Q4 2022 Rain Oncology Inc Earnings Call

Speaker 1: The.

Speaker 1: I.

Speaker 2: Greetings and welcome to the Rain on Colgate 4th Quarter and Foliar 2022 earnings call.

Speaker 2: At this time, all participants are in a listen-only mode.

Speaker 2: A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad.

Speaker 2: As a reminder, this conference is being recorded.

Speaker 2: It is now my pleasure to introduce your host, Dan Ferri of LifeSci Advisors. Thank you. Thank you.

Speaker 3: Thank you, operator, and good afternoon, everyone.

Speaker 3: With me today on the phone are Avinish Phalanke, Chief Executive Officer of Rain Oncology, Robert Doble, Chief Scientific Officer,

Speaker 3: Richard Bryce, Chief Medical Officer, and Nelson Cabotan, SVP of Finance.

Speaker 3: During today's call, Avinish will provide an update on the broader strategic vision for the Milidimaten franchise. Bob will review the biology and rationale of P53 reactivation as it relates to our Milidimaten clinical program. Richard will provide an update on RAIN's clinical strategy.

Speaker 3: 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 involves assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as the result of various risks and uncertainties as described in RAIN's annual report on Form 10-K .

Speaker 3: All forward-looking statements made during this conference call are based on management's assumptions and estimates as of today, March 9, 2023. 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 Avinish Phalanke, CEO of RAIN Oncology. Avinish? How are we doing today?

Speaker 4: Thank you, Dan. And thanks to everyone for joining us for our fourth quarter in full year 2022 earnings highlights and corporate update. To kick things off, we'd like to remind everyone of our name change to Rain Oncology in late 2022 to mark our anticipated growth as a dedicated and focused company.

Speaker 4: Precision Oncology business. We believe our new corporate name better reflects who we are and who we intend to remain.

Speaker 4: As Rang continues to drive forward with our late-stage clinical program, milodimitan, or MELA, our oral small molecule inhibitor of the MDM2P53 complex, we'd like to approach today's call by providing context around our goal of demonstrating how P53 reactivation through MELA's disruption of the complex.

Speaker 4: could potentially be transformative in treating a broad range of cancer patients.

Speaker 4: If the Montreux top-line data are favorable, we believe it will signify that reactivation of P53 matters. This will be an important validation as we begin to think about our initiatives beyond de-differentiated liposarcoma, or DDLPS. On today's call, we'll also provide highlights from our 2022 progress and achievements. As a bit of biology review, we all know that P53 is the good guy in this story. We want active P53 to do what it's supposed to be doing, which is to protect us from cancer.

Speaker 4: Today, there are no approved therapies in the treatment of cancer that are aimed at restoring or reactivating this innate anti-cancer agent. Cancer, broadly speaking, needs to find a way to get rid of P53. We all know that mutations in P53, those instances when P53 is broken and can't bind DNA to allow cancer.

Speaker 4: P53 to do what it's supposed to do occurs in approximately half of all cancers.

Speaker 4: MDM2 is a critical means of deactivating P53 in instances when there are no P53 mutations present. Therefore, in tumors that rely on MDM2 to rid cells of P53, impeding the interaction of MDM2 and P53 could be a route to restoring P53's innate protective properties. And even if MDM2 is not overexcressed, further reactivation or enhancement of wild-type P53 levels, my further enhanced anti-tumor activity of target therapies to address other oncogenic drivers. There are multitudinal potential indications to be considered.

Speaker 4: especially if the tolerability profile of Miele enables a wide-ranging set of combination partners. We believe a positive outcome in the monitor study would legitimize P53 reactivation as a route to treat a range of P53 wild-type cancers. And in that scenario, Milledimatin could be the first inhibitor of the MDM2-P53 complex to be submitted and possibly approved by the FDA and other regulatory authorities around the world. Bob will provide additional color on the P53 reactivation story.

Speaker 4: along with insights from the recent publication in the Journal of Clinical Oncology. Before Richard discusses how those data support the novel dose regimen of melodimitan, which is optimized to reduce toxicities associated with MDM2 P53 inhibition.

Speaker 4: Our clinical strategy, while starting in DDLPS, based on the totality of the data present at the time of licensing the program in 2020, will aggressively move to larger patient populations based on the experience we have gained with Mila in the clinic. We point out that after our initial indication in DDLPS, we find Whether or not our team has developed this procedure well enough, we do not want to go all the way to our success P15 stateswide Spacemen. In group length, Dr.

Speaker 4: targeting approximately 1,400 patients per year in the US.

Speaker 4: Our subsequent studies in the mantra 2 basket study targets 8,000 patients per year in the US and our third plan study The mantra 4 study will target over 40,000 patients per year domestically.

Speaker 4: That pattern should convey how we approach creating value for the MILA franchise, and as we evaluate the potential of both monotherapy and combination opportunities across the approximately 50% of the cancer population possessing wild-type P53 tumors.

Speaker 4: I will ask Bob and Richard to talk in more detail around recent data presented and the clinical strategy for melodimatam. I do want to comment briefly, however, on our preclinical research program focused on developing an inhibitor of RAD52. We have made a strategic determination to terminate this program based on data we have generated for the RAD52 research effort.

Speaker 4: on identifying new indications for milodimitan or additional precision oncology programs by external licensing or internal development, it may represent a more efficient deployment of capital for rain.

Speaker 4: In the prior quarter, we also remind you that we further improved our cash position with a $50 million registered offering concurrent with the release of the early Monks or Two Data.

Speaker 4: We're excited to welcome several new large healthcare focus funds to rain as part of that financing.

Speaker 4: Our year-end cash position of approximately $130 million provides a runway to complete all current, ongoing, and planned clinical trials of melodimatam. This includes the Phase III mantra trial in DDLPS, for which data is expected in the second quarter of this year. It includes the ongoing Phase II mantra II basket trial.

Speaker 4: and the planned phase one, two mantra four basket trial, which we expect to commence by mid-year.

Speaker 4: With that, I'd like to turn it over to our President and Chief Scientific Officer, Dr. Bob Doble. Bob? With that, I'd like to turn it over to Dr. Bob Doble

Speaker 4: Thanks, Abhayesh. Let's start by continuing the discussion around the rationale for P53 for the treatment strategy in cancer.

Speaker 4: MDM2 is a negative regulator of P53, blocking P53 transcriptional activity, promoting P53 export from the nucleus, and ultimately targeting the P53 protein for degradation. Thus, dysregulated MDM2 can provide an alternate and important mechanism for P53 loss in tumor cells and therefore facilitate...

Speaker 4: regulator of MDM2 activity and is encoded by the CDKN2A gene, which is lost in a large percentage of cancers.

Speaker 5: In January of this year, we published clinical trial data from the prior phase 1 study of milidametan in the Journal of Clinical Oncology, or JCO.

Speaker 5: This detailed the results of the first-in-class human phase 1 study of milidametam that evaluated the safety, PK, PD, and preliminary efficacy in patients with advanced liposarcoma, solid tumors, or lymphomas.

Speaker 5: These results indeed showed restoration of P53 levels and activity in patients with various cancers.

Speaker 5: Tumor biopsies of patients treated with meladamitin showed increased P53 protein levels and increased expression of P53 gene targets, such as P21.

Speaker 5: Additional pharmacodynamic marker testing showed an exposure dependent increase in the p53 target gene, MIC1, or GDF15, in patient blood samples following treatment with Nellie Gamfield.

Speaker 5: Although all tested DDLPS patients had MDM2 amplification, median PFS and DDLPS patients did not differ by levels of key biomarkers, including MDM2 or CDK4 copy number, nor by mRNA expression levels of MDM2, CDK4, or MDM4.

Speaker 5: These data are consistent with our preclinical data showing that while MDM2 amplification is an important biomarker,

Speaker 5: Higher levels of gene amplification do not correlate with increased milidametin sensitivity or improved clinical outcomes with MDM2 inhibitor treatment.

Speaker 5: Moving on to the MONTRA2 basket study, we continue to enroll patients with MDM2 amplified P53 wild-type solid tumors and plan to expand to additional sites worldwide with the goal of targeting full enrollment of approximately 65 patients across a range of solid tumors.

Speaker 5: Regarding the upcoming mantra four study, there is significant biological rationale to pursue combination of milodamatam and an immune checkpoint inhibitor. In this case, rocha is a tazolizumab or tascentic.

Speaker 5: CDKN2A encodes a critical regulator of the MDM2 P53 pathway, P14-ARF.

