IDH1 Mutation Acute Myeloid Leukemia

The Gavreto baton is being passed on from Roche to Rigel Pharma. As Roche officially abandoned cancer drug Gavreto, its former partner Blueprint Medicines has found the RET inhibitor a new owner in the U.S. Rigel Pharmaceuticals will pay Blueprint $15 million to gain U.S. rights to Gavreto, the two companies said Thursday, just as Blueprint and Roche ended their collaboration. Under the new Rigel deal, Blueprint is also eligible to receive up to $102.5 million in future regulatory and commercial milestone payments, plus tiered royalties ranging from 10% to 30% depending on Gavreto’s sales level. In 2023, Gavreto generated about $28 million in U.S. sales, Rigel noted. Roche announced its intention to cut off Gavreto a year ago, with the termination going into effect today. After paying $775 million upfront to in-license the drug on the cusp of an FDA approval in 2020, Roche found that the drug wasn’t living up to its sales expectations. Then in July 2023, Roche decided to pull an accelerated approval for Gavreto in RET-mutant medullary thyroid cancer, citing an infeasible confirmatory trial. With Big Pharma support, Blueprint in January said it will discontinue work on Gavreto outside the U.S. and Great China, where CStone takes the charge. Thursday, Blueprint said it has also ended the ex-U.S. royalty interest deal it had signed with Royalty Pharma in mid-2022. The pact was based on Gavreto sales-related royalties from the Roche collaboration. For Rigel, Gavreto grows the California company’s oncology portfolio. The FDA in December approved Rigel’s Rezlidhia—which Rigel in-licensed from Forma Therapeutics—to treat IDH1-mutated acute myeloid leukemia. Rigel’s commercial offerings also include Tavalisse, which is indicated to treat adults with low platelet counts due to chronic immune thrombocytopenia. “The addition of Gavreto will be highly synergistic with our current product portfolio, leveraging our existing commercial infrastructure and enabling us to expand into solid tumors,” Rigel’s chief commercial officer, Dave Santos, said in a statement Thursday. Rigel will go up against Eli Lilly in the RET field. Last year, Lilly’s rival drug Retevmo ginned up $254 million in sales, including $175 million from the U.S. Retevmo also boasts a unique FDA nod to treat RET fusion-positive tumors regardless of their location. In October, phase 3 data showed that Retevmo reduced the risk of progression or death by 53.5% compared with the combination of Merck & Co.’s Keytruda and chemotherapy in patients with newly diagnosed RET fusion-positive non-small cell lung cancer. The Lilly med also aced its own confirmatory trial in RET-mutant medullary thyroid cancer. By comparison, Gavreto’s phase 3 AcceleRET-Lung trial in front-line RET fusion-positive NSCLC has yet to read out. Rigel and Roche have entered a transition period, in which Roche’s Genentech will still help ensure that patients can access Gavreto without interruption. Rigel expects to complete the transition and start recognizing sales from Gavreto in the third quarter of 2024. For its part, Blueprint expects the wind-down will significantly lower its operating expenses around Gavreto, though with little impact on the company’s overall numbers. Blueprint is currently focused on the systemic mastocytosis treatment Ayvakit, for which the company just dialed up the peak sales target to $2 billion.

