Rigel Pharmaceuticals, Inc. (RIGL) Earnings Call Transcript & Summary

Greetings, and welcome to the Rigel Pharmaceuticals conference call to discuss the approval of REZLIDHIA. [Operator Instructions] As a reminder, this conference is being recorded. It's now my pleasure to introduce our first speaker, Dean Schorno, Rigel's Chief Financial Officer. Thank you, Dean. You may begin.

Welcome, and thank you for joining us today to discuss the U.S. FDA approval of REZLIDHIA. As a reminder, during today's call, we may make forward-looking statements regarding our financial outlook and our plans and timing for regulatory and product development. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in our most recent annual report on Form 10-K for the year ended December 31, 2021 and subsequent filings with the SEC, including our Q3 quarterly report on Form 10-Q on file with the SEC. Any forward-looking statements are made only as of today's date, and we undertake no obligation to update these forward-looking statements to reflect subsequent events or circumstances. At this time, I'd like to turn the call over to our President and CEO, Raul Rodriguez. Raul?

Thank you, Dean, and thank you, everyone, for joining today. We are delighted by the early FDA approval of REZLIDHIA, the brand name for olutasidenib. This is an exciting time for both Rigel and for patients with relapsed or refractory AML, a patient group who typically experiences poor clinical outcomes despite available therapies. During today's call, I will provide a few key highlights from the approval of REZLIDHIA. Dr. Wolfgang Dummer, our Chief Medical Officer, will then provide a clinical overview of REZLIDHIA and the incredible data that we have seen today. We're also very excited to have Dr. Jorge E. Cortes, Director of the Georgia Cancer Center, Cecil F. Whitaker Jr., GRA Eminent Scholar Chair in Cancer and Phase II trial investigator to provide a clinical perspective on REZLIDHIA. Following Dr. Cortes, our Chief Commercial Officer, Dave Santos, will discuss U.S. launch readiness as he and his team have been working diligently to prepare for this approval. Then at the end of the call, we'll open up for questions. We are also joined today with -- by our Chief Financial Officer, Dean Schorno, who introduced me. Turning to Slide 4. REZLIDHIA is now approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test. We believe REZLIDHIA has the potential to be a market-leading mutant IDH1 inhibitor, and our commercial and medical affairs too have been planning diligently to help patients get access. This is an exciting milestone for Rigel, marking the second approved treatment in our commercial hematology oncology portfolio. One of our strategic priorities is growing our commercial business, and today's news is an important step in executing on that goal. Now I would like to turn the call over to Wolfgang for an overview of REZLIDHIA, our newly approved product. Wolfgang?

