Servier Presents Updated Results for TIBSOVO® (ivosidenib tablets) in IDH1-mutated Relapsed/Refractory Myelodysplastic Syndromes at the 2023 European Hematology Association (EHA) Congress

Treatment with TIBSOVO resulted in durable remissions, including complete response in nearly 40% of patients, and an acceptable safety profile

Servier plans to submit a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA)

BOSTON, June 9, 2023 /PRNewswire/ -- Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, today announced updated data from the Phase 1 trial of TIBSOVO^® (ivosidenib tablets) as monotherapy for patients with isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS). The results presented today at the European Hematology Association (EHA) 2023 Annual Congress in Frankfurt, Germany demonstrate that the efficacy and safety profile of TIBSOVO may provide an important new treatment option for MDS patients within this molecularly defined subset.

The Phase 1, open-label study included an evaluation of the safety, tolerability, and clinical activity of TIBSOVO in patients with IDH1-mutated R/R MDS. The primary endpoint was complete remission (CR) plus partial remission (PR) rate and key secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.

In the efficacy analysis set (n=18), a complete remission (CR) rate of 38.9% and overall response rate (ORR) of 83.3% were documented in patients treated with TIBSOVO. In addition, the median time to CR was 1.87 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*).

"We are pleased to share these updated efficacy results that demonstrate durable remissions and an acceptable safety profile in patients with IDH1-mutated relapsed or refractory MDS at this year's EHA Congress," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "These data add to the growing body of evidence behind targeted IDH inhibition, and we look forward to taking the next steps with regulatory authorities to potentially expand the use of TIBSOVO in the United States to include the treatment of IDH1-mutated relapsed or refractory MDS."

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. Further, of the nine patients who were transfusion independent with red blood cells or platelets at baseline, 77.8% (n=7) maintained transfusion independence during any ≥56-day post-baseline period.

"Patients with IDH1-mutated relapsed or refractory MDS currently have no targeted therapy options, and outcomes are generally poor for those who experience disease progression after treatment with standard care," said Courtney D. DiNardo, M.D., MSCE, Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, and investigator on the study. "This updated analysis demonstrates that TIBSOVO has the potential to improve outcomes in the treatment of IDH1-mutated relapsed or refractory MDS and reinforces the importance of molecular analysis to ensure we're harnessing the potential benefit of targeted therapies."

Overall, treatment-related adverse events (TRAEs) were consistent with the known safety profile of TIBSOVO. Among 19 patients included in the safety analysis set, TRAEs occurred in eight (42.1%) patients, including a grade 1 QTc interval increase in one (5.3%) patient, grade 3 fatigue in one patient, and grade 3 hyponatremia in one patient, none of which led to discontinuation with treatment.

In 2019, the U.S. FDA granted Breakthrough Therapy designation for TIBSOVO (ivosidenib) for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes with a susceptible isocitrate dehydrogenase 1 (IDH1) mutation as detected by an FDA-approved test. Servier plans to submit a supplemental New Drug Application (sNDA) based on these results to the U.S. FDA for TIBSOVO in adult patients with R/R IDH1-mutated myelodysplastic syndromes.

TIBSOVO is currently approved in the U.S. as monotherapy 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. TIBSOVO was recently approved by the European Commission as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. TIBSOVO has also been approved in the U.S. and Australia for patients with previously treated IDH1-mutated cholangiocarcinoma. TIBSOVO is also approved in China[i] for the treatment of adult patients with relapsed or refractory AML who have a susceptible IDH1 mutation. 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.

* Denotes a censored observation.

About the Study
In the Phase 1 dose-escalation and expansion study evaluating TIBSOVO in adults with advanced hematologic malignancies with IDH1 mutations, the clinical activity, safety, tolerability, pharmacokinetics and pharmacodynamics of TIBSOVO in adult patients with relapsed or refractory MDS with a susceptible IDH1 mutation is being assessed. (NCT03503409)

About Myelodysplastic Syndromes (MDS)
MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The Leukemia and Lymphoma Society estimates that more than 20,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body's ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML¹. Chemotherapy, supportive therapy, stem cell transplant, growth factors, and similar approaches are used to treat MDS.

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-tread 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 IDH inhibitor approved in the U.S. and the European Union, and the company continues to drive the science behind targeted mutant IDH inhibition throughout its pipeline.

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 (U.S.)
Julia Ferreira
[email protected]

Servier Group (France and worldwide)
[email protected]
+33 (0)1 55 72 40 21 / + 33 (0)7 84 28 76 13

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 an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for patients with a susceptible 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 the use of intensive induction chemotherapy 

Relapsed or Refractory AML

• For the treatment of adult patients with relapsed or refractory AML

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: In the combination study AG120-C-009, 15% (11/71) of patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome. 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. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine, 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis. 

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, or electrolyte abnormalities, or in 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 cholangiocarcinoma, the most common adverse reactions (≥15%) 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

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for 1 month after the last dose.

Please see Full Prescribing Information, including BOXED WARNING for AML patients

¹ Leukemia and Lymphoma Society. Myelodysplastic Syndrome (MDS) Research Funded by LLS. Available at: https://www.lls.org/research/myelodysplastic-syndrome-mds-research-funded-lls

SOURCE Servier Pharmaceuticals

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