Data in acute myeloid leukemia reinforces TIBSOVO® as a front-line therapeutic option for IDH1-mutated AML BOSTON, Dec. 5, 2023 /PRNewswire/ -- Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, will present data in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego from December 9-12, 2023. The latest data underscores Servier's commitment to advancing scientific research, including gaining a more robust understanding of real-world treatment patterns for patients with difficult and hard-to-treat cancers. "ASH is a tremendous opportunity to connect with the broader hematologic community and share scientific advances with the power to improve the treatment landscape for patients in need of innovation," said David K. Lee, CEO, Servier Pharmaceuticals. "On the heels of our recent FDA approval for TIBSOVO® (ivosidenib tablets) in relapsed/refractory IDH1-mutated myelodysplastic syndromes (MDS), the fifth FDA approval for Tibsovo across hematology and solid tumors, our data at this year's ASH continue to add to Servier's leadership in mutant IDH inhibition, including additional evidence for Tibsovo + azacitidine as the standard of care for newly diagnosed IDH1-mutated AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy." Servier data being presented at ASH are listed below and are available online on the ASH website here. A large retrospective study comparing two first-line combination regimens for newly diagnosed patients with IDH1-mutated acute myeloid leukemia (mIDH1 AML), ineligible for intensive chemotherapy, to gain insight into real-world treatment patterns, effectiveness and safety A global longitudinal study of patients with AML, with or without mIDH1 disease, who received first-line intensive chemotherapy to gain insight into treatment patterns and clinical outcomes in the real-world setting An analysis of the Phase 3 AGILE study in patients with newly diagnosed AML, who are not eligible for intensive induction chemotherapy, using next-generation sequencing to determine measurable residual disease (MRD), a negative prognostic marker, among patients who had a best overall response to treatment in the study A retrospective study in adolescents and young adults with acute lymphoblastic leukemia, to gain real-world insight into treatment approaches for this population across diverse cancer care settings "As we continue to advance our clinical development programs across hematology, we are simultaneously focused on generating real-world evidence data that can help the entire treatment community gather the broadest picture possible to identify the best individualized treatment options," said Becky Martin, PhD, Chief of Medical, Servier Pharmaceuticals. "Looking to the future, improving patient outcomes is going to be a collaborative effort across industry, academia and the community. Servier is proud to serve as a bridge across these stakeholders in our goal of improving patient outcomes." Among Servier data being presented is real-world evidence comparing Tibsovo in combination with hypomethylating agents (HMA) versus venetoclax in combination with hypomethylating agents in patients with newly diagnosed AML (intensive chemotherapy induction ineligible - ICIE ) and a susceptible IDH1 mutation. In the analysis, Tibsovo+HMA elicited a higher complete response (CR) rate versus venetoclax+HMA at 42.9% vs. 26.7% (p=0.007). 6-month event-free survival also favored Tibsovo+HMA at 56.0% vs. 39.6% (p=0.044), as well as 11.5% of patients on Tibsovo+HMA achieving bridge to transplant versus 5.0% on a venetoclax+HMA regimen (p=0.066). The full analysis will be presented on Monday, December 11 at 5:30 p.m. PST. Additional data being presented at ASH includes molecular measurable residual disease (MRD) in ICIE patients with newly diagnosed mIDH1 AML treated with Tibsovo+azacitidine, further bolstering the clinical profile of Tibsovo in the front-line setting, as well as real-world analyses examining treatment patterns in both ALL and AML. Abstract #971 (Oral): A Comparison of Acute Myeloid Leukemia (AML) Regimens: Hypomethylating Agents Combined with Ivosidenib or Venetoclax in Newly Diagnosed Patients with IDH1 Mutations: A Real-World Evidence Study Date & Time: Monday, December 11, 5:30 p.m. Lead Author: B. Douglas Smith, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Abstract #3816 (Poster): Real-World Treatment Patterns and Clinical Outcomes in Newly Diagnosed Acute Myeloid Leukemia with and without mIDH1 Treated with Intensive Chemotherapy from an International Real-World Database (REAL-IDH) Date & Time: Sunday, December 10, 6:00 p.m.-8:00 p.m. Lead Author: Joshua F. Zeidner, The University of North Carolina, Chapel Hill Abstract #4305 (Poster): Molecular Measurable Residual Disease in Patients with Newly Diagnosed mIDH1 Acute Myeloid Leukemia Treated with Ivosidenib + Azacitidine Date & Time: Monday, December 11, 6:00 p.m.-8:00 p.m. Lead Author: Courtney DiNardo, M.D., MSc, The University of Texas MD Anderson Cancer Center, Houston Abstract #3704 (Poster): Patterns of Care Among Adolescents and Young Adults Treated for Acute Lymphoblastic Leukemia: A Retrospective Study Across Diverse US Practices Date & Time: Sunday, December 10, 6:00 p.m.