Thank you, Raul. Slide 5. I want to take a moment to remind you of some thoughts from our Q3 call explaining why AML is a very interesting disease area for us. First, AML is an aggressive, highly complex malignancy in the primarily, a disease of older adults. In 2022, the American Cancer Society estimates that more than 20,000 patients will be diagnosed with AML, and unfortunately, about 11,500 patients will die from the disease this year. One of the biggest advances in AML over the last 5 years has been the establishment of guideline-driven molecular and cytogenetic analysis for immediately actionable mutations or chromosomal abnormalities. That means that depending on which mutations are predominant, different therapies may be indicated. One such important mutation is in IDH1 and is seen in around 6% to 9% of AML patients. Since looking for the IDH1 mutation is part of the standard widespread testing upon diagnosis and prior to initiation of a new line of treatment, leukemia-treating physicians are well aware of their IDH1-positive patients. Within this well-defined patient population, about 60% of patients are considered fit for intensive therapy with the goal of hopefully getting those patients to transplant if they have a complete remission or a CR. The remaining 40% of patients are not treated with intensive therapy and are given less intensive outpatient therapy. In both cases, there are a substantial number of patients who are refractory to the upfront treatment for who relapse after getting a response. So even though there are new agents to treat AML patients, a substantial unmet medical need persists for these patients. An mIDH1 inhibitor with a high rate of complete response, a longer duration of response and an improved safety profile, including less cardiotoxicity is a positive new treatment option. Slide 6. Forma, with the help of KOLs in the area, developed a very comprehensive plan and trial for the development of REZLIDHIA with multiple cohorts, both as a single agent monotherapy and in combination with other agents. I'd like to review the Phase II registrational trial that provided the data to support REZLIDHIA's approval. The registration and monotherapy cohort of the study, highlighted in orange on this slide, included patients with mIDH1 relapsed refractory AML. These were older adults with a median of 71 years. 73% had an intermediate AML cytogenetic risk, 17% had a poor cytogenetic constellation. 75% of patients have greater or equal to 1 co-occurring mutation. 97% had prior induction chemotherapy and a median of two prior treatments, including 8% with prior venetoclax. All patients were naive to an IDH1 inhibitor. Slide 7. Today, I'm showing you the clinical efficacy results in the label. The registrational Phase II clinical trial evaluated REZLIDHIA in 153 patients with mIDH1 relapsed/refractory AML who received REZLIDHIA monotherapy 150-milligram twice a day. The primary efficacy evaluable population was 147 patients. The primary endpoint was a composite of a complete remission, or a CR, plus a complete remission with partial hematological recovery or CRH. As you can see in the table, 35% of mIDH1-positive relapsed refractory AML patients met this composite endpoint. It is worth emphasizing that of the 35% of patients who achieved the primary endpoint, over 90% were CRs, which speaks for the high quality of the response. Achieving CR is the ultimate response goal for clinicians and patients in AML. The median duration of response in those high-quality complete responders was 28.1 months. The other important outcome here is the median duration of the CR plus CRH, which is 25.9 months. Reporting their patients receiving REZLIDHIA achieved a durable remission with a median of more than 2 years is highly meaningful, especially for patients in a relapsed/refractory setting. And for the patients who achieved the CR, or a CRH response, the median time to CR or CRH was 1.9 months, representing a fast time to response. Moving to Slide 8. With regards to safety, REZLIDHIA has a well-characterized safety profile with AEs, largely characteristic of symptoms experienced by patients undergoing treatment for AML. The most common adverse reactions occurring with REZLIDHIA, not including lab parameters, were nausea, fatigue, malaise, arthralgia, constipation, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea and transaminitis. On Slide 9, a comment on AEs of special interest. Differentiation syndrome was observed in 16% of the patients with Grade 3 or 4 differentiation syndrome occurring in 8% of the patients. Differentiation syndrome can be life threatening or fatal. However, most cases were successfully managed with dose interruptions and supportive treatment with steroids, diuretics or hydroxyurea. The incidence rate of differentiation syndrome for REZLIDHIA was comparable to that reported for FDA-approved IDH1 and IDH2 inhibitors in similar patient populations. Hepatotoxicity presenting as increases in liver function tests occurred in 23% of patients. Most cases were manageable with dose modifications and many were successfully rechallenged. Slide 10. I'd like to repeat some key takeaways from the data shown today that give us confidence in the differentiation of our potential market-leading therapy. First, 35% of mIDH1 R/R AML patients achieved the primary endpoint of CR plus CRH, and kept their responses for a median duration of 25.9 months. Importantly, 92% of those responders had a complete response, which is very exciting with an even longer median duration of response of 28.1 months. We believe this combination of a high initial rate of complete responders in the long duration of response, positions the product very well within treatment options for relapsed refractory AML patients with the IDH1 mutation. Further, other practically important outcomes were favorable as well. For example, patients in all subgroups achieved transfusion independence, a valuable data point highlighting a reduced burden on patients and reduced strain on health care system resources. Importantly, REZLIDHIA has a well-characterized safety profile without evidence of cardiovascular side effects. We believe these key factors as well as the totality of data observed across REZLIDHIA in patients with mIDH1 relapsed refractory AML demonstrates strong potential to be a market-leading IDH1 inhibitor. We are thrilled to add this much needed treatment option to the physicians' armamentarium. Now I'd like to turn the call over to my colleague, Dr. Jorge Cortes for his clinical perspective on REZLIDHIA. Dr. Cortes?

Thank you very much. Can you hear me well?

Yes.