Speaker 5: Loss of the CDKN2A gene therefore leads to increased MBM2 activity and decreased P53 levels in tumors. Preclinical work confirms that cancer cell lines with both CDKN2A loss and wild type PP53 are sensitive to milodamatone. Furthermore, a strong Steroidglot mix of K thermal cell and ClíRelease

Speaker 5: CDK and Trey loss is associated with poor clinical outcomes and patients with non-small cell lung cancer, bladder cancer, and melanoma treated within the intract point inhibitors. Even in those patients with favorable predicted biomarkers such as high PBL1 or high TMB. Reactivation of P53 has been shown to lead to enhanced immune surveillance due to increased

Speaker 5: The demonstrated ability of milidametan to reactivate P53, both in cancer models and in patients, as well as our early MONCHO2 trial results have demonstrated that the NDM2-P53 complex matters in cancer biology.

Speaker 5: We have shown that milidametan, an inhibitor of the MDM2P53 complex, restores wild type P53. Thus, milidametan should not be limited to liposarcoma, as it may become part of a broader strategy to reactivate P53 in numerous tumor types that harbor wild type P53.

Speaker 5: Ultimately, up to 50% of cancers may be addressable by disrupting the MDM2-P53 interaction. Given the critical importance of P53 and the large number of patients potentially affected by MDM2-mediated P53 loss, there's a great interest in targeting the MDM2-P53 complex to restore P53 activity. And finally, as Avinash mentioned, we have terminated the RAD52 pre-clinical trial.

Speaker 5: additional avenues to innovate with biomarker-driven precision therapeutic strategies, we believe a better use of resources from the research team will be to evaluate the additional potential for milodamitin across new indications, in addition to evaluating other novel cancer targets. At this point, I will hand it over to our Chief Medical Officer, Richard Brace, to discuss additional updates.

Speaker 6: that evaluated the safety, PK, PD, and preliminary efficacy in a range of tumor types, including dedifferentiated liposarcoma.

We have adopted a novel intermittent dose and schedule of 260 milligrams daily given for three out of 14 days.

Preliminary results from this study demonstrated encouraging single agent activity in DDLPS

prompting our randomized Phase III mantra trial.

from which we expect top-line data in the second quarter of 2023. Among the 53 DDLPS patients in the phase 1 trial published in the JCO,

The median progression-free survival of all patients, regardless of dose and schedule, was 7.2 months.

which is already longer than that observed with the current standards of care of trabectatin or erythrin of approximately two months. And as previously discussed, for those patients who received the optimized dose and schedule of milledemptins, the median PFS was 7.4 months.

And within this cohort of 16 patients, when we exclude the five treatment-9 patients,

The median PFS was actually 8.0 months.

we previously announced that we had completed enrollment of 175 patients five months ahead of our prior year-end 2022 guidance.

We believe the accelerated enrollment completion speaks to the tremendous unmet need in patients with DDLPS, for which milidimatan offers a targeted therapeutic strategy relative to standard cytotoxic options.

We continue to affirm our expectations for top-line data in the second quarter.

As a reminder, this is an event-driven trial requiring at least 105 progression events to trigger the primary PFS analysis.

And our revised guidance to top-line data readout reflects the number of PFS events taking longer to occur than originally anticipated.

Rain met with the FDA and EMA prior to the start of the mantra study regarding the potential filing for marketing authorization.

And we anticipate that if the mantra data are supportive, we would intend to submit an NDA for mila demitan in DDLPS in the United States with similar submissions in Europe and possibly other regions as well.

Moving on to the Mantra 2 basket study of milidimatone in patients with MDM2 amplified tumors.

We provided an update on the last quarter's call with the latest data cutoff date of October 26, 2022.

And at that time, we reported two unconfirmed partial responses and two near PRs.

Using the same three out of 14 day dosing schedule in this study, safety was consistent with what was reported in the prior phase 1 study.

with no new safety signals being observed. The toxicity profile and adverse event frequencies are consistent with the previous experience that was done in schedule and also published in the JCO paper earlier referenced. We view these early data as encouraging.

with respect to both anti-tumor activity and safety.

particularly in this histologically and genetically diverse set of patients. Per our initial protocol, we are continuing to enroll up to 65 patients.

and we'll be expanding the study to new sites, including several outside the US. At present, we have 12 active sites in the United States.

We are not providing guidance on the next data update from the Manch2 study at this time.

We previously stated that it would be most logical to present an update from the Manchtout study when the data reveal the path forward.

The MANTRA2 study was designed with milli-derm monotherapy across all solid tumors exhibiting a certain degree of MDM2 amplification.

And if the data support meaningful confirmed responses across a range of cancers, we would intend to pursue a discussion with the FDA to better understand the requirements for a tumor-agnostic, registrational filing. That is the preferred path. learning.

If the data support meaningful confirmed responses across a range of cancers, we would intend to pursue a discussion with the FDA to better understand the requirements for a tumor-agnostic registrational findings. That is the preferred path. Let's call it path A.

The timing of those discussions with the FDA, if at all, will be driven by the data.

Part B, on the other hand, might represent a scenario where data suggests preferential activity in one or more tumor types, but not broad sensitivity.

In this scenario, RAIN might consider implementing tumor-specific expansion cohorts in the MANTRA2 as part of a protocol amendment.

In the event that milletimatan were to not show sustained meaningful monotherapy activity across a broad range of tumors, PAS-C might involve evaluation of a combination strategy. The most logical time to present an update on the MANTRA2 trial will therefore be when we are better informed by the data.

to better understand which of those three potential paths might be the most appropriate way forward.

On to mantra four. This is a phase one, two trial designed to enroll 30 patients with wild-type p53 advanced solid tumors that also exhibit loss of function of the CDKN2A gene.

This strategy could target over 40,000 patients per year in the U.S. We expect the start of MANTRA4, our second tumor-agnostic basket study, in the middle of the year.

This trial will be our first combination regimen with miladimitan using a checkpoint inhibitor, in this case, Roche's placentric or a Tisser-Lissimab. We recently pushed back the start of Mantra IV from the first quarter to the middle of the year.

to accommodate the FDA's suggestions around this trial protocol study design.

With multiple clinical strategies for milidermatin underway and in planning, we are excited by all the emerging and potential new clinical data and the associated potential commercialization opportunities and benefits to patients while providing a potentially best in class MDM2 inhibitor to patients across multiple tumor types.

With that, let me now turn it over to Nelson to review our financial results. Nelson. Thank you.

Thank you, Richard, and good afternoon, everyone.

I am pleased to provide an update of financial results for the fourth quarter when the full year ended December 31, 2022.

I would also like to invite you to review our Form 10-K filed today for more details. For the three months and year ended December 31, 2022, RAINN reported a net loss of $22.7 million and $75.7 million, respectively, as compared to a net loss of $18 million and $51.4 million for the same periods in 2021, respectively.

Net loss per share for the three months and year ended December 31, 2022 was $0.70 and $2.71, respectively, as compared to a net loss per share of $0.068 and $2.65 for the same periods in 2021, respectively.

Research and development expenses were $19.1 million and $61.4 million for the three months and year ended December 31, 2022 respectively as compared to $14.7 million and $40.8 million for the same periods in 2021 respectively. The increases were permanently related to clinical trials cost formula.

higher payroll related costs for R&D personnel, and various other R&D costs for Mila.

Non-cash-based compensation expenses included in R&D expenses were approximately $1 million and $3.8 million in the three months a year ended December 31, 2022, respectively, as compared to $1.1 million and $2.5 million in the same periods in 2021, respectively.

General and Adm. expenses were $4.5 million and $15.7 million for the three months and year-end of December 31, 2022, respectively, as compared to $3.4 million and $10.7 million for the same periods in 2021, respectively.

The increases were primarily due to the higher payroll costs for arranged GNA personnel, outside consulting, legal costs, and various third-party GNA costs.

Non-cash stock-based compensation expense included in G&A expenses were approximately $0.3 million and $1.1 million for the three months and year ended December 31, 2022 respectively, let's compare it to $0.2 million and $0.6 million for the same periods in 2021 respectively.

Total non-cash tax-based compensation expenses were approximately $1.3 million and $4.9 million for the three months and year ended December 31, 2022 respectively as compared to $1.3 million and $3.1 million for the same periods in 2021 respectively. As of December 31, 2022, total non-cash tax-based compensation expenses were approximately $1.3 million and $4.9 million for the same periods in 2021 respectively as compared to $4.9 million

REIN had $130.5 million in cash, cash equivalents and short-term investments. REIN will not provide guidance on cash runway at this time. We will continue to assess our cash runway and provide further guidance, if appropriate, after the release of our mantra top-line results in the second quarter of this year.

