Rigel Pharmaceuticals, Inc. Price & Performance (RIGL)

At this time, I'd like to turn the call over to our President and Chief Executive Officer, Raul Rodriguez Raul. You, Ray, and thank you everyone for joining today.

Also with me today are Dave Santos, our Chief Commercial Officer Lisa Roiker, our Chief Medical Officer and Dean Chornau, our Chief Financial Officer.

Beginning on Slide four, we will provide an overview of Rigel's business and our numerous accomplishments in 2024. For those that are new to the company, let me take a moment to review Bridgeland's overall corporate strategy. To grow our hematology and oncology business. Our strategy is focused on three main goals: First, expand our commercial portfolio and increasing product sales. Second, advancing and growing our pipeline through internal development, and strategic collaborations. And third, maintaining financial discipline. 2024 was a transformational year for Rigel. As we delivered on all three of these goals, I will take you through each of these accomplishments in more detail. 2024, we set another record year of sales.

As a result of our effective commercial execution we reached our highest commercial portfolio sales ever. At $145,000,000 39% growth over 2023. This significant revenue growth was driven by the strength of TAVALISSE, and ResLydia sales and the addition of DEVREITO. Our third product and our second in license product, which contributed $17,100,000 in net product sales since we added it to our portfolio in June. We also generated revenues from our partners where TAVALISSE is commercially available. And our partners continue to make progress towards expanding TAVALISSE access in other geographies. Recently, Knight, and Kisse announced regulatory approvals for TAVALISSE in two new countries, Mexico and The Republic Of Korea, respectively. Once commercially launched, ITP patients in these countries can also benefit from JAVALISSE. [indiscernible] For Reslidia, we actively pursued new collaborations and executed new license agreements with our partner Kissei in three countries in Asia, and with Doctor. Reddy for numerous territories outside of The U. S. Also in 2024, on our second goal, we made significant progress in our development pipeline. We continue to evaluate R289, our dual IRAC1 and four inhibitor in an ongoing Phase 1b study in patients with lower risk MDS. Presented encouraging initial safety and efficacy data from that study at the ASH Annual Meeting in December.

Enrollment in the dose escalation portion of the trial where we recently completed the fifth dose level and have now opened for enrollment a new sixth dose. Level at five hundred milligrams BID. For oludacitinib, our strategic collaborations with MD Anderson and Connect organization continue to progress. These trials provide us with the opportunity to explore luducitinib in a range of IDH1 mutant cancers in a time and cost efficient manner. We're excited to report that all four studies from our multiyear strategic development alliance with MD Anderson have now opened for enrollment. And the Phase two study of oleucinib in high grade glioma in collaboration with KENNECT has also recently opened for enrollment. [indiscernible] Lisa will provide you an update on these development programs in a few minutes. And lastly, in 2024, on our third goal, maintaining financial discipline. By maintaining financial discipline, we were able to, for the first time, generate full year net income of $17,000,000 and our cash balance increased by more than $20,000,000 for the year. All of these accomplishments enabled Rigel to continue to successfully implement our strategy. Moving on to the next slide. [indiscernible] have continued to grow our net product sales over time.

With a compound annual growth rate of 32% up from between 2021 and 2024. TAVALISSE grew nicely over that period and the addition of Brasilidia in late 'twenty two and Garetto in 2024 has provided additional contributions to that growth. All three of these products achieved new highs in 2024. And in 2025, as you can see on Slide six, we we're expecting approximately $145,000,000 to $192,000,000 in net product sales for the year. Approximately a 28% to 32% growth compared to 2024. So just to summarize, 2024 was a transformational year where we continue to grow our hematology and oncology business, while at the same time becoming a profitable company. And with that, I'll turn the call over to Dave to provide a commercial update. Dave?

Thank you, Raul. On Slide eight, you'll see our three commercial products.

TAVALISSE, RESLIDIA and GIVERETA. We are very pleased with the strong growth in revenues in the fourth quarter and full year 2024. Moving to Slide nine, you see how our quarterly and annual sales have evolved since 2021. We've grown each quarter's sales over the previous year and that growth continues. Particularly from last year to this year. We started the first quarter of twenty twenty three are now reporting $46,500,000 for the fourth quarter of twenty twenty four. [indiscernible] That growth has been driven by our strong commercial execution and consistently building quarterly demand for TAVALISSE and driving broader awareness of Reslidia through the first two years of its launch. In addition, our ability to successfully and seamlessly trans Compared to the fourth quarter of twenty twenty three, we generated 58% growth in the fourth quarter of twenty twenty four.

