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spk05: Hello, and welcome to EpiVine's conference call. At this time, all participants are in a listen-only mode. There will be a question and answer session after the prepared remarks. Please be advised that this call is being recorded at EpiVine's request. I would now like to turn the call over to Bill Slattery, Jr. You may begin.
spk12: Thank you, Operator. This morning, Epizyme issued a press release providing a business update in addition to first quarter 2021 financial results. That press release, as well as slides to accompany today's call, can be found in the investor section of the company's website at epizyme.com. On the call with me today is Rob Bazemore, President and Chief Executive Officer, Paolo Tambesi, Chief Financial Officer, Vicki Bikiner, Chief Commercial Officer, Matt Ross, Executive Vice President and Chief Strategy and Business Officer, and Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer. As a reminder, today's discussion will include forward-looking statements related to Epizyme's current plans and expectations, which are subject to certain risks and uncertainties. Actual results may differ materially due to various important factors, including those described in the risk factors section of our most recent forms 10Q, 10K, and other SEC filings. These forward-looking statements represent our views as of this call and should not be relied upon as representing our views as of any subsequent date. We undertake no obligation to publicly update these statements. At this time, I would like to turn the call over to Rob Basemore. Rob.
spk10: Thank you, Bill, and good morning, everyone. It's great to be here with you to provide an update on our Q1 results and how we see our business progressing this year. As we moved from March into the second quarter, we began to see some very encouraging signs that things are slowly beginning to return to normal, perhaps even a bit earlier than we expected. Vaccinations are now much more broadly available. Offices report that they're busier and they're starting to see more patients than before. At the end of March, we eased the travel restrictions for our vaccinated field-based employees and are allowing them to travel again to reach their customers for in-person discussions in the institutions and the offices that allow it. Some accounts have reopened to representatives calling on them, although this is still more the exception than the norm. And some educational programming is beginning to return to in-person, like regional medical conferences. All of this is happening slowly and is happening in pockets of the country at very different rates. but it's encouraging to at least begin to see these changes. However, that was not yet the case for Q1 of this year, as we were still dealing with a second wave of infection that started late in 2020 and resulted in the extension or heightening of restrictions in some areas. As a result, in Q1, Epizyme continued to execute almost entirely virtually as we had been previously, and the significant challenges we experienced last year due to the pandemic persisted. Despite these challenges, we continue to build positive momentum on the metrics that we have control over that will ultimately be important to Tasveric adoption, like growth in awareness, growth in number of accounts prescribing, and continued broad unrestricted access as coverage was renewed at the beginning of the year. We continue to see quarter-over-quarter and month-over-month growth in Tasveric adoption, with March 2021 representing the most successful month yet in terms of Tasveric models sold. Total revenues for the first quarter were $7.6 million, of which Tesveric net revenues in the U.S. were $6.2 million, a 37% increase over Q4 2020, which was driven primarily by increased adoption in follicular lymphoma, or FL. Epithelial sarcoma, or ES, sales continue to contribute to total revenue at approximately the same level as Q4. Commercial bottle demand increased quarter over quarter by 31%. And the remainder of the revenue booked in Q1 was collaboration and other revenue of $1.4 million. In early March, Epizyme hosted a strategic vision call entitled The Next Episode, where we unveiled our strategy for how we'll create value for patients and the physicians who treat them at Epizyme shareholders over the next five years. I encourage you to listen to the event webcast if you haven't already. But to quickly recap, this strategy for long-term growth relies upon our execution across four pillars. Obviously, the first and most important focus in the near term is maximizing our commercial effectiveness to ensure adoption of Tasverix among as many eligible FL and ES patients as possible, including our development efforts to bring Tasverix into earlier lines of therapy by combining with other agents or as monotherapy. Second, continuing to build on Tasverix pipeline and the drug potential, including moving our programs into additional solid tumor and hematological malignancies and produce a steady stream of data over the next five years and beyond. Third, expanding our pipeline and portfolio beyond TAS Barrett, bringing novel epigenetic therapeutics into clinical development. And fourth, leveraging all available options to expand our patient reach and increase shareholder value, both resourcefully and responsibly. In the first quarter, we made good progress across these four pillars. As I mentioned earlier, despite the COVID headwinds persisting in Q1, we continue to build momentum on metrics needed to ensure accelerated adoption once the pandemic challenges begin to subside. On the clinical side, during our vision call, we outlined a comprehensive and innovative clinical development plan for TASBERIC, for which we anticipate a steady stream of data beginning in 2021 and over the next five years. And we highlighted some encouraging early data from the second-line FL and prostate cancer studies. We plan to further explore tazometastat as both monotherapy and in combinations across multiple new hematological and solid tumor cancers in two basket trials, which are on track to initiate during the second half of this year. Finally, our novel CETD2 inhibitor, which addresses a long sought-after pathway and was introduced during the vision call, remains on track for planned IND submission mid-2021. I'd now like to turn the call over to Vicky, who will provide additional color on our Q1 progress in TASVIRIC adoption and FL and ES, and then to Shefali, who will provide an update on our TASMETISTAT development efforts. Followed by Paula, who will briefly review our first quarter financials before we open the call for Q&A. Vicky?