-8:00 p.m. Lead Author: Julie Wolfson, M.D., MSHS, The University of Alabama at Birmingham About Servier in Oncology Servier is a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves. Governed by a non-profit foundation, Servier approaches innovation with a long-term vision, free of influence from investors and outside pressure to chase short-term monetary targets. As a leader in oncology, Servier has significantly accelerated its investment in difficult and hard-to-treat cancers, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout oncology with the potential to change the lives of the patients it serves. Within these areas, Servier is the leader in mutant IDH inhibition, with the first ever mutant IDH1 inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition. Servier's commitment to therapeutic progress guides its collaboration strategy. While many companies across the industry are scaling back investments, Servier is actively building alliances, completing acquisitions, conducting licensing deals and entering new partnerships that can help to accelerate access to therapies for patients in need. With the company's commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier is dedicated to bringing the promise of tomorrow to the patients it serves. Press Contact Servier Pharmaceuticals Nathan Mellor [email protected] Disclosures This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect. Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks. This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA. Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. TIBSOVO IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS INDICATIONS TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy Relapsed or Refractory AML For the treatment of adult patients with relapsed or refractory AML Relapsed or Refractory Myelodysplastic Syndromes (MDS) For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes Locally Advanced or Metastatic Cholangiocarcinoma For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Differentiation Syndrome in AML and MDS: 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 TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe. QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome. ADVERSE REACTIONS In patients with AML, the most common adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia In patients with MDS, the most common adverse reactions including laboratory abnormalities (≥25%) are creatinine increased, hemoglobin decreased, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash In patients with cholangiocarcinoma, the most common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased DRUG INTERACTIONS Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation. Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO. Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO. QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation. LACTATION: Advise women not to breastfeed. Please see Full Prescribing Information , including BOXED WARNING for AML and MDS patients. SOURCE Servier Pharmaceuticals

TIBSOVO is the first and only approved targeted therapy for R/R MDS patients with a susceptible IDH1 mutation Fifth approved indication for TIBSOVO solidifies Servier's leadership in mutant IDH inhibition BOSTON, Oct. 24, 2023 /PRNewswire/ -- Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, today announced the U.S. Food and Drug Administration (FDA) has approved TIBSOVO® (ivosidenib tablets) for the treatment of patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS). This is the fifth indication for TIBSOVO across IDH1-mutated cancers, and the first and only approved targeted therapy for people diagnosed with R/R MDS within this molecularly defined subset. "Servier is proud to lead the way in mutant IDH inhibition through continued innovations that support patients living with difficult and hard-to-treat cancers," said Arjun Prasad, Head of Commercial, Servier Pharmaceuticals. "As the first and only targeted therapy available for patients with IDH1-mutated relapsed or refractory myelodysplastic syndromes, today's FDA approval for TIBSOVO reinforces our commitment to deliver significant advances in areas of high unmet need and bring the right treatment, to the right patient, at the right time." The FDA approval of this indication is supported by a pivotal Phase 1, open-label study in IDH1-mutated R/R MDS patients (n=18) where a complete remission (CR) rate of 38.9% and objective response rate (ORR) of 83.3% were documented in patients treated with TIBSOVO. In addition, the median time to CR was 1.9 months (range: 1.0, 5.6). At the time of data cutoff, the median duration of CR had not been reached (range: 1.9, 80.8+*) and the median overall survival was 35.7 months (range: 3.7*, 88.7*). Additionally, of the nine patients who were transfusion dependent with red blood cells or platelets at baseline, 66.7% (n=6) became independent of transfusions during any ≥56-day post-baseline period. Overall, treatment-related adverse events were consistent with the known safety profile of TIBSOVO. "The novel use of targeted therapy across IDH-mutated cancers has become a powerful therapeutic option for patients within this molecularly defined subset," said Amir Fathi, M.D., hematologist, medical oncologist, and expert in myeloid malignancies. "This new indication in IDH1-mutated relapsed or refractory myelodysplastic syndromes reinforces the importance of mutational testing to inform treatment decisions and potentially improve patient outcomes." An estimated 16,000 people in the U.S. are diagnosed with MDS each year.1 Approximately 3.6% of MDS patients have an IDH1 mutation,2 which is considered an early "driver" mutation.3 For MDS patients with an IDH1 mutation, the prognosis has often been associated with worse overall outcomes and an increased risk of transformation to AML.2 "This approval for TIBSOVO is welcome news for the MDS community," said Tracey Iraca, Executive Director, MDS Foundation. "Before today, there were no approved targeted therapies available to relapsed or refractory MDS patients harboring the IDH1-mutation. We want to thank the study participants, their families and caregivers, as well as the researchers at Servier and clinical investigators involved in this study for helping to bring a new treatment option to patients where there has been a significant unmet need." "An MDS diagnosis is ambiguous. I remember feeling confused trying to make sense of my diagnosis, what having an IDH1-mutation meant, and what options were available for my treatment plan," said Susan, a patient living with IDH1-mutated MDS.