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spk12: Ladies and gentlemen, thank you for standing by. Welcome to the Infinity Pharmaceuticals conference call to discuss the company's operations and full year 2021 financial results. My name is Crystal, and I'll be your operator for today's call. At this time, all participants are in a listen-only mode. There will be a question and answer session to follow. Please be advised that this conference is being recorded at Infinity's request. Now, I would like to introduce your host for today's call, Jane Kaufman. Please go ahead.
spk00: Thank you, Crystal, and good afternoon, everyone. Welcome to today's call to discuss our recent business progress and review of our full year 2021 financial results and company highlights. On the call with me today are Adeline Perkins, Chief Executive Officer and Chair, Larry Block, President, and Robert Alaria, Jr., Chief Medical Officer. We'll open the call for Q&A following our remarks. The press release issued today details our results and is available on our website at INFE.com. Please note that during this call, we may make forward-looking statements about our future expectations and plans, including clinical development objectives, the therapeutic potential of our product candidates, our strategic plans and strategies, and financial projections. Our actual results may differ materially from what we project today. due to a number of important factors, including the considerations described in the risk factor section of our annual report on Form 10-K for 2021 and in other filings we make with the SEC. These forward-looking statements represent our views only as of today, and we caution you that we may not update them in the future, whether as a result of new information, future events, or otherwise. Now, I'd like to turn the call over to Adeline.
spk01: Thanks, Jane. And thank you to everyone for joining us today to review Infinity's key 2021 accomplishments and 2022 goals. Even against the challenging backdrop of a global pandemic, geopolitical tensions, and deteriorating capital markets, Infinity was able to make meaningful progress during 2021 and is well positioned to weather future storms. The four foundational pillars necessary to create great value are all in place. with a differentiated drug, good clinical data, an augmented leadership team, and a strengthened balance sheet. Building on these in 2022, we are now poised to initiate the first aganalysib registration study, expand aganalysib clinical evaluation in multiple additional solid tumor indications, and establish the best path forward to continue to fund and maximize the value of aganalysib for patients and shareholders. Before turning to 2022, I'll review the four foundational pillars which are enabling us to optimize the value of aganalysib, our first-in-class drug that reprograms macrophages in the tumor microenvironment to reduce immune suppression and activate an immune attack against cancer. The power of this unique mechanism has been underscored by robust clinical and translational data presented over the last 18 months. We disclosed positive results in five solid tumors across CITC 2020, San Antonio Breast Cancer Symposium in 2020 and 2021, as well as ASCO-GU 2021. These presentations included data in three different combination regimens and multiple lines of therapy and tumor types, including metastatic triple negative breast cancer, or TNBC, metastatic urothelial cancer, or UC, ovarian cancer, as well as checkpoint inhibitor resistant squamous cell cancer of the head and neck, and melanoma. All settings where checkpoint inhibitors have provided more limited patient benefit to date. These data validate aganalysis potential to increase the effectiveness of current standards of care including in the PD-L1 negative patient populations for whom checkpoint inhibitors alone are particularly ineffective. The encouraging results across five distinct tumor types are impressive in their own right, and yet the totality of the data are even more compelling in light of the consistent patient benefit seen across multiple settings. Improvements in both median progression-free survival and median overall survival further underscore the promise of aganalysib to drive the next generation of immuno-oncology combination therapy. On today's call, we'll focus specifically on the data from two of these studies, in patients with frontline metastatic TNBC from our MARIO3 study and in patients with second-line metastatic UC from our MARIO275 study. In addition to having a first-in-class drug with good data, The broad potential began to listen, has enabled us to strengthen another foundational pillar, our team. In 2021, we expanded our clinical and scientific leadership and are already benefiting from the experience and momentum being driven by our chief medical officer, Dr. Robert Alaria Jr., our chief scientific officer, Dr. Stefan Peluso, and our former chief medical officer and now board member, Dr. Brian Schwartz. In addition, Today I am very pleased to announce the addition of Sujay Kengo to our Board of Directors. Sujay was most recently the Chief Commercial Officer at Acceleron, prior to its acquisition by Merck late last year, and previously served as Infinity's Executive Vice President and Chief Commercial Officer. Sujay will be providing important commercial and strategic insights as a member of our Board, which is very timely as we initiate our first registration study for a GANalyst of this year. And last but not least, in 2021, we strengthened our balance sheet, having raised $92 million in the first quarter of last year. With over $80 million on our balance sheet at the beginning of 2022, we have the resources required to initiate our registration trial in frontline metastatic TMDC and expand our development of Eganilisa through our MarioP study this year. Altogether, we are very encouraged that even in the face of global uncertainty and market volatility, Infinity's future is bright. I'll now turn the call over to Rob to review the data that supports this bright future for the studies we are initiating this year, as well as potential future development paths.