As of December 31, 2022, RAINN had approximately 36.3 million shares of CommonStacks Outstanding. To that, I'm going to turn the call back over to Avinash.

Thanks Nelson. With that we'll be happy to answer any questions. Operator?

Thank you. We will now be conducting a question and answer session.

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One moment please while we poll for questions. Our first question is from the line of Michael Smith with Guggenheim Partners. Please go ahead.

Hi guys, good evening and thanks for taking my questions. I had a follow up on your comments regarding Mantra 2. I think you mentioned the different potential clinical avenues you could take in the future depending on how the data pans out.

I guess, can you comment a little bit about how enrollment in the study has been going since you lowered the MDM2 amplification cutoff recently? I know you've added some more sites as well. And then I guess how many patients with data would you need to see to feel comfortable to determine next development steps for the basket study?

Let me take that one. In terms of how many more patients are we going to need to see before we figure out the next step, that's a hard one to answer before we see the data. It's going to be highly dependent on the data. We're going to have to figure out how many more patients are we going to need to see before we figure out the next step.

And certainly I think it may be reasonable to think that the more patient data that we have, the more confidence we're going to have in the next steps. So that it may be a function of how much confidence we want to have, which we can't comment on today without seeing the robustness of the results.

In terms of the first part of your question, in terms of where we sit today with enrollment, we have said prior, previously, that since the initial interim update, we have seen acceleration of enrollment, but we're not providing clarity today on where that enrollment currently sits. But we certainly did see an uptake since that initial update back in November .

and the dropping of the copy number threshold as previously stated. Okay, great. And then just on mantra, as we are closing out the first quarter soon, can you comment if you have reached the number of required events at this point? And if not, are you planning to disclose that publicly? We will open up the Power differential once this documentAm Jordan and Brandon will complete the note because it is based only for proper purpose. I was petoglio from Boston and

I'll take that one too, Michael. So, no, we are not disclosing whether or not we've hit a number of events and we don't plan to.

Thanks for taking my questions. Thanks Michael. Thank you. Our next question is from the line of Joe Catanzaro with Piper Sandler. Please go ahead.

Hey guys, thanks for taking my question here. Maybe one following up on the last one, appreciate you're not going to disclose when you hit events, but wondering if you could comment around your expectations around the amount of time it will take to lock the database, clean the data, and run the stats. And then maybe just a follow up on mantra four.

Just curious if that trial is taking into consideration any prior exposure to prior immune checkpoint inhibitor and if so what are some of those considerations?

Let me turn both those questions over to Richard. Richard, do you want to handle them? Sure, happy to. Regarding the mantra, there's a standard several weeks between database lot cleaning and cleaning weeks between database lot cleaning.

and then having the final data set ready for analysis. As you can imagine, I mean, this is a complex study with a number of different vendors involved with various components of the study. So it will take several weeks to do that. And, you know, beyond that, I'm not really gonna comment. Some is within.

checkpoint immune refractory patients. So they will all have failed resistance or refractory to prior IO therapy before they come on to our trial in combination with a tazibizumab.

Okay, got it. Appreciate you taking my questions. Thanks.

Got it. Appreciate you taking my questions. Thanks. Thank you.

Thank you. Our next question is from the line of Sumit Roy with Jones Research. Please go ahead. Non-cat reddit.

Hi everyone, thank you for taking the question. One question on MONTHRA 2 trial, the BASCET study, how extensive are the background genomic mutations status analysis are you doing? Are you just primarily focusing on the known obvious mutations in pancreas or breast and lung or is it fairly extensive?

I'll turn that one over to Bob.

diagnostic vendor. All patients are getting the Tempest XT test, which is currently comprised of more than 600 genes, really comprehensive and covers almost all cancer-related genes.

Are you doing any parallel preclinical analysis with those kind of co-mutations in the system to see if there is a p53 activation without adding any combination agent? There are multiple reasons for a p Honolulu button.

We've published several models already, some which have co-alterations and we believe that there is reason to think that there should be activity even in patients with co-alterations.

Thank you for taking the question. Thanks, Sumit. Thank you. Our next question is from the line of Jeff Jones with Oppenheimer.

Thank you for taking the question. Thanks, Sumit. Thank you. Our next question is from the line of Jeff Jones with Oppenheimer. Please go ahead.

Thanks guys for taking the question. Two questions. In the BASCAT trial, what type of signal are you looking for that would be considered supportive of approval down, call it Path A, and thenseyanpaul clue lib quiet.

A follow-up question to Bob's discussion on the mechanism of action. Something I only caught part of, you had mentioned that higher levels of MDM2 amplification didn't necessarily correlate with higher sensitivity. Could you... So the question being, what matter on the impact of edge beckoning and at the end, the concern when you feel you shouldn'tph Poles promise you wiJt would leave us with an easier way to yeah, forgive her... Did the thrust block from being and keep offering mercy Chinatown you sum correctly Law Heather law tons ph clear legislation created

give a little more detail on that. Thanks, Jeff. I'll hand both those questions over to Bob.

Yeah, Jeff, thanks for the question. So in terms of the threshold, you know, again, it's a bit of a guessing game, but based on several agnostic approvals by the FDA for targeted therapies, we believe that the response rate probably needs to be in the range of around 30%, obviously with reasonable durability. So that's the benchmark for an agnostic path.

may be still an unknown target what that level is, but higher levels won't necessarily expect for that. So we looked in the U101 study...

and looked at clinical outcomes versus copy number and patients with higher copy numbers in liposarcoma did not fare better than patients with lower copy numbers of MDM2. We've also seen no correlation yet also in the MONTRA 2 study.

And then you'll recall that we've also said that in preclinical data, there's no correlation between copy number and sensitivity to milidametam. So as long as we're above a certain threshold for amplification, greater amplification doesn't seem to predict for better outcome.

Thanks, guys. Thanks, Jeff. Thanks, Jeff.

Great, thanks guys. Thanks Jeff. Thank you. Our next question is from the line of Eagle.

Nojomovitz with Citigroup, please go ahead. Hi, thanks. I had three quick questions. On mantra 2, I think you mentioned that the part C scenario would involve potential combos. I'm curious what you could say more there in terms of which combos, whether you'd use the Etezo or something else. And then on RAD 52, I'm just curious if you'd expand a little bit on the lessons learned from the presentation later on if this is a big help.

days, is it weekly, you know, every few weeks, and is it possible that you might exceed the 105 at the point where you actually do the analysis? Thank you. Thanks, Yigal. I'll take the first one around the potential combos, and the rest, if you could question over to Bob and then have Richard address the frequency of checking the mantra.

So for the first part for mantra two, the path C, it doesn't necessarily just need to be a tesalizumab for additional combinations. I think we will refer you to some of the recent discussed data in combination with other non-IO combination partners such as MEK inhibitors. So for the first part for mantra two, the path C, it doesn't necessarily just need to be a tesalizumab for additional combinations.

So we will certainly look to other combinations that are far more broad reaching than just the Tazolizumab and just other I.O. strategies. But we're not ready to comment specifically on what we're planning to do there without knowing which path we're going to go down.

For RAD52, I'll turn it over to Bob. Yeah, so your goal in terms of the RAD52 program, just to give a little bit more clarity, you know, the goal of our screening was to identify biochemical assays that would predict potency in BRCA deficient, but not BRCA expressing.

chemical compounds further based on that lack of a valuable screen. Obviously we think it's an important target still, you know, perhaps given more time and not a need to prioritize other...

other programs we might have continued, but we believe that it would take a significant amount of time to get to a meaningful drug in that space. Time and money. Yeah. Yeah.

And the third question with regard to some frequency of mantra checking number of events. Thanks Richard.

Sure, thanks, Miguel. So currently we have the data transfers from the central readers, the Blinded Independent Review Committee every two weeks. The events are relatively infrequent at the tail end as you would expect. And so the second part of your question was, you know, could we potentially...

analyze a data set greater than 105 events, absolutely. It will depend on how many north, if you like, of 105, which is the minimum, will be in that data transfer. Okay, awesome. Thank you.

greater than 105 events, absolutely. It will depend on how many north, if you like, of 105, which is the minimum, will be in that data transfer. Okay, awesome. Thank you. Thank you, Garl.

Thank you. Our next question is from the line of Sam Slutsky with LifeSci. Please go ahead. Hey, good evening, everyone. Thanks for the question. I've got two for my end. I guess first, for the control arm assumption of three months in the ongoing mantra study, I realize that there's literature showing about a two-month KFS with trabectidin and DDLPS, which—

Yeah, so you know obviously the literature that we're referring to in the 2.2 months is the prospective registrational trial of Trevectidins. We believe that's the most useful data set. All other data that has been published has either been small single institutional studies or retrospective data which is never as

rigorous or unbiased as a phase three registrational trial. There may be some variations there, but we believe the largest study and the most meaningful is a prospective study of Trevectin that led to its registration.

