Constellation Pharmaceuticals, Inc.
Q1 2021 Earnings Call Transcript

Published: 10 May 2021

[Operator:]

Good day, and thank you for standing by, and welcome to the Constellation Pharmaceuticals First Quarter 2021 Earnings Conference Call. Please be advised that today’s conference is being recorded. I would now like to hand the conference over to your speaker today, Kia Khaleghpour, Vice President of Investor Relations and Communications. Please go ahead.

[Kia Khaleghpour:]

Thank you, operator. Good morning, everyone, and welcome to this conference call to discuss Constellation’s first quarter 2021 financial results and operational performance.

[Jigar Raythatha:]

Thank you, Kia, and good morning, everyone. Constellation is poised to transition from a development-focused organization to a fully integrated commercial stage biopharmaceutical company. Our lead asset, pelabresib, is currently in a global Phase III pivotal trial and enrollment is now underway. Our goal is to transform the standard of care for these patients and to make pelabresib the backbone of MF therapy. In addition, we have opened a new cohort in the Phase II trial to evaluate pelabresib in essential thrombocythemia. We are exploring opportunities to evaluate additional indications. We believe that our broad development program could position pelabresib as a cornerstone hematology product in the future. We also intend to demonstrate best-in-class potential for CPI-0209, our EZH2 inhibitor, which we believe may have broad therapeutic potential in a number of cancer indications. Please turn to Slide 5. Turning your attention to our pipeline, pelabresib is in a Phase III program in myelofibrosis. The focus of that program is first-line JAK-inhibitor-naïve patients. We recently completed the dose escalation portion of our Phase I/II trial of CPI-0209, and we are advancing this program to the Phase II portion -- the Phase II proof-of-concept portion, which Jeff will tell you about shortly. We anticipate presenting results from the Phase I portion of this study at ASCO. Our next program is CPI-482, which we believe has the mechanism that can impact myeloid biology and expand our footprint in hematologic malignancies. This program is in IND-enabling studies. Our discovery efforts are aimed at continuing to identify novel mechanisms to drive additional growth for the company.

[Dr. Jeff Humphrey:]

Thank you, Jigar. Please turn to Slide 9. Trial sites for MANIFEST-2 have been initiated in both the U.S. and Europe, and dosing is underway in the Phase III MANIFEST trial of pelabresib. We’ve received health authority and ethics committee approvals in many countries, we’re pleased with the level of investigator interest in the trial, and we’ve already brought on board some of the larger academic centers. We have, however, seen some impact from COVID-19 on-site initiation as certain clinical sites have experienced staffing shortages, trial backlogs, COVID-19 trial prioritization and overall country lockdowns. We expect to have more visibility on MANIFEST-2 execution over the next several months, and we expect to provide a further update in the third quarter as more sites come online. Regarding genotoxicity related efforts, I’m pleased to say that study reports, including the most recent study reports we mentioned on our last earnings call, have now been submitted to FDA without further comment from the agency to date. We have updated our investigators for sure and informed consent to reflect these findings and patients and investigators have been notified. We do not expect any impacts from the updated assay results on the conduct of MANIFEST-2. Turning to the Phase II study. We expect additional analysis from MANIFEST trial to be presented at the European Hematology Association, or EHA, based on our September 29 data cut focusing on translational data. We continue to be very excited about the effects we are seeing on bone marrow fibrosis, and we’ll be presenting centrally reviewed data for the first time. We have also assessed cytokine level at baseline, cytokine level changes during pelabresib treatment, pharmacodynamic assessments and extensive baseline mutational analyses. In addition, we will also present 2 other posters.