spk05: Thanks, Rob, and good morning, everyone. TASVIRIC continues to gain traction while we navigate the unique environment presented by COVID. Adoption is steadily increasing, and we saw sequential month-over-month growth, with March representing our highest demand to date. We continued to add new prescribing accounts in both the academic and community setting, increasing 38% in the first quarter compared to Q4 of 2020. Aided and unaided awareness among our FL treating physicians improved, and TASER continued to lead and share a voice related to other therapies in the FL space. Tasveric-aided awareness among all physicians is now over 70%, which is aligned with other agents that have been on the market for years. And our market research suggests that physician intent to prescribe remains high. Commercial bottle demand was 31% in the first quarter compared to fourth quarter of 2020, while total revenue grew by 37% to 6.2 million. We didn't see any changes in payer coverage or policies at the start of the year, And as we expected, there was some transition from patients utilizing our patient assistance program, Epizyme Now, in the fourth quarter to commercial patients in the first quarter. As a result of our efforts, Casveric use is coming from all lines of relapsed refractory therapy in both follicular lymphoma and epithelial sarcoma. Within FL, the largest growth and share has been in the third line and later treatment setting, and we continue to see some utilization in second line. Since 60% of our sales now come through the specialty distributor channel, we have limited visibility to utilization split by mutant and wild type or untested. However, based on market research, we know that we are seeing utilization in both. As Rob mentioned, CASVERIC sales for patients with ES and Q1 contributed at the same level as Q4. We continue to see new patients start therapy in the first quarter. though some of the early patients treated in later lines of therapy cycled off treatment. Our focus for this year is on gaining broader adoption of TASVERIC in earlier lines in order to provide the most benefit for patients living with this extremely rare disease. As we alluded to on the fourth quarter call in late February, the environment we operated in during Q1 did not substantially change from the end of last year. The two distinct challenges that have persisted early this year include First, decreased frequency in patient visits to their treating doctors following the onset of COVID-19, which has been accentuated in SL compared to other cancers due to the indolent nature of the disease and the general age of the patient population. And second, our field teams limited face-to-face access to treating physicians and their staff. In the first quarter, data have shown that SL new patient treatment starts on any therapy remain depressed approximately 20 to 30% compared to pre-COVID levels consistent with the fourth quarter. While secondary data sources have yet to confirm that the epidemiology of FL has fundamentally changed as a result of COVID, the number of patients receiving any new treatment has been suppressed now for many months. We do anticipate that as vaccinations continue to increase, patients will slowly return to in-person visits and expect we will see new treatment starts begin to rebound. We are beginning to see positive signs that the opportunities for live customer engagements are improving and are happy to share that following vaccinations and appropriate consent, we have eased restrictions and allowed our field team to travel again and visit accounts in person wherever possible. This is particularly encouraging because it has taken more time to get traction with physicians virtually that might otherwise be the case in person. And compounding this, while our approved label allows for very broad use of TASBARIC in patients with relapsed refractory FL, it can require explanation to prescribers given the two distinct indication statements. We expect that improving direct access to our customers will particularly benefit our ability to properly define the use of TASBARIC in earlier treatment lines and EZH2 wild type patients. We continue to see an increase in new accounts prescribing Tadveric and new patients start in Q1. At the same time, we have also seen some patients discontinue their therapy within the first few months of treatment. There are a variety of reasons for why this may occur, but some of it appears to be driven by later line treatment where patients quickly dropped off therapy. We saw this same phenomena in our Phase II clinical trials. As you might expect, with any new launch in oncology, the patients most in need of new treatments are often very late stage with high disease burden, and they've been through many other drugs. In order to ensure that physicians utilize Tesveric in earlier patients in need of new treatments, we recently rolled out marketing tools to assist our sales team with identifying the most appropriate patients for Tesveric. As physicians continue to gain experience with Tesveric, Particularly with using Tasveric earlier in the treatment journey, we expect duration of treatment and satisfaction with the drug will improve, enhancing adoption as a result. Overall, we're encouraged with the field team's performance in reaching physicians and driving awareness for Tasveric under the current circumstances. As we continue to gain feedback from our customers, we see that physicians are increasingly more likely to test for EZH2 mutational status as part of their patient's treatment plan. Market research indicates that approximately 60% of physicians now test for EZH2, but they're not testing in everyone, with still only about 37% of FL patients being tested. It's also important to note that EZH2 testing is often being done at diagnosis or before initiation of their patient's first-line treatment. While most physicians have access to next-generation sequencing via their institution or other commercially available panels, Around one quarter of physicians noted that they would like to test and would like to have an easier way to do so. Physicians are interested in understanding EZH2 mutational status for multiple reasons, including a better understanding of the patient's cancer and helping set expectations with patients once prescribed Tesveric. We will continue to support the physician community with regards to their inquiries around testing. and provide new solutions to make testing easier. Looking forward, we are confident in our ability to execute commercially and continue to find ways to expand the adoption of TESBERIC. We are optimistic that with broader vaccine rollout, we will have more and more opportunities to engage face-to-face with our customers, and patient-physician interactions will also begin returning to normal. At this time, I'd like to pass the call to Shefali, who will provide an update on our ongoing clinical trials and development plans. I look forward to addressing your questions during Q&A. Shefali?
