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spk04: And additional just-in-time sites will be opened as necessary from referrals from the Tempus and Carus Genomic Testing Services. We anticipate enrolling 65 patients across a range of solid tumors and using the same treatment protocol as in the Registrational Mantra Trial. That is with melidometan dosed at 260 milligrams in the three out of 14-day schedule. We anticipate an early data readout in the fourth quarter of this year and reporting patient responses, duration of response, and safety in approximately 10 evaluable patients. Based on the progress made with our Milodermatan clinical program thus far, we're looking forward to commencing two additional studies in the fourth quarter of this year. As Avinash mentioned, we anticipate starting the Mantra 3 study of Milodermatan in patients with Merkel cell carcinoma who are resistant or refractory to checkpoint inhibitor therapy. As a reminder, we believe the majority of patients with Merkel cell carcinoma, up to 80% of them, have a cancer induced by the polyomavirus, which induces MDM2 overexpression. We are also encouraged by data from other MDM2 inhibitor programs revealing monotherapy activity in the tumor setting. and hence believe that there is an opportunity for an MDM2 inhibitor program that may be better able to manage the on-target cytopenic toxicities. And finally, we're excitedly anticipating the initiation of our fourth study before year-end to evaluate our first combination regimen with milidimetan. This study, the Mantra 4 study, will evaluate the combination of milidimetan and rocistocentric, or atezolizumab. in a phase 1-2 study in approximately 30 patients with wild-type P53 advanced solid tumors that also exhibit loss of the CDKN2A gene. As a reminder, we believe loss of the gene CDKN2A and loss of its protein product, P14R, leads to increased MDM2 levels. P14R is a natural regulator of MDM2. There are a significant number of patients with wild-type p53 solid tumors with advanced disease that exhibit loss of CDKN2A. This is estimated at over 35,000 patients per year in the U.S., as many as 6% to 7% or more of all solid tumors, and is the second most common tumor suppressor aberration after p53 mutations. The Mantra 4 study will be primarily focused on confirming the safety of the combination regimen but we'll also evaluate efficacy. With multiple clinical strategies for Melodermatin underway, we're excited for all the potential new data. So let me turn now over to our Chief Scientific Officer, Bob Doble. Bob.
spk07: Thanks, Richard, and good afternoon, everyone. First, RAINN recently presented additional data relating to the Montreux 2 patient population at the AACR annual meeting in New Orleans. This work further detailed the variety of tumors that harbor high-level MDM2 gene amplification using RAIN's copy number threshold of 12 and showed a meaningful number of patients with lung, breast, bladder, and gastroesophageal tumors, amongst others. Although CDK4 is commonly co-amplified with MDM2 in dedifferentiated liposarcoma and other sarcoma subtypes due to its proximity on chromosome 12, This presented work demonstrated a notable lack of CDK4 co-amplification in lung, breast, bladder, and gastroesophageal tumors, amongst others, particularly at the copy number 12 threshold. Although the impact of oncogenic drivers remains unknown with respect to clinical benefit of MDM2 inhibition, this analysis only found approximately 20% of patients with MDM2 amplification and a known oncogenic driver mutation. Analysis of TCGA data demonstrated a worse overall survival for patients whose tumors have MDM2 copy number 12 or greater with wild-type TP53, highlighting the unmet need in this patient population. We presented a population analysis of over 50,000 patients with solid tumors across the AACR Genie and TCGA databases. which confirmed the presence of MDM2 copy number 12 or greater with wild-type TP53 in 1.2% of all cancer patients. Second, Dr. DiCaprio's group at Dana-Farber presented preclinical data last month at the Second International Symposium of Merkel cell carcinoma, demonstrating robust activity of niladiametanin in in vivo PDX models of Merkel cell. This preclinical data supports our upcoming Mantra 3 study. Third, RAINN will present an abstract of the upcoming ASCO annual meeting in Chicago relating to the patient population eligible for the upcoming Mantra 4 clinical study. In addition to tumor-specific frequencies of CDKN2A loss in the setting of wild-type TP53, RAINN plans to present new data supporting the rationale behind our first combination trial of noledatatin and atezolizumab. Finally, we remain excited about RAD 52 as a synthetic lethal target, and internal research efforts at RAINN are ongoing to advance this program. And with that, let me now turn it over to Nelson to review our financial results. Nelson?
