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spk05: Today's conference is scheduled to begin shortly. Please continue to stand by and thank you for your patience. Thank you. Thank you. Thank you. Good day. And thank you for standing by. Welcome to the Business Highlights conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star 1 on your telephone. Please be advised this call is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your host today, Christy Grabowski. Please go ahead.
spk00: Thank you, Operator, and good afternoon, everyone. With me today on the phone are Avinish Vallanki, Chief Executive Officer, Robert Doble, Chief Scientific Officer, Richard Bryce, Chief Medical Officer, and Nelson Kebatawan, Senior Vice President, Finance. During today's call, Avinish will provide an overall business update. Richard will provide an update on RAINN's clinical programs. Bob will provide an update on research efforts, and Nelson will review the financials. Before we begin, I'd 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. Factual 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, March 3rd, 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?
spk03: Thank you, Christy, and thanks to everyone for joining us for our fourth quarter earnings call. In this most recent quarter and since the end of 4Q, RAIN continues to advance the Melodematan program with two clinical trials currently active and enrolling. and two additional clinical trials planned. As a reminder, we may refer to milidimetan as Mila on occasion. First and foremost, our phase three trial, the Mantra study for Mila in patients with liposarcoma is proceeding according to plan with sites being activated on a regular basis around the world. At the end of 2021, we exceeded the number of site activations that we had articulated as a goal and continue to be on pace for all sites to be up and running by the end of the first quarter of this year. As a potential registration-enabling study, there is no interim read with final data anticipated in 2023. Richard will provide some more color here. Second, in November of 2021, we announced that the first patient had been dosed in the phase two tumor agnostic Mantra 2 study. This trial will evaluate MILA in a signal finding basket trial across approximately 65 patients in the U.S. with solid tumors that exhibit strong MDM2 gene amplification. We anticipate to reveal early data from this trial in the second half of this year. Third, we announced the Mantra 3 study in the fourth quarter and articulated that it will be focused on patients with Merkel cell carcinoma that test positive for the Merkel cell polyoma virus. The majority or up to 80% of Merkel cell carcinomas are induced by a virus. This virus induces MDM2 protein overexpression and is P53 wild type. We'll enroll second line patients relapsing to checkpoint inhibitors where there is an immense unmet need. We now anticipate this trial to start in the second half of this year, gated upon progress of our first two trials so that we may better control the timing of expenses as we strive to maintain our fiscal prudence. Finally, for our fourth trial for meledimetan, which we are calling the Mantra 4 study, Ray intends to combine meledimetan with Roche's PD-L1 monoclonal antibody atezolizumab in our first combination trial. This initial combination trial has a goal of confirming an appropriate combinatorial dose for the two agents and evaluate the safety, tolerability, and efficacy of this combination in a cancer population that could exceed 35,000 patients per year in the U.S. The MONTRA-4 study will represent another tumor-agnostic basket trial, this time in patients with P53 wild-type cancers that have lost function of the gene CDKN2A. The Mantra 4 study is anticipated to commence in the second half of this year. We also held an R&D day in November of 2021, which featured several key opinion leaders in oncology, along with members of RAIN's management team, who discussed the company's R&D program, as well as select clinical and preclinical data. We encourage interested parties to review the materials on our website. While we continue to focus on the most sensitive MgA2-dependent cancers, and have outlined four distinct strategies for milodimetan, it's perhaps key to emphasize that our cash balance is sufficient to complete all of these trials and should help inform the best manner to deploy future investment into the milodimetan franchise. We're very excited about the potential for a range of opportunities for Mila having a meaningful impact on patient care. Regarding our research program for inhibitors of RAD52, the preclinical work continues to move forward and we're very excited to note substantial improvements in both potency and selectivity of rain-generated compounds versus the initial set of compounds we acquired from our licensing efforts. However, in order to prioritize our resources on the Melodematan clinical trials to ensure ample cash cushion for the key data inflection points, And in light of what the BATCA capital markets have been doing, we will moderate the pace of expansion for the RAD52 effort. We plan to update investors on next steps for this program as details become available. With that, I'd like to turn it over to our Chief Medical Officer, Dr. Richard Rice.