spk02: Rob? Thanks, Adeline. I'm thrilled to be part of Infinity at this exciting time, guiding the design and execution of the first registration enabling study for GANALYSSA, and laying the foundation of the next stage of development with MarioP. While approved immuno-oncology drugs have led to important advances, we still have much work to do to fully harness the immune system to effectively combat cancer. That's why I'm so enthusiastic about the positive results we are observing with the Ganalysib, a highly specific small molecule inhibitor of PI3 kinase gamma to reprogram macrophages in the tumor microenvironment and enhance immune activation. The strength and consistency of aganalysib's data across multiple indications and treatment settings, including PD-L1 negative subgroups, provide solid evidence that aganalysib has the potential to be a transformative therapy in immuno-oncology. Only a few months ago, at the December 2021 San Antonio Breast Cancer Symposium, we provided updated data from our MARIO3 trial, a single-arm study in advanced metastatic triple-negative breast cancer. The strategic objective was to characterize the safety and efficacy of the addition of aganalysib to atizolizumab, marketed as Dicentric, and nabpaclitaxel, marketed as Abraxane, in metastatic TNBC, compared to the benchmarking Passion 1-30 study. We reported safety data from 50 patients and efficacy data from 44 valuable patients with a data cutoff of October 2, 2021. Tumor reduction was observed in 92.8%, or 13 out of 14 patients, with PD-L1 positive tumors, and 85.2%, or 22 out of 27 patients, with PD-L1 negative tumors. In patients with PD-L1 positive tumors, the median PFS in MARIO3 was 11 months compared to 7.5 months reported for tezolizumab and napaclitaxel in the IMPASSION 130 benchmark study, a 47% relative improvement. In patients with PD-L1 negative tumors, the median PFS was 7.3 months compared to the 5.6 months reported in the IMPASSION 130 study, a 30% relative improvement. The MARIO3 safety profile was consistent with expectations for the three component drugs and did not show any new safety signals compared to the benchmark trial. Overall, we're encouraged with the efficacy findings in both PD-L1 negative and positive metastatic TNPC patients We plan to provide more follow-up data from this trial in the second half of 2022. In January, we reported encouraging median overall survival data from MARIO275, a randomized Phase II study in platinum refractory immune checkpoint inhibitor-naive advanced or metastatic urethral cancer patients. In the PD-L1 negative patient population, which represented the majority of the intent-to-treat patient population, we observed a median overall survival of 15.4 months with the combination of aganalysib and nivolumab compared to 7.9 months on the nivolumab control arm with a hazard ratio of 0.60, which reflects a 40% lower probability of death on the aganalysib combination arm. These findings are consistent with data presented earlier last year that showed at the one-year landmark, 59% of patients received The aganilisib plus nivolumab arm remained alive compared to 32% in the nivolumab control arm. Although the data in MARIO-275 and MARIO-3 are both strong and mutually supportive, aganilisib has a broad potential as a TME-modulating drug. We've made the decision to prioritize metastatic TNBC as our initial registration-enabling study due to the greater unmet need, particularly in PD-L1-negative patients who are still receiving chemotherapy alone as the standard of care. Towards that end, we plan to initiate MARIO4, a randomized double-blind registration study in frontline metastatic TNBC by the end of this year, with PFS and OS as key study endpoints. All patients will receive the MARIO3 triplet of aganalysib, an immune checkpoint inhibitor, and chemotherapy, which will be compared with standard of care which is either chemotherapy alone for PD-L1 negative patients or chemotherapy and a checkpoint inhibitor for PD-L1 positive patients. We are now preparing for our end of phase two meeting with the FDA and for meetings with global regulatory authorities to review the design of our registration study and we'll provide updates on our progress later this year. Our encouraging phase two clinical data in two, mostly PD-L1 negative tumor indications, have been bolstered by an equally strong translational, or TM, data package with support that, again, ELISA delivers on its intended mechanism of action. At the San Antonio Breast Cancer Symposium this past December, we presented data from paired tumor biopsies in MIRO3, showing an increase in the M1 to M2 ratio, reflective of macrophage reprogramming, an increase in immune activation, and an increase in PD-L1 expression in both PD-L1 negative and PD-L1 positive patients compared to baseline. These findings in tumors are consistent with what we had observed in peripheral blood gene expression analysis from MARIO-275 that showed enhanced immune activation of the aganilis of nivolumab combination compared to the nivolumab control arm. Armed with these very encouraging clinical and TM data in two solid tumor indications, one of my highest priorities since joining Infinity is to quickly identify other opportunities for aganalysib to advance cancer treatment, particularly in areas where immune checkpoint inhibitors have had more limited success. In support of this mission, we will initiate a platform study called MarioP to evaluate the clinical benefit of aganalysib in additional solid tumor indications on a rolling basis starting in the third quarter of this year. And with that, I'll turn the call over to Larry to review the full year financials. Larry?
