Slides
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Corporate Presentation January 12, 2026 1
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Please visit www.TAVALISSE.com for Full Prescribing Information. Please visit www.REZLIDHIA.com for Full Prescribing Information, including Boxed WARNING. Please visit www.GAVRETO.com for Full Prescribing Information, including Boxed WARNING. This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 ("PSLRA") relating to, among other things, continued development and expansion of our business, projected financial performance including sales and revenue growth, continued advancement of our R289 study, expanded indications for olutasidenib alone or in combination with other agents, potential identification of opportunities and completion of acquisition or in-license of complementarylate-stage assets, efficacy of products in clinical trials and related future performance, potential clinical benefit and market opportunity for our commercial portfolio, ability to complete clinical studies on schedule,regulatory agency approval in other markets or indications for fostamatinib or olutasidenib, pralsetinib or R289, success of our partnering efforts including business growth and financial and commercial milestone achievements, and Rigel’s ability to achieve the projected 2026 financial outlook and future growth objectives. Any statements contained in this presentation that are not statements of historical fact may be deemed to be forward-looking statements and as such are intended to be covered by the safe harbor for “forward-looking statements” provided by the PSLRA. Forward-looking statements can be identified by words such as "plan”, "potential", "may", "outlook", "anticipates", "expects", "will", “promising” and similar expressions in reference to future periods. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on Rigel’s current beliefs, expectations, and assumptions and hence they inherently involve significant risks, uncertainties and changes in circumstances that are difficult to predict and many of which are outside of Rigel’s control. Therefore, you should not rely on any of these forward-looking statements. Actual results and the timing of events could differ materially from those anticipated in such forward looking statements as a result of these risks and uncertainties, which include, without limitation, the finalization and audit ofRigel’s fourth quarter and 2025 fiscal year financial results which could potentially result in changes or adjustments to the selected preliminary financial resultsand projectionspresented herein;risks and uncertainties associated with the commercialization and marketing of fostamatinib, olutasidenib or pralsetinib; risks that the FDA, European Medicines Agency, PMDAor other regulatory authorities may make adverse decisions regarding fostamatinib,olutasidenib, pralsetinib or R289; risks that clinical trials may not be predictive of real-world results or of results in subsequent clinical trials; risks that fostamatinib,olutasidenib, pralsetinibor R289 may have unintended side effects, adverse reactions or incidents of misuses; the availability of resources to develop, manufacture and commercialize Rigel’s product candidates; market competition; and those other risks detailed from time to time in Rigel’s reports filed with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2024 and subsequent filings. Any forward-looking statement made by us in this presentation is based only on information currently available to us and speaks only as of the date on which it is made. Rigel does not undertake any obligation to update forward-looking statements, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise, and expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein, except as required by law. Forward Looking Statements 2
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Rigel’s Transformational Growth Strategy 3 Grow Commercial Business Maintain Financial Discipline Advance Development Pipeline In-Licensing / Business Development
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Rigel’s Transformational Growth Strategy 4 Grow Commercial Business Maintain Financial Discipline Advance Development Pipeline In-Licensing / Business Development • Growth of three commercial products • Growth from potential in-licensing / M&A transactions • Transformational development pipeline, including R289 portfolio and other potential opportunities2 • One commercial product • Limited development pipeline • Three commercial products • Development pipeline opportunity advancement, including R289 in lower-risk MDS • Profitable since Q3 2024, with $100+ million increase in cash during period1 2020 2025 2030s MDS, myelodysplastic syndrome. 1. Cash, cash equivalents & short -term investments balance was $49.1 million as of 6/30/24 and $154.6 million as of 12/31/25. 2025 cash, cash equivalents & short -term investments is preliminary, has not been audited and is subject to change upon completion of the audit of the company's finan cial statements as of and for the year ended December 31, 2025. 2. Investigational compounds in these indications and not approved by the FDA.
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76.7 104.3 144.9 232.0 260.0 2022 2023 2024 2025 2026 Guidance Mid-PointTAVALISSE REZLIDHIA GAVRETO CAGR, compound annual growth rate. 1. 2025 revenue is preliminary, has not been audited and is subject to change upon completion of the audit of the company's fina ncial statements as of and for the year ended December 31, 2025. Future Transformational Revenue Growth Opportunities 1 5 Future Potential Opportunity Annual Net Product Sales ($M)
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6 Grow Commercial Business