Assuming that Milledimitin ultimately gets approved for DDLPS, remind us how big of a Salesforce you think you will need in the US and how you think about XUS strategy. I'm happy to take that one. Again, it is a smaller patient opportunity. As mentioned earlier, you know,

We think in the range of 25 to 35 sales reps in the US would be sufficient. And the strategy currently entails pursuing commercialization effort in the US from rain with partnering ex-US. Thank you for joining us today let's pick out this technical product and see how we put on on ahead of date background a few back hiding

Thanks, Sam.

Okay, thanks. Thanks, Sam. Thank you. Thank you.

Our next question is from the line of Greg Souvarnavian with Mizuho Securities. Go ahead.

Hey, good afternoon. Thanks for taking my questions. I had a couple, but one, if you could just remind us with the mantra study, the powering assumptions in what you need to show in order for the trial to be considered a win. Is it simply just stat sig? Is there proof that you can prove that you cannot.

just want to get your thoughts again on how confident you feel that second quarter is the appropriate timeline and that it won't potentially slip further. Thanks.

Thanks, Greg. I'll take the second one first. I'll throw it over to Richard for the first part of your question, but starting with the second question first, we're not going to provide any additional granularity beyond the second quarter timeline. Currently, we are highly confident that it'll be in that quarter.

So hopefully that addresses the second part of your question. Richard, if you want to review the power assumptions for mantra? Sure. So, excuse me, as we've previously disclosed, Greg, the study is powered at 94% to show a hazard rate of 0.50. So we're estimating within the study three months versus six months difference.

but it's 94%, and then the standard 5% type 1 error, two-sided type 1 error. Great. Thanks so much. Maybe just a quick follow-up. I was curious as to the comments from a...

financial side of things. So I guess this is for Nelson. Just the comments around I guess the withdrawing of cash runway guidance versus the prior guidance from a third quarter that you had runway to 2025. It's something I haven't really seen before and I know you.

had some prepared comments, but I'm just curious as to why you decide to change the language per se, especially in light of the recent equity raise. Thanks.

Thanks, Greg. So that really is predicated on the proximity of the top line results for MATRA, knowing the extent of the activities that we need to do after that. The prior guidance of the issue may be irrelevant anymore. So as I've said in the comments...

We will continue to evaluate this in the light of the staff line data and we'll provide further guidance after that if appropriate.

And just to follow up on that Greg, there's been no meaningful change in terms of our expected cash burn rate. So we don't want to convey that we are withdrawing guidance because of some meaningful change in the business. It's just that given a very near term large catalyst, which will influence the path forward.

Okay, understood. Thanks so much. Thank you. Our next question is from the line of Mitchell Kapoor with HC Wainwright. Please go ahead.

Hi everyone, thanks for taking the questions. I wanted to start off with mantra two and just talk about those patients. So you've shown efficacy in patients with a median of four prior lines of therapy, but I wanted to kind of relate that to the population that you continue to enroll, and trying to understand are they more or less healthy.

Does a higher copy number have anything to do with this disease severity? Thanks, Mitchell. I'll turn that question over to Bob in terms of the profile of the patients on mantra two. But just a broad comment, we're not providing any meaningful detail.

around what we're seeing in terms of the patients being enrolled just yet. So we can't give you a lot of color, but I'll throw it over to Bob to add any additional color you can add. Yeah, if I can understand your question. Well, we haven't changed any of the other inclusion exclusion other than copy number.

So that's unlikely to change the number of prior lines of therapy. We know that MDM2 gene amplification as a whole carries a worse prognosis, but again, we don't think that the change in copy number is going to necessarily affect.

the kind of clinical status of the patients in terms of prior lines of therapy or other meaningful clinical characteristics.

Okay, great. Thanks. That's helpful. Then on mantra four, just wanted to understand a little bit of the rationale for the pushback. I know you had mentioned that FDA recommendations were some of the reasons, but could you just comment a little bit more on why that might be? That's okay.

Okay, great. Thanks. That's helpful. And then on mantra four, just wanted to understand a little bit of the rationale for the pushback. I know you had mentioned that FDA recommendations were some of the reasons, but could you just comment a little bit more on why that might be? Sure. We'll turn that one over to Richard.

Sure, yeah, happy to answer that. So, I mean, there's nothing contentious there. Broadly speaking, I mean, I won't go into the fine detail, but broadly speaking, there were some helpful suggestions around essentially the inclusion criteria and some stopping rules.

which we were very happy to implement and incorporate into the protocol. So that was essentially it, nothing major or contentious at all.

Okay, great. Thank you all very much. Thanks, Mitchell. Thanks, Mitchell.

Thank you all very much.

Our next question is from the line of Tony Butler with EF Hutton. Please go ahead. Thanks very much. Two very brief questions, if I may. One is, what is the rationale or may I ask......

the rationale for utilizing a PD-L1 antibody. I mean, I recognize you've got a supply agreement with Roche versus a PD-1 antibody, and I say this.

the rationale for utilizing a PD-L1 antibody. I mean, I recognize you've got a supply agreement with Roche versus a PD-1 antibody. And I say this really—

for a couple of reasons, but one is in your K, you do make a comment about nonclinical data in immune competent mouse models in CRC with CDK N2A loss did demonstrate some common control activity with an ATP.

Just because there's a second site mutation, do you know or do you have a hypothesis as to where that exists? Or is there some other explanation? Thank you very much.

Thanks for the question, Tony. So I'll turn both those, I'll turn the first part of the first question, the nonclinical rationale for the IO combination with Mila to Bob before turning it, asking Richard to comment on the reason for the PD-L1 versus the PD-1. Let's address that first question first. Bob? Yes, sir.

Yeah, so in terms of patients progressing on miladametan, and I think this could apply to our mantra study with liposarcoma patients or really any patients, I would say we are not expecting second site mutations within MDM2. The binding pocket that our drug binds to is the same pocket that...

emergence of p53 mutations. There could be other mechanisms as well. And we have the ability to monitor and look at those resistance mechanisms through the use of ctDNA analysis.

And I believe that was your second question Tony so let's on the first part I think you're asking about the non clinical support that we have for the combination of An IO agent and no demo can is that right? Yes, but in the K Avenue says an ATP d1 I'm trying to split anti PD one from

And if there was a rationale for one over the other, because you have chosen a TESO in the Montreux-Fort study. Yeah, as you know, PD-1 and PD-L1 really target two sides of the same binding interaction, so we don't see a meaningful difference between the two.

then maybe as it applies to where these are at least being tested. So I'm grateful for that, Bob. Thank you.

Thanks, Tony.

Thank you. Our next question is from the line of Kumar Raja with Roth Capital Partners. Please go ahead. Oops.

Thanks for taking my questions again with regard to the mantra 2. Part B where you are thinking about one or two histologies. How do we get there given that we are seeing such a diverse histology in the interim data.

The question was with respect to path B of the scenarios we are considering for mantra 2, how do we get there because we have already seen activity across multiple tumor types. Did I restate that correctly? Yes, and also trying to get a sense like you know.

whether you think that there will be, you know, enriching for some populations there, or you know, just trying to get a sense how we get from like 7 or 8 to like 1 or 2.

Yeah, so just as a reminder, I'll take this one. As a reminder, we showed two early unconfirmed PRs. One of those patients with the PR was going to remain unconfirmed because of a death due to COVID. And then we had two near PRs.

So, as of the cutoff back in October , so four different tumor types with encouraging activity. Now since that moment in time, we're not revealing any additional patient data, but we'd want to make sure that we see meaningful confirmed responses, again, preferably across a range of tumor types. I think scenario B, path B, as we highlighted.

tumor types. So from the point of interim data release, again we're not providing you any additional color on this call, but I think we would want to see confirmed responses with meaningful durability of response and if we see that only in a few tumor types that would be the path B that we highlighted.

Yeah, and also in terms of the patient population size, right, like looks like breast and lung cancer as well as bladder, those are the predominant ones with greater than eight copy numbers. So how should we think about it?

So it's still too early to tell, but I'll ask Bob to review for the MDM2-AMP patient frequencies what the top tumor types are, just in terms of absolute patient numbers, but we are too early to make a call on where it's going to go. Yeah, you'll recall that the...

Top three tumor types are breast, lung, and bladder. So those three tumor types comprise about 75% of all the MDM2-amplified patients. Obviously, they have a very large incidence in their own right. And so the majority of MDM2-amplified patients fall under one of those.