spk10: Thank you, Rob. This past year has been a foundational year for Gantt-Elizabeth and Infinity. As we prepare for Gantt-Elizabeth's first registration study, as well as prioritize initiation of additional clinical studies and indications where GANalysib has the largest potential benefit for patients. In early 2021, based on the strength of GANalysib data across multiple solid tumor indications, including metastatic TMBC and metastatic UC, Infinity raised $92 million to enable our continued execution on our strategic development plans for GANalysib, including the commencement of our first GANalysib registration study. This resulted in Infinity having total cash and cash equivalents and available for sale securities of $80.7 million December 31st, 2021 compared to $34.1 million December 31st, 2020. Research development expenses for the year ended December 31st, 2021 with $31.6 million compared to $26.8 million for the same period of 2020. And this increase is primarily related to an increase in clinical development expenses, an increase in compensation expense due primarily to new hires during the year, and an increase in consulting expenses to support continued development of Gantt-Olesen. General administrative expense for the year into December 31st, 2021 was $14.2 million, compared to $12.4 million for the same period in 2020. And this increase in G&A expense is primarily due to an increase in stock compensation, professional services, and consulting expense. Debt lost for the year into December 31st, 2021 was $45.3 million, or a basic and diluted loss per common share of 53 cents. compared to a net loss of $40.5 million, or a basic and diluted loss per common share of 68 cents for that same period in 2020. In FITNESS 2022, financial guidance remains unchanged, and we continue to expect net loss for 2022 to range from $45 to $65 million, and to end 2022 with the year-end cash and cash equivalent ranging from $25 million to $35 million. And in FITNESS financial guidance, does not include any additional financing or business development activities. This is an execution-focused year for Infinii, and we're aggressively advancing the development of Eganilisib in our first Eganilisib registrational study, as well as a platform study in other solid tumor indications. We're truly excited about the continued advancement of Eganilisib's clinical program to lay the foundation for the initiation of potential future registration studies. And in parallel, we'll leverage Eganilisib's unique method of action and differentiated clinical data to evaluate and execute on the best paths forward to fund its ongoing development and maximize the value of again for patients as well as shareholders. So on behalf of Infinity, we thank you for your continued support and look forward to updating you on our progress in the coming months. At this time, we can open up the call for questions. Operator?
spk12: Thank you. As a reminder, to ask a question, you will need to press star and then 1 on your telephone. To withdraw your question, please press the pound key. Once again, that's star and then one to ask a question. And our first question comes from Anupam Rama from J.P. Morgan. Your line is open.
spk03: Hey, guys. Thanks so much for taking the question. Larry, I want to follow up on a comment that you just made, which is, you know, you talked about the guidance not including any business development issues. Strategically, how are you thinking about, again, sort of the OUS rights or regional partnerships as a potential source of non-diluted capital? And how do you think about maximizing that, you know, from a timing perspective?
spk10: So, you know, from a business development perspective, we certainly feel that it's not feasible to slice and dice again by indications the way you think about it in terms of geography. is certainly the way we look at it. But ultimately, because of the breadth of the potential indications that the panelists can reach across the broad swath of solid tumors, PD-L1 low and PD-L1 high, we think ultimately a strategic collaboration that's global is probably going to be more advantageous than a regional collaboration because the complexity of the potential clinical development paths forward.