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12.4 16.2 23.8 26.0 43.617.1 18.5 23.9 33.5 58.9 16.0 19.2 27.1 38.9 64.1 17.6 22.8 29.5 46.5 65.4 63.1 76.7 104.3 144.9 232.0 0 50 100 150 200 250 2021 2022 2023 2024 2025 Annual Net Portfolio Sales ($M) Q1 Q2 Q3 Q4 1. This information is preliminary, has not been audited and is subject to change upon completion of the audit of the company's financial statements as of and for the year ended December 31, 2025. US Net Product Sales Growth Q4 2025 Net Portfolio Sales grew $18.9M (41%) vs. Q4 20241 7
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$9.6M Q4 2025 Net Product Sales Growth vs. Q4 2024 29% 1. This information is preliminary, has not been audited and is subject to change upon completion of the audit of the company's financial statements as of and for the year ended December 31, 2025. Q4 2025 Commercial Performance 1 8 Net Product Sales ($M) 31.0 45.6 8.1 10.2 7.4 9.6 46.5 65.4 Q4 2024 Q4 2025 Axis Title TAVALISSE GAVRETO REZLIDHIA $45.6M Q4 2025 Net Product Sales Growth vs. Q4 2024 47% $10.2M Q4 2025 Net Product Sales Growth vs. Q4 2024 27%
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9 Please see Important Safety Information on slide 49. Please visit www.TAVALISSE.com for Full Prescribing Information. Select Important Safety Information Adverse Reactions: • Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%). • Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia. Kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (cITP) who have had an insufficient response to a previous treatment
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cITP, chronic immune thrombocytopenia. 1. Symphony Health, PatientSource®, 10 years ending September 2019; 2. Internal market research conducted in October 2020. Please see Important Safety Information on slide 49. Please visit www.TAVALISSE.com for full prescribing information. Creating Opportunities to Gain Market Share 44,300 Patients Actively Treated2 • 24,300 patients are 2L or later Patients Need Additional Treatment Options as They Move through Therapies Significant National Commercial Coverage 10 81,300 U.S. Adult cITP Patients1 37,000 Watchful Waiting 20,000 1st Line 11,400 2nd Line 6,900 3rd Line 3,500 4th Line 2,500 5L+
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FIT, Fostamatinib in ITP 1. Fostamatinib is an effective 2nd -line therapy in patients with immune thrombocytopenia, British Journal of Haematology. 2. Percentage of Patients Achieving Target Platelet Counts at Any Visit. 3. Assessment of thrombotic risk during long -term treatment of immune thrombocytopenia with fostamatinib, Therapeutic Advances in H ematology, 4/30/21. Please see Important Safety Information on slide 49. Please visit www.TAVALISSE.com for Full Prescribing Information. Efficacy Across All Post-Steroid Lines of Therapy 11 Post-hoc Data Analysis Demonstrated Use as 2nd-Line Therapy Resulted in Higher Response Rates1,2 78% 64% 52% 36% 54% 94% 86% 59% 50% 70% 2nd line (n=32) 3rd line (n=42) 4th line (n=27) 5th line (n=14) All lines of therapy (n=145) ≥ 50 x 109/L ≥ 30 x 109/L Response Durable Efficacy was Observed in Responders to TAVALISSE in the FIT Studies (combined results from FIT-1, FIT-2, and FIT-3)3 Median Platelet Counts Over Time
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12 Please see Important Safety Information on slides 50 & 51, including Boxed WARNING regarding differentiation syndrome APPROVED AND AVAILABLE IN THE U.S. REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test
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IDH1, isocitrate dehydrogenase -1; mIDH1, mutated IDH1; R/R, relapsed or refractory; AML, acute myeloid leukemia. 1. American Cancer Society, Key Statistics for Acute Myeloid Leukemia (AML). 2025. 2. Abbas S et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood (2010) 116 (12): 2122 -2126. 3. Chotirat S et al. Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients. J Hematol Oncol 5, 5 (2012). 4. Rigel HCP Quantitative Market Research, 2022 (Data on File). mIDH1 Relapsed/Refractory AML Background 13 mIDH1 AML Fit (~65%)4 Unfit (~35%)4 Treated with Intensive Therapy Consolidation → Transplant Treated with Non-Intensive Therapy No Further TreatmentRelapsed or Refractory • AML will be diagnosed in over 22K patients and result in nearly 11.1K deaths in 20251 • IDH1 mutations are found in 6-9%2,3 of AML • mIDH1 patients are well-identified, and have limited options for treatment, particularly in relapsed/refractory (R/R) disease • A significant unmet need exists for targeted treatments for mIDH1 R/R AML that are well- tolerated and efficacious
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BID, twice daily; R/R, relapsed or refractory; IDH1, isocitrate dehydrogenase -1; mIDH1, mutated IDH1; AML, acute myeloid leukemia; CR, complete remission; CRh, CR with partial hematologic recovery ; ORR, overall response rate; DOR, duration of response, OS, overall survival. 1. Cortes, J., Curti, A., Fenaux, P. et al. Olutasidenib for mutated IDH1 acute myeloid leukemia: final five -year results from the phase 2 pivotal cohort. J Hematol Oncol 18, 102 (2025). REZLIDHIA Phase 2 Clinical Trial Highlights 1 • Elderly population (median age 71) with a median of 2 (1 -7) prior treatments (all naïve to m1DHI -inhibitor) • CR+CRh rate of 35%, with a median duration of response of 25.3 months • 92% of CR+CRh responders were CR, with a median duration of response of 25.3 months • Transfusion independence was achieved in all subgroups • REZLIDHIA has a well characterized safety profile with no cardiac events leading to discontinuation 14
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15 Please see Important Safety Information on slides 52 & 53, including Boxed WARNING regarding serious infections * This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). GAVRETO is indicated for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer as detected by an FDA -approved test, and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion -positive thyroid cancer who require systemic therapy and who are radioactive iodine -refractory (if radioactive iodine is appropriate) * APPROVED AND AVAILABLE IN THE U.S.