As there are no further questions at this time, I would like to turn the floor back over to Avinish Walanki.

for the questions at this time. I would like to turn the floor back over to Abhneesh Walanki for closing comments.

Thanks, operator, and thanks to everyone that dialed into our call today. As a reminder, we expect top-line data from the pivotal phase 3 melodimatan trial in de-differentiated liposarcoma in the second quarter of this year. We also anticipate the start of the phase 1, 2 basket study, the mantra 4 study, and other60 studies in jeopardy.

in patients with p53 wild-type advanced solid tumors that have lost CDK N2A gene function around middle of the year. So we believe this will be an exciting year for RAIN and the MILA program, and we look forward to providing further update after the first quarter of 2023. Thank you.

Thank you. This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation. Goodbye.

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Greetings and welcome to the Rain on Call G, 4th Quarter and full year 2022 earnings call. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation.

If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dan Ferri of LifeSci Advisors.

Thank you. You may begin.

Thank you. You may begin. Thank you, operator. Good afternoon, everyone.

With me today on the phone are Avinish Phalanke, Chief Executive Officer of RAIN Oncology, Robert Doble, Chief Scientific Officer, Richard Bryce, Chief Medical Officer, and Nelson Cabotan, SVP of Finance. During today's call, Avinish will provide an update on the broader strategic vision right after having received and horned by Freelander drew right after that. He will also direct a information series for the group to identify and help them knew

for the Milodemitan franchise. Bob will review the biology and rationale of P53 reactivation as it relates to our Milodemitan clinical program.

Richard will provide an update on RAIN's clinical strategy.

Jared will provide an update on RAIN's clinical strategy, and Nelson will review the finagels.

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 involves assumptions that may never materialize or may prove to be incorrect.

Actual results could differ materially from those anticipated in such forward-looking statements as the result of various risks and uncertainties as described in Rain's annual report on Form 10-K .

for the year ended December 31, 2022, filed with the Securities and Exchange Commission and other SEC filings. All forward-looking statements made during this conference call are based on management's assumptions and estimates as of today, March 9, 2023. coronavirus in the country in awesome the

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 Avinish Phalanke, CEO of Rain Oncology.

Avinash? Thank you, Dan. And thanks to everyone for joining us for our fourth quarter and full year 2022 earnings highlights and corporate updates. To kick things off, we'd like to remind everyone of our name change to Rain Oncology in late 2022 to mark our anticipated growth as a dedicated and focused industry.

precision oncology business. We believe our new corporate name better reflects who we are and who we intend to remain. As RAIN continues to drive forward with our late-stage clinical program, Mila Demitan or Mila, our oral small molecule inhibitor of the MDM2-P53 complex, we'd like to approach today's call by providing context around our goal of demonstrating how P53 reactivation

through Miele's disruption of the complex, could potentially be transformative in treating a broad range of cancer patients. In the spirit of this, we anticipate the readout from our mantra study to potentially serve as the first validation of P53 reactivation in a Phase III clinical setting. If the mantra top-line data are favorable, we believe it will signify that reactivation of P53 matters. This will be an important validation as we begin to think about our initiatives beyond de-differentiated liposarcoma, or DDLPS.

On today's call, we'll also provide highlights from our 2022 progress and achievements. As a bit of biology review, we all know that P53 is the good guy in this story. We want active P53 to do what it's supposed to be doing, which is to protect us from cancer.

Today, there are no approved therapies in the treatment of cancer that are aimed at restoring or reactivating this innate anti-cancer agent. Cancer, broadly speaking, needs to find a way to get rid of P53. We all know that mutations in P53, those instances when P53 is broken and can't bind DNA to allow...)

P53 to do what it's supposed to do occurs in approximately half of all cancers. In the other half where P53 itself is not broken, cancer has to find other ways to get rid of it.

MDM2 is a critical means of deactivating P53 in instances when there are no P53 mutations present. Therefore, in tumors that rely on MDM2 to RID cells of P53, impeding the interaction of MDM2 and P53 could be a route to restoring P53's innate protective properties.

And even if MDM2 is not overexpressed, further reactivation or enhancement of wild-type P53 levels might further enhance anti-tumor activity of targeted therapies to address other oncogenic drivers. There are a multitude of potential indications to be considered.

especially if the tolerability profile of Miele enables a wide-ranging set of combination partners.

We believe a positive outcome in the monitor study would legitimize p53 reactivation as a route to treat a range of p53 wild-type cancers. In that scenario, milledimatan could be the first inhibitor of the MDM2-P53 complex to be submitted and possibly approved.

by the FDA and other regulatory authorities around the world. Bob will provide additional color on the P53 reactivation story, along with insights from the recent publication in the Journal of Clinical Oncology. Before Richard discusses how those data support the novel dose regimen of milodimitan, which is optimized to reduce toxicities.

associated with MDM2 P53 inhibition. Our clinical strategy, while starting in DDLPS, based on the totality of the data present at the time of licensing the program in 2020, will aggressively move to larger patient populations based on the experience we have gained with Mila in the clinic. We point out that after our initial indication in DDLPS, a traditional experimental laboratory in kidnapping patients and families over

targeting approximately 1,400 patients per year in the US. Our subsequent studies in the mantra two basket study targets 8,000 patients per year in the US. Our third plan study, the mantra four study, will target over 40,000 patients per year domestically.

That pattern should convey how we approach creating value for the MILA franchise, and as we evaluate the potential of both monotherapy and combination opportunities across the approximately 50% of the cancer population possessing wild-type P53 tumors. I will ask Bob and Richard to talk in more detail around recent data presented.

and the clinical strategy for melodimatam. I do want to comment briefly, however, on our preclinical research program focused on developing an inhibitor of RAD52. We have made a strategic determination to terminate this program based on data we have generated for the RAD52 research effort.

we do not anticipate a meaningful probability of success. Therefore, we are electing to focus our resources on identifying new indications for milodimitan or additional precision oncology programs by external licensing or internal development that may represent a more efficient deployment of capital for RAIN. In the prior quarter, we also remind you that we further improved our cash flow.

all current ongoing and planned clinical trials of melodimatam. This includes the Phase III mantra trial in DDLPS, for which data is expected in the second quarter of this year. It includes the ongoing Phase II mantra 2 basket trial and the planned Phase I-II mantra 4 basket trial, which we expect to commence by mid-year.

With that, I'd like to turn it over to our President and Chief Scientific Officer, Dr. Bob Doble. Bob? Thanks, Abhayesh. Let's start by continuing the discussion around the rationale for P53 reactivation for the treatment strategy in cancer.

MDM2 is a negative regulator of P53, blocking P53 transcriptional activity, promoting P53 export from the nucleus, and ultimately targeting the P53 protein for degradation. Thus, dysregulated MDM2 can provide an alternate and important mechanism for P53 loss in tumor cells and therefore facilities for P53 loss.

regulator of MDM2 activity and is encoded by the CDKN2A gene, which is lost in a large percentage of cancers. In January of this year, we published clinical trial data from the prior phase 1 study of milidametan in the Journal of Clinical Oncology, or JCO.

This detailed the results of the first-in-class human phase 1 study of milidametam that evaluated the safety, PK, PD, and preliminary efficacy in patients with advanced liposarcoma, solid tumors, or lymphomas.

These results indeed showed restoration of P53 levels and activity in patients with various cancers.

Tumor biopsies of patients treated with milidametan showed increased P53 protein levels and increased expression of P53 gene targets, such as P21. Additional pharmacodynamic marker testing showed an exposure-dependent increase in the P53 target gene MYC1, or GDF15, in patient blood samples following treatment with milidametan.

Although all tested DDLPS patients had MDM2 amplification, median PFS and DDLPS patients did not differ by levels of key biomarkers, including MDM2 or CDK4 copy number, nor by mRNA expression levels of MDM2, CDK4, or MDM4.

These data are consistent with our preclinical data showing that while MDM2 amplification is an important biomarker, higher levels of gene amplification do not correlate with increased milidametin sensitivity or improved clinical outcomes with MDM2 inhibitor treatment. Moving on to the mantra 2 basket study.

We continue to enroll patients with MDM2-amplified P53 wild-type solid tumors and plan to expand to additional sites worldwide with the goal of targeting full enrollment of approximately 65 patients across a range of solid tumors. Regarding the upcoming mantra 4 study, there is significant biological rationale to pursue combination of miladamitin and an immune checkpoint inhibitor.