** "The news of an FDA approval for a targeted therapy in IDH-1 mutated MDS has given me a tremendous sense of gratitude and provides hope to patients – like me – who are living with this disease. I want to thank everyone who played a role in this major step forward for the MDS community." TIBSOVO was granted Breakthrough Therapy designation for the treatment of adult patients with R/R (MDS) with an IDH1 mutation and received Priority Review, which accelerated the review timeline and is granted to applications for medicines that, if approved, would provide significant improvements in the effectiveness or safety of the treatment, diagnosis, or prevention of serious conditions.4 The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for TIBSOVO. * Denotes a censored observation. **Last name withheld to protect privacy. About the NCT02074839 Clinical Trial 5 This Phase I, open-label multinational study evaluated the safety, tolerability, and clinical activity of ivosidenib in patients with relapsed or refractory myelodysplastic syndromes with an IDH1 mutation. The primary endpoint was complete remission (CR) plus partial remission (PR) rate and key secondary endpoints included duration of CR+PR, duration of transfusion independence, and time to transfusion independence. About TIBSOVO® (ivosidenib tablets) TIBSOVO is a precision medicine that targets a specific type of mutation known as isocitrate dehydrogenase 1 (IDH1). TIBSOVO is approved in five indications globally, including approvals in the U.S., European Union, Australia, and China. In the U.S., TIBSOVO is approved for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy, as monotherapy for the treatment of adult patients with IDH1-mutant relapsed or refractory MDS, and for patients with previously treated IDH1-mutated cholangiocarcinoma. Servier has granted CStone a co-exclusive license for the development and an exclusive license agreement for the commercialization of TIBSOVO in Mainland China, Taiwan, Hong Kong, Macao and Singapore. For more information about TIBSOVO in the U.S., please visit . About Myelodysplastic Syndromes Myelodysplastic Syndromes (MDS) are disorders in which progenitor (stem) cells do not mature into healthy blood cells.6 In the U.S., approximately 16,000 new cases of MDS are reported each year.1 Approximately 3.6% of MDS patients have an IDH1 mutation,2 which is considered an early "driver" mutation.3 For MDS patients with an IDH1 mutation, the prognosis has often been associated with worse overall outcomes and in an increased risk of transformation to AML.2 Prior to the approval of TIBSOVO, there were no approved targeted therapies for this molecularly defined subset. About Servier in Oncology Servier is a global leader in oncology focused on delivering meaningful therapeutic progress for the patients it serves. Governed by a non-profit foundation, Servier approaches innovation with a long-term vision, free of influence from investors and outside pressure to chase short-term monetary targets. As a leader in oncology, Servier has significantly accelerated its investment in difficult and hard-to-treat cancers, with more than 50% of its research and development dedicated to delivering significant advances in areas of high unmet need throughout oncology with the potential to change the lives of the patients it serves. Within these areas, Servier is the leader in mutant IDH inhibition, with the first ever mutant IDH1 inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition. Servier's commitment to therapeutic progress guides its collaboration strategy. While many companies across the industry are scaling back investments, Servier is actively building alliances, completing acquisitions, conducting licensing deals and entering new partnerships that can help to accelerate access to therapies for patients in need. With the company's commercial expertise, global reach, scientific expertise and commitment to clinical excellence, Servier is dedicated to bringing the promise of tomorrow to the patients it serves. Press Contact Servier Pharmaceuticals Nathan Mellor [email protected] Disclosures This release contains general information about the Servier Group and its entities (hereinafter "Servier and its Affiliates") and is intended for informational purposes only. The information is thought to be reliable; however, Servier and its Affiliates make no representation as to the accuracy or completeness of the information contained herein or otherwise provided and accept no responsibility or liability, in contract, in tort, in negligence, or otherwise, should the information be found to be inaccurate or incomplete in any respect. Servier and its Affiliates are not acting as an advisor to the recipient of this information, and the ultimate decision to proceed with any transaction rests solely with the recipient of this information. Therefore, prior to entering into any proposed transaction, the recipient of this information should determine, without reliance upon Servier or its Affiliates, the economic risks