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RET, rearranged during transfection; NSCLC, non -small cell lung cancer. 1. Market Research conducted in Q2 2023 with 60 oncolo gists managing RET fusion -positive patients; *Multi-Kinase Inhibitors; **Immune Checkpoint Inhibitors (anti PD -1/PD-L1) • Enables entry into a well-identified subset of large solid tumor market – Immediately recognizable population of RET fusion-positive patients – Challenging to treat with platinum-based chemotherapy and checkpoint inhibitors • Leverages patient access – Efficient product distribution – Responsive Rigel ONECARE patient services – Strong coverage and reimbursement • Complementary to our field capabilities – Commercial and Medical Affairs teams in both academic and community settings Growing Our Oncology Targeted Therapy Portfolio 16 A Compelling and Synergistic Opportunity 1L Treatment of RET Fusion-Positive NSCLC Patients1 ~75% Treated with RET Inhibitor ~60% ~15% ~20% ~5% MKIs* Chemo±ICI** GAVRETO
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Pralsetinib Has a Differentiated Value Proposition NSCLC, non-small cell lung cancer; RET, rearranged during transfection; 1L, first -line. 1. Besse B et al. Ann Oncol. 2022; 33(suppl 7). Please visit www.GAVRETO.com for Full Prescribing information, including Boxed WARNING. • The only once daily, oral, RET inhibitor approved for patients with NSCLC and thyroid cancer with RET gene fusions • High and durable response rates regardless of prior treatment history1 • Promising intracranial efficacy in patients with brain metastases1 • Established safety and tolerability profile • NSCLC practice guidelines now recommend as a preferred 1L treatment option for RET+ patients, including for patients identified during 1L treatment with systemic therapy 17
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Expanding Commercial Access Globally 18
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Expanding Commercial Availability in Global Markets 19 1. This information is preliminary, has not been audited and is subject to change upon completion of the audit of the company's financial statements as of and for the year ended December 31, 2025. 2. Forma, now Novo Nordisk, is entitled to a certain portion of Rigel’s sublicensing revenue from olutasidenib. 3. Dr. Reddy’s territory includes Latin America, South Africa, certain countries in the Commonwealth of Independent States (CIS), India, certain countries in Southeast Asia and North Africa, Australia and New Zeal and. Q4 2025 Collaboration Revenues1 • Grifols $3.4M • Kissei $0.3M • Medison $0.2M TAVALISSE Regulatory Approvals • Knight announced regulatory approval in Mexico (Dec 2024) REZLIDHIA Opportunity2 • Executing on ex-U.S. opportunities for development and commercialization ‒ Expanded relationship with Kissei to include REZLIDHIA in Japan, South Korea, and Taiwan ‒ Entered relationship with Dr. Reddy’s in Latin America and other territories3 TAVALISSE is commercially available in key European countries (TAVLESSE), Japan, South Korea, Canada and Israel
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20 In-Licensing / Business Development
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In-Licensing / Business Development Strategy 21 R/R, relapsed or refractory; IDH1, isocitrate dehydrogenase -1; mIDH1, mutated IDH1; AML, acute myeloid leukemia; RET, rearranged during transfection; RET+, RET-fusion positive; NSCLC, non -small cell lung cancer; NDA, new drug application; FDA, U.S. Food and Drug Administration. Differentiated asset(s) in hematology, oncology or related areas • Acquired global rights to REZLIDHIA in 2022; first commercial sale in patients with R/R m IDH1 AML in Q4 2022 • Acquired U.S. rights to GAVRETO in 2024; first commercial sale in patients with RET+ NSCLC and thyroid cancer in Q3 2024 Late-stage programs Synergistic to current in-house capabilities and capacity • Seeking assets that have completed registrational trial • Assets ready for NDA filing, NDA filing is in process / under review with FDA or product is currently commercially available • Leverage existing commercial and operating infrastructure • Rapid accretion, increased cash flows, and enhanced business value
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22 Advance Development Pipeline
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Hematology and Oncology Development Portfolio 1 23 • Evaluating in a Phase 1b study for patients with R/R lower-risk MDS – Granted Fast Track and Orphan Drug designations by the FDA 2 • Other potential indications under consideration • Strategic collaborations: – MD Anderson : Monotherapy or combination therapy in m IDH1 AML, MDS, CCUS, CMML and MPN – CONNECT: Combination therapy in mIDH1 high-grade glioma – MyeloMATCH : Combination therapy in mIDH1 AML and MDS R289 IRAK1/4 Inhibitor Olutasidenib mIDH1 Inhibitor R/R, relapsed/refractory; IRAK1/4, interleukin receptor -associated kinases 1 and 4; MDS, myelodysplastic syndrome; FDA, U.S. Foo d and Drug Administration; IDH1, isocitrate dehydrogenase -1; AML, acute myeloid leukemia; CCUS, clonal cytopenia of undetermined significance; CMML, chronic myelomonocytic leukemia; MPN, myeloproli ferative neoplasm; mIDH1, mutated IDH1. 1. Investigational compounds in these indications and not approved by the FDA. 2. R289 granted Fast Track designation for previously -treated transfusion dependent lower -risk MDS and Orphan Drug designation for MDS by the U.S. FDA.