Great. Well, thank you very much for giving me the opportunity to present some thoughts about the approval of olutasidenib. I think that this approval represents a major addition to the treatment that we have for patients with acute myeloid leukemia with IDH1 mutation. These patients are not rare. It's certainly not the most common mutation, of course, but it is a significant fraction of patients. And because we are -- nowadays, we are doing molecular monitoring molecular assessments in the great majority of patients even in standard practice, in community practice and all, we are identifying these patients. So I think the frequency, these patients continue accumulating, continue coming to our clinics. And particularly, it's a little bit higher even on these patients that are more fragile. The older patients, the incidence is a little bit higher than what you heard today, which is representing the overall patient population. The drug has been very remarkably, a very good surprise for us in terms of its efficacy and its safety profile. I think some of these things you have heard on this presentation. But I do want to emphasize because I think that these are important elements to my patients. The response rate is very good. The CR/CRH, that composite response is what has been used for these kind of agents, and it's very good. But I find it particularly attractive that the great majority of these responses are actually CRs. So 32% of CR is really very valuable. So pretty much 1/3 of the patients get a true CR. We know that CRH are welcome in these patients, the refractory relapse, I like them. If I have that, I'm very excited about these. But CRs are unquestionably better. So having them predominating the response rate is very important. But also very important, and here is where I am welcoming these drugs, in particular, is the duration of remission. A durable remission, particularly in these patient population that really doesn't want to -- once you get past this kind of growth, they don't have too many treatment options. They were going to -- you're going to have to think about giving them intensive chemotherapy and so on. I think that having a remission that lasts more than 2 years is very, very valuable. This allows the patient -- as this is an oral medication, this allows the patients to be mostly at home. You also saw that there's a transfusion independence, particularly in these patients who respond. So that allows these patients to have a much better quality of life. Of course, that was not measured, but you can imagine a patient in remission that needs very few or no transfusions is going to be feeling much better than a patient that needs to continue treatment or start a new treatment very soon. And the safety profile has also been very rewarding. And I bet it not just on the data that you heard. I've treated many of these patients because I've been using these drugs in the Phase I. So I have experienced this. And the differentiation syndrome is something we learned about from these drugs, and we are understanding better. So now we monitor this closely. We identified them. And because of that, you saw that although it's common, most patients can be treated successfully through that differentiation syndrome, continue the therapy and we offer the possibility of a response. That is in nature. Actually, these drugs are not cytotoxic. So that's part of the mechanism of action of these drugs. They induce differentiation. So that's a good thing. And as long as you monitor and detect early, this is quite manageable. The liver toxicity, of course, is an issue. But one thing that stands out when you see the full data is that overwhelmingly, this liver toxicity can be manageable. Most patients who had this elevation of transaminases, and keep in mind that the Grade 3 or 4 was around 10% only, they can be managed with those adjustments and transient treatment interruptions. There were only there are few patients who could not continue through the therapy, and it's very seldom, if ever, associated with the bilirubin increase. There's only a couple of patients that had bilirubin elevation Grade 3 or 4. One big advantage for this drug is the absence or very low incidents, probably more accurate, of QTC prolongation. That's important because these patients -- again, we're talking in particular, the patients who have multiple comorbidities or older, et cetera, they take multiple other drugs. And drugs that prolong QTC are very common. Zofran is one very common one. Quinolones, which we very frequently use for antimicrobial prophylaxis. Many cardiac medications that these patients are taking. So with olutasidenib, we had an incidence of just 1% or so of QTC prolongation Grade 3 or 4. So that is very, very welcome. It allows for better management on patients that are taking all these other concomitant medications that prolong QTC. So I think that this offers a great alternative for patients who have IDH mutations, which are relatively common. It's a subset of significance in my patient population with AML. And who unfortunately, when you give them any other treatment frontline, very likely are going to relapse. So having this treatment option and having alternatives, and alternatives that have meaningful advantages, again, more towards CR, more durable remissions, less cardiac toxicity, I find that particularly attractive. And I'm very, very excited to see that I will now be able to prescribe these in regular practice and not just on a clinical trial. So to me, this represents a major advance. Sure, we do have one drug, and I've used it and I like it. But because of all these benefits that I emphasized, I think it offers many good opportunities for our patients, and that's something that I welcome very much. So I'm going to stop here, but I'll be happy to take any questions when the time comes.

Thank you, Dr. Cortes for your valuable insights. I would now like to turn the call over to Dave.

