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spk05: Your conference call shall begin momentarily. Again, thank you for saying goodbye. Your conference call shall begin momentarily. Thank you. Thank you. Thank you for standing by, and welcome to the Reign Therapeutics Third Quarter 2021 Financial Results 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 at that time, please press star then 1 on your touchstone telephone. As a reminder, today's conference call is being recorded. I will now turn the conference over to your host, Mr. Bob Yedit, for you may begin.
spk10: Thank you, Operator, and good afternoon, everyone. With me today on the phone are Avinash Valanki, Chief Executive Officer, Robert Doble, Chief Scientific Officer, Richard Bryce, Chief Medical Officer, and Nelson Kabat-Toon, Senior Vice President of Finance. During today's call, Avinash will provide an overall business update. Richard will provide an update on Rand's clinical program. 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 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 on RAINN's current expectations and involve assumptions that may never materialize or prove to be correct. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties as described in RAINN's quarterly report on Form 10-Q for the quarter ended March 31, 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. RAINN undertakes an obligation to update such statements to reflect events that may occur or circumstances that exist after today, except as required by law. With that, it's my pleasure to turn the call over to nomination Filanki, CEO of RAINN. Avinish?
spk02: Thank you, Bob, and thanks to everyone for joining us for our third quarter earnings call. As a matter of principle for these earnings calls, we're going to make it standard practice to be very brief, and we'll leave it to the Q&A to address the details that are of the most interest. In this most recent quarter and since the end of the third quarter, RAINN continues to advance the Mila Demetan and RAD 52 programs forward. As a reminder, we'll continue to refer to milodimetan as MILA wherever appropriate. 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. 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, we also expect to dose our first patient in the Phase 2 tumor-agnostic Mantra 2 study shortly, and we'll announce that when it happens. This trial will evaluate Mila in a tumor-agnostic signal-finding basket study across 65 patients in the U.S. with solid tumors that exhibit a certain threshold of MDM2 gene amplification. We expect to provide an interim update for Mantra 2 in the second half of next year. Third, we announced that we will reprioritize our clinical strategy for our third planned study towards Merkel cell carcinoma, replacing our prior planned study of intimal sarcoma. This new trial will be called Mantra 3. The decision to prioritize Merkel cell was made for three key reasons. One, new non-clinical data presented by the Dana-Farber Cancer Institute demonstrating compelling efficacy for meledematans. which already adds to the biologic rationale that many Merkel cell tumors are MDM2 dependent. Two, we note there's already been presented signs of activity with MDM2 inhibition in Merkel cell from other MDM2 inhibitor programs. And three, the larger addressable market size of Merkel cell as compared to intimal sarcoma, hence representing the most appropriate use of our financial resources. Based on the larger population of Merkel cell, faster projected patient accrual rates and an expected shorter trial duration, the new planned Merkel cell study has no significant impact on RAIN's cash runway. We expect Mantra 3 to enroll 34 patients in the U.S. in the second line or later settings amongst patients relapsed to checkpoint inhibitors, which is the standard of care in the front line. And we expect to start the study in the middle of 2022. Finally, we held an R&D day yesterday where we hosted several prominent key opinion leaders across various treatment specialties where we think MDM2 inhibition could be applied. Speakers included Dr. Wafiq El-Diri from Brown University, who many of you may know for his discovery of P21, Drs. Murnal Gounder and David Hong from Memorial Sloan Kettering and MD Anderson Cancer Centers, respectively, who will be participating in RAINN's first two clinical studies for MELF, and Drs. Glenn Hanna and James Sid Caprio from Dana-Farber for their expertise in Merkel cell carcinoma. We also included talks from Drs. Francois Clement Bedard and Silvia Stacchiati, who shed light on some additional clinical opportunities for MILA. Our strategy continues to be to focus our early effort on the most sensitive MDM2-dependent tumor types first, and will be followed by combination strategies to further enhance patient outcomes and other P53 wild-type cancers. We're very excited about the potential for a range of opportunities for Mila to have a meaningful impact on patient care. Last, the early preclinical workaround programs targeting RAD52 continues to move forward, and we expect to provide updates at future scientific symposia as appropriate. With that, I'd like to turn it over to our chief medical officer, Dr. Richard Bryce.
