expand the reach of milodimetan, but I don't think we necessarily want to talk about it ahead of seeing what the MONTRA data shows us. I hope that's helpful to you all.
spk02: Yeah, thank you very much.
spk00: Next question comes from Jeff Jones with Oppenheimer. Please go ahead.
spk09: Thanks, guys. Can you hear me?
spk04: Yep. Hi, Jeff.
spk10: Hi, Avinash. Appreciate you taking the question. I just wanted to see any guidance on timing around the enrollment on the fall tumor basket trial, given you're at 25% now or around 25% now. Just what your thoughts are as far as timing to the next data update or full top line data. And then the second question was around the AEs observed in the basket trial and whether you are allowing anti-nausea medications in the trial at this stage. Thanks.
spk04: Thanks, Jeff. I'll take the first question and ask Richard to comment on the safety question. We're not going to provide any additional guidance at the current time, Jeff, in terms of subsequent milestones for the Montreux Q study, so sorry we can't be more discreet there, but nothing additional on Montreux Q guidance. Richard, want to talk about that?
spk06: Sure. So the AE profile that we've observed and we published or presented is pretty much identical to what's been shared before with the phase one Daiichi Sankyo study, the U101 study, that study that will be published shortly in JCO. So we're very happy with that and very pleased with the consistency. The question regarding anti-nausea agents, anti-emetics, this is not mandated in the basket study. It's at the physician's discretion, entirely at the physician's discretion.
spk10: Great. Appreciate that. Thank you.
spk04: Thanks, Jeff.
spk00: Once again, if you would like to ask a question, please press star 1 on your telephone keypad. Your next question comes from Mitchell Kapoor with HC Wainwright. Please go ahead.
spk09: Hi, everyone. Thanks for taking the questions and congrats on the recent data. The first question we have is what kind of analyses could we see in the top line phase three LPS data? Do you have any details on how many patients about we could see or any other details about that readout? And then if data are positive, how soon could you file for regulatory approval and potentially be on the market?
spk04: Hi, Mitchell. Thanks for the question. So let me take that first question. So we're not going to provide a ton of detail in terms of what we're going to say in terms of what data is going to be included in a top line news release. And I think in terms of the timelines to potentially following a regulatory approval, you know, we're not going to provide that specific guidance at this point other than saying that we expect it to be within conventional timelines post the phase three. So we don't expect that. anything materially to delay that process if the monitor data are supportive. So other than that, we're not going to provide any additional clarity, Mitchell.
spk09: Yeah, no problem. And then I guess just on the benchmarks for the data, would you be able to share kind of what would be considered positive on PFS? And should we also be looking at response rate to some degree?
spk04: Yeah, so no to response rates. We said before that liposarcomas tend to not respond to essentially any therapy with very modest single-digit response rates to a variety of regimens that have historically been tried in this patient population. So response rate is not an adequate measure of efficacy in this population. As a reminder, we designed the MONTRA study based on an assumption of a doubling of progression-free survival from the standard of care, trabectin. We think if that is achieved, that is a very clinically meaningful benefit, especially in light of the AE profile that goes with melodimethan versus the conventional therapies. So we think as designed, achieving that primary endpoint with the doubling of PFS would be rather substantial. and really largely agreed by many of the KOLs in the space as well.
spk09: Great. Thank you for taking the questions.
spk04: Thank you.
spk00: Next question, Sumit Roy with Jones Research. Please go ahead.
spk01: Hi, everyone. Congratulations on all the progress and the data. My apologies. I missed the top part of the call, so if you have answered this already. But curious, if you're going to put out the – In the basket, from the basket tumor trial, the spider plot of these patients, how rapid is the tumor, the rate of reduction, and do you see deepening of response with time, or they kind of flatten out after the initial drop in the tumor size?
spk04: Hi, Sumit. Actually, let me turn it over to Bob.
spk07: Yeah. Thanks for the question. It's an interesting one. You know, we don't yet, I guess the short answer is we don't yet know enough about whether this protein-protein interaction disruptor, milodimetan, will have similar kinetics to, for example, TKIs in terms of rapid responses. We have seen some responses and anti-tumor activity on the first scan. We have seen some deepening, but I think it's still too early to understand the kind of average kinetics of response for this drug and this type of mechanism.
spk01: Are you planning to put out these pilot plots later on the more mature update?
spk04: We could soon. We haven't declared our intent as to what data we're going to put out when. But I think it's important to mention that in the swim lane plot that we did include in our corporate presentation and did release, Given that many of the comments that we've included in the press release around some of those early responders and the timing associated with those responses in the swimmer's plot, I think you can kind of back into what a preliminary spider plot is going to look like. As we did mention that both the early responders did respond in the first scan. I think we do highlight, you know, how long we've been on study. So we'll leave it at that, but we don't want to be more descriptive here and commensal to what's already been released.
spk01: Certainly. Thank you for taking the questions, and congratulations again. Thanks, Suman.
spk00: There are no further questions. I would like to turn the floor over to Avinash for closing remarks.
spk04: Thank you, Operator. We look forward to updating everyone on our year-end 2022 call next, and I want to thank everyone for joining us today.
spk00: This concludes today's teleconference. You may disconnect your lines at this time, and thank you for your participation.
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