For full year 2024, we delivered dollars an increase of $41,000,000 or 39% compared to 2023 net sales of $104,000,000 Our commercial team has been dedicated to execution driving continued momentum for TAVALISSE and improving both and successfully transitioning GIVERITO patients and accounts to Rigel label product. My sincere thanks to the entire team for all their hard work to grow our business in 2024. Slide 10 shows a summary of our commercial performance by product. First on TAVALISSE, I'm pleased to report another strong quarter in which we generated $31,000,000 in net product sales, an increase of 21% compared to the fourth quarter of twenty twenty three. This growth was driven by strong patient demand, with another consecutive quarterly record high. We continue to grow TAVALISSE demand through both refills from patients who stay on the product and new prescriptions for patients who are starting TAVALISSE for the first time. Moving to ResLydia, we reported $7,400,000 in net product sales, almost doubling revenue from the prior year period as we focus on improving Reslity adoption both in institutions and the community, by raising awareness of Reslidia's efficacy particularly in patients who have failed upfront therapy with venetoclax. And lastly for GIVERETO, in our second full quarter selling the product, we delivered $8,100,000 in net product sales in Q4.

Are very happy with the success in transitioning over GIVERETA patients prescribers and accounts to Rigel's distribution network. Importantly, our $8,100,000 of net product sales in the fourth quarter represent a run rate above the $28,000,000 in annual sales of Gevretto in 2023 under prior ownership. Are especially pleased with GIVERATO's upward trajectory during last year's transition and are now focused on building on that momentum. In 2025. Moving to Slide 11, we hit several meaningful milestones with our portfolio in 2024. Importantly for TAVALISSE, 2024 was the first year to achieve more than $100,000,000 in net sales. It continues to grow steadily as the foundation of our portfolio. Consistently hitting new record quarterly highs in bottle shipped [indiscernible] That steady growth has been driven by more new patients starting on TAVALISSE each quarter and the subsequent increased carryover that's generated. In 2025, we expect that trend to continue. Res Lidia more than doubled both bottles shipped to patients and clinics as well as net sales in 2024 and we believe we still have significant opportunity to grow Reslidia's use in mutant IDH1 relapsed [indiscernible] We continue to find that as clinicians become more aware of Resilidias' efficacy efficacy in post venetoclax patients, they believe it's clinically meaningful as these patients are very difficult treat with other therapies.

We believe we can build on the scientific data currently available in this important population of AML patients and continue to grow Reslidia's use in 2025. Lastly, in 2024, our successful transition of Gevareto demonstrates our nimble and highly adaptable organizational capabilities. We fully leveraged our commercial and medical affairs infrastructure and expertise to meaningfully expand and quickly generated $17,100,000 of incremental net sales in 2024. [indiscernible] The Q4 Gevreto net sales result of $8,100,000 reinforces how smoothly and effectively both new and existing patients were transitioned. And furthermore, the fact that we were also able to significantly grow TAVALISSE and ResLydia, while that transition was ongoing, is a testament to our organizational capabilities and operational efficiency. In 2025, we can continue to grow Gevredo particularly since the use of RET inhibitors in non small cell lung cancer should continue to expand in the frontline setting. New non small cell lung cancer treatment guide or NCCN in January now recommend that if a RET inhibitor was not used in the frontline setting, clinicians may switch frontline therapy to a RET inhibitor once the RET fusion is confirmed. We believe that RET inhibitor use will expand in non small cell lung cancer in 2025 and beyond and Gevareto will grow in turn.

Finally, moving to Slide 12, we're incredibly excited about our work to expand access to our patients in market outside of The U. S. TAVALISSE is commercially available in Japan, in Europe under the brand name TAVALISSE partners Kisse, Rigel and Metasat. And that's generating sustainable revenues each quarter. In addition, our partners continue to pursue regulatory approvals for TAVALISSE in new markets. As Rahul mentioned, Knight Therapeutics announced it has received received regulatory approval for TAVALISSE in Mexico and recently Kissei announced regulatory approval for TAVALISSE in Korea. In 2024, we also look to find partners to develop and commercialize ResLydia in ex U. S. Markets. We expanded our relationship with Kissei to include Japan, Korea and Taiwan for Reslidia in all potential indications And in late twenty twenty four, we entered into an [indiscernible] Potential indications throughout Doctor. Reddy's territory. Which includes Latin America and other territories. We are pleased that access to our products is expanding outside The U. S. And we continue to explore other opportunities for partnerships outside The U. S. To bring our products to other markets and patients. Around the globe. I will now pass the call over to Lisa to provide an update on our development pipeline.

Lisa?