spk14: Thank you, Evan. And good afternoon, everyone. Following on from our last earnings call in August, where we announced a start to our pivotal Phase III Mantra study, indeed differentiated liposucoma, we are progressing with site activations throughout the U.S. and Europe, anticipating approximately 30 sites to be opened by the end of the year, with the remaining 45 sites in Europe, North America, and certain Asia-Pacific countries coming on stream before the end of the first quarter of 2022. Patient enrollment continues as expected. I am pleased to announce today that our second trial, the Mantra 2 basket study, is now active and open to enrollment. We will make a separate announcement when the first patient is dosed. We expect that the Mantra 2 study will ultimately be opened in a total of approximately 10 sites throughout the United States, with additional just-in-time sites as necessary from the Tempus and Karras referrals. The study is open to patients that are P53 wild type and MDM2 amplified with a minimum gene copy number of 12 or a six-fold increase in copy number by local testing methods. As we previously discussed, this threshold is chosen because the high gene amplification at these levels has been observed to exclude P53 mutations. thereby ensuring MDM2 as the oncogenic driver in these tumors. As well as the in-house genomic screening at the selected U.S. sites, we have partnered with Tempus and Carus for referral of patients meeting these particular criteria. The study aims to enroll 65 patients across a range of solid tumors, and the treatment protocol is the same as in the registrational mantra study. That is 260 milligrams orally, once daily, for three consecutive days out of 14. And as we previously advised, we anticipate an interim analysis and data readout in the second half of next year. As Avanish mentioned, we have deprioritized our intimal sarcoma program to focus on the opportunity in Merkel cell carcinoma in the second-line setting, following immune checkpoint inhibitor therapy. The incidence of this aggressive skin cancer in the U.S. is estimated to be around 3,000 patients in 2020 and is rising year on year. Between the years 2000 and 2013, we note there was a 95% increase in reported cases. And this compares to 57% growth rates for melanoma and 15% for all solid tumors. Due to the aging baby boomer generation, the US incidence of Merkel cell carcinoma is expected to climb to 3,300 cases by 2025. Current standard of care in the U.S. for patients with advanced or recurrent Merkel cell carcinoma is with Pembrolizumab or Avalumab, but there is no standard therapy for patients who progress on or are refractory to treatment with these immune checkpoint inhibitors, or indeed for those patients who are ineligible to receive treatment with immunotherapy. Response rates and duration of response to chemotherapy in this setting are very low, and no survival benefit has been published from treatments in this setting. We expect to commence our Phase 2 study, the Mantra 3 trial, in mid-2022. To conclude, for Mantra, we have partnered with the key liposucoma sites around the U.S., Europe, and elsewhere internationally, all with a strong track record of enrollment into liposucoma trials. In the Mantra 2 basket study, a selection of major academic sites with ready access to genomic testing and MDM2 copy number reporting, coupled with a large potentially eligible patient population, should ensure rapid enrollment once the trial sites are all open. In Mantra 3, we have attracted the major national and international Merkel cell experts to help develop our Mantra 3 protocol and development strategy in this indication. And we recently concluded an advisory board of renowned thought leaders treating Merkel cell carcinoma, where they reiterated their excitement for milidimetan investigation in this setting. Our dedicated team within RAINN continues to build personal relationships with all of our investigational sites around the world, and our selection of experienced oncology CROs, equally committed to success, will ensure we do all we can to develop milidimetan as quickly as possible for patients. Let me now turn it over to our Chief Scientific Officer, Dr. Bob Doble. Bob.
spk09: Thanks, Richard, and good afternoon, everyone. Since acquiring milidimetan approximately one year ago, RAINN'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 recent conferences, including the AACR NCI EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics, or the TRIPLE Conference, highlighting important preclinical collaborations with researchers around the world. We also hosted our first RAINN Research and Development Day yesterday. This event featured both clinical and research experts who highlighted multiple opportunities for the use of milodimetan in different tumor settings where MDM2 plays a critical role. Let's turn to our conference presentations. First, Dr. Vijaya Tirunegaru, Senior Vice President and Head of Research at RAIM, presented both preclinical and clinical data to support the use of milodimetan in patients with MDM2 amplification and wild type P53. Preclinical models, including cancer cell lines, patient-derived organoids, and patient-derived xenografts from numerous different solid tumor types demonstrated robust anti-tumor activity. We also presented the rationale for our MDM2 amplification of at least 12 copies using a mutual exclusivity analysis in relation to p53 mutations from over 40,000 solid tumor patients derived from the AACR Gini database. Finally, clinical data from the Phase 1 study of milodimetan demonstrated three patients with breast cancer, synovial sarcoma, and small cell lung cancer with MDM2 amplification above the 12 copy number threshold, all experiencing tumor regression, and two of the three patients experiencing a partial response. These exciting data support the rationale for the MONTRA-2 basket trial. Also presented at the triple conference was work from Dr. DiCaprio's lab at the Dana-Farber Cancer Institute. The polyomavirus induces Merkel cell carcinoma in up to 80% of all Merkel cell cases and leads to overexpression of MDN2 and correlates with wild type P53 status. Dr. DiCaprio's presentation highlighted the potency of milodimethan and multiple in vitro and in vivo virus-positive Merkel cell carcinoma models. This activity for milidamotan was P53-dependent, as milidamotan induced gene expression of critical P53 targets, such as P21 and PUMA. The presentation also showed that knocking out P53 abrogated the effect of milidamotan. This exciting preclinical work formed part of the basis to prioritize a Phase II trial for patients with Merkel cell carcinoma. At our R&D day held yesterday, Dr. James DiCaprio also presented additional new patient-derived xenograft data from Milodamatam that exhibited compelling antitumor activity and tumor regression, which was not previously presented from his team's work at Dana-Farber. Further, Dr. Glenn Hanna gave an overview of the treatment landscape for Merkel cell carcinoma and highlighted the unmet need in the second-line setting following the treatment with checkpoint inhibitors. The view offered in Merkle Cell is that many patients don't respond in the frontline setting with checkpoint inhibitors, and the second-line setting offers very few options. MDM2 inhibition is the only targeted strategy that is being evaluated in Merkle Cell, and there was great enthusiasm for its opportunity. RAINS R&D Day also featured several prominent clinical and research experts to highlight opportunities for Northampton and several cancer types. Dr. Wafiq Alderi, director of the Brown Cancer Center, gave an overview of the MDM2-P53 axis, highlighting the role for P53 reactivation as an important anti-cancer strategy. He stressed the non-overlapping strategies of restoring wild-type P53 activity, which is what we hope to do with amitam via MDM2 inhibition, versus programs that target P53 mutations. He also noted the potential for combination of MDM2 inhibitors with immunotherapy strategies in cancer, given the association of MDM2 amplification with hyperprogression on checkpoint inhibitors. Additional speakers from MD Anderson, the Curie Institute, Italy's National Cancer Institute, and Memorial Fund Kettering all highlighted the rationale for the current planned strategies for milidametan and several additional opportunities which are being considered by RAINN. These presentations provide support for RAIN's clinical strategy and prioritization of de-differentiated liposarcoma and 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 large cancer populations. With that, let me now turn it over to Nelson to review our financial results. Nelson?