Thank you, Wolfgang and Dr. Cortes for your clinical perspective. Now I'd like to take a few minutes to highlight the commercial opportunity with REZLIDHIA, the work our team has already done in advanced launch and our excitement around adding a second approved treatment to our commercial portfolio. Moving to Slide 13. As Wolfgang outlined, the American Cancer Society estimates that more than 20,000 patients will be diagnosed with AML in 2022, and unfortunately, about 11,500 patients will die from the disease this year. In terms of the eligible relapsed/refractory IDH1-positive AML patients, our research showed that up to 60% of fit patients progress in 2 years and for unfit patients, most are refractory or relapse within 2 years. With 6% to 9% of patients IDH1 positive, that gives us a near-term opportunity to impact the lives of around 1,000 IDH1-positive patients in the relapsed refractory year. Moving to Slide 14. In market research and focus group discussions with leukemia-treating physicians, we hear that a high unmet need remains for patients who need an efficacious and tolerable therapy in the relapse setting. First, even though there are several approved options for AML, clinicians continue to perceive an unmet need for efficacious targeted treatments, particularly for their relapsed and refractory patients. And it's clear that while response rates are important, the quality of response and its clinical outcome are the key drivers of decision-making. So having a longer duration of response in the relapse setting where responses can be quite short would be particularly meaningful and differentiating. And finally, for patients and clinicians, it is highly important in the relapsed or refractory setting to have options that balance both efficacy and toxicity, especially as this is intended to be non-intensive therapy. On Slide 15, I'd like to talk a little bit about why we believe REZLIDHIA has the potential to address many key patient and HCP needs. It's a promising new treatment for relapsed/refractory AML, targeting mutant IDH1 that has shown robust responses in patients who have failed previous therapies. As clinicians review the demographics of our relapsed/refractory patient population in our pivotal cohort, and put that together with a complete response rate of 32%, a CR/CRH rate of 35% and especially the median duration of CR/CRH of longer than 2 years, they see the value of an agent like REZLIDHIA in their treatment armamentarium. Combining that response efficacy with a side effect profile that is mostly manageable without the requirement of cardiac monitoring, it becomes even more compelling to adopt REZLIDHIA in their relapsed/refractory IDH1-positive patients. Overall, we see exciting potential to become a market-leading treatment in mutant IDH1 relapsed/refractory AML and are looking forward to a great launch. Moving to Slide 16. Immediately, our team is ready to execute our critical priorities for launch. First, we aim to drive awareness across leukemia treaters. In addition to our now approved website that's already live at rezlidhia.com, we will engage customers through both nonpersonal activities such as e-mail and personal interactions using our approved package insert. In order to maximize access, we already have our patient enrollment forms in place for our Rigel One Care Hub, and we have a distribution network in place. So we are poised to deliver REZLIDHIA to patients and clinics as soon as possible after we have commercial products available. And once we have commercial bottles available, our goal is to optimize the REZLIDHIA experience for both HCPs and patients to ensure they get product quickly and are encouraged to continue using REZLIDHIA. In terms of our field team, we have a highly experienced hematology/oncology team ready to call on customers. Our sales team is supported by regional marketers from our marketing team, national account directors from our market access team and of course, our medical science liaisons, working together as one Rigel team with customers across the country, they will ensure that we immediately drive awareness of REZLIDHIA, identify all opportunities to ensure future access for patients and clinicians and answer any medical questions leukemia treaters have. My thanks to the entire team for ensuring we are off to a great start with REZLIDHIA. Moving to Slide 17. Importantly, this is our second approved hematology oncology treatment in our portfolio, and we already have the synergistic infrastructure and capabilities in place to market both drugs. As previously mentioned, we are already calling on the majority of Hem/Oncs as part of our existing efforts with TAVALISSE. Soon, we will be calling on additional leukemia treaters who are practicing in these same institutions. So it's a highly targeted and efficient audience, bringing two important products, REZLIDHIA and TAVALISSE, to the attention of our customers is a proposition we believe can increase the overall awareness and utility of both. We believe our existing infrastructure of 54 hematology/oncology experienced salespeople, combined with our strategically experienced brand team and a highly efficient business operations team, will be able to quickly raise awareness of REZLIDHIA with the right messages to the right clinicians while continuing to generate new patient starts on TAVALISSE. And finally, our expertise in market access will enable us to efficiently distribute REZLIDHIA to patients and clinics and ensure patients have access to coverage, reimbursement and assistance. Overall, this REZLIDHIA launch fits extremely well into our commercial infrastructure, and we have the resources and people in place to ensure we bring REZLIDHIA and TAVALISSE to clinicians and patients as expeditiously and efficiently as possible. And finally, on Slide 18, I wanted to reiterate how important this year's ASH in New Orleans will be to us. This will be our first major conference having abstract presentations for both TAVALISSE and REZLIDHIA. We view this as a great opportunity to increase awareness of Rigel, our Hem/Onc pipeline and our approved treatments, TAVALISSE and REZLIDHIA. In addition to our exhibit booth, where REZLIDHIA now approved will be prominent, we have numerous key customer events plan to engage with clinicians, gain their insights on our products and data and answer any questions they have. It promises to be a productive meeting that the entire Rigel team is looking forward to. Thanks for your attention, and I will now turn the call back over to Raul for closing comments.

Thanks, Dave, and we are absolutely excited to discuss this with you some more at the ASH meeting. To conclude, we are thrilled to bring a potentially market-leading IDH1 inhibitor to AML patients in need of new treatment options. Further, we are excited to leverage the strength of our commercial infrastructure to successfully launch REZLIDHIA, and expect to have product to be commercially available in the second half of December. Let me repeat that, and expect the product to be commercially available in the second half of December. As we look ahead, we are evaluating plans for international regulatory filings, so stay tuned for more updates. In addition to the successful launch of REZLIDHIA, we are committed to growing sales of TAVALISSE and ITP, our other key product in Rigel's Hem/Onc portfolio. With two approved products, we believe there are synergies that exist, chooses the broadened reach of our sales force that can help drive the growth of ITP sales as well as REZLIDHIA's. And lastly, we remain focused on advancing both our internal and partner programs for the continued growth of our Hem/Onc business. Before I open the call for your questions, on behalf of Rigel management, I'd like to pass along our sincere thanks to all of our employees who have worked diligently preparing for this approval. Additionally, to the patients, the caregivers and the investigators, all of whom made this approval possible. And lastly, to our partner, Forma Therapeutics, who conducted the Phase II registrational trial. So with that, I'd like to open up the call for your questions. Operator?

[Operator Instructions] Our first question today is coming from Yigal Nochomovitz from Citigroup.

Congratulations on the very early approval. Obviously, I think everyone has this basic question. Given the approval came 2.5 months before the PDUFA, could you just provide a little bit more context on that early timing. Did you have a sense that this was happening? Or did it come as a welcome Christmas gift?

Thank you for the questions, Yigal. I appreciate those. We've worked very closely with our partners, Forma and with the FDA in terms of their review and have had very positive interactions throughout including, as we may have said in prior calls, a very positive mid-cycle review meeting and very, very positive feedback, back and forth, as we answered their questions. So we had a sense that we're going in a very positive direction for an approval. And like you, though, we are surprised that we are able to get this approval so early on, and delighted by it, simply because we think this product could really help some of these patients. Dave mentioned 1,000 relapsed-refractory patients with IDH mutations. And to be able to get this product to those patients 2.5 months earlier, I think will help them tremendously. And so we're incredibly excited about that. And while we've been working hard to prepare for the launch, and now the launch is now, we're even more excited and we'll redouble our efforts to make sure we're able to convey the information supporting this product and the product -- the commercial product itself as early as we can to help those patients out. We're so excited about this. And I think -- obviously, the FDA did a fantastic job in helping expedite this review, but it's based on very strong data. Dave, Wolfgang, any other comments?