Thanks, Dave. We made meaningful progress in 2024 and look forward to continued execution on our strategy to expand our hematology oncology portfolio in 2025. I'm on Slide 14. First, from our development pipeline, R289 is our novel dual IRAC one and inhibitor that is currently being evaluated in a Phase Ib study in patients with relapsedrefractory lower risk myelodysplastic syndrome or MDS. We're excited that R289 has been granted both fast track designation for the treatment of patients with previously treated trans Furthermore, as part of our Rigel sponsored development programs, and alongside our partners, MD Anderson and the Connect Cancer Consortium, elutacitinib is being evaluated in new indication. We believe elutacitinib has potential in in several cancers where mutated IDH1 plays a role, such as glioma, additional AML segments and MDS. Either as monotherapy or in combination. We expect to initiate a Rigel sponsored Phase two study to evaluate in recurrent glioma in 2025. We expect to initiate a Rigel sponsored Phase two study to evaluate ileutasitinib in recurrent glioma in 2025. We expect to initiate a Rigel sponsored Phase two study to evaluate ileutasitinib in recurrent glioma in 2025. In addition, as Raul mentioned, all four clinical trials under our MD Anderson collaboration are now open for enrollment, as is the Connect study focused on high grade glioma.

Also remain focused on evaluating potential opportunities to in license or acquire products that would be a strategic fit for our portfolio. We're looking for differentiated products in hematology oncology or related areas. Products that are late stage, possibly with registrational data, soon to have registrational data or more advanced and products that can leverage our hematology and oncology infrastructure. As demonstrated with our acquisitions of ileutacitinib and pralcetinib, our goal is to continue to find assets that align with our organization Now we'll spend a few moments discussing the updates from our R289 program. To help frame the discussion, Slide 16 prevents presents an overview of the value proposition of R289 and lower risk MDS. There are about twelve thousand previously treated lower risk MDS patients in The U. S. Recent development efforts in lower risk MDS have focused primarily on first line therapies, However, there is a high unmet need for next line therapies. Particularly for previously treated transfusion dependent patients. Dysregulation of inflammatory signaling is key to the pathogenesis of lower risk MDS and IRAC1 and IV mediate this process. Blocking both IRAC one and four may suppress marrow inflammation and leukemic stem and progenitor cell function and restore hematopoiesis.

R835, the active moiety of R289, blocks Toll like receptor and IL-one receptor signaling in vitro. And was active in various preclinical models of inflammation. Clinical proof of concept of this anti inflammatory effect came from a healthy volunteer study in which R835 markedly suppressed LPS induced cytokine release compared to placebo. As a reminder, R289, which is currently being evaluated in the clinic, is the oral prodrug that is rapidly converted to RA35 in the gut. RA289 has both FDA fast track and orphan drug designations. Giving the molecule an expedited regulatory pathway potential priority review and seven years of market Both of these designations underscore the agency's interest in this rare disease and their willingness to collaborate with Rigel in the development of R289. [indiscernible] In addition, R289 has thus far demonstrated a promising preliminary clinical profile in a Phase Ib study. The initial dose escalation data that were recently present On Slide 17, you see the treatment landscape for lower risk MDS. MDS is a clonal disorder of hematopoietic stem cells leading to dysplasia and ineffective hematopoiesis. The main consequences for patients are anemia and transfusion dependence, which adversely impact their quality of life. In addition, infections, iron overload from transfusions and subsequent organ dysfunction all negatively impact the patient.

Aside from transfusions, initial erythropoiesis stimulating agents or ESAs if patients are eligible and luspatercept Imetelstat was approved earlier this year for ESA failure high transfusion burden, lower risk MDS. [indiscernible] With eight week transfusion independence rates approaching forty percent with luspatercept and imetelstat, many patients require an alternative treatment option. Although hypomethylating agents or HMAs are approved, percentage of patients achieving transfusion independence is low. Therefore, there is a high unmet need for safe effective treatment option On Slide 18, you'll see the design of our ongoing open label dose escalation, dose expansion Phase Ib study and relapsedrefractory lower risk MDS patients with either symptomatic anemia or transfusion dependence. The study was recently updated to include a six dose level, five hundred milligrams BID, and to facilitate the randomized comparison of two dose levels and expansion to optimize selection of the recommended Phase two dose. The primary endpoints are safety and selection of the recommended dose for expansion and secondary endpoints include transfusion independence, hemologic improvement, response rates and PK. Study continues to progress well with the six dose level five hundred milligrams BID now open for enrollment.