spk03: Got it. Thanks so much for taking my question.
spk12: Thank you. Our next question comes from Ted Tenthoff from Piper Sandler. Your line is open.
spk09: Great. Thanks so much for taking my question, too. So don't take this the wrong way because it's not intended to be impertinent in any way. I'm trying to get a sense for what's going into arranging Mario P and Mario 4, specifically what's taking so long. Again, not meant to be confrontational, but what are the steps that are being required? There are obviously drug supply, things like that, but what's really going into preparing to launch those two studies. Thanks so much.
spk01: Yeah, so thanks, Ted, for the question. And I'll start and then I'll turn it over to Rob. What's important to note is this is moving quite quickly, the preparation for the launch of these studies. So while we're not in a position to describe all of it yet, you know, as we are designing the trial and planning to operationalize it, lots and lots of decisions about exactly the patient population inclusion and exclusion, the endpoints, whether there's interim analysis, what sites, what investigators, and all of that is actively underway. And as soon as the trial design and the plan is finalized and has the input from global regulatory authorities, will be sharing it. It's just simply premature to do so until we've finalized it. So the old analogy about, you know, the duck can calm along the top of the water, but the paddle's going rapidly underwater. The team is rapidly doing all the things underwater. It just may not be as visible until we can describe what that final trial design is. And Rob, I'd see if you have anything to add.
spk02: Well, I guess one thing I will mention is, you know, time, I guess, goes quickly in certain respects, you know, we just presented our updated data at the San Antonio Breast Cancer Symposium in December. And when you think about it, that's not very long ago, and we really wanted to wait until we had more mature follow-up. And that was a median duration of follow-up in the 10-month range. And we really moved from looking at that data, reacting to that data, and to expand on what Adeline was saying, you know, it does take a lot of pieces, you know, writing briefing books, planning global regulatory engagements, and things like that. So there's a lot going on. We're on track to do the things that we say that we're going to do. We only recently identified the four tumor types we want to do for the MarioP platform study. So I think that's a good start too. So again, I know sometimes it seems like things are slow, but actually things are moving quite quickly for us in all the planning steps.
spk08: Great. Well, I'd rather get it right. So I appreciate that. Thanks so much.
spk12: Thank you. Our next question comes from Kevin DeJeter from Oppenheimer. Your line is open.
spk13: Hey, guys. Thanks for taking our question. I guess on MarioP, can you help us think about dose for a basket study? I mean, I guess we did see some liver AEs that required adjustment downward in the protocol with regard to dose in Mario275. And, you know, one could imagine different tumor types having different you know, different, you know, potential rates of liver tox or risk of liver tox. Just, you know, will all these patients, you know, sort of be getting the same dose and how should we think about, you know, appropriate dosing for a basket study?
spk02: Yeah, I mean, I think you bring up some good points. I mean, you know, we had started the Mario 275 at the 40 milligram dose of, again, Elizabeth Daly and then had gone down to 30. You know, I think we're really encouraged that 30 milligrams seems to be a winning dose because, you know, that's something we're dosing now in a triplet regimen with, you know, a tizolizumab and a chemo, a braxane. So I think, you know, if you think about a platform study, I don't tend to think of toxicity being all that different across tumor types. So, you know, I think 30 milligrams is a very solid dose for that. Now, you know, of course, as we design the study, will we decide to explore that dose a little bit? It's possible, but I think the fact that we're able to dose 30 milligrams a day in a triplet bodes very well for a lot of combinations that we can do across different tumor types and across different agents.
spk13: Great. Thanks for that. And then just how should we think about sort of pace of opening sites in MarioP? It kind of sounds like that study may kick off before a registrational study in TNBC. I'm just wondering, in a resource-constrained world, how we should think about, you know, potential pace of site opening and kind of, you know, breadth of learning as we move into, you know, 2023.