[Emma Reeve:]

Thanks, Jeff. Moving on to the financials on Slide 13. We had a net loss of $40.1 million or $0.84 per share in the first quarter of 2021, in line with our expectations. Our cash, cash equivalents and marketable securities at the end of the first quarter totaled $382.1 million, sufficient, we believe, to fund our operations into mid-2023. We plan to use these resources to fund MANIFEST-2, the Phase III clinical trial for pelabresib, and to start building the commercial organization needed to launch the product candidate, as well as to explore the utility of pelabresib in other indications. In addition, we believe we have sufficient funds to complete the Phase I/II clinical trial for CPI-0209, as well as to progress our discovery and preclinical pipeline of compound and fund general corporate operation. Moving on now to Slide 14, which shows our corporate milestone for 2021. Overall, we’re pleased with the position we’re in. For the remainder of this year, we expect to share with you further updates from our Phase II clinical trial, MANIFEST, with a translational update in the midyear time frame at EHA and a clinical update by the end of the year. We also aim to provide an update on potential new indications by the end of the year. For CPI-0209, we plan to provide an update from the Phase I portion of the study by midyear at ASCO. And as Jeff announced earlier, now that we’ve opened up the Phase II expansion cohort, we expect to provide an update from those cohorts by the end of the year. That concludes our prepared remarks for this morning. So I’ll turn things back over to the operator. Operator, could you please open the line for questions.

[Operator:]

Our first question comes from Brian Abrahams with RBC Capital Markets.

[Brian Abrahams:]

a bit more on what you observed -- what you’re observing clinically with 0209. I guess, how the biology, the PK/PD and the efficacy and safety guided your choice of recommended Phase II dose and the populations that you’re going into? And how -- what you’re observing differs from what you saw with 1205?

[Jigar Raythatha:]

Brian, this is Jigar. I missed the first half of your question. Could you repeat it?

[Brian Abrahams:]

Yes, absolutely. Just wondering if you could elaborate a little bit more on what you’ve observed clinically with 0209. And just sort of curious how the biology, the PK/PD, the efficacy and safety that you’re observing is guiding your dose selection and choice of populations to go into for the Phase II portion? And then how -- what you’re seeing may differ from 0205 clinically?

[Jigar Raythatha:]

Yes. Yes. We will be presenting the full data set at ASCO, but maybe Jeff can give you a little bit of color.

[Dr. Jeff Humphrey:]

Yes. Brian, this is Jeff Humphrey. So for 0209, the Phase I portion, as you know, is about PK safety, and we did this study with pharmacodynamics and saw really what I would consider to be a dramatic dose gene expression response not seen with CPI-1205. That certainly does help guide our selection of recommended Phase II dose. However, recommended Phase II dose is typically chosen based upon safety findings. And we did have toxicity results not unexpected that guided our selection of recommended Phase II dose. And as Jigar said, we don’t want to run the -- we don’t want to front-run the ASCO abstract. We worked hard on the ASCO poster, and you’ll find a lot of information there.

[Jigar Raythatha:]

Maybe if I can just add to that. I think as we embarked on discovering and developing 0209, we had a vision in mind, which was to really induce a step change difference in the level of target engagement. And we’ve shown ample data preclinically that we can induce those levels of comprehensive changes in target engagement with EZH2 with 0209. And I think now with the clinical profile that we have, we feel very comfortable that we’re able to replicate that type of step change in target engagement relative to first generation EZH2 inhibitors, including 1205.

[Brian Abrahams:]

Got it. That’s really helpful. Look forward to that presentation. And then maybe 1 more for me, if I could. With respect to the ongoing MANIFEST-2 Phase III study, congrats on getting that underway. Just wondering if you could talk about maybe the latest on your -- the mechanism for potential resizing of that study based on spleen and TSS. What your powering assumptions were there? And just given the COVID headwinds to site initiation, whether you expect that could potentially still be by the end of this year or early next year? How we should be thinking about potential disclosure of an upsizing of the study?

[Dr. Jeff Humphrey:]

Let me make a couple of comments, and then I’ll turn it over to Jigar. But the powering assumptions are based on the response data we saw in MANIFEST and the historical data of rux from SIMPLIFY-1. We will power the study to have the best answers and success, and we will provide additional data later on in the year. I think, as you mentioned, there’s a mechanism for resizing of the study. And again, those would be details that we would provide later in the year.