spk11: Thank you, Bob, and good afternoon, everyone. I'm pleased to provide an update to our financial results for the third quarter of 2021. I would also like to invite you to review our Form 10-Q file today for more details. For the third quarter of 2021, we reported a net loss of $18.4 million compared to a net loss of $10.4 million in the third quarter of 2020. Research and development expenses were $15.3 million in the third quarter of 2021, as compared to $7.9 million in the third quarter of 2020. The increase was primarily driven by the milestone fees that the Asia Sankeo Company limited of $5.5 million related to the initiation of a Phase III clinical trial in DD-LTS, R&D costs mainly for our lead candidates from the ongoing Phase III pivotal mantra trial, as well as personal costs. General and immersive expenses were $3.2 million for the third quarter of 2021 compared to $600,000 for the third quarter of 2020. The increase was primarily due to increases in various third-party G&A costs, including legal, outside consulting, accounting, and audit fees, as well as personal costs. As of September 30, 2021, RAINN had $150.1 million in cash, cash equivalents, and short-term investments which provides funding to advance our research and development pipeline. Also, as of September 30, 2021, RAINN had approximately 26.5 million shares of common stock outstanding. We continue to expect our full year 2021 operating spend to be approximately $50 million to $60 million and projected year-end balance of approximately $137 million to $147 million in cash, cash equivalents, and short-term investments. With that, I'll now turn the call over back to Avinash.
spk02: Thanks, Nelson. Let me now turn it back to the operator for a Q&A session.
spk05: Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star then one on your touchtone telephone. One moment, please. Our first question comes from Yigal Kachapovitz of Citigroup. Your line is open. Great.
spk16: Hi, I'm Anish Anteem. Thanks for taking the question. I have two. The first one is, could you be a bit more specific about what you found so compelling in the recent non-clinical data from the Dana-Farber that caused you to displace the previously announced trial in intramural sarcoma for the Phase II and Merkel cell? And the second question, it's a bit of a strange question, but I was wondering, regarding the basket trial, what happens if you have multiple biopsies and you get heterogeneity and MDM2 copy number with some biopsies below and others above the copy number of 12 threshold? Thanks.
spk02: Thanks, Miguel. Appreciate the question. Let me turn the first question over to Bob and ask Richard to chime in on the second question. Bob?
spk09: Hi, you all. Thanks for the question. So in terms of the compelling data, you know, I think the biology of Merkel cell has been well understood for quite some time now in terms of the virus positive patients. showing dependency on MDM2 to rid cancer cells of P53. I think what we found compelling is, for the first time, we were able to demonstrate in multiple preclinical models activity of milodamatam that was potent in both cell line and patient-derived xenograft models, including data that showed significant tumor regression and patient-derived xenograft models. And so I think the rationale there is to move forward based on the biology and the unmet need in those microcell patients.
spk14: And the second question related to potential heterogeneity from sampling in terms of MDM2 copy number. in the basket study. So we will accept local testing as a criteria for entry, and so any sample that meets the criteria, any biopsy sample that meets the criteria, MDM2, COVID number 12 or greater, will be accepted. We do have retrospective testing at a central lab, which we've discussed before, and so all patients entering will have their tumors And that will provide the homogeneity, if you like, across the sites and to some extent will address potentially the heterogeneity that may be seen within sites. I don't know, Bob, with your experience in the run-up to this, whether you have anything further to comment on that?
spk09: Just that, you know, our belief is that, like a lot of oncogenic drivers, this is likely an early event, and the same way that P53 mutations are very early event in cancer, those tend to be truncal and thus not display as much heterogeneity as non-relevant mutations in cancer.
spk23: Great, thank you.
spk05: Thank you. Our next question comes from Michael Schmitt of . Your line is open.
spk06: Hi, good afternoon. This is for Michael. Thanks for taking our questions. We had a question on the Mantra 2 basket study. So based on the observation of the MDM2 amplification across different tumor types, how should we think of the mix of the tumor types in this study? And perhaps related to this, what would be your registration strategy Would you, for example, pick certain tumor types, or are you going to consider a registration with a basket? Thank you.
spk02: Thanks, Shige, for the question. Let me turn it over to Richard.
spk14: So, yeah, thank you again for the question. The study is open to all tumor types, so at the present time, it's not restricted to any particular pathology. We know that some Tumor types are likely to be more prevalent. That's very clear from the analysis of the various genomic databases that are out there. But there is no general cap on them at the moment. The expectation is that probably the top five tumors will yield the most from the genomic databases. At present, the strategy is tumor agnostic. In other words, we expect to see a response that's across all tumors, regardless of the disease site. And biologically, that's kind of rational. That's the oncogenic tumor driver in these diseases. As with everything, this is a signal-seeking study. This is a basket study. We have the opportunity to look on an ongoing basis at the responses in the various tumor types and take action accordingly. But at the present time, we're setting out with a pure tumor agnostic approach, and we'll see where it goes.
spk02: And just to add a little color there, so in terms of the top few tumor types, it would be lung, bladder, breast, and melanoma, which would be a would be expected to yield the greatest number of patients with that copy number of 12 or greater.
spk08: And just one final addition.
spk09: And just one final addition. There was anecdotal data from the Phase I trial of milidimetan with high-level MDM2 amplification showing tumor regressions in three different and very unique tumor types, a small cell lung cancer, a breast cancer, and a synovial sarcoma. So some evidence already.
spk07: Got it. That's super helpful. Thank you, guys.