spk01: Thanks, Vicky, and good morning, everyone. During the vision call, we shared preliminary safety and activity data from a consummated Phase 1b3 study in the year 302 of Tadberg in combination with R-square in relapsed refractory follicular patients that provides early signals that this could be a meaningful combination approach for treating patients in the second line and later. As of the vision call, of the 13 patients enrolled in the study, all seven available patients responded to treatment, with three patients having a complete response and four patients having a partial response. No DLTs were observed, and adverse events were consistent with the safety profile of the individual agents. We plan to provide an update to the safety run-in data set at the ASH annual meeting later this year, where we expect to have additional data on the patient treated and longer follow-up. As a normal procedure of any phase three study, after completion of plan enrollment of the safety run-in, we submitted the protocol with the selected recommended phase three dose to the FDA for the review. We aligned with the agency on an important change to the protocol to allow for a potential efficacy readout at the second interim analysis. Once we have the 65% of PFS events in the Phase III portion of the study, we will have an opportunity to conduct an efficacy analysis at the second interim as long as the predefined treatment effect in the protocol is achieved. This may provide an opportunity for stopping the study early and data availability earlier than the completion of all PFS events. Although the selection of the 800 milligram dose as an RP3D was endorsed by an external safety committee and steering committee, during the review, the agency requested additional dose optimization efforts to support initiation of the randomized phase three portion of the EDS302 study. This was to ensure that we've well characterized the effect of combining tazometastat with R-squared, given that we enrolled only a small number of patients to date since we observed no DLTs in our pre-specified Phase 1b design. Based on these discussions with the agency, EpiSan has expanded the Phase 1b cohorts of 600 mg BID and 800 mg BID to include a minimum of 15 patient total per cohort, which will allow for the collection of additional patient data at these doses, including PK, exposure, safety, and efficacy. It's important to note that the request for additional patients at these two dose levels is based on continued effort to dose optimize and not for any particular concerns of safety signals observed in the safety run-in of the EVF-302 study. Due to the fact that we have continued to enroll the study, we have nearly completed enrollment for those two cohorts with the required patient number at both the dose level requested by the agency. Once the required data has been collected and analyzed after three months of follow-up, we will promptly submit our findings to the agency. In the meantime, we continue our efforts to complete all operational start-up activities for the initiation of the Global Safety Study to minimize the impact of the study enrollment completion. We expect to report updated safety and activity data from the safety run-in and at ASH later this year. Separately, studies such as ETH-1401, Evaluating Tazerix Plus Detectin in the Relapsed Refractory SL, the Lysol Sponsored Trial, evaluating Tadveric in frontline high-risk FL and DLBCL, and the EZS301 confirmatory study in the ES continue to move forward as planned. We look forward to sharing safety and preliminary activity data related to EZS301 study as part of a post-presentation at ASCO in a few weeks. Additionally, our two proposed basket studies evaluating multiple combinations with TADS in both hematological and solid tumors remain on track to be initiated second half of this year. We also continue to work with EMA to define the registration path for Tazverix in ES and SL in Europe and expect to have alignment by the end of this year. During the vision call, we also provided an update on preliminary data from the phase 1v2 study of Tazometastat in metastatic castration-resistant prostate cancer or MCRPC, called EZH1101. In the safety-run-in portion of the study, the protocol allowed patients to enroll who had previously failed enzalutamide, abituron, first-generation anti-androgen receptor therapies, or short-posed chemotherapy. In this study, patients received either abituron plus chasmetastat plus prednisone or enzalutamide plus chasmetastat. In this population of prostate cancer patients, With the need for new options besides chemotherapy substantial, we are encouraged by the early data we have generated, particularly in combination with enzalutamide, where we saw 6 out of 13 patients with a PSA 50 response, which is those patients having a decrease in their PSA of greater than 50%. We also highlighted one patient in particular that had an investigator-confirmed PSA 50 response after receiving casometastat and enzalutamide, who also had a confirmed radiographic response with a 36% reduction in target vision diameter. Importantly, we were able to combine both the drugs without any additional safety concerns at the Phase II dose of 1,200 mg BID. The Phase II portion of this study, comparing enzutamide alone versus enzutamide plus chasmatisat, is actively enrolling patients, and we expect to share updated Phase I data on the patient's previous and longer follow-up at a medical conference later this year. we introduced our novel SETD2 inhibitor during the vision call, which remains on track for our planned IND submission mid-2021 and our intent to move into clearance by year end. We are planning a first-in-human trial in relapsed refractory DLBCL and multiple myeloma with dose escalation to evaluate a maximum tolerated dose and expand to a proof-of-concept in three cohorts, including T414 relapsed refractory multiple myeloma, non-T414 relapsed refractory multiple myeloma, and relapsed refractory DLBCR. In the near term, we look forward to sharing preclinical data on SEGI-2 at the European Hematology Association Congress in June. At this time, I'd like to pass the call to Paolo, who will review our first quarter financial results. Paolo?
spk08: Thank you, Shefali, and good morning, everyone. We ended the first quarter with $298.9 million in cash, cash equivalent and marketable securities. Our total non-GAAP operating expenses for the first quarter 2021 were $63.7 million, of which R&D and SG&A accounted for approximately $30.3 million and $31.5 million respectively. Turning to revenue, we recorded first quarter 2021 revenue of $7.6 million, which includes $6.2 million of TASVERIC ES and FL net sales and $1.4 million in collaboration and other revenue. We are reiterating our non-GAAP adjusted operating expenses guidance in the range of $235 to $255 million for the full year 2021, which will support additional clinical development and continued investment in our commercial launches, including investment in manufacturing capabilities to ensure an interrupted supply of TASVERIC for commercial patients and our clinical trials. As a reminder, we are not providing revenue guidance, given that our launch is continuing the early stages and uncertainty related to the evolving COVID-19 pandemic. Finally, we remain well-famous today with cash and cash equivalents to support our current operating plans into 2023. Over the past few years, we have deployed multiple strategies to maintain sufficient capital to fund important value-creating initiatives. We will continue our prudent expense management and make new investments with a stage-gated approach based on the evolution of our studies and revenues. We also have a number of options available to us to enhance our cash runway to support our operating plans well into the future. And with that, I'd now like to return the call back over to Rob for closing comments.