[Operator:]

Our next question comes from Marc Frahm with Cowen and Company.

[Marc Frahm:]

Congrats on the progress. Just 1 quick one, following up on Brian’s questions. Jeff, I think you mentioned that the recommended safety dose was selected again based on DLTs that were observed. Can you just say what those were? And then I’ll have a follow-up on the pelabresib progress.

[Dr. Jeff Humphrey:]

Yes. No, thank you for the question, but we really prefer that you see the ASCO presentation, which is only a short while away. So that will be coming. Again, the safety profile is manageable for CPI-0209 at the dose selected.

[Jigar Raythatha:]

Maybe just to add, nothing unexpected based on kind of what we’ve seen from our preclinical work or work from other EZH2 inhibitors.

[Marc Frahm:]

Correct. Okay. And then maybe, Jeff, just on pelabresib, just there’s the ET expansion cohort. Can you give an update there on kind of where enrollment is, and, I guess, plans to disclose data later this year? And how definitive do you expect that data set to be? Or is it really going to be still very much a work in progress?

[Dr. Jeff Humphrey:]

Yes. Thank you. So the amendment to MANIFEST is open for Arm 4. And again, it will -- these are patients that are not frequent in the community, and we’ll be providing an update on enrollment later in the year. So the trial is open for enrollment of ET now.

[Jigar Raythatha:]

Yes. I think, previously, in the past, Marc, we said that certainly wouldn’t be the full kind of cohort of patients, but it’s possible that we would have data from a handful later in the year, and we’re still working hard towards that. As Jeff noted, 1 of the things that we were looking to learn about this is kind of the frequency presentation of these patients. And I think, certainly, as we work through this cohort of patients, we’ll have a good view on that.

[Operator:]

Our next question comes from Kripa Devarakonda with Truist Securities.

[Kripa Devarakonda:]

Regarding the data to be presented at EHA, can you talk a little bit more about what do we expect, especially in the abstracts? And should we expect an investor event at EHA like you hosted last year? And then 1 follow-up question on 0209. In addition to the ARID1A mutant solid tumors, you also plan to initiate trials you said in mesothelioma and in lymphoma. Just to get ahead a little bit. Can you talk a little bit about the total opportunity you’re looking at from the added 1A or the BAP1 mutant patients? I know it’s maybe a little too early to talk about it. But how are you thinking about proceeding? Like is it tumor agnostic ARID1A, once you see these patients in these 3 indications that you’re initiating your trials in?

[Dr. Jeff Humphrey:]

Yes. Thank you. So the data at EHA as mentioned is really around dose relatedness of reduction in inflammatory cytokines, the reduction in bone marrow fibrosis. There’s a cohort of paired bone marrow biopsies that have been centrally reviewed. That data will be presented as well. And there will be data that talk about the responses regardless of mutational status. So I think those are -- in terms of pelabresib, those are some of the very important presentations as well as the effect of pelabresib on anemia in patients under treatment. When it comes to the planned cohorts in mesothelioma and lymphoma, as you mentioned, we are very interested in ARID1A and in BAP1. ARID1A is really about the solid tumors that were mentioned -- the endometrial urothelial cohorts that are mentioned. And in terms of the size of the opportunity, so mesothelioma is a fairly uncommon tumor, I think, roughly around 3,000 patients in the SEER database in the U.S. We’re looking at BAP1, but we’ll be looking at -- at BAP1 loss, but we’ll be looking at wild type as well, but with an initial focus on BAP1. I think for -- you are focusing both on mesothelium and lymphoma. I think there our cohorts are designed as 2-stage enrollment, and we’re looking at enrolling up to 29 patients. And based on the observed response rate, we’ll design our development plan from there.