spk24: Thank you.
spk05: Our next question comes from Joe Cancizaro of Piper Family. Your line is open.
spk17: Hey, guys. Thanks for taking my question. Maybe just one quick one for me. Maybe it sounds a little naive, but I know MDM2 amplification is considered universal in well-diff, D-diff, LPS amplification. But do you have a sense of the average copy number amplification that you see there and whether it frequently meets that threshold of being mutually exclusive with P53? And is there any plan as part of the mantra study to sort of retrospectively look at that? Thanks.
spk02: Thanks, Joe. I'll hand it over to Bob.
spk09: Yeah, thanks for the question, Joe. So, yes, we do know the average copy numbers for well-diff and dedifferentiated liposarcoma. For well-diff, it's approximately 10 copies. For dedifferentiated liposarcoma, it's closer to 17 copies per cell, so a pretty high-level amplification in both populations. And as far as the mutual exclusivity, yes, this is a pattern that we see across many tumor types that we think have MDM2 dependency. And all of liposarcoma, sorry, all of well-deferred, de-differentiated liposarcoma has a p53 mutation rate as low as 2%. So very, very rare p53 mutations compared to all cancers, which run around 50% p53 mutated. So that relationship seems to hold up in multiple populations. Oh, and sorry, the second part of the question was in terms of retrospective look. Yes, we are going to collect archival tumor samples and look at MDM2 copy number, P53 status, and other biomarkers as well in the Mantra LPS study.
spk17: Okay, got it. And if I could just maybe ask a real quick follow-up question. appreciating that you already have a pretty broad clinical development strategy, but what needs to happen to commit to exploring the GATA mutant ER-positive signal that you've seen pre-clinically and take that into the clinic?
spk02: So, great question, Joe. I'll take that one. So, we are considering the GATA3 continuously, and we will articulate when We make a decision as to whether a company-sponsored study or whether another manner of evaluation is going to be most appropriate for RAIN. But we're certainly taking into consideration the totality of our financial resources and the cash runway that we have to bear, and we want to direct those resources towards the highest probability tumor types and those tumor types where we think that there's going to be a much clearer rate on a registration path. So we're continuing to do work there, continuing to do a lot more work on mechanism as to what's going on with the the GATA3 frameshift mutations and the sensitivity to MDM2 inhibition. And as we make that progress, we'll keep the street updated.
spk17: Okay, got it. That's clear. Thanks for taking my question.
spk24: Thank you.
spk05: Thank you. Our next question comes from Corinne Jenkins of Goldman Sachs. Your line is open.
spk04: Hi, good afternoon. So clearly you've prioritized this Manchester study partly because of the market opportunity, but can you just help us frame out a little more specifically how you think about the size of that opportunity?
spk02: Sure, happy to. I'll take that one. So, again, from the population statistics, around 3,000 patients, those are 2020 statistics. Richard did mention that this is a population that's growing far more quickly than the overall solid tumor population, given the primary demographic. 80% of those patients are going to be MDM2 dependent based upon that viral positivity. And about a third of those patients are going to be amenable to systemic therapy on an annual basis. We also know that from prior years of diagnosis, many of those patients with local disease are going to become metastatic. So we ultimately derive a patient population that's amenable to systemic therapies per year of between 1,000 to 1,500 patients.
spk04: Okay, that's really helpful. And then I know it's still, you know, we just started this study, but in terms of the clinical bar for Mantra 2, how would you think about framing out the clinical bar, given it'll be a mix of tumor types and lines of study in that basket trial?
spk09: Sure, let me turn that over to Bob. Yeah, thanks for the question, Corinne. So the clinical bar is quite low. You know, in discussing this indication with KOLs from across the country, there is really no second-line standard following first-line pembrolizumab or abelumab, so both checkpoint inhibitor therapies. You know, the second-line preferred therapy is a clinical trial. And after that, a distant option is chemotherapy, which, although it has decent response rates, has incredibly short durability, perhaps as low as in the range of three months. So the feedback from the Merkel cell KOL community is that response rate in the range of 15% to 20% and durability as low as four months may be meaningful in this patient population with limited options.
spk02: Apologies, Corinne. Was your question with regards to mantra 3 or mantra 2?
spk00: Mantra 2.
spk09: Sorry about that, Corinne. Yeah, no worries. For mantra 2, you know, I think we don't fully know what the FDA would consider approvable for an agnostic indication. There's only been three to date, intractinib, larotractinib, and pembrolizumab in MSI-high patients. I think the feeling is that for patients who've exhausted most other cancer therapies, that a response rate in the range of 40% with durability in the range of five to six months would probably be meaningful for patients who've exhausted standard of care therapies, which is the criteria for our patients. But there aren't a lot of examples, to be honest, in terms of precedence.
spk04: Yeah, just one quick follow-up. Given the interim readout will be about 12 months from now, do we expect to mostly see response rates, or will you be in a position at that point, given kind of pace of enrollment, to have at least early indicators of what durability of response is?
spk25: Yes, Richard, did you take that one?
spk14: Sure. So what we plan to do actually is have a meaningful follow-up so we can quote not just the response rate but the duration of response. The likelihood is that we'll wait until we have about four months' worth of follow-up data so that at least we know those responses are meaningful in terms of clinical durability.
spk01: That's helpful. Thank you.
spk21: Thanks, Ray.
spk05: I'm sorry. I'm sure no questions at this time. I'd like to turn the call back over to Avinash Belanki for any closing remarks.
spk02: Thank you, and thanks, everyone, for dialing in today. We look forward to giving you an update on our next quarterly results.