spk02: Sure. Well, you know, as we announced, we are going to be opening these in a rolling basis. And, you know, one of the nice things about a platform study is that by focusing on specific tumor types, you can focus on specific centers of excellence that, you know, see a lot of that tumor type. And so it allows kind of almost like a cassette that you can open one tumor type, decide what you're going to, you know, what combinations are you going to look at, and then move to the next module and do it kind of in a nice orderly fashion. So I think, you know, that we would probably take a very tumor-centric approach. That would probably be the most logical way of doing it, and I think that's how we're envisioning doing this in a rolling basis. And, of course, that is, as you mentioned, you do learn as you go in sort of an iterative process.
spk13: Thanks for taking our questions.
spk12: Thank you. Our next question comes from Sumit Roy from Jones Research. Your line is open.
spk07: Hello, everyone, and congrats on all the progress. Could you help us think through what we should expect from the Mario 3 RCC cohort in second half 22? Is it like number of patients we could expect to see data from would really help?
spk01: Sure. I'll start and then Rob can elaborate. So that study is a 30-patient study. It is single-arm combining a GAN elicit with Ticentric and Avastin. And What we're really, the purpose of that study was to see proof of concept of the utility of adding, again, a list of two of VEGF inhibitor. As you know, the Tocentric Avastin regimen is not approved in renal cells, so it's unlikely that we would be, with any proof of concept, be taking that regimen forward. So we would then be looking at, there's been great progress with other oral TKIs and we'd be evaluating if we did want to go forward, what would the right drugs be and what would that design be. So this is different from the Mario 3 TNBC where we were very much, we got the right modalities of drugs and we could be moving directly to registration and the renal cells, a different objective out of that study.
spk02: Yes, for us, I mean, you know, it was an interesting question to understand what modulating of VEGF, and again, this is not one of these oral TKIs. Bevacizumab is really a VEGF, big molecule antagonist, whereas a lot of, as you know, the field has moved on now to be these multiple kinases in RCC. But for us, it was getting some clinical data with a drug like Bev, and of course, in combination with a checkpoint inhibitor. And we're looking to So, you know, as we're reviewing that data to give an update on that later this year.
spk07: Got it. That really helps. So, essentially, in second half, we are going to look into the 275 and Mario 3 TNBC long-term, like, survival data, and that remains the main goal here, catalyst-wise, data catalyst-wise. Yes, yes. Thank you. Thank you again for taking the questions.
spk12: Thank you. Our next question comes from Kaupit Patel from B. Reilly Securities. Your line is open.
spk04: Yes, hi. Thanks for taking our questions. One for the MARIO-P study. I know you're initiating on a rolling basis, but have you finalized which tumor type you will likely prioritize first? You know, based on the mechanistic profile of the , is there one tumor type that you would ideally start with first? And then are you also planning to enroll or restrict enrollment based on any underlying biomarker status where applicable, you know, maybe just focusing on PD-L1 negative patients for certain indications like lung cancer?
spk02: Yeah, so I think we like all four tumor types. And so we are still discussing which one we'd like to start with. You know, I have to admit I'm anxious to learn about all of them. But, you know, I think we're still working through which one we will start. You know, I think we keep an open mind about, you know, narrowing the indication as far as, you know, restricting it to a certain PD-L1 subtype, for example, particularly in unmet needs like prostate cancer or something where it's not quite so clear that would be good. Of course, in lung cancer, people do take that approach sometimes. But one of the encouraging things we found is the drug, you know, we're encouraged by our data across PD-L1 expression. So I don't think we have any a priori thoughts that we're going to narrow it coming out of the gate. But again, we're anxious to get started. We like all four of those. And, you know, we're in the midst of deciding which one we'd like to prioritize this year.
spk01: And CalPET, as you would know, you know, Rob is, not only enthusiastic about all, but we just are not yet in a position to provide the specific rank order or prioritization. But we do have sentiments on that and are executing on that. And as soon as we're ready to share those details, we'll be happy to.
spk04: Okay. And then one question on the Mario Flores study. Based on the safety results that you realized to date with the triplet, you know, does that tolerability profile in any sense restrict the type of patients that you would enroll in MARIO4? I'm just trying to understand if, you know, MARIO4, the timeline should be similar to what we have seen with impassioned 130.