spk10: Rob? Thank you, Paolo, Shefali, and Vicky. As we emerge from the first quarter, we are encouraged by our positive momentum, and we're optimistic that some of the dynamics that have complicated our launches will start to improve in the second quarter and beyond. Looking forward, we expect a number of important milestones for the company in the remainder of the year. We'll provide quarterly updates on our progress with U.S. TASVARIC adoption. We'll present updated data with longer follow-up on our safety run-ins in EZH302 and SL and EZH1101 and prostate cancer at upcoming medical meetings. We plan to submit our IND for study two and eventually initiate the phase one study. We will initiate the two basket trials in heme malignancies and solid tumors. And finally, we expect to reach alignment with the EMA on registration path for TASVARIC in Europe. Above all, we remain optimistic in the long-term potential of TASVARIC to change the lives of patients living with cancer. Operator, we'll now open the line for questions.
spk05: As a reminder, to ask a question, you'll need to press star 1 on your telephone. To withdraw your question, press the pound key. Our first question comes from Michael Yee with Jefferies. Your line is open.
spk07: Hi, Rob. Good morning, and thanks for the update. That was very helpful. We had two questions. Yeah.
spk06: First was just on the commentary about the, I guess, physician office or patient visit environment getting better and March being much better. Can you maybe just talk to how you think that will lead to perhaps accelerated sales? Do you have confidence in accelerating sales? Or do you think it's sort of a general trend of increasing incremental growth quarter over quarter? Maybe just talk to that as you think about the sales trajectory in 2021. And then second question is on the R-squared study, maybe for Shefali. I thought there were two interesting things. One was the comment about a futility or efficacy analysis at 65% events? Is that the first efficacy? And then make a comment on the 600 versus 800, because I think that's very interesting and new, and is there a chance you'd actually have to use 600? Thank you.
spk10: Certainly. So, Mike, let me start. I'll answer your first question around just how we see the year unfolding with regards to the COVID dynamics that we talked about. As I said on the call, you know, we were encouraged to see that First quarter, we continued to grow the number of accounts prescribing Tasveric. We continued to grow the use and number of bottles. We saw a commercial adoption of 31%, which was actually up quarter on quarter compared to Q4. If you just go back to the two things that we've said that have had the most significant impact on our ability to launch this drug, and remember, we've launched it entirely virtually from the beginning, the two things that have made the most difference have been our ability to get to physicians face-to-face and access them and have conversations about the data, have conversations about the label. That's just always more inefficient when you have to do it virtually. So we're encouraged that with two things happening, us putting the reps back out in the field now, allowing them to travel when they're vaccinated and comfortable doing so, and the majority of our reps are back in the field, that this is going to allow for more substantial access and more substantial interactions with physicians around a label and the data. The second has always been the fact that the patients just aren't there seeing their physicians. We've seen that this has been down, visits have been down, as well as new patient startups have been down since the beginning. First quarter was no different than fourth quarter. So we're encouraged to see that that's starting to change. We're starting to see patients come back in the office. We're starting to see physicians bring their patients back. And obviously for a new drug that just was launched, you can't get adoption if the patients aren't there and the physicians aren't making switch decisions. And as we know, they typically don't change patient's therapy if they're not in the office, if you're just seeing them remote. So we're encouraged about both of those things being the leading indicators of seeing adoption continue to grow over the course of the year. Those have been the two most substantial barriers. That being said, it's not the same nationally. I think like we saw with things closing down, it's happening regionally. You see pockets of where some areas are opening more quickly than others. Some areas have better access where we're able to go back into the customer's offices already, and then there are others who remain closed for a bit longer. So it's not uniform across the country. But again, we're encouraged that we're starting to see that happen already, sooner than we had anticipated. We thought by mid-year, we'd really start to see this start to open up and change. And fortunately, based on the availability of vaccines, some of that started to happen even sooner. So that's why we encouraged it, because those are the two things that really are most going to help drive the adoption of TASBERIC, and both of those are directly influenced by how quickly those changes happen with respect to our access and patients getting in to see their physicians. And I'll turn it over to Shefali to answer your question around 302, Mike.
spk01: Good morning, Mike. This is Shefali here. So I think just answering your first question about the interim, as you recall, the randomized study for the Phase III has two interims, The first interim is based on objective response. That is strictly for futility. So that's just giving you a trend of how the study is going. It does give you a signal, but it's not for efficacy. The one that we recently aligned with FDA is about the second interim, which is based on PFS events. And you're absolutely right. It's 65% of PFS events. This gives an opportunity to actually stop the study early on, and you don't have to do all your PFS events immediately. So, you know, you could have the data availability to as long as you have met the predefined events of the study. So it's an important alignment that we had with FDA for the 302 study. In regards to your second question about the dose, so, you know, as you recall, we actually had aligned with FDA on the study design at the time of the approval for the safety run-in. However, we did complete the safety run-in very quickly without any DLTs. So in order to well characterize the combination of Tasveric with R-square, you know, the agency asked us to enroll additional 15, minimum 15 patients at 600 and 800 milligrams. This is not a safety issue. This is basically to get more data in terms of PK, in terms of all the other characteristics, including PD. The safety profile that we observed in the study was consistent with both the package inserts. There was no additional safety concerns we saw. And this is very similar basically with other sponsors or other products that have been combined with R-squared. So the goal is to be able to enroll these patients. And as I mentioned in my script, that we basically have nearly completed the enrollment for these 15 patients. And we are looking forward, we are doing everything we can to do the startup activities for the phase three to minimize any impact on the phase three and hope to be able to enroll that study quickly.