Not really, Raul. Yes, I can confirm the discussions with the FDA went very well. The mid-cycle review, end-cycle review. And apparently, if you don't have a lot of questions and comments, the hopes go up a little bit, that timeline gets expedited and that's exactly what happened.

Yes. I would just say Yigal that when you bring in an in-license, you just hope and pray you have the right kind of partner who's committed to do things incredibly diligently, and you hope that you've got a team that can literally work around the clock, which is what we -- our team has been doing here at Rigel. And so it's -- we're very thankful to the folks here. We are thrilled that we are earlier than the PDUFA date and frankly, a perfect timing for ASH. I think as you know, whenever you launch early, there are some things you'd love to be able to do, but you're not. But I'd just tell you, to have our website, rezlidhia.com live today with patient enrollment forms on there and all of the things that we have prepared, I'm telling you, it is a magnanimous effort on the part of our team across Rigel. Every function has done just outstanding work to get us where we are. So we'll have more to come as we launch, but we're ready to do what we want to do first, which is drive awareness.

Okay. Great. I just had two follow-ups for your expert, Dr. Cortes, if he didn't -- don't mind. Dr. Cortes, obviously, you know there is the drug already approved. I think you mentioned it that TIBSOVO for relapse/refractory AML with the IDH1 mutation. So what's your plan now as far determining who's going to get to TIBSOVO versus who will get the new drug, REZLIDHIA? And would you be willing to venture any kind of prediction as far as the percent of patients longer term in the mutant IDH1 relapse/refractory AML population that you think would end up on the REZLIDHIA as opposed to the TIBSOVO?

Thank you. I'll start my answer by telling you that that's a problem that in oncology, you love to have options, and having to then decide what fits better your patient than when you're facing them in the clinic. There's no perfect drug. So having one that gives me the -- having another one that gives me the opportunity to select based on the data, the efficacy, the known safety, et cetera, is a great advantage. I've used both extensively. Of course, olutasidenib so far only in clinical trials. I've used the olutasidenib in both clinical trials and in clinical practice, and I mean both are good drugs. I certainly welcome the higher CR rate, the longer remission duration, the lesser cardiac toxicity. So I think that those -- all these elements are going to drive me more frequently to use olutasidenib. Certainly, if there's a patient where I'm a little bit more worried about liver toxicity, that's one area where I may say, I mean, olutasidenib less liver issue. So that may be something where I may want to select that. The long-term data -- the long-term prediction, of course, the physicians who have had these patients so far, they have only use the available drug post, olutasidenib, and there's something to say about having experience and comfort with the use of the drug. But I think as they see the data, little by little, olutasidenib is going to start taking more and more of the space. And my prediction is that in the not very distant future, it is going to take more than half of the patients because of these elements that I mentioned that I think that most of us oncologists, hematologists dealing with leukemia, we value. And then there will be studies looking at whether -- when you develop mutations, that develop resistance to one, olutasidenib may still be effective and other elements, biomarkers, et cetera. But based on the clinical data, that will be what I would predict that over time, olutasidenib could become -- I don't think it's going to be exclusively used. Like I don't think that olutasidenib would be exclusively used, but I do think it will be a majority, certainly more than 50%.

Okay. And just one more real quickly, which I think is very interesting. I didn't see this data in the original data set. Did you ever look at the CR/CRH rate broken out by the specific IDH1 mutation like, for example, R132C versus R132H, those are the two most common ones? Because I'm just wondering if you know the mutation and you could maybe be a little bit more smart about predicting response based on knowing the mutation, if you had that type of data.

That's an excellent question, but I think that the numbers are still relatively small to address that, and particular, considering that the -- there's some subsets of mutations that are relatively uncommon. I can tell that it works against both mutations, and we've seen responses against both mutations. So I don't think we yet can say that there's a preference. Certainly, nothing that differentiates the two drugs based on that. So -- but yes, as we treat more patients, as more patients come and these cohorts become a little larger, we'll have more of that valuable information.

Your next question today is coming from Kristen Kluska from Cantor Fitzgerald.

This is Rick on for Kristen. First, after recently announcing publication of early olutasidenib data in Lancet Hematology, could you talk about how you're implementing this and other peer review data in your outreach to physicians ahead of the launch?

Sure. If we could talk about that. This publication that you're referring to was the Phase I data, very nice data. I'll let Dave comment on how we're using it. The Phase II publication, that is the data that's the basis of the approval is coming, hasn't published as yet, but that's in the works. Dave?