spk02: You know, I think overall, we're very encouraged with the triplet safety profile. You know, if you may recall from the San Antonio Breast Cancer Symposium in December, the treatment discontinuation rate was pretty similar for the triplet compared to the doublet in Passion 130, which actually is really gratifying because usually when you have a triplet, there's a, you know, sort of a trade-off. So I think the reason for that is we have an oral drug system So it's very easy to adjust, or if you dose hold it for a few days, it quickly washes out. So I don't really see any limitations per se. You know, I would expect that, you know, of course, checkpoint inhibitors are sometimes restricted for patients, you know, who have autoimmune diseases and things like that. But I don't see anything particularly unique of anything we would restrict just because, again, a list is in the mix.
spk04: Okay. Thanks for the call, Eric.
spk12: Thank you. Our next question comes from Mike King from HC Wainwright. Your line is open.
spk11: Hey, guys.
spk10: Can you hear me okay? Yeah, you're going through great, Mike.
spk11: All right, thanks. Just wanted to pick up, for starters, pick up where Ana Palm left off, and that has to do with BD. Seems like, you know, it's not... pragmatic to be able to have any kind of conclusive discussions until you know what the parameters are going to be for Mario 4. I mean, is that a reasonable thought process? Do you have to lock down the protocol so that you know how to size it, how long it needs to be, et cetera, before anybody can understand what the expense is going to be for the entire study?
spk10: So that's certainly the approach we took the last time we put in place a global collaboration for development of one of our programs. We had started our global phase three for Duvalisib and on the heels of that brought in a partner, in this case it was AbbVie, to complete the global registration study campaign. I don't think it's necessarily a requirement to do so, but it certainly, I think as you alluded to, sort of makes the alignment easier to do. On the flip side, you know, some partners like to have some input on the actual design parameters and once it's locked and loaded, and have FDA and XUS alignment on that, you don't really want to reopen that, you know, relitigate that again. So there's pluses and minuses both sides, but certainly the last time that Infinity did this, we followed the track that you're recommending.
spk11: Okay. But is it fair to say that even if you do not secure either a regional or global partner before Mario 4 is ready to go, you'll start the study.
spk10: Yeah, our guidance is we're going to be starting the study by year, and then we think that's, you know, completely consistent with the timeline that Rob has laid out in terms of engagement with the regulatory authorities.
spk11: Okay. All right. And then just a quick clarification. I apologize. I missed. What are the four contemplated tumor types for Mario P.?
spk02: The planned tumor types are soft tissue sarcoma, ovarian, prostate, and non-small cell lung cancer.
spk11: Okay. Thanks for that. And then finally, just wanted to ask, are you deprioritizing UC? You know, you had a very nice signal there, and it just sounds like that one's not making the cut.
spk10: It's not that we're, I mean, I guess we're prioritizing TMBC, so I guess implicitly it deprioritizes urothelial cancer. If we had the resources to do two parallel registration studies, we'd love to do both of those. But given the fact that the standard of care for especially P1 low patients in frontline metastatic TMBC, the standard of care is just chemotherapy. There is no immune oncology opportunity for those patients. That seemed like such a glaring unmet medical need that it was, you know, it was very hard to pass up. In the context of additional resources, whether from the capital markets or from a potential future business development collaboration, you know, we would certainly like to, you know, bring urethral cancer up to the front as well, but we just can't do two global registration studies in parallel at this time.
spk11: Okay, so I guess you're saying, Larry, I guess you're saying, I don't want to put words in your mouth, but I guess you're saying that the only logical course forward for UC is in a randomized registration-directed study versus making it part of, let's say, MarioP. Is that a fair statement?
spk10: Yeah, I think we've already got, you know, randomized controlled data from Mario275, so... sort of going back to phase two for additional data. It seems like that would be a misuse of the opportunity. As Rob said, he wants to explore additional indications through MaryOP, and we think there's a pretty clear path forward towards the registrational study in urophil cancer based on the Mary275 data we've already analyzed.
spk11: Okay, fair enough. Sorry, if I could just sneak in one more. Shoot. What's that? Oh, shoot. Go ahead. Oh, no. Now I've forgotten. I would say successful. Don't come back to me before you wrap up.
spk05: Okay.
spk12: Thank you. And again, ladies and gentlemen, to ask a question, please press star and then one now. And our next question comes from Robin Kronoskis from Truist Securities. Your line is open.