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R289 IRAK1/4 Inhibitor in Lower-Risk MDS 24
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MDS, myelodysplastic syndrome ; IRAK1/4, interleukin receptor-associated kinases 1 and 4; IL-1R, interleukin 1 receptor; TLR, toll -like receptor; LPS, lipopolysaccharide. 1. R289 is an investigational compound not approved by the FDA. 2. Sallman DA, et al. Front Oncol. 2016;6. 3. Lamagna C et al. Ann Rheum Dis 2020;79 (suppl 1). 4. Yan L et al. Ann Rheum Dis 2020;79 (suppl 1). Targeting Inflammatory Pathways in Lower -Risk MDS Dysregulation of immune/inflammatory signaling isassociated with MDS 25 • IRAK1/4 are critical for downstream signaling of the IL-1R family and most TLRs, leading to a proinflammatory marrow environment and persistent cytopenias in patients with lower-risk MDS2 • Co-targeting IRAK1/4 may suppress inflammation and leukemic stem/progenitor cell function and restore hematopoiesis in MDS • R835 is a selective dual inhibitor of IRAK1/4 that blocks TLR4 and IL-1R-dependent cytokine release in vitro and in vivo3 and markedly suppressed LPS–induced cytokine release vs placebo in healthy volunteers (HV) 4 • R289, an oral prodrug that is rapidly converted to R835 in the gut, is now being evaluated in a Phase 1b study in lower-risk MDS R289
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Targeting IRAK1 & IRAK4 Pathways in Inflammatory Disease 26 IRAK1/4, interleukin receptor -associated kinases 1 and 4; TLR, toll -like receptor; IL, interleukin; LPS, lipopolysaccharide. Note: No head-to-head clinical study has been conducted evaluating R835 against other agents included herein. 1. Rigel data on file. Lamagna C et al. Ann Rheum Dis 2020;79 (suppl 1). 2. R835 is an investigational compound not approved by the FDA. LPS LPS IL-23 IRAK4 P IRAK1P TLR4 TLR4 IL1R IL1R Myd88 IL1b IL1 Myd88 IL-6 Kinase Assays Cell-Based Assays IRAK4 IRAK1 Substrate Substrate P Substrate Substrate P IRAK4-Selective Inhibitor Inhibition of Cytokine Release IRAK4 IC50 = 0.2nM IRAK1 IC50 = Inactive IRAK1/IRAK4 Dual Inhibitor Rigel R8352 [R769] LPS THP1 IL-23 IL-1 Huvec IL-6 RLU [R835] RLU LPS THP1 IL-23 IL-1 Huvec IL-6 Inhibition of Cytokine Release IRAK4 IC50 = 15nM IRAK1 IC50 = 14nM Dual inhibition of IRAK1 and IRAK4 provides stronger suppression of inflammatory cytokines compared to IRAK4-selective inhibitor1 40-80% 100%
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R8351 Proof-of-Mechanism in Healthy Volunteer Study 2 27 LPS, lipopolysaccharides; TNF ⍺, tumor necrosis factor-⍺; IL, interleukin; PK, pharmacokinetics; PD, pharmacodynamics. 1. R835 is an investigational compound not approved by the FDA. 2. EULAR 2020 Poster Presentation -Abstract THU0219 - First-in-human Study of Safety, Pharmacokinetics and Pharmacodynamics of IRA K1/4 Inhibitor R835 in Healthy Subjects. First-In-Human study (n=82) • R835 was well tolerated • Linear PK profile and dose proportional exposure Proof-of-Mechanism • R835 markedly inhibited LPS- induced cytokine production vs placebo in HVs • Inhibited TNF, IL-6, and IL-8 Placebo Group R835 Treatment Group Placebo Dose TNF IL6 Cytokine Response After LPS Challenge Time (hour) Mean profileIndividual profile R835 Dose Time (hour) Cytokine Concentration Time (hour) Time (hour) Cytokine Concentration Cytokine Concentration Cytokine Concentration LPS Challenge LPS Challenge
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Lower-Risk MDS Treatment Landscape 28 MDS, myelodysplastic syndrome; AML, acute myeloid leukemia; ESAs, erythropoiesis -stimulating agents; TD, transfusion dependent; LR -MDS, lower-risk myelodysplastic syndrome; R/R, relapsed or refractory . 1. Investigational compound not approved by the FDA. • MDS is a clonal disorder of hematopoietic stem cells (HSCs) leading to dysplasia and ineffective hematopoiesis – Consequences: Cytopenias (anemia), infections, iron overload and organ dysfunction, progression to AML • Primary goal of therapy: Reduce/limit transfusion -dependency • Modest efficacy thus far with available therapies; there is room for improvement New therapies needed for previously-treated TD LR-MDS patients that are R/R or ineligible for ESAs Non-del(5q) Del(5q) First Line Post-ESA/ESA-Ineligible Relapsed/Refractory Disease Luspatercept Imetelstat Hypomethylating agent R2891 potential indications ESAs Luspatercept Lenalidomide
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• ~12,200 lower-risk MDS patients that have been previously treated2 • Therapies for previously-treated transfusion dependent lower-risk MDS patients are lacking • Dysregulated inflammatory signaling is associated with MDS • Co-targeting IRAK1/4 may suppress inflammation and LSPC function and restore hematopoiesis • Blocks TLR and IL-1R signaling in vitro; active in preclinical models of inflammation3 • Markedly suppressed LPS-induced cytokine release was observed in a randomized controlled trial in healthy volunteers4 • Fast Track designation for previously-treated transfusion dependent LR-MDS (Nov 2024) • Orphan Drug designation for treatment of myelodysplastic syndromes (Jan 2025) • Promising preliminary safety and efficacy in a Phase 1b study in elderly, heavily pre-treated patients with R/R LR-MDS (n=33) (presented at ASH 2025)5 R2891 Program Value Proposition for Lower -Risk MDS 29 MDS, myelodysplastic syndrome; LR -MDS, lower-risk myelodysplastic syndrome; ESAs, erythropoiesis -stimulating agents; LSPC, liver stem/progenitor cells; TLR, toll-like receptor; IL-1R, interleukin 1 receptor; LPS, lipopolysaccharide; R/R, relapsed or refractory. 