spk07: Thank you, Avinash. And good afternoon, everyone. Following on from our last earnings call in November 2021, where we announced we are progressing with site activations throughout the U.S. and rest of the world, for a pivotal phase 3 mantra study of milidimetan compared to trabectin in dedifferentiated liposaccoma, I can report that we were ahead of expectations for site activations at the end of the year 2021, and we anticipate having all sites activated before the end of this month. Patient enrollment continues as expected. As a reminder, this pivotal trial will compare milidimetan monotherapy at our preferred dose of 260 milligrams and three-out-of-14-day schedule to the approved agent Yondellis or Trebectin, which has a published median progression-free survival in a de-differentiated liposucoma patient population of 2.2 months. In the prior 107-patient clinical trial at Milodermatan, in which 53 patients with de-differentiated liposucoma were enrolled, the lowest median PFS observed was 6.3 months. At our preferred dose and schedule, a median PFS of 7.4 months was observed, representing a greater than three-fold improvement versus trabectodon. Our phase three trial is powered to show a doubling of benefit. We anticipate final data in 2023, but we'll refine that guidance as we move through enrollment. I am pleased to announce that the first patient was dosed in our second trial, the Mantra 2 basket trial in November. The Mantra 2 study is currently planned to run only in the United States, and all primary sites are expected to be activated by the end of this month, with additional just-in-time sites being opened as necessary from referrals from the Tempus and Karas Genomic Testing Services. This trial is open to patients with tumors that are p53 wild type and have a specific threshold of MDM2 amplification. As previously reported, we have defined MDM2 amplification for the purposes of the clinical trial as a minimum gene copy number of 12. And as discussed in the third quarter call, this threshold was chosen because the high gene amplification at these levels has been shown to essentially exclude concomitant P53 mutations, thereby ensuring MDM2 as the oncogenic driver in these tumors. We anticipate enrolling 65 patients across a range of solid tumors, and the treatment protocol is the same as in the registrational MANTRA trial. That is, with milidimethan dosed at 260 milligrams orally once daily for three consecutive days out of 14. We anticipate an interim analysis and early data readout in the second half of this year. Also, as announced in November, we plan to evaluate the efficacy of milidimetan as a monotherapy for the treatment of patients with Merkel cell carcinoma in the second-line setting, i.e., for patients who are refractory or resistant to immune checkpoint inhibitor, which we call the Mantra 3 trial. We note MDM2 inhibition appears to have gained validation in the Merkel cell carcinoma based on other programs, whereas we believe the improved tolerability of milidimetan may offer improved responses and durability. In the second line setting, post-checkpoint inhibitors, the commonly used chemo doublet of carboplatin etoposide exhibits very short durability of response, and no survival benefits has been published from treatments in this setting. We anticipate commencing the Mantra 3 trial in the second half of this year. And we believe this indication has a high probability of a favorable outcome. At the beginning of January, we announced plans to conduct a phase one clinical trial, mantra four, to evaluate the safety, tolerability, and efficacy of milidimetan in combination with Roche's atezolizumab in patients with advanced solid tumors with loss of CDKN2A gene function and wild type P53. We'll talk more about the mechanism shortly. This will be a dose de-escalation study design where we will start at the full doses of both milidimetan, again, the 260 milligrams on three out of 14-day schedule, and the approved dose of atezolizumab or Tocentric on the Q4 week schedule. We will reduce the dose of milidimetan if we observe a dose-limiting toxicity. However, as we would not anticipate any overlapping toxicity between milidimetan and the tezolizumab, this trial could effectively become a 30-patient efficacy signal-finding basket trial across a range of solid tumor types. We're anticipating starting Mantra 4 in the second half of this year. Upon a favorable safety signal, subsequent Phase II clinical trials may evaluate combination of milidimetan and the tezolizumab in various additional tumor types. To conclude, we have outlined four clinical trials for milodermatin led by the flagship Mantra Pivotal Phase III trial in liposucoma. The Mantra II and Mantra IV trials reflect unique basket study approaches, and with Mantra III and Merkel cell carcinoma representing an important unmet medical need. We look forward to presenting some data later this year from the MANTRA2 basket study. And the MANTRA3 and MANTRA4 trials will start in the second half of this year. Let me now turn it over to our Chief Scientific Officer, Dr. Bob Doval. Bob.