Once the recommended Phase two dose has been determined, an exploratory cohort of first line lower risk MDS patients will be open to evaluate R289 in an earlier line of therapy. Now I'd like to walk you through the initial dose escalation data that were recently presented at the ASH Annual Meeting. On Slide 19, we start with patient characteristics. [indiscernible] Data on twenty two patients were reported using an 10/25/2024 data cutoff date. The median age was 76 and about sixty percent of the patients were aged 75 or above. Median number of prior therapies was three, ranging from one up to eight, and more than seventy percent of patients had received an HMA or luspatercept. The majority of patients, seventy three percent were high transfusion burden at baseline. The median time on therapy was four point six months. In summary, these were elderly, heavily pretreated patients with a high transfusion Moving to Slide 20, we'll review the safety findings. R289 was generally well tolerated. The most common treatment emergent adverse events in twenty percent or more patients which are not shown on the slide, were diarrhea and fatigue followed by chills, nausea and pruritus, all of which were grade one or two.

The most frequent grade three or four adverse events was two events each, anemia, platelet count decreased, pneumonia and alanine aminotransferase or ALT increased. The treatment related adverse events are shown on the slide. Importantly for this patient population, the incidence of grade threefour cytopenias and infections was low. There was one dose limiting toxicity reported a grade threefour transaminase increase in one patient at seven fifty milligram daily dose level. Serious adverse events occurring in two or more patients were pneumonia and upper GI bleed, Both occurred in two patients each and were unrelated to therapy. On Slide 21, we show the preliminary efficacy data. [indiscernible] swimmer plot shows each patient and the red cell transfusions by dose group. Starting with the lowest dose group two fifty milligrams daily on top. Per the IWG twenty eighteen criteria, the transfusion history for each patient was collected for sixteen weeks prior to our February administration to establish the baseline transfusion free shown to the left of day zero indicated by the red arrow. Two patients, numbers nine and nineteen were not transfusion dependent at baseline. Eighteen patients were valuable for efficacy meaning that they had one or more R289 doses and at least one assessment.

Red blood cell transfusion independence lasting eight weeks or longer was achieved by three patients, one receiving five hundred milligrams daily, and two receiving seven fifty milligrams daily. In two patients, RBC transfusion independence lasted for more than six months and one patient also achieved a marrow complete response. The median duration of transfusion independence was twenty nine weeks. One high transfusion burden patient receiving five hundred milligrams daily achieved a minor HIE response with a 64% reduction in red blood cell Regarding PK, at doses at or higher than five hundred milligrams once daily, R835 plasma concentrations reach or exceeded those associated with 50% or 90% LPS induced cytokine inhibition, that was previously observed in healthy volunteers. We thought it was interesting that at these doses, hematologic responses occurred in four out of 10 or 40% of the valuable On Slide 22, we see a summary of the responding patients. [indiscernible] majority were high transfusion burden at baseline and had received a variety of prior therapies including luspatercept, hypomethylating agent and some experimental therapies. The two patients with durable transfusion independence lasting more than six months patients four and ten were both high transfusion burden at baseline and had received HMAs.

Beneath the table are the hemoglobin levels over time for the three patients that achieved transfusion independence. Peak hemoglobin increases ranging from 2.3 to 5.6 grams per deciliter compared to baseline were observed. Indicating that R289 has the potential to correct anemia. Providing support for its evaluation earlier in treatment.

In summary, the initial data is encouraging showing R289 as generally well tolerated with promising signs of efficacy and heavily pretreated transfusion dependent patients. Now I'll shift focus to elutasidinib, our IDH1 inhibitor. Beginning on Slide 24, we glioma is an area that is incredibly challenging where there has not been much advancement. Therapeutic options.

Diffus gliomas are the most common primary brain tumor in adults. Affecting approximately twenty thousand in The U. S. Each year. IDH1 mutations occur in about seventy percent of patients with grade two and three glioma and are found in up to almost forty percent of younger patients. Unfortunately, most disease recurs and there is no standard of care therapy for relapsed patients. The recent approval of vorasidinib an IDH1 and two inhibitor in grade two gliomas has highlighted the potential for IDH inhibitors in glioma. [indiscernible] Allutacitinib was previously evaluated in a Phase 1b2 study in 26 patients, which was published in the Journal Neuro Oncology. Two patients with high grade glioma achieved partial responses. Both had enhancing tumors and 10 patients achieved stable disease. For a disease control rate of forty eight percent. This clinical proof of concept supports further evaluation of lutocidinib and glioma Moving to Slide 25, Last year, we entered a collaboration with the global neuro oncology consortium, Connect, IN CONNECT's target trial, a molecularly guided Phase II umbrella clinical trial for high grade glioma the Rigel sponsored arm of the study, Target D, will evaluate a post radiotherapy maintenance regimen of ileutacitinib in combination with temozolomide followed by ileutasitinib monotherapy newly diagnosed patients between 12 and 39 years of age with IDH1 mutation positive high grade glioma.