1. Investigational compound not approved by the FDA. 2. Rigel data analysis on file. Patient population represents previously -treated patients. 3. Sallman DA, et al. Front Oncol. 2016;6. 4. Yan L et al. Ann Rheum Dis 2020;79 (suppl 1). 5. ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in Patients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). Unmet Medical Need Clinical Proof of Concept Regulatory Designations Encouraging Clinical Profile Novel Mechanism of Action
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R2891: Phase 1b Study inRelapsed/Refractory Lower-Risk MDS 30 MDS, myelodysplastic syndrome; LR -MDS, lower-risk MDS; PK, pharmacokinetics; QD, daily; BID, twice daily; RP2D, recommended Phase 2 dose; Tx, treatment; Hb, hemoglobin; TD, transfusion dependent; TI, transfusion independence; HI -E, hematologic improvement - erythroid; PD, pharmacodynamics; FACIT -Fatigue scale, The Functional A ssessment of Chronic Illness Therapy – Fatigue Scale. 1. Investigational compound not approved by the FDA. 2. Jaki T et al. Cancer Chemother Pharmacol. 2013; 71. 3. Split dose: 500 mg q AM, 250 mg q PM. 4. Platzbecker U et al. Blood 2019;133(10). 5. Cheson BD et al. Blood 2006;108. Open-label, multicenter study to evaluate the safety, tolerability, PK and preliminary efficacy of R289 in patients with LR-MDS (NCT05308264) Key Eligibility Criteria • R/R LR-MDS or inadequate response to prior therapies. Del(5q): R/R to lenalidomide • Symptomatic anemia (Hb ≤9.0 g/dL) or TD (≥2u RBCs/16wks) in dose escalation; TD in dose expansion Assessments • Hematologic responses [TI and HI -E] per IWG 2018 criteria4 and other responses per IWG 2006 criteria 5, from 8 weeks Primary Endpoints • Incidence of adverse events and dose -limiting toxicities Secondary Endpoints • Transfusion independence, hematologic improvement, response rates • PK / PD • Patient-reported outcomes (FACIT -Fatigue scale) Updated data presented at ASH 2025 Dose Expansion PhaseDose Escalation Phase Modified 3+3 Design2 Dose level 2 500 mg QD Dose level 4 250 mg BID Dose level 1 250 mg QD Dose level 3 750 mg QD Dose level 5 500/250 mg3 Dose level 6 500 mg BID 500 mg QD (n= up to 20) 500 mg BID (n= up to 20) Post-ESA, Tx naïve LR-MDS (n=10) Once RP2D selected, open exploratory cohort of 1L LR-MDS Randomize
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Safety and Efficacy Results from a Phase 1b Study of R289 in Patients with Relapsed/Refractory Lower-Risk MDS 31
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Patient Characteristics Elderly, heavily pre-treated patient population with a high baseline transfusion burden 32 IPSS-R, International Prognostic Scoring System -Revised; RBCs, red blood cells; ANC, absolute neutrophil count; Plts, platelets. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). Data cutoff: October 28, 2025 All Patients (n=33) Median age, years (range) ≥ 75 years 75 (50 - 84) 19 (58%) Sex (M : F) 70% : 30% IPSS-R Classification (Low: Intermediate: Ring sideroblast (RS)- : RS+) 67% : 33% : 67% (22) : 33% (11) Median no. prior therapies 3 (1 - 8) Prior hypomethylating agent (HMA) 22 (67%) Prior luspatercept 25 (76%) Prior erythropoiesis stimulating agent (ESA) 24 (73%) Prior imetelstat 2 (6%) High transfusion burden (HTB) (≥ 8u RBCs/prior 16 weeks) 20 (61%) Low transfusion burden (LTB) (3-7u RBCs/prior 16 weeks) 11 (33%) Non-transfused (NT) 2 (6%) Mean baseline ANC (range), 109/L (range) 2.4 (0.3 - 5.4) ANC <1.0 x 109/L 5 (15%) Mean baseline platelet count (range) 183 (32 - 524) Plts <100 x 109/L 7 (21%)
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Safety R289 was generally well tolerated with a low incidence of Grade 3/4 cytopenias and infections 33 DLT, dose limiting toxicity; G, grade; ALT, alanine aminotransferase; AST, aspartate aminotransferase; QD, once daily; AE, ad verse event; TEAE, treatment -emergent adverse event; BID, twice daily. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). 