Yes. The -- this is, of course, as you know, our data in the package insert is directly to the Phase II data and cohort 1, the pivotal cohort of the trial, whereas the Phase I study with a different patient population. And while it's out there, that would only be available via medical request. It is out there. But we are hoping that soon the Phase II data will be published. It will be presented at ASCO as -- or at ASH, I'm sorry, as you know, in a poster presentation. And so we will have some supporting materials. But for now, we will not be using the Phase I study, or that publication promotionally because it's not consistent with the label that we have on the Phase II trial. I hope that answers your question.

Okay. And -- yes, it was great, and just one more. Do you have any sense for how the differentiation syndrome warning could potentially influence uptake as it relates to different hospital settings, particularly in the community setting, given potential requirements for monitoring in patients that may develop it?

Thank you, Rick. Why don't I ask Jorge to maybe address that since he practices and deals with differentiation syndrome regularly.

Yes. I was going to mention that I could take that. I think the advantage by now is that we've known this. I remember the early days of the development of -- actually, the IDH2 inhibitor, which was the first one that came to the clinic, and it took us by surprise. We didn't know that, and there were so many -- some patients that were having what we thought was progressive disease, were taking off study, and we didn't recognize that in the early days. By now, after having used these drugs and others that also cause differentiation syndrome and understanding that it's so similar to the APL phenomenon, I think physicians who treat leukemia feel much more comfortable about a patient with differentiation syndrome, their management, they know how to recognize it early. There's been a lot of education in various forums, even from olutasidenib manufacturers and from just experts and in board reviews and things like that. I think that an institution that feels comfortable managing a patient with acute leukemia, right nowadays, they feel comfortable using these drugs. I've seen these drugs used in -- now I practice in a different setting than when I used to for the last 27 years, and certainly, that's a big institution, you have everything. Here, we don't. This is a smaller place, and I see patients referred that had already been treated with these agents. And I cannot say that the decisions have hesitation. Of course, there are clinics that know that they cannot manage acute leukemia patients because they don't have access to, I don't know, blood transfusions and emergency rooms nearby and so on. But the institutions would treat leukemias. I think they feel comfortable, they will be able to manage it well. Of course, even when there's been a lot of education, I would encourage additional education. It never hurts. But I don't think that that's going to be a deterrent for the use of the drug in general practice, not only in academic institutions.

Thank you, Jorge.

And I just add to Dr. Cortes' comment that we will -- obviously, we have a black box warning differentiation syndrome. It will be clear in every communication that we have, and we will be providing education, just as Dr. Cortes mentioned. We have things like differentiation syndrome patient wallet card that we've already prepared. So we -- even for those clinicians who might not be familiar, we will continue to educate.

The next question is coming from Do Kim from Piper Stanley.

Congratulations on the early approval. I don't know if I missed this, but did you provide a price for REZLIDHIA?

Dave, where's the price?

We did not. But as Raul said, again, due to tremendous work across the organization, we expect to have product available in the second half of December. And -- I mean, again, thinking about how early this is for approval, to have that happen, it's just outstanding work by the team. And so as I said, we have the distribution system in place. We're just waiting for product. And it's just a matter of getting product into our distributors, and once it's there, be ready to ship. And at that point, we will announce the pricing of REZLIDHIA.

So second half of this month is the answer timing-wise.

Got it. And just a follow-up, what needs to be done to get the commercial product to distributors? Do you have to do manufacturing, create labels for the bottles? What specifically more do you need to do?

We have product, which is great. Our colleagues at Forma worked on this, and that work transferred over to us this summer as we work to get pills in the bottle. And so we have that. Now it's a matter of making sure the label is done and make sure those two meet. The labeling is all done correctly and then shipping out to various distributor through our distribution network. So very mechanical things. There's nothing, frankly, difficult about it or challenging. It's just a matter of things need to get done to get the product out. The fact that we're delighted with the 2.5-month approval -- early approval, and obviously, it means that things aren't out there as quickly as we would like. But trust me, we are making every single effort to get the product out and available to these patients because we know how valuable and important it is to some of those.

Great. That's helpful. And a question for Dr. Cortes. Could you possibly expand on why liver toxicity is a concern for the FDA for REZLIDHIA? And not so much for TIBSOVO, even though TIBSOVO had a fairly decently high rate of Grade 3, 4 bilirubin elevation.

Well, obviously, these are studies that we're going to need to do to understand better those differences on what the mechanism of liver toxicity for both drugs because, as you mentioned, the they manifest in different ways. With the olutasidenib, we see very little bilirubin elevation, and with -- it's mostly transaminase elevation. So I don't know that I can answer the question with any certainty, just speculation. Fortunately, the transaminase elevation is fairly transient. Most patients recover. Many of my patients were able to be rechallenged after proper management of -- with those treatment interruptions and with those adjustments. And with that, it went well. So there were a few patients who were not able to continue, I remember distinctly one of my patients. But for the most part, this is manageable. So again, we'll need to understand they are chemically very different structures, and that's why we see different kinds of adverse events. One more cardiac, the other one more liver. The differentiation syndrome, again, it's not so much of a toxicity. It's a mechanistic issue. So it's just like I tell the students, the tumor lysis syndrome, for example, is a complication of a good thing. Same thing here. You want that differentiation. You just need to manage it well so that the patients don't suffer. But yes, the liver toxicity, we're going to need to understand it better. But again, I don't see it as a major issue. It's not at a level that worries.