spk07: Thank you, guys.
spk05: Thank you. Our next question comes from Mohit Bensal with Citigroup. Your line is open.
spk09: Thanks for taking my question and very good morning. A couple of questions from my side, one on clinical side for Shupali. So this FDA is asking for exploring 600 milligram BID. Has it something to do with, you know, new FDA is looking for a better dose optimization? We saw that with Amgen as well. Is it something related to that, given that you did not see anything at 800 milligram BID in terms of tolerability issues?
spk01: Hi, Mohit. Good morning. I think it is mainly, as you said, right, it's very consistent with what other people are doing. The goal is to ensure that there is, you know, when we combine it with R-squared, there is no impact on the R-squared backbone. And I think it's mainly dose optimization. It's not a safety signal. As I mentioned, we didn't see any DLGs. We were able to go at the highest dose of 800 milligrams at TAS without any DLGs. So I think, you know, the idea is to be able to look at two doses, which are, you know, 600 and 800, with minimum of 15 patients and do dose optimization, not a safety signal.
spk09: Got it. Very helpful. And the other question is related to – so in response to Briar's question, you kind of mentioned that things are opening up a little bit better. So just trying to understand, do you – Is it better than your expectations going into the year in terms of how physicians are coming back to the offices and how things are turning out? And then the second part of this question is can you comment on the usage of EZH2 test? Is it restricting the usage only in EZH2 mutations patients or if you can provide any metrics how many, how much usage is in EZH2 mutants versus biotyped patients. Thank you.
spk07: Sure. Go ahead.
spk10: I'll start. This is Robin. I'll ask Vicky to add on if there's anything that I missed. First of all, with regards to our view on how things will progress this year, my comment was specifically on the timing of how early this is starting. I think just for, to be conservative, we'd assume that we'd really start to see a massive amount of immunizations and therefore things starting to return to normal around the middle of the year and then slowly progressing and improving over the second half of the year. So it's encouraging to see that things are starting to open back up. As you've seen, many states have removed their restrictions around COVID, whether that's a good thing or a bad thing. You're seeing a lot of states that are now doing that, lifting their restrictions. I think in terms of how it progresses, I wouldn't want to give guidance on it because it's happening in pockets. As I said, you have some accounts that have opened already, some that have not. When we talk to physicians about patients coming back in, many of them say that their offices are very busy again. Some of them say that they have had patients not come back in because they didn't want to put them at risk. But others have said it's the patients who actually canceled because they didn't want to be at risk. So I think there's a lot of things at play here. Obviously, you know, with things like the J&J vaccine being pulled for a period of time that affected the supply chain of vaccine, those are kinds of things that we can never anticipate. So I've tried not to be too specific on how we're thinking about the year other than the fact that it seems to be starting sooner than we thought. There seems to be a real desire to go back to doing things more normally. We said, I think Vicki said on her script in the prerecorded remarks that we're starting to see even regional medical conferences go back to face-to-face because they desire to hear from industry. They want to be educated. They want to know about new drugs that are coming out. And so some of the regional medical conferences are also starting to go back to being live face-to-face meetings as opposed to virtual. So those are the things that encourage us, and they're the things that we think are most going to be useful to the increased adoption to TASBARIC as those things return to normal. I think with regards to testing, I'll start, and Vicki can add to it, but the testing, as you asked, you know, is this a barrier for use of TASBARIC? And I think one of the things that we've observed in our research is the testing isn't often even done as a part of the decision whether to use TASVIRIC or not. In fact, about half of the patients who are tested are tested in the front line of diagnosis before they're even treated. So some of that is for prognostic reasons. Some of it is, again, physicians just wanting to understand the type of follicular lymphoma their patients have. So that accounts for almost half of the testing. And then the other half of the testing is coming in patients who have relapsed refractory disease. Our research says it's not because they're looking to use it to determine whether or not to use Tesveric. They're just trying to better characterize the type of patient and perhaps set treatment expectations for patients who are on Tesveric. But I think the use of the test is actually being done for a number of different reasons across different lines of therapy. And, Vicki, I'll ask if you want to comment further on that.
spk05: Yeah, I think the only other point I would add is, you know, while we're seeing testing increase, This is the first time, really, in follicular lymphoma that these physicians have had an opportunity to really understand this particular mutation and the disease. And so there's a lot of interest. We've done a lot of focus groups, and the physicians consistently say, you know, I just want to know what the status is for the patient. I may not necessarily use that information to make a treatment decision, but it certainly is helpful for setting expectations if I'm going to treat them with Tesveric. One of the things we want to make sure that physicians have access to the testing if they choose to do so. And while the NextGen sequencing panels are available for most physicians, there are a group, I mentioned that, about 25% that say, you know what, I just don't want to run a full panel when I only need the one EZH2 mutation results. So While some of the institutions, there's a handful that have COBOS testing available, which is, you know, the PCR test, we're looking at opportunities to bring an innovative solution to these physicians. Granted, we just want to meet their needs and make sure that there's not any significant reason for them not to prescribe PESVIR and make sure that we're bringing every solution possible to them. So we'll be announcing some things soon in the near future. Got it. Really, really helpful. Thank you, Robin. We really appreciate it.