[Jigar Raythatha:]

If I could just add a couple -- a couple of comments. I think, again, EHA -- I think what we laid out is really the -- I mean, the intense focus will be for us to start the drumbeat on defining what disease modification means. And it will be the first of kind of a building data set. Patrick and his team have been generating some of that data over the past year or 2. And we’re kind of further deepening into some of these types of analyses that we’ve done, but also taking them to the next level. And we’ll see more of that likely at ASH and beyond. But what we’d like to have is that by the time that Phase III data are in hand, that there is a really good understanding of some of the disease-modifying mechanisms and the data that we see from the pelabresib studies really become synonymous with disease modification. And so that’s kind of the -- it’s kind of an early step in that -- in building that drumbeat. And then shifting just to your questions around 0209 and kind of size of the opportunity, it’s a good question. It is a little early. As you can see from the approach that we’re taking, we’ve really set up for ourselves a broad development plan that gives us a lot of optionality and where to go. We’re following the science at this point. We think there’s a lot of good rationale around the genomic features that we’ve chosen as well as some of -- following some of the data that have been presented with other EZH2 programs and in total should lead to a very significant commercial opportunity, but it’s a little early for us to kind of more precisely define that today.

[Operator:]

Our next question comes from Ho Chen with Jefferies.

[Unidentified Analyst:]

So, maybe just a follow-up. It could be early, but what percentage of patients having ARID1A mutations or maybe BAP1 mutations across indications based on your study?

[Jigar Raythatha:]

Actually, yes, it depends on the indication itself. I think we’ve talked about this in the past, where there are certain tumor types like bladder cancer, where roughly 1/4 of patients have ARID1 mutations. There are other tumors where close to half of them have ARID1 mutations, but they’re smaller patient populations to begin with. BAP1 loss, in particular, is highly prevalent in mesothelioma. In terms of certain types of mesothelioma that we’re targeting, more than half of the patients would have BAP1 loss mutations.

[Operator:]

Our next question comes from Do Kim with BMO Capital Markets.

[Do Kim:]

First, on 209, do you still have a plan to combine 209 with standards of care in solid tumors and do a dose escalation Phase I? And what exactly is the timing of when you’ll initiate the cohorts of mesothelioma and prostate cancer?

[Jigar Raythatha:]

Thanks, Do. I think it is very reasonable for us to try to combine 0209 with standard of care. Where I think we would like to kind of sequence that step is to first generate very compelling single-agent activity and then be ready to then quickly move into combination studies. But so we have taken the step to gate some of that combo work until we see some of the single agent activity that we’re looking to see from these cohorts where the biology is quite strong. And with a molecule like 0209, we would expect to see it. And sorry, can you repeat your second question?

[Do Kim:]

Yes. When the cohorts mesothelioma and prostate cancer will start? You said you’re planning on initiating those cohorts.

[Jigar Raythatha:]

Yes. I think we’re not ready to comment on the exact start time for those cohorts. Those were certainly things that we brought into view -- into our own planning a little later than the ARID1A in the lymphoma activities. And so we’ll certainly be able to provide an update on that in the near future.

[Do Kim:]

Got it. And a question on MANIFEST-2. You said that COVID had -- is impacting enrollment. And just wanted to know if that changes your expectations for when you will get data for that trial. Or is there an opportunity to regain the speed in that enrollment rate by the addition of active sites?

[Dr. Jeff Humphrey:]

Yes. Thanks for the question. I mean the impact of COVID is inescapable, and we’re managing through it the best that we can, and we’re in the mode of site start-up and site activation. Most of our clinical trials are in trial sites are in areas that are affected by COVID-19. And as you mentioned, we are experiencing delays in clinical trial site initiation. Those delays include very commonly disruptions at the site, included limited resourcing and staffing. However, the enthusiasm for pelabresib from both the physician community and from patients is high based on e-mails that we’re receiving for trial participation. We’re working very closely with our CRO in order to address issue. We have a field medical affairs force that is finding additional sites for participation. And they’re actively strengthening relationships with physicians and finding new sites. So, I think we can provide more information at a later time, but we’re strongly initiating the study at this time.