In this case, rocha is a tazolizumab or tascentric. CDKN2A encodes a critical regulator of the MDM2P53 pathway, P14ARF. Loss of the CDKN2A gene therefore leads to increased MDM2 activity and decreased P53 levels in tumors.

Preclinical work confirms that cancer cell lines with both CDK-N2A loss and wild type TP53 are sensitive to melodamatan.

Furthermore, CDK and Tres loss is associated with poor clinical outcomes in patients with non-small cell lung cancer, bladder cancer, and melanoma treated with immune checkpoint inhibitors.

even in those patients with favorable predictive biomarkers such as high PVL1 or high TMB. Reactivation of P53 has been shown to lead to enhanced immune surveillance due to increased MHC class 1 antigen presentation, interferon gamma signaling, and other mechanisms. Based on this rationale, we are excited to launch the Monfer4 study in patients with P53.

as well as our early MONCHA 2 trial results have demonstrated that the MDM2-P53 complex matters in cancer biology. We have shown that milidametan, an inhibitor of the MDM2-P53 complex, restores wild-type P53. Thus, milidametan should not be limited to liposarcoma, as it may become part of a broader strategy to reactivate P53 in numerous tumor types that harbor wild-type P53. Ultimately, up to 50% of cancers may be addressable by disrupting the MDM2-P53.

deficient tumors. We did not achieve meaningful success with our early research efforts around this target because we determined that the current biochemical assays to screen novel RAD52 inhibitors did not correlate with the desired cellular effect of potency and selectivity.

While we continue to evaluate additional avenues to innovate with biomarker-driven precision therapeutic strategies, we believe a better use of resources from the research team will be to evaluate the additional potential for milodametin across new indications, in addition to evaluating other novel cancer targets.

At this point, I will hand it over to our Chief Medical Officer, Richard Brace, to discuss additional updates around RAIN's clinical trial pipeline. — Richard.

At this point, I will hand it over to our Chief Medical Officer, Richard Brace, to discuss additional updates around RAIN's clinical trial pipeline. Richard? Thank you, Bob, and good afternoon, everyone.

As both Avanish and Bob iterated, we recently published in the JCO the results from the phase one first in human study of milledimatone that evaluated the safety, PK, PD, and preliminary efficacy in a range of tumor types including dedifferentiated liposarcoma. We have adopted a novel intermittent dose and schedule of 260 milligrams daily.

given for three out of 14 days. Preliminary results from this study demonstrated encouraging single agent activity in DDLPS, prompting our randomized phase three mantra trial.

from which we expect top-line data in the second quarter of 2023. Among the 53 DDLPS patients in the phase 1 trial published in the JCO,

the median progression-free survival of all patients, regardless of dose and schedule, was 7.2 months, which is already longer than that observed with the current standards of care of Travectatin or a ripulin of approximately two months.

And as previously discussed, for those patients who received the optimized dose and schedule of Milidimetan, the median PFS was 7.4 months.

And within this cohort of 16 patients, when we exclude the five treatment naive patients,

The median PFS was actually 8.0 months. We believe these data further support the opportunity for millidemic return to exhibit a favorable outcome in the pivotal mantra study.

Moving on to our phase 3 mantra study, we previously announced that we had completed enrollment of 175 patients five months ahead of our prior year-end 2022 guidance. We believe the accelerated enrollment completion...

speaks to the tremendous unmet need in patients with DDLPS, for which milidimitin offers a targeted therapeutic strategy relative to standard cytotoxic options. We continue to affirm our expectations for top-line data in the second quarter. As a reminder, this is an event-driven trial.

requiring at least 105 progression events to trigger the primary PFS analysis. And our revised guidance to top line data readout reflects the number of PFS events taking longer to occur than originally anticipated. RAIN met with the FDA and EMA prior to the start of the mantra study regarding the potential filing for marketing authorization.

We anticipate that if the mantra data are supportive, we would intend to submit an NDA for the NDA in the United States with similar submissions in Europe and possibly other regions as well. Moving on to the mantra two basket study.

of millidimatone in patients with MDM2 amplified tumors, we provided an update on the last quarter's call with the latest data cut off date of October 26, 2022.

At that time, we reported two unconfirmed partial responses and two near PRs. Using the same three out of 14 day dosing schedule in the study, safety was consistent with what was reported in the prior Phase 1 study.

with no new safety signals being observed. The toxicity profile and adverse event frequencies are consistent with the previous experience that was done in schedule, and also is published in the JCO paper earlier referenced. We view these early data as encouraging.

with respect to both anti-tumor activity and safety, particularly in this histologically and genetically diverse set of patients. Per our initial protocol, we are continuing to enroll up to 65 patients and will be expanding the study to new sites, including several outside the US.

At present, we have 12 active sites in the United States. We are not providing guidance on the next data update from the Manch2 study at this time. We previously stated that it would be most logical to present an update from the Manch2 study when the data reveal the path forward. The Manch2 study was designed with milli-derm monotherapy across all follow tumors.

exhibiting a certain degree of MDM2 amplification. And if the data support meaningful confirmed responses across a range of cancers, we would intend to pursue a discussion with the FDA to better understand the requirements for a tumor-agnostic, registrational finding.

a certain degree of MDM2 amplification. And if the data support meaningful confirmed responses across a range of cancers, we would intend to pursue a discussion with the FDA to better understand the requirements for a tumor-agnostic, registrational filing. That is the preferred path.

Let's call it path A. The timing of those discussions with the FDA, if at all, will be driven by the data. Path B, on the other hand, might represent a scenario where data suggests preferential activity in one or more tumor types, but not broad sensitivity. In this scenario, RAIN might consider implementing tumor-specific expansion cohorts in the MANTRA2 vein.

as part of a protocol amendment. In the event that milidimatan were to not show sustained meaningful monotherapy activity across a broad range of tumors, path C might involve evaluation of a combination strategy. The most logical time to present an update on the MANTRA2 trial will therefore be when we are better informed by the data to better understand which of those three potential paths might be the most appropriate way forward.

In the event that millet amitane were to not show sustained meaningful monotherapy activity across a broad range of tumors, path C might involve evaluation of a combination strategy. The most logical time to present an update on the MANDTRO2 trial will therefore be when we are better informed by the data to better understand which of those three potential paths might be the most appropriate way forward. On to MANDTRO4.

This is a phase 1, 2 trial designed to enroll 30 patients with wild type P53 advanced solid tumors that also exhibit loss of function of the CDKN2A gene. This strategy could target over 40,000 patients per year in the U.S.

We expect the start of MANTRA4, our second tumor-agnostic basket study, in the middle of the year. This trial will be our first combination regimen with milidimatan using a checkpoint inhibitor, in this case, rosacea centric, or a system of this human.

We recently pushed back the start of MENTRA 4 from the first quarter to the middle of the year to accommodate the FDA's suggestions around this trial protocol study design.

With multiple clinical strategies for Milledermoten underway and in planning, we are excited by all the emerging and potential new clinical data and the associated potential commercialization opportunities and benefits for patients.

while providing a potentially best in class MDM2 inhibitor for patients across multiple tumor types. With that, let me now turn it over to Nelson to review our financial results. Nelson. Thank you, Richard, and good afternoon, everyone.

I am pleased to provide an update of financial results for the fourth quarter and the full year ended December 31, 2022. I would also like to invite you to review your Form 10-K filed today for more details.

For the three months and year ended December 31, 2022, RAIN reported a net loss of $22.7 million and $75.7 million respectively as compared to a net loss of $18 million and $51.4 million for the same periods in 2021 respectively. Net loss per share for the three months and year ended December 31, 2022.

was $0.70 and $2.71, respectively, as compared to a net loss per share of $0.068 and $2.65 for the same periods in 2021, respectively. Research and development expenses were $19.1 million and $61.4 million for the three months and year ended December 31, 2022, respectively, as compared to $14.7 million and $40.8 million for the same periods in 2021, respectively.

The increases were permanently related to clinical trial cost formula, higher payroll-related costs for R&D personnel, and various other R&D costs formula. Non-cash stack-based compensation expenses included in R&D expenses were approximately $1 million and $3.8 million in the three months and year ended December 31, 2022, respectively.

as compared to $1.1 million and $2.5 million in the same periods in 2021, respectively. General and immersive expenses were $4.5 million and $15.7 million for the three months and year-end of December 31, 2022, respectively, as compared to $3.4 million and $10.7 million for the same periods in 2021, respectively. The increases were permanently due to the higher payroll yield costs for range TNA per...

Total non-cash tax-based compensation expenses were approximately $1.3 million and $4.9 million for the three months and year ended December 31, 2020 respectively as compared to $1.3 million and $3.1 million for the same periods in 2021 respectively. As of December 31, 2022, total non-cash tax-based compensation expenses were approximately $1.3 million.