spk09: Thanks. Go ahead.
spk05: Thank you. Our next question comes from Peter Lawson with Barclays. Your line is open.
spk11: Thanks for the update and good morning. Just April, is that getting better? You've seen that kind of similar trend for for scripts, for revenues? Any color around April would be great.
spk10: Well, I think our commentary is not so much on scripts and revenues because it's probably too early to comment on that, Peter. But I think it's on things that we see that are happening in the market that we've always thought of being very positive leading indicators to our ability to continue to drive adoption of TASDARIC. And that is, again, our ability to access the customer and the ability for patients to get back in and see their physicians. And to see that trend that we've seen pretty consistently on new prescriptions that have been trending down 20% to 40%, depending on the line of therapy, actually start to right itself. Those are both very important to achieving adoption of any new product, but TASVERIC in particular since we launched just in the middle of the pandemic last year. So those are the things that give us optimism that this is going to bode well for our ability to access the customer, but also their ability to see their patients and start to change the prescriptions in patients who need a change. And many of these patients, keep in mind, they've been away for some time. Not in all offices, but there are patients who've been away from their office for many, many months now. And so I think it's going to be imperative for physicians to get those patients back in. as quickly as they can because many of them are likely, either because they've dropped off of treatment, they've progressed, it will be important that they're able to get them back in and make that treatment change.
spk11: Gotcha. Thank you. And then the basket study for, I guess, the expansion for tismetastat, what indications could read out first?
spk01: Yeah. So, hi, Peter. This is Shafali. So, the basket study is a very innovative design. It's basically looking at the safety run-ins. And then you're looking at all the indications together. So it's basically all the different cohorts with different indications, starting with the heme basket study. The indications that we are looking at is follicle lymphoma, TLCL, multiple myeloma and mantle cell. The goal would be able to actually look at all the cohorts together. And because it's open labor, you know, you can enroll patients in each cohort and look at the cohort on itself. You know, you don't have to really see which one is first because they would be enrolling simultaneously And then, you know, we are using a Bayesian method by looking at a certain number of patients and understanding what the biomarker is, what's the right population, how is it faring in terms of efficacy, and we'll be able to read that data out regularly starting from 2022. So that's the goal, both for heme and solid basket studies.
spk11: Gotcha. Thank you. Thank you so much. I'll get back into the queue.
spk10: Thanks, Peter.
spk05: Thank you. Our next question comes from with Cowan & Company. Your line is open.
spk02: Hi there, thank you for taking my questions and good morning. A couple of the dose optimization questions, just to follow up on the basket trial in the heme malignancies. If you do see a signal in one of these combination baskets, do you anticipate there's going to be sort of substantial additional dose finding work with the combination, like you said, to sort of optimize the efficacy of both aspects there? And then in the SETD2 initial study, is this going to be a monotherapy study or is this also going to be in combination? And how are you thinking about the necessary dose in those two settings? Thank you.
spk01: Yeah, thank you. This is Shepali. Let me start with the heme basket study. So I think just to reflect on the dose optimization, I just want to kind of clarify that we have studied more than 1,000 patients at 800 milligrams dose, and we optimized the dose in the monotherapy study. Of course, you look at the combination and you study the two dose together. So the goal is to be able to do the safety run-in with these combinations early on, and then be able to do a dose escalation plan with this. You know, based on the data and based on multiple combination studies that we have done, like ARCHOP, we are doing the Dux Rubicin, You know, we have showed with a checkpoint inhibitor, there are different combinations that we have done so far where we showed that we can combine at the highest dose of 800 milligrams. We showed that with R-squared as well. So I think the goal would be able to do the escalate in this combination in the heme-bacteria study. And once we know that we can see the signal, expand that to different multiple cohorts, as we mentioned, in terms of different indications. In terms of SETD2, the first in human study, you know, as you know, the first in human study is really to optimize the dose from the beginning to understand your MTD or maximum efficacious dose. So the goal would be able to escalate in monotherapy because we have to find the dose first in monotherapy and then expand, particularly in T414. In the vision call, we showed that, you know, there's great data preclinically where we believe that it may be really effective in T414, which is a big unmet need in multiple myeloma. So we would expand in the T414 multiple myeloma and also studying, you know, the non-T414 as well as the LBCL as monotherapy. Once we have information about the signal in monotherapy, we absolutely will look at different combinations in those indications and many more. So I think, as I said, we have a big life cycle plan, not only to those optimized, both for Tanveric as well as for CENDI2, but also have a great life cycle plan. I think overall, I want to say that based on the data we have so far, we feel comfortable that 800 milligrams that we chose in our safety run is the optimized dose. But of course, we look at the combination. Let's see.
spk02: Perfect. Thanks so much.
spk05: Thank you. Our next question comes from David Liebowitz with Morgan Stanley. Your line is open.
spk03: Thank you very much for taking my question. Hello. specifically with respect to vaccinations. How is the dynamic with patients getting multiple myeloma patients getting vaccinated? Is there resistance within the population itself? And how do you see that dynamic going forward?