spk03: Thank you, Bob, and good afternoon, everyone. I'm pleased to provide an update to our financial results for the first quarter ended March 31, 2022. I would also like to invite you to review our Form 10-Q file today for more details. For the first quarter of 2022, we reported a net loss of $17.4 million compared to a net loss of $6.8 million in the first quarter of 2021. Research and development expenses were $13.6 million in the first quarter of 2022 as compared to $5.3 million in the first quarter of 2021. The increase was primarily driven by R&D costs, mainly for our lead candidate, melidematin, from the ongoing Phase II Mantra clinical study, or ongoing Phase II Mantra II study, as well as personal costs. General and administrative expenses were $3.9 million for the first quarter of 2022, compared to $1.5 million for the first quarter of 2021. The increase was primarily driven by higher third-party G&A costs, including personnel, insurance, legal, accounting and audit, and outside consulting fees. As of March 31, 2022, RAINN had $123.2 million in cash, cash equivalents, and short-term investments. And we anticipate that our 2022 year-end cash position will provide runway in the first half of 2024. We expect our Melodematon clinical program to be well-funded. With that, I'll now turn the call back to Avinash.
spk08: Thanks, Nelson. Again, our focus with the milodimetan program has been on clinical execution. We're very happy with our rate of progress thus far. With the anticipated start of the Mantra 3 and Mantra 4 studies by year-end, on top of the ongoing progress of both Mantra and Mantra 2, RAINN anticipates a broad clinical effort for milodimetan with a steady cadence of updates over the next two-plus years. In particular, for our Phase 3 Mantra study, We highlighted rapid enrollment in liposarcoma and top-line data anticipated in the first half of 2023, earlier than previously guided. Overall, the RAIN team is poised to generate significant new data from meledimetan that will potentially lead to a new targeted therapy for cancer patients. With that, we'll turn it back to the operator to take your questions.
spk02: We will now begin the question and answer session. To ask a question, you may press star then 1 in your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press Start and 2. At this time, we will pause momentarily to sum up our roster. Our first question will come from Corin Jenkins with Goldman Sachs. You may now go ahead.
spk06: Corin Jenkins Good afternoon, everybody. So I think you're expecting to have 10 patients and previously have been guided to a response rate of about 30% in the phase 2 update later this year. And so I'm curious, what would you anticipate based on precedent or whatever else you can think of for the FDA to require to support an accelerated approval with just the phase 2 single arm? What kind of cohort size are you expecting there?
spk08: Hi, Corinne. Thanks for the question. Let me turn that question over to Bob. And just to reiterate the question, I believe the question was what type of cohort size for Mantra 2, the tumor agnostic basket study, do we think would be appropriate for a registrational effort? Is that correct?
spk06: Correct. Assuming you have 10 patients and that they're even percent ORR that I think you've previously guided to.
spk07: Yeah, sorry, 10 patients and the previous, what was the second part of that?
spk06: I think previously you've all said that 30% ORR is a reasonable expectation for that update, and so assuming that's kind of in the range of where you come, what should we expect for cohort size based on what you've seen the FDA do previously? Okay.
spk07: Let me first, I guess, answer. So, you know, in terms of cohort size needed for an accelerated approval, you know, we can obviously look to prior examples. So there are previous targeted therapies that have gotten accelerated approval in a diagnostic setting with approximately 50 to 60 patients. Obviously, that depends on the magnitude of the benefit and response rate and other things. I think we previously said... that in terms of what is expected of an approvable agent in the agnostic setting, currently the bar is set by a prior example again with pembrolizumab and MSI high with a response rate of 40%. But we are following closely other targeted therapies that are seeking agnostic approvals and we will follow that data closely. In terms of clinical meaningfulness, typically patients with later line therapeutic options such as chemotherapy only experience response rates in the perhaps 8% to 12% range. And so the bar for clinical meaningfulness may be quite a bit lower than that 40%, which is the current lowest example of an agnostic approved drug.
spk06: Okay, but then, I guess, is there a cohort size? It sounds like 50 would be kind of the best case scenario, but is there a cohort size or some sort of requirement that would be prescriptive as you think about the future development in this particular indication, or is it just a plan to go forward and have a little more visibility on what the FDA requires?
spk08: Sorry, Corinne, we're getting a lot of background noise from your audio, so we're trying to make out the entirety of the question.
spk06: Yeah.
spk08: But, yeah.
spk06: Sorry, I'm at the airport. You need me to repeat.
spk08: So size of the cord, if we have a 30% response rate, duration of response in excess of five months, which is kind of what we think is clinically meaningful responses, we would expect the cord size to expand to maybe in the 90 to 120 patient range.
spk06: Okay. Helpful. Thank you.
spk02: Our next question will come from Sumit Roy with Jones Research. You may now go ahead.
spk05: Hi, thank you for taking the question. And congratulations on progress on multiple fronts. One quick question on the MONSRA trial, the FADE-THROUGH trial. Are you looking into any biomarker to detect if there is any resistance mechanism going on, akin to cal-binding that your peer have alluded, if that could cause a reduction lower clinical benefit.
spk08: Hi, Simon. Thanks for the question. And that question was regarding clinical biomarkers for the Mantra 2 study, correct?
spk05: For the Mantra trial in liposarcoma in the phase 3, just thinking ahead, if you see less than predicted clinical benefit, are you looking at cal-binding or this kind of biomarkers to see if they're a certain subgroup is kind of pulling back the entirety of the data set.