spk04: Thanks, Richard, and good afternoon, everyone. Since acquiring milidimetan in September 2020, RAIN's team has been working diligently to identify and validate the most relevant cancer populations for this MDM2 inhibitor. Our work has recently culminated in the presentation of multiple abstracts at conferences in October 2021, including the AACR-NCI-URTC Virtual International Conference on Molecular Targets in Cancer Therapeutics, highlighting important preclinical collaborations with researchers around the world. We also hosted our first RAINN Research and Development Day in November 2021. This event featured both clinical and research experts who highlighted multiple opportunities for the use of milodamatam in different tumor settings where MDM2 plays a critical role. These presentations provide support for RAIN's clinical strategy and prioritization of de-differentiated liposarcoma, an MDM2-amplified agnostic tumor strategy, and Merkel cell carcinoma. These presentations also help to provide the basis for exploration of clinical trials and other indications such as breast cancer and other larger cancer populations. More recently, we were excited to announce an initial phase one clinical trial, Mantra 4, as part of a new collaboration with Roche for the supply of atezolizumab or Ticentric. As Avinash stated, the Mantra 4 trial is anticipated to enroll patients with any solid tumors harboring CDKN2A loss and wild type T53. CDKN2A encodes for the tumor suppressor P14-ARF, an inhibitor of MDM2, and the loss of CDKN2A may lead to MDM2-dependent cancers. CDKN2A alterations are very frequent in cancer. Loss of CDKN2A occurs in the context of wild type P53 in more than 35,000 patients per year in the United States. Preclinical data in a large array of cell lines demonstrates that using only the genetic selection criteria of CDKN2A loss and wild-type TP53 predicts for milidamotan sensitivity. In vivo data demonstrate milidamotan-induced tumor growth inhibition in several tumor xenograft models with CDKN2A loss. Notably, a syngeneic tumor model with CDKN2A loss shows the exciting potential of milodimethan combination therapy. The combination of milodimethan with a checkpoint inhibitor demonstrated significantly improved activity versus either agent alone. We also note clinical reports showing checkpoint inhibitor resistance in tumors with CDKN2A loss. We believe reactivation of p53 by MDM2 inhibition will enhance immune surveillance. The Mantra 4 trial is anticipated to commence in the second half of this year. Subsequent phase 2 clinical trials evaluating the combination of milodimetan and atezolizumab may span various additional tumor types. And with that, let me now turn it over to Nelson to review our financial results. Nelson?
