Rain Enhancement Technologies Holdco, Inc. Q4 FY2021 earnings call

Avanish Vellanki discussed progress on milademetan clinical trials, including the MANTRA-1 Phase 3 trial for liposarcoma, MANTRA-2 tumor-agnostic basket trial, MANTRA-3 for Merkel cell carcinoma, and MANTRA-4 combination trial with Roche's atezolizumab. Richard Bryce provided details on the MANTRA-1 trial's progress, MANTRA-2's patient enrollment and interim analysis plan, and MANTRA-3's start timeline. Robert Doebele talked about preclinical work on RAD52 inhibitors and the mechanism behind the MANTRA-4 trial. Nelson Cabatuan reviewed financial results, noting a net loss of $18M in 4Q 2021 vs $5.4M in 4Q 2020, increased R&D expenses, and a cash position of $140.2M as of Dec 2021 with runway into 2024.

No product segment breakdown with revenue contribution provided in the transcript.

Rain anticipates having runway into the first half of 2024 with its cash position. Management will be prudent with capital to prioritize data generation for milademetan. MANTRA-2 is expected to have early data readout in the second half of 2022, MANTRA-3 will start in the second half of 2022, and MANTRA-4 will commence in the second half of 2022.

The current capital markets environment in the biotech industry poses a challenge for further financing. Uncertainties exist regarding clinical trial outcomes and the interpretation of data from the trials.

Q: Hi, guys. Thanks for taking the question. Just a question on the atezo combo. Just wondering, is there any scientific reasoning behind picking a PD-L1 as opposed to a PD-1? Does it matter which way you do that when you combine with milademetan?

A: How are you doing? Thanks for the question. I'll hand it over to Bob. Yeah. Thanks for the question. At this time, no, we see no significant scientific differentiation between PD-L1 and PD-1 or significant differences in clinical activity. So at this time we don't see a reason to distinguish between the 2 for the purposes of the combination trial for MANTRA-4.

Q: Hey, good afternoon. This is Yige on for Michael. Congrats on the progress, and thanks for taking our questions. I guess a quick one from us. According to some recent literature CDKN2A sometimes co-deletion with MTAP. So first of all, do we know how frequent is the co-deletion? And in that case, how would targeting CDKN2A through MDM2 inhibition position relatively to some of the other strategies to target MTAP deletion?

A: Thanks for the question, Yige. Let me turn that over to Bob. Yeah. Thanks for the question. The co-deletion of MTAP with CDKN2A is thought to be incredibly frequent, probably approaching 100%, it's actually the next adjacent gene to CDKN2A, so it's probably co-deleted in the vast majority, if not all, CDKN2A loss tumors. I think the relative contribution of the 2 genes are still being worked out and whether MAT2A or PRMT5 inhibitors may have potential effect in CDKN2A loss tumors or if there are other criteria that need to be factored in. It still remains to be known, but we have been thinking about this question with regard to CDKN2A loss and the use of our milademetan, our preclinical research program.

Q: Perfect. Thanks, guys, for taking my questions here. Maybe the first one on MANTRA-2. I'm wondering if you could speak to the early experience around screening and identifying patients with MDM2 amplification and where expectations are currently for the interim readout expected later this year in terms of number of patients and extent of follow-up. Thanks, and I have a follow-up.

A: Thanks, Joe. Let me turn that one over to Richard. Hi, Joe. Thanks for the question. So MANTRA-2, as you recall, we kicked off in November of last year, first site activated, first patient in. We're still in the process of activating sites, so it's still very early in the game here. Most of the sites really won't be open until the end of this month, so it's still a little bit early to comment on that and the distribution of tumors and other things that are sort of implicit in the question that you asked. I think, generally, in terms of what data we're going to be able to share toward the end of the year, our expressed opinion is that, we hope to come up with a data set of somewhere around 10 to 12 patients with a meaningful duration of follow-up, in other words, 4 or 5 months, something of that order. So that's what we're aiming to do, and we're tracking toward that at the moment. That's as best as I can answer at this time.