and merits, as well as the legal, tax, and accounting characterizations and consequences, of the transaction and that it is able to assume these risks. This statement also contains forward-looking statements that are subject to varying levels of uncertainty and risk. Investigational new drugs and indications are subject to further scientific and medical review and regulatory approval. They are not approved for use by the FDA. Any reliance placed on this document is done entirely at the risk of the person placing such reliance. The information contained in this document is neither an offer to sell nor the solicitation of an offer to enter into a transaction. The content of this document is a summary only, is not complete, and does not include all material information about Servier and its Affiliates, including potential conflicts of interest. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates disclaim all representations, warranties, conditions and guarantees, whether express, implied, statutory or of other kind, nor does it accept any duty to any person, in connection with this document. Without prejudice to the generality of the foregoing, Servier and its Affiliates do not warrant or represent that the information or opinions contained in this document is accurate or complete. To the maximum extent permitted by applicable laws and regulations, Servier and its Affiliates shall not be liable for any loss, damage or expense whatsoever, whether direct or indirect, howsoever arising, whether in contract, tort (including negligence), strict liability or otherwise, for direct, indirect, incidental, consequential, punitive or special damages arising out of or in connection with this document, including (without limitation) any course of action taken on the basis of the same. The estimates, strategies, and views expressed in this document are based upon past or current data and information and are subject to change without notice. TIBSOVO IMPORTANT SAFETY INFORMATION AND INDICATION FOR U.S. PATIENTS INDICATIONS TIBSOVO is indicated for patients with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test with: Newly Diagnosed Acute Myeloid Leukemia (AML) In combination with azacitidine or as monotherapy for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy Relapsed or Refractory AML For the treatment of adult patients with relapsed or refractory AML Relapsed or Refractory Myelodysplastic Syndromes (MDS) For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes Locally Advanced or Metastatic Cholangiocarcinoma For the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma who have been previously treated IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Differentiation Syndrome in AML and MDS: 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 TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe. QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary. Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. Guillain-Barré Syndrome: Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome. ADVERSE REACTIONS In patients with AML, the most common adverse reactions including laboratory abnormalities (≥25%) are leukocytes decreased, diarrhea, hemoglobin decreased, platelets decreased, glucose increased, fatigue, alkaline phosphatase increased, edema, potassium decreased, nausea, vomiting, phosphate decreased, decreased appetite, sodium decreased, leukocytosis, magnesium decreased, aspartate aminotransferase increased, arthralgia, dyspnea, uric acid increased, abdominal pain, creatinine increased, mucositis, rash, electrocardiogram QT prolonged, differentiation syndrome, calcium decreased, neutrophils decreased, and myalgia In patients with MDS, the most common adverse reactions including laboratory abnormalities (≥25%) are creatinine increased, hemoglobin decreased, arthralgia, albumin decreased, aspartate aminotransferase increased, fatigue, diarrhea, cough, sodium decreased, mucositis, decreased appetite, myalgia, phosphate decreased, pruritus, and rash In patients with cholangiocarcinoma , the most common adverse reactions (≥15%) in patients with cholangiocarcinoma are fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash. The most common laboratory abnormalities (≥10%) in patients with cholangiocarcinoma are hemoglobin decreased, aspartate aminotransferase increased, and bilirubin increased DRUG INTERACTIONS Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation. Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO. Sensitive CYP3A4 substrates: Avoid concomitant use with TIBSOVO. QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation. LACTATION: Advise women not to breastfeed. Please see Full Prescribing Information, including BOXED WARNING for AML and MDS patients. 1 SEER MDS Incidence Rates. ; U.S. Census Bureau Population Estimates 2017 National Population Projections Tables: Main Series (census.gov) . 2 Thol, F., Weissinger, E. M., Krauter, J., Wagner, K., Damm, F., Wichmann, M., Göhring, G., Schumann, C., Bug, G., Ottmann, O., Hofmann, W. K., Schlegelberger, B., Ganser, A., & Heuser, M. (2010). IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica, 95(10), 1668–1674. . Accessed May 19, 2023. 3 DiNardo CD, et al. Leukemia. 2016;30(4):980-984. doi:10.1038/leu.2015.211. 4 United States Food and Drug Administration (FDA). Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review. . Accessed June 27, 2023. 5 Clinicaltrials.gov website. . Accessed September 1, 2023. 6 Pagliuca, S., Gurnari, C., & Visconte, V. (2021). Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments. Cancers, 13(4), 784. . SOURCE Servier Pharmaceuticals