spk05: Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day. Thank you. Thank you. Bye. Thank you. Thank you. Thank you. you Thank you. you Thank you for standing by and welcome to the Reign Therapeutics Third Quarter 2021 Financial Results Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question at that time, please press star then one on your touchstone telephone. As a reminder, today's conference call is being recorded. I will now turn the conference over to your host, Mr. Bob Yedit, for you may begin.
spk10: Thank you, Operator. Good afternoon, everyone. With me today on the phone are Avinash Vellanki, Chief Executive Officer, Robert Doble, Chief Scientific Officer, Richard Bryce, Chief Medical Officer, and Nelson Kabat-Toon, Senior Vice President of Finance. During today's call, Avinash will provide an overall business update. Richard will provide an update on Rand's clinical program. 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 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 on RAIN's current expectations and involve assumptions that may never materialize or prove to be correct. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, as described in RAINN's quarterly report on Form 10-Q for the quarter ended March 31, 2021, and subsequent filings with 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. RAINN undertakes an obligation to update such statements reflect events that may occur or circumstances that exist after today, except as required by law. With that, it's my pleasure to turn the call over to Navanesh Palanki, CEO of RAINN. Navanesh?
spk02: Thank you, Bob, and thanks to everyone for joining us for our third quarter earnings call. As a matter of principle for these earnings calls, We're going to make it standard practice to be very brief, and we'll leave it to the Q&A to address the details that are of the most interest. In this most recent quarter and since the end of the third quarter, RAINN continues to advance the Mila Demetan and RAD52 programs forward. As a reminder, we'll continue to refer to Mila Demetan as Mila wherever appropriate. First and foremost, our Phase III 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. 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, we also expect to dose our first patient in the Phase II tumor-agnostic Mantra II study shortly, and we'll announce that when it happens. This trial will evaluate MILA in a tumor-agnostic signal-finding basket study across 65 patients in the U.S. with solid tumors that exhibit a certain threshold of MDM2 gene amplification. We expect to provide an interim update for Mantra 2 in the second half of next year. Third, we announced that we will reprioritize our clinical strategy for our third planned study towards Merkel cell carcinoma, replacing our prior planned study of intimal sarcoma. This new trial will be called Mantra 3. The decision to prioritize Merkel cell was made for three key reasons. One, new non-clinical data presented by the Dana-Farber Cancer Institute demonstrating compelling efficacy for meledematans. which already adds to the biologic rationale that many Merkel cell tumors are MDM2 dependent. Two, we note there's already been presented signs of activity with MDM2 inhibition in Merkel cell from other MDM2 inhibitor programs. And three, the larger addressable market size of Merkel cell as compared to intimal sarcoma, hence representing the most appropriate use of our financial resources. Based on the larger population of Merkel cell, faster projected patient accrual rates and an expected shorter trial duration, the new planned Merkel cell study has no significant impact on RAIN's cash runway. We expect Mantra 3 to enroll 34 patients in the U.S. in the second line or later settings amongst patients relapsed to checkpoint inhibitors, which is the standard of care in the front line. And we expect to start the study in the middle of 2022. Finally, we held an R&D day yesterday where we hosted several prominent key opinion leaders across various treatment specialties where we think MDM2 inhibition could be applied. Speakers included Dr. Wafiq El-Diri from Brown University, who many of you may know for his discovery of P21, Drs. Murnal Gounder and David Hong from Memorial Sloan Kettering and MD Anderson Cancer Centers, respectively, who will be participating in RAIN's first two clinical studies for MILA, and Drs. Glenn Hanna and James Sid Caprio from Dana-Farber for their expertise in Merkel cell carcinoma. We also included talks from Drs. Francois Clement Bedard and Silvia Stacchiati, who shed light on some additional clinical opportunities for MILA. Our strategy continues to be to focus our early effort on the most sensitive MDM2-dependent tumor types first, and will be followed by combination strategies to further enhance patient outcomes and other P53 wild-type cancers. We're very excited about the potential for a range of opportunities for Mila to have a meaningful impact on patient care. Last, the early preclinical workaround programs targeting RAD52 continues to move forward, and we expect to provide updates at future scientific symposia as appropriate. With that, I'd like to turn it over to our chief medical officer, Dr. Richard Bryce.