spk10: Yeah, it's a great question, David. I'll turn that over to Shefali because she's been interacting with physicians about this, both from a commercial point of view, but also from the standpoint of interaction in our clinical trials. So I'll turn that over to Shefali to answer.
spk01: Yeah, good morning, David. It's a very interesting question. You know, ideally we would think that all patients, especially elderly patients with follicle lymphoma, as well as other multiple myeloma, heme malignancies, would be able to get vaccination, would want to get vaccination. I think what I'm hearing from physicians is majority are, but not all. because there's a concern about the immune therapies as well as some of them are getting rituximab. And as you know, the concern is about having antibodies or you have to stop the drug because you have to ensure that you have antibodies with the vaccine. So what we are hearing is that there is an increase, but not all patients are actually getting vaccinated because of the fact that they don't want to stop their therapy. They want to continue on their therapy. So I think it may change in future and eventually patients may be comfortable. I think it's more in like less aggressive diseases and for lymphoma, but if you look at multiple myeloma or DLBCL, they're very aggressive and they don't want to stop their therapy, especially the ones that they have to stop to get the vaccination. So I think we may see in future how it changes.
spk03: How long do you think it, I guess, foresee you could take to this dynamic shift?
spk01: I think it's hard to comment, you know, as people get comfortable about the long-term data with vaccination and that, you know, even if you stop the medication for a couple of weeks, like rituximab, it's still okay. I think it has become better. It's hard to comment how long, but I feel that as I talk to physicians, they feel that it is increasing and gradually we'll see that improvement this year and in coming years. Yeah.
spk03: Have doctors given some sort of vision or estimate on how many patients have that level of resistance?
spk01: You know, it's very anecdotal because I talk to, you know, physician by physician. But what this is, you know, I would say majority of the patients want to get vaccinated, but some subsets. don't. It's like they don't really give the quantification number. They just kind of give like anecdotally. But as you know, it all depends on individual patient, whether they want to stop therapy or not and take the vaccination. But I'm hoping as a physician myself that eventually this will get better and people will start taking vaccinations.
spk03: Thanks for taking my question.
spk10: But we haven't seen, David, just to follow up on that, David, maybe Shefali will comment on this as well, but So, for example, in the 302 study where we left enrollment open because we were in discussions with the agency about potential ways that we could finish the dose optimization work. But there's been a great interest in enrolling patients in the 302 study. And as we left it open, as Shefali mentioned, we're nearly complete with even the additional patients that the FDA wanted to see as a part of that dose optimization. We've not seen it had a significant impact on the ability to enroll 302, for example. So to her point about many patients are being vaccinated, physicians are more comfortable with treating these patients. That is what we're seeing in terms of how it's impacting 302, which would be really relevant to us. And Shefali, do you want to comment further on that?
spk01: Absolutely. I think we are seeing a lot of enthusiasm in the R-squared study, even the R study, I think. Overall, if your question is whether the physician will come back, whether the patient will come back and take the therapy, absolutely. I think it will be gradual change and people will start doing that. We are seeing no impact on the 302 study. Actually, we had patient enroll, like Rob said, in the safety done and even before, you know, FDA asked us differently for the number. So I think we are seeing that interest and patients are coming for their therapy, irrespective of vaccination or not.
spk03: Excellent. Thank you very much for that.
spk05: Thank you. Our next question comes from Andrew Bairns with SVB Learing. Your line is open.
spk04: Hi, thanks. A couple of questions on testing. Hi, Rob. A couple of questions on testing to follow up on Mohit's questions and then one on the pipe. How long is it taking to get patients tested and where is that actually being done when clinicians want to sequence a patient with unknown EZH2 status? What's the bottleneck? that you alluded to in the prepared comments. And then you said in the Q&A session, a fair number of patients are now being treated in the frontline for EZH2. When did that actually start happening? And when do you think those patients will be presenting and be candidates for TASVERIC? And then also, I know you said you have limited visibility on wild-type versus mutant patients are getting tasveric because of the channels. But I thought usually that gives you better access to that type of information. So just trying to get a sense of what percentage of patients that are actually getting the drug are wild-type versus mutant. And then if you want me to ask the question on the interim analysis, I can do that now or I can wait until after I answer those questions.
spk10: Why don't we address the questions on testing first, and I'll Let's go through them one by one, and then I'll ask Vicki to comment as well if I miss anything. But your first one was how are they doing it now and what's the bottleneck for that 25 or so percent that Vicki spoke about. There are actually a number of ways that they can test. Many institutions have their own tests. So if a physician is an academic physician, many of those are using their institutions panel. There are other panels available. There are commercial panels. There's a Quest diagnostic panel. There's a foundation medicine panel. all that have EZH2 on them. And so there are many different ways physicians can choose to test patients for EZH2. I think what Vicki had indicated is if you're a community physician, you're not in an institution, you don't have access to the institutional panel, those commercial panels have many, many tests on them. And so what they really are desiring is a test that actually is just specific for EZH2 so that you don't have to do that complete panel. But they do have access to panels today. It's just not ideal. And so one of the things we're looking for is to see if we can make things simpler for that group of physicians who want to test that is specific for EZH2. But I wouldn't say it's a bottleneck for getting tested or a bottleneck even for patients going on test there. That's not always the reason that they're looking to test patients. I think your other question was how quickly, when did we start seeing testing in the first line? And I just want to restate what you said or make sure I heard you right. when are we starting to see use in the first line? I didn't comment, so I'm seeing tasveric use in the first line. Patients are tested there. EZH2 is one of the parts of the Flippy Severity Index, and so there's a reason that physicians will be testing in the newly diagnosed patients or frontline because it's a part of that, and they're testing as a part of their severity scoring. But it also is just because now, as Vicki said, it's one new test. It's one new piece of information about the disease. that wasn't relevant or wasn't well known before we brought Casveric to market. And now it's one more piece of information they could obtain around the disease. Vicki, anything else you'd add to those two things?