Great. I appreciate your thoughts. And congrats again.

Thank you, Do. Appreciate it.

Next question today is coming from Gary Nachman from BMO Capital Markets.

Okay. My congrats as well on the early approval. So of the 1,000 IDH1 AML patients each year that it seems that they're well identified, so how many of those are already getting an IDH1 inhibitor like TIBSOVO? How much more awareness is necessary in this space to improve penetration with REZLIDHIA? And then just a little more on how the current sales force is going to commercialize REZLIDHIA. Will there be dedicated reps? Or they'll have it in a bag with TAVALISSE? Will they share positioning? How are you going to handle that?

I'll turn to Dave for both of those questions. Thank you, Gary.

So great questions, Gary. The 1,000 patients are well identified. And what's really important for everybody to understand is they're identified not only in the relapse setting, but they're identified upon diagnosis. So they get therapy upfront, and they're diagnosed and then often tested there and then retested many times in the relapse setting. So we don't believe there's a significant issue in terms of identification of those patients. Getting to how many are treated with an IDH1 inhibitor, well, it's just those things that I talked to you about before. Clinicians have the ways, as Dr. Cortes was saying, the patient's efficacy as well as tolerability of the drug. And so there are other options besides targeted therapies for these patients, and I can't really tell you a number of those addressable 1,000 patients that would be treated each year. But we think most IDH1 patients would either get it in the upfront setting or sometime in the relapse setting. And then I think your last question was on the sales force. Our sales force will carry both products in the bag in all 54 territories. There is obviously some more rural territories, which won't have as many leukemia specialists. But that's okay because they'll continue to focus on TAVALISSE. But in a more urban area with large academic centers, obviously, those folks will be working together with all their counterparts in the field to promote REZLIDHIA and TAVALISSE. So yes, we're definitely capitalizing on the existing infrastructure, and most importantly, those relationships that we have with these accounts and clinicians.

Okay. Great. And then for Dr. Cortes, it seems that REZLIDHIA was approved on the monotherapy data. So will it potentially be used in combination with other AML treatments? Maybe just talk to that a little bit because there is some data available in combination. And then just back to the company, maybe you, Dave, just talk a little bit more about the whole payer situation and how quickly you're going to get access? If you're launching it towards the end of this year, and a lot of plans have made their decisions going into next year, how quickly will you be able to get access with the drug?

So I can address the -- yes. I can address this issue of the combination. Of course, the approval right now is in refractory relapse and in single agent. So you kind of follow the label. But as you know, in oncology is not uncommon to do things off label on drugs that are approved and there's multiple Azacitidine -- even Azacitidine have been used in combination, particularly with hypomethylating agents. We use Gilteritinib in combination with hypomethylating agents. And there's a lot of -- when you need -- when you feel the need, you -- there's a lot of these things. And fortunately, we do have data with combination. There is data that's been -- this development plan for -- you briefly saw the whole program of the development of the drug from the very beginning that has multiple arms, both single agent and in combination. So we have data. We have data about the safety, we have data about the efficacy. There's more cohorts, but it gives you assurance that -- of what you can expect. So I think that I do expect that we're going to be using combinations and in various settings just like it's happened with some of these -- some of the other drugs that have been on this space or with other similar targeted agents or others.

Thank you, Dr. Cortes. And Gary, to your question on our efforts to ensure that patients get access, this is one of the things we're really proud about. Our Rigel One Care Hub is just outstanding at helping patients get access to products. In addition, I keep using these words, but these are the folks that we haven't committed here after in-licensing this product just 4 months ago. We have a payer team that's outstanding and getting to customers. And so we believe, first of all, it's a very targeted population of patients. And we believe, and in our discussions with payers, we believe we will be covered pretty much out of the gate. Obviously, there will be prior authorizations. But the other piece that, again, I'm just so proud of our medical affairs team and everything that's being done, we have already submitted to NCCN, and we're hoping that they will be able to add olutasidenib to options in relapsed/refractory AML. And if they do so, it just makes it that much more smooth for patients. But again, we just have a lot of things in place, as I already told you. The enrollment form is already on our rezlidhia.com website and our Rigel One Care is ready to begin helping patients get access to products.

Great.

And just on the other comment about combination with Dr. Cortes. Again, we won't be promoting obviously, any combination therapy. And so those are clinicians decisions, and we'll be able to answer questions through our medical affairs group.

Next question is coming from Joe Pantginis from H.C. Wainright.

Congrats as well. So Raul, I guess -- I'm assuming this is a bit of a rhetorical question, but when we talk about Forma already having the pill, and it's just the mechanical things you need to go through, do you have all the pills that you need for the immediate needs and even the capacity, say, from 1 to 3 years from now as well? Are there any capacity constraints that need to be addressed, especially from the early approval?