spk14: Thank you, Evan. And good afternoon, everyone. Following on from our last earnings call in August, where we announced a start to our pivotal Phase III Mantra study, indeed differentiated liposucoma, we are progressing with site activations throughout the U.S. and Europe, anticipating approximately 30 sites to be opened by the end of the year, with the remaining 45 sites in Europe, North America, and certain Asia-Pacific countries coming on stream before the end of the first quarter of 2022. Patient enrollment continues as expected. I am pleased to announce today that our second trial, the Mantra 2 basket study, is now active and open to enrollment. We will make a separate announcement when the first patient is dosed. We expect that the Mantra 2 study will ultimately be opened in a total of approximately 10 sites throughout the United States, with additional just-in-time sites as necessary from the Tempus and Karras referrals. The study is open to patients that are P53 wild type and MDM2 amplified with a minimum gene copy number of 12 or a six-fold increase in copy number by local testing methods. As we previously discussed, this threshold is chosen because the high gene amplification at these levels has been observed to exclude P53 mutations. thereby ensuring MDM2 is the oncogenic driver in these tumors. As well as the in-house genomic screening at the selected U.S. sites, we have partnered with Tempus and Karis for referral of patients meeting these particular criteria. The study aims to enroll 65 patients across a range of solid tumors, and the treatment protocol is the same as in the registrational mantra study. That is 260 milligrams orally, once daily, for three consecutive days out of 14. And as we previously advised, we anticipate an interim analysis and data readout in the second half of next year. As Avanish mentioned, we have deprioritized our internal sarcoma program to focus on the opportunity in Merkel cell carcinoma in the second-line setting, following immune checkpoint inhibitor therapy. The incidence of this aggressive skin cancer in the U.S. is estimated to be around 3,000 patients in 2020 and is rising year on year. Between the years 2000 and 2013, we note there was a 95% increase in reported cases. And this compares to 57% growth rates for melanoma and 15% for all solid tumors. Due to the aging baby boomer generation, the US incidence of Merkel cell carcinoma is expected to climb to 3,300 cases by 2025. Current standard of care in the U.S. for patients with advanced or recurrent Merkel cell carcinoma is with Pembrolizumab or Avalumab, but there is no standard therapy for patients who progress on or are refractory to treatment with these immune checkpoint inhibitors, or indeed for those patients who are ineligible to receive treatment with immunotherapy. Response rates and duration of response to chemotherapy in this setting are very low, and no survival benefit has been published from treatments in this setting. We expect to commence our Phase 2 study, the Mantra 3 trial, in mid-2022. So to conclude, for Mantra, we have partnered with the key liposucoma sites around the U.S., Europe, and elsewhere internationally, all with a strong track record of enrollment into liposucoma trials. In the Mantra 2 basket study, a selection of major academic sites with ready access to genomic testing and MDM2 copy number reporting, coupled with a large potentially eligible patient population, should ensure rapid enrollment once the trial sites are all open. In Mantra 3, we have attracted the major national and international Merkel cell experts to help develop our Mantra 3 protocol and development strategy in this indication. and we recently concluded an advisory board of renowned thought leaders treating Merkel cell carcinoma, where they reiterated their excitement for milidimetan investigation in this setting. Our dedicated team within RAINN continues to build personal relationships with all of our investigational sites around the world, and our selection of experienced oncology CROs, equally committed to success, will ensure we do all we can to develop milodimetan as quickly as possible for patients. Let me now turn it over to our Chief Scientific Officer, Dr. Bob Doble. Bob.
spk09: Thanks, Richard, and good afternoon, everyone. Since acquiring milodimetan approximately one year ago, RAINN'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 recent conferences, including the AACR NCI EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics, or the TRIBEL Conference, highlighting important preclinical collaborations with researchers around the world. We also hosted our first RAINN Research and Development Day yesterday. This event featured both clinical and research experts who highlighted multiple opportunities for the use of milodimetan in different tumor settings where MDM2 plays a critical role. Let's turn to our conference presentations. First, Dr. Vijaya Tirunegaru, Senior Vice President and Head of Research at RAIM, presented both preclinical and clinical data to support the use of milodimetan in patients with MDM2 amplification and wild type P53. Preclinical models, including cancer cell lines, patient-derived organoids, and patient-derived xenografts from numerous different solid tumor types demonstrated robust anti-tumor activity. We also presented the rationale for our MDM2 amplification of at least 12 copies using a mutual exclusivity analysis in relation to p53 mutations from over 40,000 solid tumor patients derived from the AACR Gini database. Finally, clinical data from the Phase 1 study of milodimetan demonstrated three patients with breast cancer, synovial sarcoma, and small cell lung cancer with MDM2 amplification above the 12 copy number threshold, all experiencing tumor regression, and two of the three patients experiencing a partial response. These exciting data support the rationale for the Mantra 2 basket trial. Also presented at the triple conference was work from Dr. DiCaprio's lab at the Dana-Farber Cancer Institute. The polyomavirus induces Merkel cell carcinoma in up to 80% of all Merkel cell cases and leads to overexpression of MDM2 and correlates with wild type P53 status. Dr. DiCaprio's presentation highlighted the potency of milodimethan in multiple in vitro and in vivo virus-positive Merkel cell carcinoma models. This activity for milidamotan was P53-dependent, as milidamotan induced gene expression of critical P53 targets, such as P21 and PUMA. The presentation also showed that knocking out P53 abrogated the effect of milidamotan. This exciting preclinical work formed part of the basis to prioritize a Phase II trial for patients with Merkel cell carcinoma. At our R&D day held yesterday, Dr. James DiCaprio also presented additional new patient-derived xenograft data from Milodamatam that exhibited compelling antitumor activity and tumor regression, which was not previously presented from his team's work at Dana-Farber. Further, Dr. Glenn Hanna gave an overview of the treatment landscape for Merkel cell carcinoma and highlighted the unmet need in the second-line setting following the treatment with checkpoint inhibitors. The view offered in Merkle Cell is that many patients don't respond in the front-line setting with checkpoint inhibitors, and the second-line setting offers very few options. MDM2 inhibition is the only targeted strategy that is being evaluated in Merkle Cell, and there was great enthusiasm for its opportunity. RAINS R&D Day also featured several prominent clinical and research experts to highlight opportunities for Northampton and several cancer types. Dr. Wafiq Alderi, director of the Brown Cancer Center, gave an overview of the MDM2-P53 axis, highlighting the role for P53 reactivation as an important anti-cancer strategy. He stressed the non-overlapping strategies of restoring wild-type P53 activity, which is what we hope to do at Amitabh via MDM2 inhibition, versus programs that target P53 mutations. He also noted the potential for combination of MDM2 inhibitors with immunotherapy strategies in cancer, given the association of MDM2 amplification with hyperprogression on checkpoint inhibitors. Additional speakers from MD Anderson, the Curie Institute, Italy's National Cancer Institute, and Memorial Fund Kettering all highlighted the rationale for the current planned strategies for milidametan and several additional opportunities which are being considered by RAINN. These presentations provide support for RAIN's clinical strategy and prioritization of de-differentiated liposarcoma and 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 large cancer populations. With that, let me now turn it over to Nelson to review our financial results. Nelson?