spk06: Hi, guys. Just to follow up on a couple questions. So when thinking about the global partnership, and you mentioned that some people want to belong involved into the design, some people do not. How are you weighing the terms of someone who wants to be involved in de-risking the story because you're getting that off your plate versus waiting? Help us understand how you're thinking about the two options that you just mentioned. And second, when you're thinking about the FDA, the FDA has been very different lately. They've been surprising people with the requirements for clinical trials and being more conservative, requiring a lot more than maybe they typically have in the past. How are you thinking about maybe diversifying your trial versus doing it at centralized locations and big centers to get that diversification if needed, if the FDA is more critical of just doing it at specialized sites? Thanks.
spk10: Rob, why don't you start with the clinical diversification question? I'd be happy to take the BD question.
spk02: Okay, sure. You know, I think for diversification, you bring up a good point because, you know, the nowadays Pembrolizumab in the United States and chemo is the standard of care. And so a lot of that is going on in community sites versus the centers of excellence necessarily. So I think we would be diversified in the way we did enrollment. I think we would want, of course, centers of excellence, but I think we would also want plenty of other community-based practices to be able to really do a great job of enrolling across both PD-L1 positive and PD-L1 negative patients.
spk10: And maybe also, Robin, to your point about the sort of conservatism upon regulatory authorities We've seen some of that just recently with discussions about PI3K delta in the hemological lignancy front. And from our perspective, we don't believe that touches on PI3K gamma at all in the solid tumor front because there's, as far as we can tell, no overlap in terms of the toxicity profile. So we're really gratified that, you know, there has been review of both accelerated approval in immunoncology, which we're really happy to see that we've seen correlation between our PFS and our our OS data, which was one of the big challenges, obviously, last year at the ODACs for the accelerated approval. And we're also very pleased, as Rob said, with our tolerability and safety profile that even in triplet, we see no new safety signals or signals that we wouldn't expect to see from the individual components. So what we will certainly want to diversify from a, as Rob said, sort of a standard of care in centers of excellence versus the community centers, but from a general regulatory perspective, we think that the path we're pursuing is pretty well, is pretty clean.
spk06: Just as a follow-up before you get to the question around biz dev. So if you want to do a more diversified trial, it doesn't require a lot more resources, a lot more expertise. Sometimes some of pharma can get this done really quickly because they have all the connections and stuff in place. So it sort of feeds into the question around doing this, Deb, before you start the trial versus BD, before you do the trial versus afterwards and finding that partner.
spk10: Yeah, so I would totally take your point. I'd say there's two parts. One is we're going to pursue our own independent path to registration, you know, as we've lined out with our guidance for having the MARIO4 study up and running by year end. That said, you know, the critical thing for us is to get alignment with the FDA. We can obviously get alignment with the, you know, BD partner beforehand or after hand, but there is some benefit, as you said, in leveraging the resources of a partner. We didn't find any problem with doing that with AbbVie after the fact. And given the profile of our drug, we don't expect that there's going to be any things that we can't bolt on from a partner to augment the resources that Rob will be putting in place independently before the fact.
spk06: And I'll flip another one in. So any surprises you think regarding what the primary endpoint would be required to be for Mario? Because I'm just thinking out of the box how surprising and what's being required over my lifespan and how it's changed over time. Do you think there's any surprises as far as the primary endpoint and what's required to show? I know you've shown a correlation between PFS and OS, but in the larger trials, that can change. I'm just curious if you're, you know, what kind of a, what do you call that, war games you're playing in your head of what the different options the FDA is going to have for you and what would be the best case and worst case scenarios?
spk02: Well, I think, you know, FDA has been very clear, as other global regulators, is that, you know, we'd like to, we want to move overall survival. That's the gold standard. We want to get there. And that is our goal with the GANALYSIP and, you know, any new combinations of the checkpoint inhibitor and chemotherapy. So I don't, you know, I think that's evolved in a good way. I really think that that is a benchmark we should strive for. We need to improve the survival of patients with cancer. Now, the big question is, is there a surrogate that you can get that answer quickly? And I think, you know, so far in TNBC, for example, there's been a very good correlation between PFS and OS. If you've looked at Impassion 130 and the Keynote 355 study, PFS and OS benefits have really mirrored each other. You know, at least for Mario 4, I don't see a lot of controversy there. I think our goals are obviously to win on overall survival. But, you know, if we can deliver like we have so far in Mario 3 on PFS, I think that would be a very encouraging thing as well. But again, you must have that conversation, you know, with regulators.