spk10: Thank you, Bob, and good afternoon, everyone. I am pleased to provide an update to our financial results for the fourth quarter and full year 2021. I would also like to invite you to review your Form 10-K file today for more details. For the fourth quarter of 2021, we reported a net loss of $18 million compared to a net loss of $5.4 million in the fourth quarter of 2020. Research and development expenses were $14.7 million in the fourth quarter of 2021, as compared to $4.2 million in the fourth quarter of 2020. The increase was primarily driven by R&D costs, mainly for lead candidates from the ongoing Phase III pivotal mantra clinical trial or ongoing Phase II tumor agnostic basket trial or mantra II, as well as personal costs. General and administrative expenses were $3.4 million for the fourth quarter of 2021, compared to $1.3 million for the fourth quarter of 2020. The increase was primarily due to higher third-party G&A costs, including personnel, insurance, legal, accounting and audit, and outside consulting fees. For the full year 2021, we reported an up loss of $51.4 million compared to an up loss of $21.1 million in 2020. R&D expense is the main driver of our overall spending. R&D expenses were $40.8 million in 2021 as compared to $15.4 million in 2020. The increase was primarily driven by cost mainly for milidimethan from the ongoing Mantra and Mantra 2 clinical trials, as well as personal costs. We completed an IPO in late April 2021, which generated net proceeds of 121.5 million. As of December 31, 2021, RAINN had 140.2 million in cash, cash equivalents, and short-term investments. And we anticipate that our 2021 year in cash position will provide runway in the first half of 2024, including completion of all our ongoing and planned clinical trials with an ample cash cushion for the phase three mantra data timeline in liposarcoma. With the current capital markets condition in the biotech industry, we will continue to be more prudent with capital to prioritize data generation for melatonin across a diverse set of cancers. With that, I'll now turn the call over back to Avnish.
spk03: Thanks, Nelson. Without a doubt, the current capital markets environment for biotech signals for many companies that further financing may be challenging. And at Rain, we are comfortable with that based upon the strength of our balance sheet. Rain has been built around efficient trial designs and lean operations. We will continue to make efficient use of our capital resources in order to achieve key value inflection points for our company and our shareholders. With that, we will turn it back to the operator to take your questions.
spk05: And thank you. As a reminder to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. And our first question comes from Yagal Nachumovitz from Citigroup. Your line is now open.
spk09: Hi, guys, thanks for taking the question. Just a question on the atezo combo. Just wondering, was there any scientific reasoning behind picking a PD-L1 as opposed to a PD-1? Does it matter which way you do that when you combine with milodentam? Thanks.
spk03: Hi, Egon. Thanks for the question. I'll hand it over to Bob.
spk04: Yeah, thanks for the question. At this time, no, we see no significant scientific differentiation between PD-L1 and PD-1 or significant differences in clinical activity. So at this time, we don't see a reason to distinguish between the two for the purposes of the combination trial for Mantra 4.
spk09: Okay, gotcha. And then, Avani, since you're beating the targets on site activation for Mantra, Just curious if you're able to narrow down at all whether we're going to get the top line in the first or second half of next year.
spk03: Yeah, it's a great question. We're not going to refine the guidance just yet. We will do that when we can, but we're not doing that just yet.
spk09: Okay. And then one other question, I want to get your thoughts on the competitive data from Chimera's MBM2 degrader, the KT253. I'm assuming you saw the latest slides where they're showing some data in comparison to the MBM2 T53 small molecule inhibitors. They're arguing that MBM2 degradation is a better approach than inhibition. I'm just curious if I could get your thoughts on that. Thanks.
spk03: Yeah, happy to address that. And I think, first of all, it certainly does further validate that MDM2 is a target of interest and certainly has broad utility. So we're not surprised that we're seeing other competitors enter the space, and we certainly weren't surprised to see them you know, benchmark their early data against the milodimetan program. So, let me hand it over to Bob to talk through mechanistically in terms of the degrader approach versus our approach. Bob?
spk04: Yeah, thanks for the question, Ingal. In terms of the degrader approach, you know, obviously this is, you know, a potential way to inhibit MDM2. At RAINN, we still feel that one of the central problems of MDM2 inhibition, which we believe that we have solved with our dosing strategy, is the on-target toxicity that comes with MDM2 inhibition in normal cells, such as hematopoietic precursor cells. And it's not clear that a degrader strategy addresses that on-target toxicity. I think, as you know, the molecule that we're working with, RAIN32 or miladamotan, is actually quite potent at inhibiting MDM2.
spk09: Okay, thanks. And then, regarding the cash preservation, Abhinish, any more details on the steps you're taking there to preserve the cash?