spk11: Thank you, Bob, and good afternoon, everyone. I'm pleased to provide an update to our financial results for the third quarter of 2021. I would also like to invite you to review our Form 10-Q file today for more details. For the third quarter of 2021, we reported a net loss of $18.4 million compared to a net loss of $10.4 million in the third quarter of 2020. Research and development expenses were $15.3 million in the third quarter of 2021, as compared to $7.9 million in the third quarter of 2020. The increase was primarily driven by the amounts on fees that the Asia Sankeo Company limited of $5.5 million related to the initiation of our Phase III clinical trial in DD-LTS, R&D costs mainly for our lead candidates from the ongoing Phase III pivotal mantra trial, as well as personal costs. General and administrative expenses were $3.2 million for the third quarter of 2021 compared to $600,000 for the third quarter of 2020. The increase was primarily due to increases in various third-party G&A costs, including legal, outside consulting, accounting, and audit fees, as well as personal costs. As of September 30, 2021, RAINN had $150.1 million in cash, cash equivalents, and short-term investments which provides funding to advance our research and development pipeline. Also, as of September 30, 2021, RAINN had approximately 26.5 million shares of common stock outstanding. We continue to expect our full year 2021 operating spend to be approximately $50 million to $60 million and projected year-end balance of approximately $137 million to $147 million in cash, cash equivalents, and short-term investments. With that, I'll now turn the call over back to Avinash.
spk02: Thanks, Nelson. Let me now turn it back to the operator for a Q&A session.
spk05: Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star then one on your touchtone telephone. One moment, please. Our first question comes from Yigal Metchalovitz of Citigroup. Your line is open.
spk16: Great. Hi, I'm on the Eastern team. Thanks for taking the question. I have two. The first one is, could you be a bit more specific about what you found so compelling in the recent non-clinical data from the Dana-Farber that caused you to displace the previously announced trial in intral sarcoma for the Phase II and Merkel cell? And the second question, it's a bit of a strange question, but I was wondering, regarding the basket trial, what happens if you have multiple biopsies and you get heterogeneity and MDM2 copy number with some biopsies below and others above the copy number of 12 threshold? Thanks.
spk02: Thanks, Miguel. Appreciate the question. Let me turn the first question over to Bob and ask Richard to chime in on the second question. Bob?
spk09: Hi, you all. Thanks for the question. So, in terms of the compelling data, you know, I think the biology of Merkel cell has been well understood for quite some time now in terms of the virus positive patients. showing dependency on MDM2 to rid cancer cells of P53. I think what we found compelling is, for the first time, we were able to demonstrate in multiple preclinical models activity of milodamatam that was potent in both cell line and patient-derived xenograft models, including data that showed significant tumor regressions and patient-derived xenograft models. And so I think the rationale there is to move forward based on the biology and the unmet need in those Merkel cell patients.
spk14: And the second question related to potential heterogeneity from sampling in terms of MDM2 copy number. in the basket study. So we will accept local testing as a criteria for entry, and so any sample that meets the criteria, any biopsy sample that meets the criteria, MDM2, COVID number 12 or greater, will be accepted. We do have retrospective testing at a central lab, which we've discussed before, and so all patients entering will have their tumours And that will provide the homogeneity, if you like, across the sites and to some extent will address potentially the heterogeneity that may be seen within sites. I don't know, Bob, with your experience in the run-up to this, whether you have anything further to comment on that?
spk09: Just that, you know, our belief is that, like a lot of oncogenic drivers, this is likely an early event, and the same way that P53 mutations are very early event in cancer, those tend to be truncal and thus not display as much heterogeneity as non-relevant mutations in cancer.
spk05: Great, thank you. Thank you. Our next question comes from Michael Schmidt of . Your line is open.
spk06: Hi, good afternoon. This is for Michael. Thanks for taking our questions. We had a question on the Mantra 2 basket study. So based on the observation of the MDM2 amplification across different tumor types, how should we think of the mix of the tumor types in this study? And perhaps related to this, what would be your registration strategy Would you, for example, pick certain tumor types, or are you going to consider a registration with a basket? Thank you.
spk02: Thanks, Shige, for the question. Let me turn it over to Richard.
spk14: So, yeah, thank you again for the question. The study is open to all tumor types, so at the present time, it's not restricted to any particular pathology. We know that some Tumor types are likely to be more prevalent. That's very clear from the analysis of the various genomic databases that are out there. But there is no general cap on them at the moment. The expectation is that probably the top five tumors will yield the most from the genomic databases. At present, the strategy is tumor agnostic. In other words, we expect to see a response that's across all tumors, regardless of the disease site. And biologically, that's kind of rational. That's the oncogenic tumor driver in these tumors. in these diseases. As with everything, this is a signal-seeking study. This is a basket study. We have the opportunity to look on an ongoing basis at the responses in the various tumor types and take action accordingly. But at the present time, we're setting out with a pure tumor-agnostic approach, and we'll see where it goes.
spk02: And just to add a little color there, so in terms of the top few tumor types, it would be lung, bladder, breast, and melanoma, which would be expected to yield the greatest number of patients with that copy number of 12 or greater.
spk08: And just one final addition.
spk09: And just one final addition. There was anecdotal data from the Phase I trial of meledamotan with high-level MDM2 amplification showing tumor regressions and three different and very unique tumor types, a small cell lung cancer, a breast cancer, and a synovial sarcoma. So some evidence already.
spk07: All right. That's super helpful. Thank you, guys.