1. TEAEs include related and unrelated adverse events. • All dose levels were generally well tolerated • One DLT (G3 ALT/G4 AST increase) occurred at 750 mg QD – No evidence of dose-dependent toxicity across the other dose groups • 3 patients (9%) discontinued treatment due to an AE (hyperuricemia, ALT/AST increase, fall/hip fracture) • Serious adverse events (SAEs) occurred in 17 patients (52%). SAEs occurring in ≥2 patients: pneumonia (n=5), upper GI bleed (n=2); all were unrelated • No study drug -related deaths occurred in the treatment period TEAEs Occurring in at Least 18% (≥6) of Patients by Dose Level1 Total (N = 33) 250 mg QD (N = 3) 500 mg QD (N = 6) 750 mg QD (N = 6) 250 mg BID (N = 6) 500/250 mg QD (N = 6) 500 mg BID (N = 6) Preferred Term Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Any n (%) G3/4 n (%) Diarrhea 10 (30) 0 0 0 1 (17) 0 4 (67) 0 1 (17) 0 2 (33) 0 2 (33) 0 Constipation 9 (27) 0 0 0 1 (17) 0 2 (33) 0 0 0 4 (67) 0 2 (33) 0 Fatigue 9 (27) 0 2 (67) 0 4 (67) 0 2 (33) 0 1 (17) 0 0 0 0 0 ALT increased 8 (24) 3 (9) 0 0 0 0 3 (50) 2 (33) 1 (17) 0 3 (50) 1 (17) 1 (17) 0 AST increased 8 (24) 3 (9) 0 0 0 0 3 (50) 2 (33) 1 (17) 1 (17) 3 (50) 0 1 (17) 0 Creatinine increased 7 (21) 0 1 (33) 0 1 (17) 0 1 (17) 0 3 (50) 0 0 0 1 (17) 0 Cough 7 (21) 0 0 0 1 (17) 0 3 (50) 0 1 (17) 0 1 (17) 0 1 (17) 0 Anemia 6 (18) 6 (18) 0 0 3 (50) 3 (50) 1 (17) 1 (17) 2 (33) 2 (33) 0 0 0 0 Chills 6 (18) 0 0 0 0 0 1 (17) 0 3 (50) 0 1 (17) 0 1 (17) 0 Dyspnea 6 (18) 0 0 0 2 (33) 0 2 (33) 0 0 0 2 (33) 0 0 0 Nausea 6 (18) 0 0 0 1 (17) 0 3 (50) 0 1 (17) 0 1 (17) 0 0 0 Neutrophils decreased 6 (18) 5 (15) 0 0 0 0 4 (67) 3 (50) 0 0 1 (17) 1 (17) 1 (17) 1 (17) Pneumonia 6 (18) 5 (15) 1 (33) 1 (33) 1 (17) 1 (17) 1 (17) 1 (17) 0 0 2 (33) 1 (17) 1 (17) 1 (17)
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Pharmacokinetics R835 plasma concentrations (administered as R289) by dose level (Cycle 2 Day 11) 34 Observed R835 concentrations (ng/mL) * * * * * * • R835 exposure increased with increasing R289 dose • At doses ≥500 mg once daily (QD), R835 steady state plasma concentrations reached or exceeded those resulting in 50- 90% inhibition of LPS-induced cytokine release (---) previously observed in healthy volunteers 2 ---- 90% inhibition ---- 50% inhibition ---- 25% inhibition * Patients achieving RBC-TI % inhibition of LPS-induced cytokine release in HV2 Notes: R289 is an oral prodrug of R835. Star placement in table for identification purposes. Dose limiting toxicity: G3 ALT/G4 AST ↑ in 1 pt at 750 mg QD (PK data not included in table). QD, once daily; QAM, morning dose; QPM, evening dose; BID, twice daily; LPS, lipopolysaccharide; HV, healthy volunteers; RBC -TI, red blood cell transfusion independence. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in Patients with Relapsed/Refractory (R /R) Lower Risk Myelodysplastic Syndrome (LR -MDS). 1. Cycle 2 Day 1 is day 29. 2. Yan L et al. Ann Rheum Dis 2020;79 (suppl 1). Time, hour Time, hour Time, hour Time, hour Time, hour Time, hour
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RBC Transfusion Events by Dose Group 35 • Median duration of treatment: 5.5 months (range: 0.9 - 27.7 months) • 6/18 (33%) evaluable TD patients receiving ≥500 mg QD achieved RBC-TI >8 weeks; 4 >16 weeks; 3 >24 weeks • Median time to onset of RBC-TI: 1.9 months • Median duration of RBC-TI: 22.9 weeks (9 - 104.3) 500 mg QD (n=6) 500 mg BID (n=6) 500/250 mg QD (n=6) 250 mg BID (n=6) 250 mg QD (n=3) Study week Evaluable for HI-E responses RBC-TI ≥8 weeks On-going RBC transfusion day 750 mg QD (n=6) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Note: Patients listed in order of enrollment. RBC, red blood cell; QD, once daily; BID, twice daily; HI -E, hematologic improvement -erythroid; TD, transfusion dependent; RBC -TI, red blood cell transfusion independence;. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS).
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Efficacy: Summary of Patients Achieving RBC -TI Peak hemoglobin increases ranging from 2.9 - 6.1 g/dL vs. baseline occurred in patients achieving RBC-TI 36 TI, transfusion independence; ID, identification; RBC, red blood cell; QD, once daily; HTB, high transfusion burden; LTB, low transfusion burden; ALK, anaplastic lymphoma kinase; w, weeks; m, months. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). Patient 7 Patient 14 Pt ID Sex, Age Dose Level BL RBCs Prior Therapies Response Duration 7 76, M 500 mg QD HTB Darbopoetin, canakinumab, ALK2 inhibitor, decitabine 24.0 m→ 11 59, M 750 mg QD HTB Azacitidine, lenalidomide, luspatercept 28.9 w 14 50, F 750 mg QD LTB Darbopoetin, luspatercept 12.4 w 23 66, M 500/250 mg QD LTB Azacitidine, luspatercept, darbopoetin 19.7 w 30 79, M 500 mg BID LTB Canakinumab, azacitidine 26.0 w→ 33 72, F 500 mg BID LTB Azacitidine + rigosertib 9.0 w→ Hemoglobin LevelsPatient Profiles Patient 11 Hemoglobin Red Blood Cell Transfusions Platelets Patient 23 Patient 33Patient 30 Platelets (109/L) Hemoglobin (g/dL) Hemoglobin (g/dL) Weeks Weeks Weeks Weeks Weeks Weeks
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ASH 2025 Data Summary 37 MDS, myelodysplastic syndrome; RBC -TI, red blood cell transfusion independence; QD, once daily; HMAs, hypomethylating agents; LP S, lipopolysaccharides. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). 1. Yan L et al. Ann Rheum Dis 2020;79 (suppl 1). Patient Safety • R289 was generally well tolerated in this elderly, heavily pre -treated lower -risk MDS patient population, the majority of whom were high transfusion at baseline - The incidence of Grade 3/4 cytopenias and infections was low Preliminary Efficacy Initial Takeaway • RBC-TI was achieved by 33% (6/18) of evaluable transfusion dependent patients receiving R289 doses ≥500 mg QD, with durable responses >24 weeks occurring in 3 patients thus far - Peak hemoglobin increases ranging from 2.9 - 6.1 g/dL vs. baseline occurred in patients achieving RBC -TI - 5/6 patients achieving RBC -TI had received prior HMAs • At doses ≥500 mg QD, steady state R835 plasma concentrations reached or exceeded those associated with 50 -90% inhibition of LPS -induced cytokine release previously observed in healthy volunteers, 1 indicating a potential threshold for dose response