RAIN had $130.5 million in cash, cash equivalents and short-term investments. RAIN will not provide guidance in cash runway at this time. We will continue to assess our cash runway and provide partner guidance, if appropriate, after the release of our mantra top-line results in the second quarter of this year. As of December 31, 2022, RAIN had approximately

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Our first question is from the line of Michael Smith with Guggenheim Partners. Please go ahead. Hi guys, good evening and thanks for taking my questions. I had a follow-up on your comments regarding Mantra 2. I think you mentioned the different potential clinical avenues you could take in the future depending on how the data pans out.

I guess, can you comment a little bit about how enrollment in the study has been going since you lowered the MDM2 amplification cutoff recently? I know you've added some more sites as well. And then I guess how many patients with data would you need to see to feel comfortable to determine next development steps for the basket study? Hi, Michael. Thanks for the question. It's Avinish. Let me take that one. So in terms of...

How many more patients are we going to need to see before we figure out the next step? That's a hard one to answer before we see the data. It's certainly going to be highly dependent on the data. And certainly, I think it may be reasonable to think that the more patient data that we have the more confidence we're going to have in the next step. So that it may be a function of

but we are not providing clarity today on where that enrollment currently sits. We certainly did see an uptick since the initial update back in November and the dropping of the copy number threshold as previously stated. Okay, great.

Have you reached, or can you comment if you have reached the number of required events at this point, and if not, are you planning to disclose that publicly? Yeah, I'll take that one too, Michael. So, no, we are not disclosing whether or not we've hit the number of events, and we don't plan to. Great. Well, thanks for taking my questions. Thanks, Michael.

Can you comment if you have reached the number of required events at this point? If not, are you planning to disclose that publicly? I will take that one too, Michael. So, no, we are not disclosing whether or not we have hit the number of events, and we don't plan to. Great. Well, thanks for taking my questions. Thanks, Michael. Thank you. Our next question is from Michael.

reached the number of recorded events at this point? And if not, are you planning to disclose that publicly? Yeah, I'll take that one too, Michael. So, no, we are not disclosing whether or not we've hit the number of events, and we don't plan to. Great, well, thanks for taking my questions. Thanks, Michael. Thank you. My next question is from the line of...

Joe Cartanzaro with Piper Sandler, please go ahead. Hey, guys. Thanks for taking my question here. Maybe one following up on the last one, appreciate you're not going to disclose when you hit events, but wondering if you could comment around your expectations around the amount of time it will take to lock the database, clean the data, and run the stats. And then maybe just a follow-up on mantra four. Just curious if that trial is taking into consideration any prior exposure to prior immune checkpoint inhibitor, and if so, what are some of those considerations?

Let me turn both those questions over to Richard. Richard, do you want to handle them? Sure, happy to. Regarding the mantra, there's a standard several weeks between database lot cleaning and then having the final dataset ready for analysis. As you can imagine, this is a complex study with a number of different vendors involved. One of the keyrolled options for this analysis is Saoirse. The third priority for this is to make sure everything 2007 and 2016 run according to that Reporter Board runtime. Depends on where that failed and what changes, what daddy said happened in 2018. We also then use Fastasp on the network for vast potential problems and for the Hur Half tw cadence between 2010 and 2017 compared to mid 2018.

with various components of the study. So it will take several weeks to do that. And beyond that, I'm not really gonna comment. Some is within our control and some is with the external vendors to finalize and transfer the databases. I think your second question...

concerned Mancha-4. So the study is designed for checkpoint immune refractory patients. So they will all have failed, resistant or refractory to prior iotherapy before they come on to our trial in combination with atizolizumab. Okay, got it. Appreciate you taking my questions, thanks.

Thank you. Thank you. Our next question is from the line of Sumit Roy with Jones Research. Please go ahead. Hi, everyone. Thank you for taking the question. One question on MONTHRA 2 trial, the basket study.

How extensive are the background genomic mutation status analyses are you doing? Are you just primarily focusing on the known obvious mutations in pancreas or breast and lung or is it fairly extensive? I see. Thanks for the question. I'll turn that one over to Bob.

Thanks for the question. It's actually a very extensive analysis. You'll recall that we're using Tempest as our diagnostic vendor. All patients are getting the Tempest XT test, which is currently comprised of more than 600 genes. Really comprehensive and covers almost all.

We've published several models already, some which have co-alterations and we believe that there is reason to think that there should be activity even in patients with co-alterations. Thank you for taking the question. Thanks so much.

Thank you. Our next question is from the line of Jeff Jones with Oppenheimer. Please go ahead. Thanks, guys, for taking the question. Two questions. In the BASCET trial, what type of signal are you looking for that would be considered supportive of approval down?

to amplification didn't necessarily correlate with higher sensitivity. Could you...

give a little more detail on that. Thanks, Jeff. And that both those questions over to Bob.

Yeah, Jeff, thanks for the question. So in terms of the threshold, you know, again, it's a bit of a guessing game, but based on several agnostic approvals by the FDA for targeted therapies, we believe that the response rate probably needs to be in the range of around 30%, obviously with reasonable durability. So that's the benchmark for...

correlation as long as you have some level of MDM2 amplification that may be still an unknown target what that level is, but higher levels won't necessarily be fixed for that. So we looked in the U101 study and looked at

clinical outcomes versus copy number and patients with higher copy numbers in liposarcoma did not fare better than patients with lower copy numbers of MDM2. We've also seen no correlation yet also in the MONTRA2 study and then you'll recall that we've also said that in pre-clinical data there's no correlation between copy number and sensitivity than the Lidamitan.

Please go ahead.

Hi, thanks. I had three quick questions. On Montreux-2e, I think you mentioned that the Part C scenario would involve potential combos. I'm curious what you could say more there in terms of which combos, whether you'd use the TESO or something else. And then on RAB 52, I'm just curious if you'd expand a little bit on the lessons learned from that program. I think you mentioned something about…

the assay sensitivity not necessarily correlating with potency, if I understood that correctly, and how that might help you with target selection in the future. And then third on mantra, I know you have to hit the 105 and you can't comment, but can you say the frequency with which you're actually checking the events these days? Is it weekly, you know, every few weeks? And is it possible that you might exceed the 105 at the point where you actually do the analysis? Thank you. Thanks, Yigal. I'll take the first one around the potential combos.

I hand the ratchet to your question over to Bob and then have Richard address the frequency of checking the mantra events. So for the first part for mantra two, the path C, it doesn't necessarily just need to be a teselizumab for additional combinations. I think we will refer you to some of the recent discussed data in combination with other non-IO combination partners such as MEK inhibitors. So we will certainly look to other combinations that are far more broad reaching than just the teselizumab and just other IO strategies. But we are not ready to comment.

specifically on what we're planning to do there without knowing which path we're going to go down. For RAD52, I'll turn it over to Bob. Yeah, so your goal in terms of the RAD52 program, just to give a little bit more clarity, you know, the goal of our screening was to identify biochemical assays that would predict potency in BRCA deficient but not BRCA expressing.

cell lines, so again, potency and selectivity. Unfortunately, none of the existing assays that we used were able to give that, and so we weren't able to meaningfully progress candidate chemical compounds further based on that lack of valuable screen. Obviously, we think it's an important target still, perhaps given more time and not a need to prioritize other.

other programs we might have continued, but we believe that it would take a significant amount of time to get to a meaningful drug in that space. Time and money. And the third question with regard to some frequency mantra checking the number of events, Richard?

Sure, thanks, Miguel. So currently we have the data transfers from the central readers, the Blinded Independent Review Committee every two weeks. The events are relatively infrequent at the tail end, as you would expect. And so the second part of your question was, you know, could we potentially...

analyze a data set greater than 105 events, absolutely. It will depend on how many Norths, if you like, of 105, which is the minimum, will be in that data transfer. Okay, awesome. Thank you. Thank you, Paul.

Thank you. Our next question is from the line of Sam Slutsky with LifeSci. Please go ahead.

Hey, good evening, everyone. Thanks for the question. I've got two from my end. I guess first, for the control arm assumption of three months in the ongoing mantra study, I realize that there's literature showing about a two-month KFS with Trabectin and DDLPS, which you referenced. Could you just remind us if there's other data that have been published with Trabectin and DDLPS specific data?

that we're referring to in the 2.2 months is the prospective registrational trial of trabecidins. We believe that's the most useful data set. All other data that has been published has either been small single institutional studies or retrospective data which is never as rigorous or unbiased as a phase 3 registrational trial.