spk03: Yeah, you know, I think the call that we can provide is we've, of course, always maintained a pretty close eye on their cash burn. You know, one of the comments that we did make was that we minimized the expansion of the headcount of the company as one of the ways that we're moderating expense where we're still a modestly sized company as a phase three entity. You know, we're still a very small physical footprint in terms of real estate relative to comparable companies. And all of our studies, right, all of our studies are rather modest in size. So they don't require a level of cash burn, you know, that we see typical in the biotech space. And the gating mechanism, right? So we have, we've announced the subsequent two studies, mantra three and four. We have a tremendous amount of control in terms of when we flip the switch. And we want to flip the switch and turn those on at a time when we know that we have a clear line of sight towards final data for Mantra so that we preserve the integrity of completing that study with an ample amount of cash cushion. So the amount of control we have in turning on various expenses is essential.
spk09: Thank you very much.
spk05: Thank you. And our next question comes from Michael Schmidt. from Guggenheim Security. Your line is now open.
spk06: Hey, good afternoon. This is Ige on for Michael. Congrats on the progress and thanks for taking our questions. I guess a quick one from us. According to some recent literature, CDK and 2A sometimes code deleted with MTAP. So first of all, do we know how frequent is the code deletion and In that case, how would targeting CDKN2A through MDM2 inhibition, you know, position relatively to, you know, some of the other strategies to target MTAP deletion? Thank you.
spk03: Thanks for the question, Yige. Let me turn it over to Bob.
spk04: Yeah, thanks for the question. the co-deletion of MTAP with CDKN2A is thought to be incredibly frequent, probably approaching 100%. It's actually the next adjacent gene to CDKN2A, so it is probably co-deleted in the vast majority, if not all, CDKN2A loss tumors. I think the relative contribution of the two genes is still being worked out, and whether MAT2A or PRMT5 inhibitors may have potential effect in CDK into ALOS tumors, or if there are other criteria that need to be factored in, it still remains to be known. But we have been thinking about this question with regard to CDK into ALOS and the use of our milodatantin in our pre-clinical research program.
spk06: Got it. That's helpful. Thank you.
spk05: Thank you. And our next question comes from Joe Catanzaro from Piper Sandler, your line is now open.
spk08: Perfect, thanks guys for taking my questions here. Maybe the first one on Mantra 2, I'm wondering if you could speak to the early experience around screening and identifying patients with MDM2 amplification and where expectations are currently for the interim readout expected later this year in terms of number of patients and extent of follow-up. Thanks, and I have a follow-up.
spk03: Thanks, Joe. Let me turn that one over to Richard.
spk07: Hi, Joe. Thanks for the question. So Mantra 2, as you recall, we kicked off in November of last year, first site activated, first patient in. We're still in the process of activating sites, so it's still very early in the game here. Most of the sites really won't be open until the end of this month, so it's still a little bit early to comment on that and the distribution tumors and other things that are sort of implicit in the question that you asked. I think generally in terms of what data we're going to be able to share towards the end of the year, our expressed opinion is that we hope to come up with a data set of somewhere around 10 to 12 patients with a meaningful duration of follow-up. In other words, you know, four or five months, something of that order. So that's what we're aiming to do, and we're tracking towards that at the moment. That's as best as I can answer at this time.
spk08: Okay, thanks. That's helpful. And then to follow up on Mantra 4, so Richard, you mentioned the dose de-escalation. sort of built-in design there. I'm wondering if you could speak to maybe what gives you confidence that you could achieve the full monotherapy doses for each and whether the FDA needs to sign off on this design given maybe their recent push around identifying the minimally effective dose. So I'm not sure if that applies to combination strategies as well. Thanks.