spk06: Got it.
spk12: Okay, thank you. Thanks, Robin. Thank you. And we do have a follow-up from Mike King from HC Wainwright. Your line is open.
spk11: Yeah, I'm sure you were. So was I. I'm just curious about your thoughts on the... If you've gone back and pressure tested the Mario studies, Mario 3, 275, in light of the recent disappointment in Nectar. Now, I know that's a different mechanism of action, but if you look at their melanoma study... They had many of the same or similar effects, you know, again, in a single-arm study in combo with nivolumab. They had, you know, they converted PDL1 negative tumors to PDL1 positive. They had some other correlative, you know, biomarker data with respect to CD4, CD8 ratios, et cetera. And so, you know, just as a kind of belt and suspenders exercise, I just wonder if you go back and kind of reexamine the data to make sure that, the signals that you feel you lean from those studies are actually pointing you in the right direction.
spk10: I'll take a first crack at it and let Rob add for the thoughts. I think the strongest basis of our confidence in, again, Elisiv, is the concordance of our data across studies. all of the clinical studies that we presented from all the way back from Mario 1 with melanoma, you know, in patients who had just had their immediate prior therapy had progressed on a checkpoint inhibitor and were able to salvage them and get not just stable disease but objective responses to, you know, Mario 275 where we had actual overall survival data, you know, correlated back to PFS, including in the PLO1 low, but not exclusively in the PLO1 low patients. And obviously with Mario 3 in both PLO1 low and PLO1 high, as well as in the ARC2 study in a, you know, checkpoint-free regimen. And so we definitely would not hang our hat on any single biomarker or any single study, but we don't see the sort of the NECTAR example as a cautionary tale because we're not extrapolating off of a single study. It's really, you know, a safety database of over 350 patients, you know, across five individual studies.
spk02: Well, and I think also, I mean, the Nectar, you know, drug was looking at a, you know, an important signaling pathway and delivering it in a new way. But, you know, it wasn't a novel, target in the basic sort of sense. I think when we kick the tires back and, you know, we always look at things with a critical eye because I think it's always important to do that. I mean here we're dealing with a very specific small molecule inhibitor of a pathway that's in mostly myeloid and macrophage cells. And, you know, we've just been really encouraged by the fact that it does what we designed it to do. We've looked at it in peripheral blood. both in a controlled way, you know, against nivolumab and Mario 275. We look at tumors, see the same thing. So I think we have really pretty compelling data, both in peripheral blood and tumors, that the drug is doing what it's designed to do. And not only that, we actually see that it matters. We see clinical movement, too. So I think it's really important to see both of those things.
spk10: We've seen that, you know, biomarker data, both in monotherapy, we've seen in peripheral and in you know, paired tumor biopsies as Rob said, we've also seen it, you know, like Nectar in combination with the Volumab, we've also seen it in our two-study absence, you know, a checkpoint inhibitor. So it's not, it's the sort of the independence of the mechanism or lack of reliance on any single, you know, synergistic partner that I think is so compelling.
spk11: Okay. Thanks for the comprehensive answer, guys. Thanks. Appreciate it.
spk10: Okay. Thanks for the follow-up.
spk12: Thank you. At this time, I'm showing no further questions. I'd like to turn the call back over to Larry for any closing remarks.
spk10: So, in closing, you know, we really feel very fortunate to be developing this promising therapy with potential to improve the quality and length of life for people with cancer. And with our Bolstered balance sheet and our strength and leadership team, including with Rob here today, we're really well-positioned to focus on executing in 2022, which means initiating at first a Gantylisib registration study and expanding the evaluation of Gantylisib in additional solid tumor indications in MaryOP. So we remain committed to realizing the value of Gantylisib for the benefit of both patients and shareholders. And in regards to that, I'd like to thank the Infinity team, as well as our investigators, our trial sites, as well as our investors, and most importantly, our patients and their families, who've all played integral roles in advancing our work to bring better treatments to these patients. We look forward to providing updates in the coming months, and thank you very much for your continued support. Good night.
spk12: Thank you. This concludes today's conference call. Thank you for your participation, and you may now disconnect. Everyone, have a wonderful day.
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