spk05: No, you covered it well. Yep, nothing.
spk04: Rob, could I just, I didn't mean the patients being tested in the front line. I just, or being treated in the front line. I'm just curious. When they started being tested, and obviously there's a, you know, period where they, you know, will be responding to the front and second line treatment. So when do you think we'll start seeing patients with known EZH2 status being candidates for Tazeric?
spk10: Well, it's a great point, Andy. And so I think we've seen testing in the front line, you know, for some time among some physicians. That's starting to grow because, again, it's a part of the Flippy Severity Index. So it's been tested for some time as long as it's been a part of that panel. But I would say growing. In terms of when, and we're encouraged that we're seeing more frontline testing because it means that when the patient relapsed, because our label allows for use of TASBERIC as early as the second line, it's good that they could already know the EZH2 mutational status, particularly since in the second line with other combinations that have full approvals, like R-squared and bendamustine rituximab, particularly for EZH2 mutation patients, as a monotherapy, we think that TASBERIC can be very attractive in the second line setting. And so that's a good thing. It's just continued to grow, but it didn't just start because, again, just how it's used from a prognostic point of view. And in terms of how long you would expect, I mean, patients in the frontline setting often may go for many months before they relapse, and then you have POD24 patients, which are the ones who tend to progress within the first 24 months. So there's a pretty wide variety of how quickly those patients progress from frontline to second line, depending on their response to their initial treatment.
spk05: And your other question was about mutant versus wild type. So I'm happy to answer that. So what we've seen, as I mentioned, was, you know, the predominant use right now for Tasveric is in the third line plus setting, as well as we're still seeing use in second line as well. And when we look at the split, mutant versus wild type, we actually don't get that data through the claims data because it's the diagnostic piece, right, isn't in the claim, the claims for the drug. So what we have to do is we do pretty extensive market research with providers that are prescribing. And what we're seeing from that research is that we are seeing more mutant utilization in both the second-line and the third-line plus setting versus wild-type.
spk10: Does that answer your question? But I think that would be a good thing. Yeah, that would have been expected, Andy. We always have assumed that as a monotherapy that we would see a higher share in the mutant population. So that's entirely consistent with what we would have expected. And then there's the other group that Vicki has mentioned, which is untested, which is we actually don't know their status because the physician didn't feel the need to test and the policies don't require them to test.
spk04: So would you say that of the patients that are getting Tazeric, is it 75% are EZHC positive? or is it a number less than that?
spk10: I think it's hard to say, Andy, because they're the untested patients, and it's difficult to know for those which they are. Okay.
spk04: And then just a question on the second interim analysis for the R-squared trial. Is that going to be an EZH2 wild type or mutant patients, and how should we expect the control arm to perform that? Just trying to get a sense for how high the bar is for Tesveric above the R-squared regimen.
spk01: Yeah, no, that's a great question, Andy. This is Shefali. So the way we have the interim is actually to ensure, you know, we see success in the study. So we are doing a hierarchy testing so that there's a very little alpha spend. So we're starting with easiest to mute. And once that is, you know, positive, then moving on to overall population. So the goal is to be able to test for easy-as-to-mute and then overall population. The study is powered for easy-as-to-mute to ensure that we have enough power in events that we can, you know, if we wanted to, we can look at easy-as-to-mute on its own or overall population, both of them. So that is the goal, looking at the interim. And in terms of the how will the experimental arm behave, it's a little different. That's why we did an adaptive design, Adi, because You know, we know that the Augment study only enrolled rituximab-sensitive patients because that was their comparator arm. We are enrolling the rituximab refractory patient population because, you know, that's the real world, about 30% of the patients. So, you know, we are going to see in an adaptive way in the interim how the comparator arm is behaving. You know, when we hear anecdotally from the physicians, they believe that they behave less because those patients are not that responsive to treatment, especially with R-squared. So as we look at the study, as we look at the interim, we'll have an opportunity to look at how this experimental arm will behave compared to the TAS plus R-squared. And another important component that's different than the augment study is also that we have maintenance arm, and we believe that that will benefit the overall PFS because the PFS is not after TAS plus R-squared per year. It's actually after the maintenance arm of TAS and the maintenance arm of placebo. So it's a very innovative design. You have an opportunity to look at all these things at a regular interval and be able to assess and adapt your trial accordingly.
spk04: Okay. Thanks for letting me hog all the balance. I appreciate the answers. Thank you. Certainly.
spk05: Thank you, and I'm showing no other questions in the queue. I'd like to turn the call back to Rob Bazemore for any closing remarks.
spk10: Okay, thank you, operator, and thank you all for joining us today. Thanks for all the questions. We hope that you all stay safe and healthy and have a great day. Take care, everyone.
spk05: This concludes today's conference call. Thank you for participating. You may now disconnect.
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