This study was recently opened for enrollment. In addition, we recently announced that this year we plan to initiate [indiscernible] and we look forward to providing more details about that study later this year. We think this is an important opportunity as there is a significant unmet medical need in this patient population. [indiscernible] We, along with Connect, are excited about elutacitinib's potential to provide a much needed new treatment option to this underserved patient population, and we look forward to the data generation from KENNECT study in addition to our planned study in recurrent glioma. On Slide 26, you'll see another important collaboration, our strategic alliance with the MD Anderson Cancer Center to advance ALLUTIS We're pleased to report that the four studies indicated in this collaboration are now open for enrollment.

Turning to our partnered program, On Slide 28, our RIPK1 inhibitor programs are progressing well with our partner Lilly. RIPK1 is implicated in a broad range of inflammatory cellular processes and plays a key role in tumor necrosis factor signaling. Ocadussirtib, our non CNS penetrant Rib K1 inhibitor, previously referred to as R552 is currently being studied in an adaptive Phase 2a 2b clinical trial in up to three eighty patients with active moderate to severe rheumatoid arthritis. Phase 2a enrollment of approximately one hundred patients is advancing well. With preliminary analysis of the results anticipated within the first half of 2025. Our preclinical CNS RIPK1 inhibitor program is also progressing toward lead candidate nomination. In closing, as you see on Slide 29, there are several upcoming milestones for our development programs in 2025. For our R289 program and lower risk MDS, we expect to complete the dose escalation portion of the Phase 1b study. The new six dose level, five hundred milligrams twice daily is actively enrolling. We then plan to initiate the dose expansion phase later this year Also during the year, we plan to seek health authority and put on the registrational path for R289. And we're anticipating presenting the dose escalation data from the Phase 1b study in the second half of the year.

Then for lutacitinib, we plan to initiate a Phase II clinical study in recurrent glioma by year end and also plan to provide you with more details about that study In addition, we'll continue to support the four MD Anderson studies and connect study. We're excited about the progress we've made in 2024 to advance these programs and look forward to providing further updates on these planned milestones in 2025. Now I'll pass the call to Dean to discuss our financial results for the quarter.

Thank you, Lisa. I'm on Slide 31.

We reported net product sales of $46,500,000 for the fourth quarter a growth of 58% year over year, including TAVALISSE net product sales of $31,000,000 growth of 21% year over year Resilient net product sales of $7,400,000 growth of 92% year over year and DeVoretto net product sales of $8,100,000 in the fourth quarter. [indiscernible] As a reminder, GABRETA became available for Rigel in June of twenty twenty four. Our net product sales from TAVALISSE Resilient and GABREITO were recorded net of estimated discounts charge backs, rebates, returns, copay assistance and other allowance of $19,700,000 For the fourth quarter of twenty twenty four, our gross to net adjustment for Tavolese, Resili and Gabareto was approximately 332123% of gross product sales respectively. Our fourth quarter revenues reflect strong patient demand and were aided by a year end increase in inventory in our distribution channels that we've seen in the past. As we've also seen in the past, we expect to experience a drawdown in these inventory levels in our distribution channels in the first quarter of twenty twenty five. Incrementally, as we highlighted in the fourth quarter, we made certain changes to our distribution channel arrangements for TAVALISSE, that would result in continued high quality access while reducing our distribution costs and favorably impacting our gross to net adjustment into the future.

While this change is not expected to impact our bottle shipped to patients and clinics, we expect to experience a reduction in bottles remaining in our distribution channel of approximately three fifty bottles during the first quarter of twenty twenty five. We expect the effect of these distribution channels have normalized by the end of Q1. We also reported $11,100,000 in contract revenues from [indiscernible] for the fourth quarter. Primarily due to my Rigel and Kissei, along with $4,000,000 in revenue from Doctor. Reddy's, related to the upfront fee from sub licensing eluducitinib. Onto the next slide and moving down the income statement to cost and expenses. Our cost of product sales was approximately $5,800,000 for the fourth quarter of twenty twenty four. Total costs and expenses were $40,900,000 compared to $33,800,000 for the same period of 2023. [indiscernible] increase in cost and expenses mainly due to higher R and D costs driven by the timing of our clinical activities, increased personnel related costs and increased commercial related activities. In addition, increased driven primarily by increased product sales higher royalties, higher amortization of intangible assets, and sub licensing revenue fees. For the full year, Total cost and expenses were $155,100,000 compared to $137,400,000 for the full year of 2023.