[Jigar Raythatha:]

If it’s okay, if I just add, just I’ll comment. I think it’s a little early for us to comment really on enrollment, per se. I think Jeff mentioned that the impact that we’ve seen has really been on site start-up. And I think as the pandemic resolves, our hope is that there is sort of kind of pent-up demand that then kind of picks up. But it’s really early for us to really comment on enrollment trajectory specifically until the sites that we anticipate having up and running or up and running, and we’re seeing the rate of patient enrollment in those sites. And so overall, no change at this point in kind of what we have previously messaged on this point. And we’ll certainly keep a close eye on it over the coming months and provide an update as well.

[Operator:]

Our next question comes from Ren Benjamin with JMP Securities.

[Ren Benjamin:]

Congrats on the progress. Maybe Jigar or Jeff, can you just remind us why, I guess, the biological rationale for ARID1A as a mutation in BAP1 loss -- how you went about picking these 2 genes in particular? And just related to that. Is there a diagnostic development plan also in the works to help identify these patients? Or are these mutations also part of a standard foundational assay or one of the other assays that might be out there? And sort of the third question related to this is, if you look at that RNA, that PCR profile that you had, where does kind of ARID1A and BAP1 loss fit in there? Is there like a total shutdown in this 137 and 185 and presumably 350-milligram doses that you looked at? Or is there something more nuanced there?

[Jigar Raythatha:]

So I’ll start, but we also have Patrick Trojer on the line who I’ll ask to kind of pick up. I think on kind of the back part of the question on the need for diagnostic assay. It’s -- right now, it’s premature to kind of answer that question. I think as we see kind of how the patients within a wild type and mutational status perform in the expansion cohorts, we can determine that. But these are mutations that are frequently included in NGS panels. And so, we’ll have kind of the data that we need to inform that decision. On the biological rationale, maybe, Patrick, if you can pick up that question and provide kind of the -- what got you excited about these particular areas?

[Dr. Patrick Trojer:]

Yes, sure. Yes. Thanks, Ren, for the question. So ARID1A, as you may know, is part of chromatin remodeling protein complex termed BAP1 and the BAP1 complex resists with PRC2 complex that EZH2 is part of for gene control. And in the case of ARID1A mutations, EZH2 can take over gene control from the BAP1 complex, and it creates a scenario where the underlying gene expression program is rewired. And it’s -- the concept of the hypothesis is that EZH2 inhibition would restore a gene expression program that rather than promote proliferation would promote differentiation and apoptosis. So regarding the diagnostic, I’d just add that what Jigar said that ARID1A mutations are part of foundation panels, for instance, as they are part of many other NGS panels, as Jigar said.

[Ren Benjamin:]

Got it. Okay. Terrific. And then I think Jeff just mentioned on the call regarding additional genotoxicity studies that had been submitted and no comments back yet. I guess, a couple of questions. One, what were those additional studies? Can you go into -- provide a little bit more color? And regarding the no comments back yet, has there -- do you feel like there’s been sufficient time that is passed that you feel pretty confident that the FDA has kind of checked the box? Or do we still need to wait for some sort of confirmation letter or something that suggests they’ve taken a look at it and everything is good to go?

[Jigar Raythatha:]

Patrick, do you want to take this one?

[Dr. Patrick Trojer:]

Yes, sure. Yes. So as we have said previously, we had a positive signal in 1 out of the 3 initial genotoxicities assays that we ran. We informed the FDA. We followed their guidance and updated our informed consent form and our investigators, for sure, and then we ran some follow-up studies that included an in vitro micronucleus assay and a common assay. And we determined that there was a real signal. So we shared these results with the agency, and they have not asked us to do anything different. If the regulator would believe that there is an issue, they would have gotten back to us. We believe that given the severity of the disease we are studying, these preclinical findings will be acceptable.

[Operator:]

Our next question comes from Colleen Kusy with Baird.

[Colleen Kusy:]

Congrats on all the progress. On the Phase I portion of the 0209 study, can you -- are you able to share what the tumor types were that have been enrolled? And I guess, will we be able to see any patients that have tumors that are selective for the expansion cohort?