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R289 Development Next Steps 38 MDS, myelodysplastic syndrome; ESA, erythropoiesis -stimulating agent; FDA, U.S. Food and Drug Administration. Source: ASH 2025 Publication #489: Safety and Efficacy Results from a Phase 1b Study of R289, a Dual IRAK 1/4 Inhibitor, in P atients with Relapsed/Refractory (R/R) Lower Risk Myelodysplastic Syndrome (LR -MDS). 1. Yan L et al. Ann Rheum Dis 2020;79 (suppl 1). Lower-Risk MDS • Complete enrollment in the dose expansion phase and selection of the recommended Phase 2 dose for future clinical studies (2H 2026) – Share updated top-line data from dose expansion phase by end of 2026 – To open exploratory cohort of post -ESA, treatment naïve patients with lower -risk MDS following selection of recommended Phase 2 dose • Upon completion of Phase 1b study, follow-up with FDA about a potential registrational study Other Potential Indications • Evaluate R289 in other potential indications
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Olutasidenib mIDH1 Inhibitor 39
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AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; CCUS, clonal cytopenia of undetermined significance; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms 1. Investigational compound in these indications and not approved by the FDA. Please see Important Safety Information on slides 52 & 53. Please visit www.REZLIDHIA.com for Full Prescribing Information, including Boxed WARNING. Rigel and The University of Texas MD Anderson Cancer Centerare evaluating and supporting olutasidenib in combination with other agents to treat newly-diagnosed and relapsed/refractory patients with IDH1-mutated: • AML • Higher-risk MDS, CMML and advanced MPN The collaboration is also supporting the evaluation of olutasidenib as: • Monotherapy in IDH1-mutated CCUS & lower-risk MDS/CMML • Post-transplant maintenance therapy for IDH1-mutated hematologic malignancies • Combination with co-targeted therapy in patients with R/R IDH1-mutated myeloid malignancies harboring activated signaling pathway mutations Strategic Alliance with MD Anderson Cancer Center to Advance Olutasidenib in AML and Other Cancers 1 40 Five studies are open for enrollment
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IDH1, isocitrate dehydrogenase -1; mIDH1, mutated IDH1; HGG, high -grade glioma. 1. Investigational compound in this indication and not approved by the FDA. 2. Diwanji TP, et al. Adolesc Health Med Ther. 2017 Sep 22;8:99 -113. CONNECT’s TarGeT Phase 2 Clinical Study • Gliomas account for 29-35% of CNS tumors in children, adolescents & young adults2 • As part of CONNECT’s “TarGeT” study in HGG, olutasidenib is being evaluated in combination with temozolomide as a maintenance regimen in newly-diagnosed adolescent and young adult patients (ages 12 to 39 years) with IDH1 mutation positive HGG in the Rigel-sponsored “TarGeT-D” Phase 2 study arm ⎻ Study is open for enrollment Advancing Olutasidenib into m IDH1 Glioma1 41
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NIH, National Institutes of Health; NCI, National Cancer Institute; MyeloMATCH, Myeloid Malignancies Molecular Analysis for T herapy Choice; AML, acute myeloid leukemia; MDS, myelodysplastic syndromes. NIH and NCI’s MyeloMATCH is a group of precision medicine clinical trials for MDS and AML • Patients will complete initial screening and will be assigned to a trial evaluating therapies that target their specific disease mutations Planned study will evaluate olutasidenib in combination with other agents in patients with newly diagnosed mIDH1 AML and MDS Potential to Evaluate Olutasidenib in First -Line AML and MDS in MyeloMATCH Precision Medicine Trial 42
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RIPK1 Inhibitor Partner Program 43
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RIPK1, receptor-interacting protein kinase 1; CNS, central nervous system; TNF, tumor necrosis factor; RA rheumatoid arthritis; IBD, inflammatory bowel disease. Note: CNS disease program terminated by Lilly, effective December 1, 2025. 1. Investigational compound not approved by the FDA. https://www.clinicaltrials.gov/study/NCT05848258 Immune Diseases • R552, a potent and selective RIPK1 inhibitor, completed a Phase 1 study which demonstrated potential best-in-class status compared to competition • Enrollment in Lilly’s Phase 2a clinical trial studying ocadusertib (previously R552 or LY3871801) in adult patients with moderately to severely active rheumatoid arthritis (RA) is complete RIPK1 Inhibitor Programs in Immune Diseases with Partner Lilly 44 RIPK1 inhibitors play key role in TNF signaling and induction of pro-inflammatory necroptosis, which could support broad potential in RA, psoriasis and IBD, and with their experience, Lilly is the ideal partner.