The increase in cost and expenses was mainly due to higher cost of product sales driven primarily by increased product sales, higher royalties, higher amortization of intangible assets and sub licensing, revenue fees. In addition, there were increases in personnel related costs, stock based compensation expense and commercial related expenses. These increases were partially offset by decreased R and D costs due to the timing of clinical trial activities related to R289 our dual IRAP1-four inhibitor program as well as reduced trial activities related to completed Phase three clinical trials We reported net income of $14,300,000 for the fourth quarter compared to $700,000 in the same period in 2023. For the full year, we reported net income of $17,500,000 compared to a net loss of $25,100,000 for 2023. [indiscernible] ended the quarter with cash, cash equivalents and short term investments of $77,300,000 up from $56,900,000 as of the end of twenty twenty three. Turning to our financial outlook for 2025. We expect total revenue in the range of approximate $200,000,000 to $210,000,000 comprised of approximately 185 to $192,000,000 in net product sales and $15,000,000 to $18,000,000 of contract revenues from collaborations. We also anticipate reporting positive net income for the full year while funding existing and new clinical development programs.

To wrap up my section, 2024 a tremendous year of revenue growth and continued financial discipline for Rigel, that we look to continue into 2025 and beyond. With that, I'd like to turn the call back over to Raul.

Thank you, Dean. Moving on to Slide 33. As I've stated on this call, 2024 was a year of significant achievements for Rigel. [indiscernible] We reached profitability and cash flow breakeven while delivering on our corporate strategy to grow our hematology and oncology business. Going forward into 2025, our priorities are clear. Continue to grow our commercial business, advance our development programs, identify new pipeline opportunities and continue to maintain financial anticipate growing our net product sales by approximately 30% year over year. We remain focused on advancing our Phase 1b study of R289 for the treatment of lower risk MDS and complete the dose escalation portion of this We plan to initiate the dose expansion phase of the study and provide the updated data at a medical meeting later this year. Orlinxentib, we plan to initiate a new Rigel sponsored Phase two study in recurrent glioma and continue to support our strategic collaborations with both MD Anderson and the Connect organization. Even with all these investments, to advance our current and new pipeline programs, we expect to report positive net income for the full year of 2025. Moving on to Slide 34. I'm thrilled that Rigel has reached this pivotal point in the company's history.

Our implementation of our corporate strategy has brought us to a place where our commercial sales levels now allow us to grow the business in a profitable and sustainable manner. It's a really exciting time for the company. And with that, I'd like to turn the call over to your questions.

Answer session. And our first question comes from Yigal Latromovitz with Citi. Please state your question. Hi, guys. Thanks so much for taking the questions. I have a few. The first one on the product guidance, you said $192,000,000 to $195,000,000 So using the fourth quarter as a base, I'm just could you just give a little more color as far as the the comments there in terms of the range? It seems a little conservative It looks like it's about a 1% to 2% quarter on quarter CAGR. Going off the 4Q base. Was my first question. Thank you.

Yes. So the net revenue guidance is for 185 to 192. And the Q4 was $46,500,000 of net product sales. That was aided by as we said in our prepared comments, it was aided by inventory build in Q4, and we've seen this typically. That accounted for about $4,500,000 of that $46,500,000 of net revenues in Q4. As you normalize that and you start to build Q1 through Q4, that creates the revenue guidance that we described. And that's represents at the midpoint about a 30% year over year growth in net product sales.

Okay. Thanks, Dean. And then I'm curious on ResLydia, do you have any data from the field terms of the duration of therapy there? I recall from a couple of years ago, there was some very, very good data you had showing strength of that durability.

Hi, Gail. Great question. This is Dave. We won't share any of that today, but what I can tell you is we have a lot of room to grow. At the end of the day, whenever you launch a product and we're only two years into this, you're going to get a lot of later line patients. And those patients are not going to have the duration of therapy that you would have seen in the clinical trial where they were probably in the second line or third line setting. And so that's kind of where we are right now. So obviously, we do believe of of adoption, but also a significant driver of carryover as we move forward. That's why I'm optimistic about our ability to grow as awareness grows, as we get more patients on therapy and we get earlier patients on therapy, particularly those who've had first line venetoclax. We think we can drive duration higher.