Q: Okay. Thanks. That's helpful. And then a follow-up on MANTRA-4. So Richard, you mentioned the dose deescalation sort of built-in design there. I'm wondering if you could speak to maybe what gives you confidence that you could achieve the full monotherapy doses for each and whether the FDA needs to sign off on this design, given maybe their recent push around identifying the minimally effective dose? So I'm not sure if that applies to combination strategies as well. Thanks.

A: Sure. No, that's a fair question. So I'll answer the second part first, which is that we will obviously submit the protocol to the IND, and the FDA will have the opportunity to comment, but we don't explicitly need FDA buy in to the design. That's something that we do at risk. The precedent has already been said. I'm sure you're well aware of the -- a previous study with an MDM2 inhibitor has been run with a checkpoint inhibitor following a very similar process. They had a dose escalation but actually ended up with a full dose of both the checkpoint inhibitor and the MDM2 inhibitor. And I think given what I said before in the introduction here, there are no overlapping toxicities. We wouldn't expect any reason to deescalate with atezo, compromising the tolerability, if you like, of milademetan or vice versa. So we're very confident that we can save time, effort, money, and patients by going at the top dose of the standard monotherapy doses and see what happens, take it from there.

Q: Hi. This is Mansi on for Corrine. Thank you for taking my questions. On MANTRA-2, I wanted to ask about what your plan would be [indiscernible] the Phase 2 data, if you would be looking to go to FDA to see about the registrational trial? And also, are you thinking about expanding the specific cohorts there?

A: I don't think we got the first part of the question. I think we can address the second part. The second part we heard is, how we're thinking about expanding to additional tumor types or cohorts there? Let me turn that over to Richard to talk about the second part, and then maybe we'll have you repeat the first part of your question. Sure. So thanks for the question. And regarding the second part, so the study is it's currently designed, as I think we're well aware we've announced before is 65 patients. We have a cap on the number in any particular tumor type that comes in, and that's around 12 or so. And so really, what we'll be looking at, first of all, we're setting off on a tumor-agnostic approach. We would expect and hope to see similar responses across all tumor types. Given the mechanism of action, there shouldn't really be any differentiation between them. But it will give us an opportunity as the data accumulates to see whether there is greater successes, greater responses, greater durability of responses in some types and others that may give an indication to sort of move forward than one particular strategy or one particular sort of tumor type or basket of tumor types within that. But I think the beauty of this particular trial design is that it gives the opportunity to look at -- if you get suboptimal responses, you can look at combination strategies. You can look at building in other things, for example, CDKN2A deletions on top of that as a separate cohort. There's all sorts of ways you can play this game within the sort of construct of the basket study as it stands. So there's many, many opportunities, and I think it's just a question of waiting to see where we are toward the end of the year and into 2023 as data matures and see what we're actually seeing.

Q: Yeah. So I was talking about the regulatory plan for the MANTRA-2 trial post the both the Phase 2 data that you would be looking to go the FDA, talk about the registrational study.

A: I think I heard what quality of data would we look from the MANTRA-2 study to go to the FDA as compelling. Bob, would you like to talk to that? Yeah, yeah. So we've thought a lot about what would be compelling efficacy data in the context of an agnostic or basket study. When we initially designed MANTRA-2, the -- we thought that the benchmark for success based on the limited data diagnostic approved drugs, which include 2 TKIs and a checkpoint inhibitor. The checkpoint inhibitor demonstrated a response rate in the range of about 40% in the basket study, and so our study was designed to achieve a 40% response rate with a lower boundary of confident interval of 25%. Since that time, I think there are programs that are developing that we believe may have lower response rates and may be meaningful. And in fact, when we think about therapies for late-line cancer patients where single-agent chemotherapies are typically the standard of care and response rates may be as low as single-digit percentages or perhaps low teens, we think that that bar could be substantially lower than 40%. But that's how we've been thinking about that trial and the clinical efficacy that we need to see. And of course, that would need to be coupled with reasonable durability as well, probably in the range of 5 to 6 months.