[Jigar Raythatha:]

Colleen, first of all, congratulations also on your new role at Baird. It’s a pretty broad standard Phase I study. And so there’s lots of different tumor types enrolled. It’s certainly -- it’s possible that a patient here or there that we are interested in for the Phase 2 would also be enrolled. But as you know, it’s also kind of at the right dose levels. And so it’s a pretty rare event that we would see that in these kind of Phase I studies, but certainly is possible.

[Colleen Kusy:]

Okay. That’s very helpful. And for the hematologic malignancies you’re going after, at this point, do you expect to recommend a Phase II dose to be the same as for solid tumors? Or do you think there’s potential for a secondary dose?

[Dr. Jeff Humphrey:]

No. The recommended Phase II doses in part take on the safety profile and, of course, the PD profile and the PK profile. And so 350 milligrams dosed orally once-daily is the recommended Phase II dose that we would carry forward, even in lymphoma. And I would just echo Jigar’s comments previously. Phase I patients are relapsed and refractory to all available therapies. So these are -- Phase I patients are not the same as other patients.

[Operator:]

Our next question comes from Jay Olson with Oppenheimer.

[Jay Olson:]

As you continue to build evidence for disease modification for pelabresib, can you talk about whether or not that’s an indication that you expect or how that data will get into the label? And then can you talk about any work that you’ve done to prepare for the commercialization of pelabresib? And remind us about the IP protection and any additional patents you may have filed.

[Jigar Raythatha:]

So why don’t I start? And we’ve got -- I’ll start with the end of the question first, if that’s okay. We did -- we have been preparing for commercialization. It’s still relatively early innings for that. We did have -- on our last earnings call, Brendan Delaney joined us, who recently joined the company as Chief Commercial Officer, and Brendan will be building the team that would be eventually commercializing pelabresib. And so we are taking the stage appropriate steps there. He has a small group of people working with him to help us with that as well as the product positioning. In terms of IP, we’ve managed to build a fairly significant IP portfolio that covers both composition as well as various method of treatment types of patent applications that we think are also significant. And so that’s -- I think that’s all mostly kind of out in the public domain. And in terms of kind of disease modification, we spent kind of a -- I think we’ve taken a very kind of deliberate approach to making this -- the work that we’ve done with pelabresib in MANIFEST a very translationally heavy study, probably the biggest investment in translational science in myelofibrosis to date. And so with that in mind, our goal is certainly to leverage those learnings into MANIFEST-2. And if they can help us to position ourselves to find ways to include any of those types of findings like bone marrow fibrosis or the like into a label, we’ll certainly set ourselves up to be able to do that as part of the way the study is conducted.

[Dr. Jeff Humphrey:]

Yes. And Jigar, if I could just add. I mean, the reduction in bone marrow fibrosis and the normalization in the number and distribution of both megakaryocytes and erythroid precursors are findings that we think are very important. And so as you might imagine, as Jigar mentioned, we might be pursuing that in a randomized setting and would be thinking about how that might be included in future promotional use.

[Jay Olson:]

That’s super helpful. And then is there any update on your 482 program?

[Jigar Raythatha:]

I mean that program is still certainly in early days. I mean we just moved that into the IND-enabling studies. And so we’re going through all the work that would be needed to enable filing an IND for that program. So no further update on 482 right now.

[Operator:]

And there are no other questions in the queue. I’d like to turn the call back to Jigar Raythatha for any closing remarks.

[Jigar Raythatha:]

Yes. I just wanted to thank everybody for joining today and asking such great questions. We’re really excited, as we mentioned earlier on in the call, to take the next steps with both pelabresib as well as 0209 in terms of dosing patients in our next studies. And we think it really sets the company up really nicely to transition from where we are today to the goal towards becoming a fully integrated and sustainable organization with marketed products as well as the pipeline and look forward to talking in future calls.

[Operator:]

This concludes today’s conference call. Thank you for participating. You may now disconnect.