Thanks. And just one last one if I might. Do you have any data as to the percent of patients that are on GIVERITO by Rigel versus GIVERETO from the prior commercial [indiscernible] I don't have specific data, but I can tell you, our goal was to transition every single patient that was on Gaveredo over Rigel label product. I think the fact that we sold a point $1,000,000 and that our demand grew from Q3 to Q4. And our run rate was higher than the previous run rate of $28,000,000 last year. I think we achieved that. So I really don't think we lost any patients in the mix. And as a matter of fact, obviously, I think we're adding new patients It's hard for us at this point in time to say new patients on brand versus new patients to Rigel. We know they're all new patients to Rigel, but we think we are getting new patients to brand because our demand continues to move up.

You know, that was pretty remarkable achievement that transition because you typically see a sell of a product from one company to another. And for probably six months, you see a lower sales base than originally before, and that wasn't the case here. So this is really pretty remarkable. [indiscernible] that we have the entirety of the team, medical affairs, market access, the sales organization really focused on the right things getting those patients across. And so it really worked remarkably well. I'm actually incredibly impressed.

Got it. Thank you very much for taking the question.

Thank you. And our next question comes from Kalpit Patel with B. Riley Securities. Please state your question.

Hey, good afternoon and thanks for taking the questions. Maybe I want to start first with the TAVALIS sales, the increase in the fourth quarter relative to the third quarter, Maybe comment on how much of that was an organic volume increase versus maybe any pricing increases that may have occurred?

I'm sorry, can you repeat the last part of your question, Halper? You said volume versus [indiscernible] yes, exactly. This just was this accounted for by any price increases?

Yes, we didn't have any price increase in Q4. So that was all volume. What I will say is we had our highest quarterly demand ever, that's bottle shipped to patients and clinics. Matter of fact, it was the ninth consecutive We also had a higher percentage of new patient starts or new patients versus existing patients, kind of driving that volume in fourth quarter. And so again, as Dean said, we were also aided by some inventory build, which is typical in the last in the last quarter of the year. But demand definitely increased from Q3 to Q4 as in new patient starts.

And we did our press release highlight the unit volume, the demand volume as Dave suggested, the demand or the the bottle shipped to patients and clinics, that's really the key to the business. That's the those are the bottles that are going to go to patients. Incrementally, there's the the bottles left in the distribution channels that we report and those are inventory levels. For TAVALISSE, that inventory level benefit for Q4 was about $3,000,000 and that's in the $4,500,000 I described Again, TAVALISSE was benefited by about $3,000,000 That said, again, the demand is consistently growing and that's the important measure of the business.

Okay, okay, great. And then maybe switching over to your Zeoma program, the planned [indiscernible] I know you're still working on the design there. But I'm curious on the strategy here. Are you going to do a head to head study against vorasidnib or are you trying to maybe position your drug for a different grade glioma, maybe a higher grade three or four? [indiscernible] Yes. Thanks for the question. I think at this point, it's still too early to comment on the design of the study. We've just kind of started our KOL discussions and ad boards and are working on that plan, but we'd certainly be happy to give you more information on this later in the year. So for both two eighty nine and Uluta and glioma, our plan is to later this year as we have some discussions with regulatory agencies settled on what the plan is exactly. We'll come back to you and share that with you. It probably will be in the second half of the year.

Okay, great. Thank you very much.

Thank you. And our next question comes from Joe Pantginis with H. C. Wainwright. Please state your question. [indiscernible] Hi, everybody. Good afternoon. Thanks for taking the questions. So my first question is a two parter for TAVALISSE, if you don't mind. So in The U. S, I guess, how would you describe well, first, can you describe the difference or the percentages of refills and the growing aspect of new prescriptions? And what are you doing to help grow new prescriptions say today versus where you were one to two years ago? That's part one.

Yes. I think great question, Joe. I think as I said before, what we noticed in Q4, which was really nice is that a larger percent of our patients and that's total patients on therapy, those who are carrying over from previous quarters as well as new patients, a higher percentage was driven by new patients. A matter of fact, the highest percentage we've ever seen. And so clearly, I think adoption is growing. I think some of the things that we're doing now that we've learned over the past is certainly targeting of clinicians is something we've spent a lot of time and effort to make sure that we're doing expanding reach through different channels is another thing that we're doing. And then, I think the last part is community practices play a big role in the management of ITP. And I think we target the specific GPOs out there among the community practices to ensure that they're aware of our of ITP's unique value proposition. Or top of its unique value proposition in ITP. Sorry.

No, of course. So and part two is, I guess, taking some of the components that you were just discussing.

I want to discuss the ex U. S. Opportunities as you expand geographically. Are there any components that are unique to ex U. S. Like you said, community centers, for example, how are they how is the drug delivered there? Are there differences in the initial lines of therapy? Any particular components you can point to ex U. S. That might differ from The U. S?