So there may be some variations there, but we believe the largest study and the most meaningful is that in the prospective study of Trevecta that led to its registration. Got it. Okay. And then assuming that Milledimatin ultimately gets approved for DDLPS, just remind us how big of a sales force you think you'll need in the US and then how you're thinking about XQS strategy. Sure, Sam. I'm happy to take that one. So again, it's a smaller patient opportunity. We think in the range of 25 to 35 sales reps in the US would be...

had a couple, but one, if you could just remind us with the mantra study, the powering assumptions in what you need to show in order for the trial to be considered a win, is it simply just that SIG? Is there some other elements of whatever you need to see that would make it a clear win? That would be helpful.

And then my second question just has to do with the timing of when you'll get the readout. I know that the guidance is second quarter, but to get your thoughts again on how confident you feel that second quarter. Is the appropriate timeline and that it won't potentially flip further. Thanks. Thanks, Greg. I'll start. I'll take the second one. First, I'll throw it over to Richard.

for the first part of your question, but starting with the second question first, we're not gonna provide any additional granularity beyond the second quarter timeline, and currently we are highly confident that it'll be in that quarter. So hopefully that addresses the second part of your question. Richard, if you want to review the power assumptions.

within the study three months versus six months difference, but it's 94% and then the standard 5% type 1 error, two-sided type 1 error. Great, thanks so much and maybe just a quick follow-up. I was curious as to the comments from the financial side of things.

is for Nelson. Just the comments around I guess the withdrawing of cash runway guidance versus the prior guidance from the third quarter that you had runway to 2025. It's something I haven't really seen before and I know you had some prepared comments but I'm just curious as to why you decide to change the language.

you know, the prior guidance may be irrelevant anymore. So as I've said in the comments, we will continue to evaluate this in the light of the top line data and we'll provide further guidance, you know, after that if appropriate.

And just to follow up on that Greg, there's been no meaningful change in terms of our expected cash burn rate. So we don't want to convey that we are withdrawing guidance because of some meaningful change in the business. It's just that given a very near near term large catalyst, which will influence the path forward. Okay, understood. Thanks so much.

Thank you. Our next question is from the line of Mitchell Kapoor with HC Wainwright. Please go ahead. Hi, everyone. Thanks for taking the questions. I wanted to start off with mantra two and just talk about those patients. So, you've shown efficacy in patients with a median of four prior lines of therapy, but I wanted to kind of relate that to the population that you continue to enroll.

and trying to understand are they more or less healthy? And does a higher copy number have anything to do with this disease severity? Thanks, Mitchell. I'll turn that question over to Bob in terms of the profile of the patients on Lactra 2. But just as a broad comment, we're not providing any meaningful detail around what we're seeing in terms of the patients being enrolled just yet. So we can't give you a lot of color. But I'll throw it over to Bob to add any additional color you can add. Bob, are you all hooked up?

If I can understand your question, well, we haven't changed any of the other inclusion exclusion other than copy number. So that's unlikely to change the number of prior lines of therapy. We know that MDM2 gene amplification as a whole carries a worse prognosis. But again, we don't think that the change in copy number is going to necessarily affect

the kind of clinical status of the patients in terms of prior lines of therapy or other, I think, meaningful clinical characteristics. Okay, great. Thanks. That's helpful. Then on mantra four, just wanted to understand a little bit of the rationale for the pushback. I know you had mentioned that FDA recommendations were some of the reasons, but could you just comment a little bit more on why that might be?

clinical status of the patients in terms of prior lines of therapy or other meaningful clinical characteristics. Great. Thanks. That's helpful. On mantra four, I just wanted to understand a little bit of the rationale for the pushback. I know you had mentioned that FDA recommendations were some of the reasons, but could you just comment a little bit more on why that might be? Sure. I'll turn that one over to Richard.

Sure, yeah, happy to answer that. So, I mean, there was nothing contentious there. Broadly speaking, I mean, I won't go into the fine detail, but broadly speaking, there was some helpful, there were some helpful suggestions around the, essentially the inclusion criteria and some stopping rules, which we were very happy to implement and incorporate into the protocol. So that was essentially it. You know, nothing major or contentious at all.

Okay, great. Thank you all very much. Thanks, Mitchell. Thank you. Our next question is from the line of Tony Butler with EF Hutton. Please go ahead. Thanks very much. Two very brief questions, if I may. One is, what is the rationale for utilizing a PD-L1 antibody? I recognize you've got a... You've got an Aqua

a supply agreement with Roche versus a PD-1 antibody. And I say this really for a couple of reasons. But one is in your K, you do make a comment about nonclinical data in immune competent mouse models in CRC with CDK N2A loss did demonstrate, you know, some common control activity with an anti-PD-1. So that's question one. And the second question is,

In patients that actually respond to melodimitan, let's assume that these are in lipocycloma patients, and then at some point progress. Do they progress because there's a second site mutation? Do you know or do you have a hypothesis as to where that exists? Or is there some other explanation? Thank you very much. Thanks for the question, Tony. So I'll turn both those.

I'll turn the first part of the first question, the nonclinical rationale for the IO combination with Milla to Bob before turning it, asking Richard to comment on the reason for the PD-L1 versus the PD-1. Let's address that first question first. Bob? Yeah, so in terms of patients progressing on Milla Damatand, and I think this could apply, you know, to our mantra study with liposarcoma patients or really any patients, I would say we are not expecting second site mutations within MDM2. The binding pockets that are...

through the use of CT DNA analysis. And I believe that was your second question Tony. So let's on the first part I think you're asking about the non-clinical support that we have for the combination of an IO agent and milodimitin. Is that right?

Yes, but in the K, Avonesia says in anti-PD-1. So I'm trying to split anti-PD-1 from PD-L1. And if there was a rationale for one over the other, because you have chosen a TESO in the Montreault stud.

As you know, PD-1 and PD-L1 really target two sides of the same binding interaction, so we don't see a meaningful difference between the two clinically or pre-clinically. That's the short answer. I appreciate that. I think there are some clinical models.

suggests that there are differences, RCC being one and clearly lung being another. But it's irrelevant maybe as it applies to where these are at least being tested. So I'm grateful for that, Bob. Thank you. Thanks, Tony.

Thank you. Our next question is from the line of Kumar Raja with Roth Capital Partners. Please go ahead. Thanks for taking my questions again with regard to the mantra two. Part B where you are thinking about one or two histologies. How do we get there given that we are seeing such a diverse histology in the interim data job?

Sure. Hi, Kumar. Yeah, so the question was, with respect to path B of the scenarios we're considering for mantra two, how do we get there? Because we've already seen, we've already seen activity across multiple tumor types. Is that is that? Did I restate that correctly? Yes, and also trying to get a sense like, you know,

Sure. Hi, Kumar. Yeah, so the question was, with respect to Path B of the scenarios we're considering for mantra two, how do we get there because we've already seen activity across multiple tumor types. Did I restate that correctly? Yes, and also trying to get a sense like, you know, whether you

Sure. Hi Kumar. Yeah, so the question was with respect to path B of the scenarios we're considering for mantra 2, how do we get there because we've already seen activity across multiple tumor types. Is that, did I restate that correctly? Yes, and also trying to get a sense like, you know, whether you think that there will be a

be enriching for some populations there or just trying to get a sense how we get from like 7 or 8 to like 1 or 2? Yes, so just as a reminder, I'll take this one. As a reminder, we showed two early unconfirmed PRs. One of those patients with the PR was going to remain unconfirmed because of a death due to COVID and then we had two near PRs. So as of the cutoff back in October , so four different tumor types with encouraging activity. Now since that moment in time, we're not revealing any additional patient data, but we'd want to make sure that we see meaningful confirmed responses, again, preferably across a range of tumor types. I think scenario B, path B as we highlighted, suggested that if we start seeing confirmed responses with meaningful durability in a couple of tumor types, we could see a lot

Yeah, you'll recall that the top three tumor types are breast, lung, and bladder. So those three tumor types comprise about 75% of all the MDM2-amplified patients. Obviously, they have a very large incidence in their own right, and so the majority of MDM2-amplified patients fall into one of those three tumor histologies. The remaining 25% are obviously remaining.

into our call today. As a reminder, we expect top-line data from the pivotal phase 3 melodimatan trial in de-differentiated liposarcoma in the second quarter of this year. We also anticipate the start of the phase 1, 2 basket study, the mantra 4 study in patients with p53 wild-type advanced solid tumors that have lost CDK N2A gene function around middle of the year.

So we believe this will be an exciting year for RAIN and the MELA program and we look forward to providing further updates after the first quarter of 2023. Thank you. This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.