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45 Maintain Financial Discipline
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Financial Overview and Q4 2025 Highlights 46 QE, quarter end. 1. Q2 2025 includes $40 million in non-cash contract revenue related to Rigel’s agreement with Eli Lilly. 2. This information is preliminary, has not been audited and is subject to change upon completion of the audit of the company's financial statements as of and for the year ended December 31, 2025. 3. Contract revenues includes revenue from collaboration and government contracts. Net Product Sales ($M) 21.1 26.4 26.3 31.0 28.5 40.1 44.7 45.6 1.9 7.1 8.1 9.0 11.8 11.1 10.2 4.9 5.2 5.5 7.4 6.1 7.0 8.3 9.6 26.0 33.5 38.9 46.5 43.6 58.9 64.1 65.4 Q124 Q224 Q324 Q424 Q125 Q225 Q325 Q425 Axis Title TAVALISSE GAVRETO REZLIDHIA Summary Financial Information (in millions) Q1 2024 Q2 2024 Q3 2024 Q4 2024 Q1 2025 Q2 20251 Q3 2025 Q4 20252 Net Product Sales $26.0 $33.5 $38.9 $46.5 $43.6 $58.9 $64.1 $65.4 Contract Revenues3 $3.5 $3.5 $16.4 $11.1 $9.8 $42.7 $5.4 $4.4 Total Revenue $29.5 $36.8 $55.3 $57.6 $53.3 $101.7 $69.5 $69.8 Operating Cost and Expenses $36.5 $36.4 $41.3 $40.9 $40.6 $40.6 $41.0 n/a Net (Loss) / Income $(8.2) $(1.0) $12.4 $14.3 $11.4 $59.6 $27.9 n/a Cash, Cash Equivalents and Short-term Investments (at QE) $49.6 $49.1 $61.1 $77.3 $77.1 $108.4 $137.1 $154.6
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2026 Key Priorities 47 RP2D, recommended Phase 2 dose; FDA, U.S. Food and Drug Administration. Grow Commercial Business Expand adoption of commercial portfolio Maintain Financial Discipline 2026 Outlook: • Total revenue of ~$275M to $290M - Net product sales of ~$255M to $265M - Contract revenues from collaborations of ~$20M to $25M • Anticipate will report positive net income for the full year 2026, while funding existing and new clinical development programs In-Licensing / Business Development Pursue late-stage assets which leverage current capabilities and capacity Advance Development Pipeline • Phase 1b study in lower-risk MDS: - Complete dose expansion and select RP2D for future clinical studies (2H26) - Share updated top-line data by end of 2026 - Follow-up with FDA about a potential registrational study • Evaluate R289 in other potential indications • Advance olutasidenib in strategic collaborations
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Rigel’s Transformational Growth Strategy 48 Grow Commercial Business Maintain Financial Discipline Advance Development Pipeline In-Licensing / Business Development
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TAVALISSE® (fostamatinib disodium hexahydrate) Tablets INDICATION • TAVALISSE® (fostamatinib disodium hexahydrate) tablets is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. IMPORTANT SAFETY INFORMATION | WARNINGS AND PRECAUTIONS • Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required. • Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to ≥3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation. • Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE. • Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation. • TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose. DRUG INTERACTIONS • Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose. • It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406. • Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug. • Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug. ADVERSE REACTIONS • Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%). • Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia. To report side effects of prescription drugs to the FDA, visit https://www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088) 49 Please see https://www.tavalisse.com/ for full Prescribing Information
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About REZLIDHIA ® (olutasidenib) INDICATION REZLIDHIA is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. IMPORTANT SAFETY INFORMATION WARNING: DIFFERENTIATION SYNDROME Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution. WARNINGS AND PRECAUTIONS Differentiation Syndrome REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis. If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence. Hepatotoxicity REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin 50
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IMPORTANT SAFETY INFORMATION (Cont .) WARNINGS AND PRECAUTIONS Hepatotoxicity Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity. ADVERSE REACTIONS The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis. DRUG INTERACTIONS • Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers. • Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs. LACTATION Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose. GERIATRIC USE No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age. HEPATIC IMPAIRMENT In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 51 Please see https://www.REZLIDHIA.com/ for full Prescribing Information, including Boxed WARNING.
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52 About GAVRETO ® (pralsetinib) INDICATIONS GAVRETO (pralsetinib) is indicated for the treatment of: • Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test • Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)* *This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). IMPORTANT SAFETY INFORMATION WARNING: SERIOUS INFECTIONS, INCLUDING OPPORTUNISTIC INFECTIONS GAVRETO may increase the risk for serious infections, including bacterial, fungal, viral and opportunistic infections, which can lead to hospitalization or death. Withhold, reduce the dose or permanently discontinue GAVRETO based on severity. WARNINGS AND PRECAUTIONS • Serious Infections, including Opportunistic Infections: GAVRETO may increase the risk for serious infections, including fatal and opportunistic infections. In the AcceleRET-Lung trial, infections occurred in 72% of patients who received GAVRETO, including 18% with Grade 3 and 3.7% with Grade 4 and 7% with fatal outcomes. Among the patients who received chemotherapy/immunotherapy, infections occurred in 52%, including 10% with Grade 3. Infections in the GAVRETO arm included pneumonia, urinary tract infection, opportunistic infections (such as pneumocystis jirovecii pneumonia, and fungal infections) and others. Monitor patients for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity. • Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD. • Hypertension: Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with antihypertension medications. Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity. • Hepatotoxicity: Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8%. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity.
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53 IMPORTANT SAFETY INFORMATION (Cont.) • Hemorrhagic Events: events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. • Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated. • Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing. Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established. • Embryo-Fetal Toxicity: Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose. ADVERSE REACTIONS • The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. DRUG INTERACTIONS • Strong or moderate CYP3A inhibitors and/or P-gp inhibitors: Concomitant use with a strong or moderate CYP3A inhibitor and/or a P-gp inhibitor increases pralsetinib exposure, which may increase the risk of adverse reactions related to GAVRETO. Avoid coadministration of GAVRETO with a strong or moderate CYP3A and/or P-gp inhibitor. If coadministration with any of the above inhibitors cannot be avoided, reduce the GAVRETO dose. • Strong or moderate CYP3A inducers: Concomitant use with a strong CYP3A inducer decreases pralsetinib exposure, which may decrease efficacy of GAVRETO. Avoid concomitant use of GAVRETO with strong or moderate CYP3A inducers. If coadministration of GAVRETO with strong or moderate CYP3A inducers cannot be avoided, increase the GAVRETO dose. USE IN SPECIFIC POPULATIONS • Lactation: Advise not to breastfeed during treatment with GAVRETO and for 1 week after the last dose. • Pediatric Use: The safety and effectiveness of GAVRETO have not been established in pediatric patients with RET fusion-positive NSCLC or in pediatric patients younger than 12 years old with RET fusion positive thyroid cancer. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. RIGL_FRN-26004 Please see https://www.GAVRETO.com/ for full Prescribing Information.
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Thank You www.rigel.com 54