I think the best thing for me to do is kind of talk about how The U. S. May be unique and that its use of [indiscernible] endplate is probably more driven by that community practice kind of buy and bill sort of mentality. And I think particularly in Japan, some of the differences there that they've seen is a more a higher willingness to use common combination therapy. And so I think there are some differences across the globe in how patients are treated and and the way clinicians approach ITP management. But like I said, here in The U. S, it's a lot is treated. It's not It's not a disease. It's a benign hematologic condition where if a hematologist oncologist sees this they're not going to refer it, they're going to treat it. So I think we have a very kind of diffuse model here in The U. S, which I think might be a little more concentrated in other countries outside The U. S. No, that's helpful. I appreciate that color. And then my last question, if you don't mind, is more of an infrastructure question. So as of right now, would you define your sales force as right sized and as you look to add assets and are in early launch stages, what would you envision as potential growth of the size of your sales force?

Thanks.

Great question, Joe. I would say that what we've done with ResLydia and Gavereto is ensure that we have synergies and it's not just sales, Rigel? It's across the brand team, it's across market access, which is a big component in in commercializing products these days as well as our operation and analytical capabilities in business operation. So we have tremendous synergies there. But, you know, I'll just say that our we're constantly looking at our impactable market and who how many customers we need to call on to ensure [indiscernible] And depending on the product we bring aboard, the sub specialists that might be involved, it could vary in terms of whether we would need to build sales sales support or not. And if it's something that is used primarily in the community or that I think we have the capacity to cover. But if it's something that's in a sub specialty that might that we're maybe not calling on today, then obviously we need to address that.

But it's part of the assessment of each of those individual opportunities as we decide to bring them in or not.

Sure, sure. Thank you for all the comments.

Thank you, Joe.

Your next question comes from Kristen Kusco with Cantor. Please state your question.

Hi. This is Ayan on Kristen's line.

You for taking our questions. Could you talk a bit about your plan to initiate the expansion phase of the first of the Phase one study of R289 this year? Any color you can provide here, particularly when you plan to start and how you go about choosing the doses Yes. Thanks for the question. As you know, as I mentioned, we're currently enrolling in dose level six for dose escalation. So first thing we're going to have to do is complete enrollment at that dose level and have a look at the the safety and activity. Dose selection for expansion will be based on the typical things like safety, PKPD, a little bit of activity As you see on the you may have noticed on the slide, we plan to enroll up to 20 patients per arm because we really want to conduct a robust determination of of a dose to carry forward and to for further clinical evaluation. So as we mentioned, we're looking forward to opening that later this year. And the exact timing of that as I mentioned, will really depend on what's going on in dose escalation. This last cohort.

That's helpful. Thank you so much.

Thank you. Our next question comes from Farseen Hock with Jefferies. Please state your question. Hi. Thank you for taking my question. Also on R289 low risk MDS program, So I wanted to ask on the further dose evaluations that are ongoing with split dosing, how are you setting second half? And then I have a follow-up.

Yes. So as you noticed in our and thanks for the question, very interesting. As you noticed during the course of the dose escalation [indiscernible] twice daily dosing because we think biologically it makes more sense to have more or less continuous suppression of inflammation as opposed to kind of an on off on off. So we're really looking forward to seeing the data from the BID dose levels. And related to the anticipated timing of the data presentation, well, I think our best opportunity is ASH. So we're anticipating having an opportunity there to present the updated study data.

Arthur, keep in mind that we want to have four to six months of exposure in each of these patients in order to properly assess whether the product's working, its efficacy, importantly, its safety. So that does take some time to do that. So it, by necessity, has to be towards the end of this calendar year.

Got it. That makes sense. And then we'll be waiting for the mature dose escalation data prior to meeting with the regulators for a registrational path?

I think we'll give some more in information on that later as the data mature more.

But we won't wait till the end of the year to have some interaction with them. The nice thing about Fast Track designation is that it allows them and us to work more closely together. That's really helpful.

Got it. Thank you so much. Thank you. And there are no further questions at this time. I would like to turn the floor back over to Ms. Rigel Rodriguez for closing comments.

Well, thank you. I'd like to thank you for joining this call today and your good questions and specifically for your continued interest in Rigel. It's been a really monumental year for us. We're really proud of what we achieved in 2024 and incredibly excited about 2025. We have some significant things ahead of us, and I think we're really well positioned to execute successfully against them. Before we leave, I'd like to thank our employees for their continued interest in improving the lives of patients and for making 2024 such a successful year for us. So with that, look forward to updating you on future calls and have a great day.

This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.