spk07: Sure, no, that's a fair question. So I'll answer the second part first, which is that we will obviously submit the protocol to the IND and the FDA will have the opportunity to comment, but we don't explicitly need, you know, FDA buy-in to the design. That's something that, you know, we do at risk. The precedent has already been set. I'm sure you're well aware of the previous study with an MDM2 inhibitor has been run with a checkpoint inhibitor following a very similar process. They had a dose escalation, but actually ended up with a full dose of both the checkpoint inhibitor and the MDM2 inhibitor. And I think, you know, given what I said before in the introduction here, there are no overlapping toxicities. We wouldn't expect any reason to de-escalate with Atezo, you know, compromising the tolerability, if you like, of or vice versa. So we're very confident that, you know, we can save time, effort, money, and patience by going in at the top dose of the standard monotherapy doses and see what happens, take it from there.
spk08: Okay, got it. Thanks for taking my question.
spk05: Thank you. Thank you. And our next question comes from Corinne Jenkins from Goldman Sachs. Your line is now open.
spk02: Hi, this is Nancy. Thank you for taking our question. On Mantra 2, I wanted to ask about what your plans would be to revise both the data if you would be able to go to FCA to see about the registration in time. And also, are you thinking about expanding the specific cohorts there?
spk03: I don't think we got the first part of the question. I think we can address the second part. The second part we heard is how we're thinking about expanding to additional tumor types or cohorts there. Let me turn that over to Richard to talk about the second part, and then maybe we'll have you repeat the first part of your question.
spk07: Richard? Sure. So thanks, Karim, for the question. And regarding the second part, so the study as it's currently designed, as I think we're well aware we've announced before, is 65 patients. We have a cap on the number of in any particular tumor type that comes in, and that's around 12 or so. And so really what we'll be looking at, first of all, we're setting off on a tumor agnostic approach. We would expect and hope to see similar responses across all tumor types given the mechanism of action. There shouldn't really be any differentiation between them. But it will give us an opportunity as the data accumulates to see whether there is, you know, greater successes, greater responses, greater durability of responses in some types and others that may give an indication to sort of move forward than one particular strategy or one particular sort of tumor type or basket of tumor types within that. But I think the, you know, the beauty of this particular trial design is that it gives the opportunity to look at if you get suboptimal responses, you can look at combination strategies, you can look at building in other things, for example, You know, CDK and N2A deletions on top of that as a separate cohort. There's all sorts of ways you can play this game within the sort of construct of the basket study as it stands. So there's many, many opportunities, and I think it's just a question of waiting to see where we are, you know, towards the end of the year and into 2023 as data matures and see what we're actually seeing.
spk03: Can we have you repeat that first part of the question?
spk02: Yeah, so I was asking about the regulatory plan for the Mantra 2 trial, both the safety data, if you would be looking to go to FDA, talk about the registration study.
spk03: I think I heard what quality of data would we look from the Mantra 2 study to go to the FDA as compelling. Bob, would you like to talk about that?
spk04: Yeah, yeah. So we've thought a lot about, you know, what would be compelling efficacy data in the context of an agnostic or basket study. When we initially designed Mantra 2, we thought that the benchmark for success based on the limited data of agnostic approved drugs, which include two TKIs and a checkpoint inhibitor. The checkpoint inhibitor demonstrated a response rate in the range of about 40% in the basket study. And so our study was designed to achieve a 40% response rate with a lower boundary of confidence interval of 25%. Since that time, I think there are programs that are developing that we believe may have lower response rates and may be meaningful. And in fact, when we think about therapies for late-line cancer patients where single-agent chemotherapies are or typically the standard of care and response rates may be as low as single digit percentages or perhaps low teens, we think that that bar could be substantially lower than 40%, but that's how we've been thinking about that trial and efficacy that we'd need to see. And of course that would need to be coupled with reasonable durability as well, probably in the range of five to six months.
spk03: Did that answer your question?
spk02: Yeah, thank you.
spk05: And thank you. And I'm showing no further questions. I would now like to turn the call back over to Avanis Vellonke for closing remarks.
spk03: Well, thank you, everyone, for dialing in for the fourth quarter earnings results. We look forward to providing an update shortly at the end of the first quarter of 22. Thank you.
spk05: As a reminder, this concludes today's conference call. Thank you for participating. You may now disconnect.
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