spk04: Hi, it's Richard Bryce here. So for the ongoing management study, we do have, we're looking at MIK1, which is a surrogate biomarker moving forward. And the biopsies that we have will be going for central testing for MDM2. potentially downstream, but essentially that's all we're looking at in the context of Mantra, which is a kind of real-world study moving forward.
spk05: Okay, got it. And a quick question on Markov cell carcinoma. Do we know the incidence of what percent patient expressed MDM2 copy number greater than 12, akin to that bar graph you have presented for other indications?
spk08: Yeah, so Merkle cell doesn't have MDM2 gene amplification as far as we know. There's protein overexpression. So the polyomavirus in Merkle cell leads to greater protein production, but not necessarily due to gene amplification.
spk05: I see. And is that the same case with the CDN, CDK, N2 mutant patients also? It's more the overproduction rather than gene amplification?
spk07: Thanks for that question. This is Bob Doble. Yeah, it's a slightly different mechanism. So here, the main mechanism of MDM2 dependence and CDKN2A loss is that CDKN2A encodes a negative regulator of MDM2. So loss of CDKN2A leads to increased activity of MDM2. So all the same idea in terms of MDM2 dependency but not not through necessarily overexpression or genetic amplification of NBM2.
spk05: Got it. Thank you again for taking the question.
spk08: Thank you.
spk02: Our next question will come from . You may now go ahead.
spk00: Hi, this is Carly on for . Thank you for taking our questions. We have two questions. First, can you talk about how patient identification and enrollment for Mantra 2 are tracking relative to your initial expectations? I think you had laid out expectations for about a 1% positivity rate for the MDM2 copy number greater than 12. And then the second question is on liposarcoma. We saw that Boehringer Ingelheim had started a phase 2-3 for their MDM2 inhibitor where they're going straight into the frontline setting, head-to-head versus chemo. So we wanted to get your thoughts on that strategy and if Montra works, if you would consider a similar study to move milidimetan into the frontline. Thank you.
spk08: Thanks, Carly. Let me start with the second question first. I'll address the burning alarm study. So I think one thing to point out with the BI program is the phase 2-3 strategy is meant to first pick a dose. So there's a couple of arms to identify the appropriate dose before moving into the phase three component of their trial. So the phase two, three is still going to be aimed at determining the appropriate dose to carry forward. But the second part of your question is, if we see success in Mantra, would we look at the first line setting? I think it would be reasonable to assume that we would evaluate that opportunity. And in terms of the first question that you asked about... That's Mantra 2 patient tracking.
spk07: Yeah, so this is Bob Doble. So in terms of Mantra 2, we are definitely confirming that 1%, actually closer to 1.2% of all patients have this, and we are seeing these genetically identifiable patients. And as we've said, enrollment remains on track for Mantra 2.
spk00: Okay, great. Thank you very much.
spk02: Again, if you have a question, please press star then 1. Our next question will come from Michael Schmidt with Guggenheim Securities. You may now go ahead.
spk01: Hi, guys. Good afternoon. This is Ige. I'm for Michael. Thanks for taking our questions. We have two questions. The first one on Mantra. Congrats on the progress. Just wondering, is the earlier than expected top line primarily driven by faster than expected enrollment in the U.S. or ex-U.S.? And also, could you confirm there's no changes on the assumption on progression rates? And second question on Mantra 2, how should we think about the tumor reduction kinetics, I mean, based on previous data? Would one expect response to happen earlier, for example, in the first two cycles, or this could be later on? Thank you.
spk08: Thank you, Gary. Let me ask Richard to comment on the first question for the mantra enrollment, and Bob on the second for mantra two. Richard?
spk04: Sure. So I think your question was asking about... no contribution to enrollment essentially per mantra US or ex-US. It's a global study and I think it's fair to say the contribution has been, you know, across the board. So I wouldn't select one geography over another in terms of enrollment. I think what it does do is, you know, validate the unmet need out there and the requirement for treatment for this particular indication. I think the second part of your question related to assumptions around the PFS rate, have there been any changes to that? And the answer is no. The protocol remains unchanged from the outset.
spk07: And regarding the second question in terms of response kinetics in the Mantra 2 study, I'd say looking at the Phase 1 data, which was mostly either in liposarcoma patients, which don't have a high response rate, and unselected non-liposarcoma patients. We just simply don't have enough data to make an estimate on response kinetics. I can say that we have seen rapid responses in some cases, but not enough to really determine what's expected and whether it will be similar to tyrosine kinase inhibitors that typically show response at the first scan. We just don't know yet.
spk01: Great, thank you.
spk08: Thank you, Gary.
spk02: This concludes our question and answer session. I would like to turn it back over to Avanish Vallanki for any closing remarks.
spk08: Well, we want to thank everyone for joining us on today's update, and we look forward to providing an update on the second quarter call. Thank you.
spk02: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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