Thank you, Joe. It's a small molecule. It's not complicated or difficult to make. It's a much, much different challenge than having a biologic agent that requires all sorts of handling issues. It's very straightforward, which we're fortunate for. And we have ample supply for the near term. We're going to continue to make further. We make this at the API at a CRO and a contract manufacturing organization and then the capsules as well. So we will be able to supply. As Dave mentioned, it's a fairly succinct audience, 1,000 patients or so. So it's not -- and the volumes are not extraordinarily large, and we will -- and we certainly can commit to supplying patients in the near term and in the long term.

Sure. Great. And then I guess, look, it's exciting that you discussed about additional international filings and evaluating the next steps there. Is it possible to describe the status of the discussions for additional territories and when any potential visibility about potential paths forward in other geographies?

That's a very good question. Much like with TAVALISSE, our focus commercially is in the U.S. And we aim to be the best Hem/Onc company here. And this is a tremendous step forward in terms of getting us to that point. Outside the U.S., with TAVALISSE we used a constellation of partners that had expertise and tremendous capabilities in their individual territories of license, Grifols in Europe, Kissei in Japan and Asia, Medicine in Canada, Israel and our other partners. So we will probably do something similar to that, where companies that already have that capability to add infrastructure in those territories, the ability to provide this important drug to patients with tremendous needs in those territories are already there. And so we'll take probably a similar approach to that. And so we will have discussions with potential partners on total ex-U.S. basis and also on a larger regional basis like we did with TAVALISSE beginning soon, to allow us to move forward and provide the drug to those territories as well. They have different requirements, as you can imagine. In Japan, it's typical that the government there requires them to do a trial there. That might be necessary just like we did -- our partner, Kissei did with TAVALISSE successfully. And in Europe, it might be similar. So we're investigating that now and look forward to discussions with potential partners and eager to provide this product to patients globally.

Great. And then maybe just a quick logistical question to bring Dean into the conversation. What are the time frames that you need now to write the two upcoming near-term checks to Forma?

Yes, so the -- and we reviewed this on our November call. So we had an upfront of $2 million, then we had a regulatory milestone of $2.5 million. So that's happened in Q3, and the $2.5 million in Q4. Upon approval, we have a $5 million payment to Forma. And then upon first commercial sale, it's $10 million. So that's -- the great news today is that those two payments are near term for us, and we'll execute on those shortly.

So is it like you have to write the check within 30 days? Or how quickly do you need to write it?

Yes, we've -- that level of detail, we just haven't gotten into, but it's shortly thereafter after the execution or the attainment of those milestones.

So it's a check you're happy to bring.

Yes.

Exactly. Anyways, congrats, guys.

Next question is coming from Kalpit Patel from B. Riley.

Congrats on the early approval. Maybe starting with Dr. Cortes, when we make cross-trial comparisons for these two IDH1 inhibitors, it looks like Ivosidenib's trial had more patients who were -- who previously received a stem cell transplant I guess, doctor, are those patients inherently more difficult to treat? And would that maybe explain the differences in the CR/CRH rates and the durability of those responses as well in your view?

Jorge? Kalpit?

I think I was muted. Can you hear me now?

There you go. There you go.

Sorry. Sorry, I was muted. I've been doing this for -- this muting and unmuting for 2 years, and I still don't get it right. Sorry. Anyway, I was starting to say that the -- yes, the patients who have gone through a transplant may have a more difficult prognosis. Because they've gone through transplant, you could imagine also that these patients are probably in better shape. They were in better shape to go to transplant rather than the more fragile patients who are not considered to be eligible for transplant. And so actually, the median age of the patient tends to be a little bit younger on that Ivosidenib study. There were also more patients on the olutasidenib study that had gone through venetoclax which also makes them more difficult because once you failed venetoclax, it's a pretty good drug. So it's hard to tell. I would consider that in that regard, the populations are fairly balanced, I would think. And I don't think that, that alone explains the difference in the efficacy of -- on the remission duration, for example.

Okay. That's helpful. And then one follow-up question for the company on pricing. Now that we have the differentiated attributes with your drug on that duration of CR/CRH and maybe lower UTC prolongation episodes, would you expect to price at a premium relative to TIBSOVO?

Thank you for asking. I think what Dave said earlier is the case, we'll discuss the price and be more specific, obviously, precise at the launch point. But at this point, we're giving that very question that you just raised substantial thought, balancing that with our desire to make this product accessible to all the patients that might benefit from it.

We reached the end of our question-and-answer session. I'd like to turn the floor back over to Raul for any further closing comments.

Thank you for that. I thank you for your questions, and thank you for listening in on this call. It's an exciting event for this company, our second approved product, one that we are incredibly prepared to make available to these patients and quickly. And I'd like to promise to you that we will work -- continue to work as hard. As Dave has said, we've already worked because -- the hard work continues, and I very much would like to express my thanks to all our employees and our partners for helping us achieve this very noble cause. Take care, and thank you very much.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.