spk24: Thank you.
spk05: Our next question comes from Joe Canzazaro of Piper Family. Your line is open.
spk17: Hey, guys. Thanks for taking my question. Maybe just one quick one for me, Ed. Maybe it sounds a little naive, but I know MDM2 amplification is, you know, considered universal in well-diff, D-diff, LPS, but do you have a sense of the average copy number amplification that you see there and whether it, you know, frequently meets that threshold of being mutually exclusive with P53? And is there any plan as part of the mantra study to sort of retrospectively look at that? Thanks.
spk02: Thanks, Joe. I'll hand it over to Bob.
spk09: Yeah, thanks for the question, Joe. So, yes, we do know the average copy numbers for WellDiff and dedifferentiated liposarcoma. For WellDiff, it's approximately 10 copies. For dedifferentiated liposarcoma, it's closer to 17 copies per cell, so a pretty high-level amplification in both populations. And as far as the mutual exclusivity, yes, this is a pattern that we see across many tumor types that we think have MDM2 dependency. And all of liposarcoma, sorry, all of well-deferred, de-differentiated liposarcoma has a p53 mutation rate as low as 2%. So very, very rare p53 mutations compared to all cancers, which run around 50% p53 mutated. So that relationship seems to hold up in multiple populations. Oh, and sorry, the second part of the question was in terms of retrospective look. Yes, we are going to collect archival tumor samples and look at MDM2 copy number, P53 status, and other biomarkers as well in the Mantra LPS study.
spk17: Okay, got it. And if I could just maybe ask a real quick follow-up question. appreciating that you already have a pretty broad clinical development strategy, but what needs to happen to commit to exploring the GATA mutant ER-positive signal that you've seen preclinically and take that into the clinic?
spk02: So, great question, Joe. I'll take that one. So, we are considering the GATA3 continuously, and we will articulate when We make a decision as to whether a company-sponsored study or whether another manner of evaluation is going to be most appropriate for RAIN. But we're certainly taking into consideration the totality of our financial resources and the cash runway that we have to bear, and we want to direct those resources towards the highest probability tumor types and those tumor types where we think that there's going to be a much clearer rate on a registration path. So we're continuing to do work there, continuing to do a lot more work on mechanism as to what's going on with the the GATA3 frameshift mutations and the sensitivity to MDM2 inhibition. And as we make that progress, we'll keep the street updated.
spk17: Okay, got it. That's clear. Thanks for taking my question.
spk24: Thank you.
spk05: Thank you. Our next question comes from Corinne Dinkins of Goldman Sachs. Your line is open.
spk04: Hi, good afternoon. So clearly you've prioritized this MANCHES III study partly because of the market opportunity, but can you just help us frame out a little more specifically how you think about the size of that opportunity?
spk02: Sure, happy to. I'll take that one. So, again, from the population statistics, around 3,000 patients, those are 2020 statistics. Richard did mention that this is a population that's growing far more quickly than the overall solid tumor population, given the primary demographic. 80% of those patients are going to be MDM2 dependent based upon that viral positivity. And about a third of those patients are going to be amenable to systemic therapy on an annual basis. We also know that from prior years of diagnosis, many of those patients with local disease are going to become metastatic. So we ultimately derive a patient population that's amenable to systemic therapies per year of between 1,000 to 1,500 patients.
spk04: Okay, that's really helpful. And then I know it's still, you know, we just started this study, but in terms of the clinical bar for Mantra 2, how would you think about framing out the clinical bar, given it'll be a mix of tumor types and lines of study in that basket trial?
spk02: Sure, let me turn that over to Bob.
spk09: Yeah, thanks for the question, Corinne. So the clinical bar is quite low. You know, in discussing this indication with KOLs from across the country, there is really no second-line standard following first-line pembrolizumab or abelumab, so both checkpoint inhibitor therapies. You know, the second-line preferred therapy is a clinical trial. And after that, a distant option is chemotherapy, which, although it has decent response rates, has incredibly short durability, perhaps as low as in the range of three months. So the feedback from the Merkel cell KOL community is that response rate in the range of 15% to 20% and durability as low as four months may be meaningful in this patient population with limited options.
spk02: Apologies, Corinne. Was your question with regards to Mantra 3 or Mantra 2?
spk00: Mantra 2.
spk09: Sorry about that, Corinne. Yeah, no worries. For Mantra 2, you know, I think we don't fully know what the FDA would consider approvable for an agnostic indication. There's only been three to date, intractinib, larotractinib, and pembrolizumab in MSI-high patients. I think the feeling is that for patients who've exhausted most other cancer therapies, that a response rate in the range of 40% with durability in the range of five to six months would probably be meaningful for patients who've exhausted standard of care therapies, which is the criteria for our patients. But there aren't a lot of examples, to be honest, in terms of precedence.
spk04: Yeah, just one quick follow-up. Given the interim readout will be about 12 months from now, do we expect to mostly see response rates, or will you be in a position at that point, given kind of case enrollment, to have at least early indicators of what durability of response is?
spk25: Yes, Richard, did you take that one?
spk14: Sure. So what we plan to do actually is have a meaningful follow-up so we can quote not just the response rate but the duration of response. The likelihood is that we'll wait until we have about four months' worth of follow-up data so that at least we know those responses are meaningful in terms of clinical durability.
spk01: That's helpful. Thank you.
spk21: Thank you.
spk05: I'm sorry. I'm sure no questions at this time. I'd like to turn the call back over to Avinash Belanki for any closing remarks.
spk02: Thank you, and thanks, everyone, for dialing in today. We look forward to giving you an update on our next quarterly results.
spk05: Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.
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