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CStone receives approval in China to initiate ivosidenib Phase I bridging registrational study for the treatment of IDH1 mutant relapsed or refractory AML

PR Newswire Asia Monday, 22 July 2019
CStone receives approval in China to initiate ivosidenib Phase I bridging registrational study for the treatment of IDH1 mutant relapsed or refractory AMLSUZHOU, China, July 22, 2019 /PRNewswire/ -- CStone Pharmaceuticals ("CStone"; HKEX: 2616) announced today that it has received approval from China National Medical Products Administration (NMPA) to initiate a Phase I bridging registrational study of ivosidenib (TIBSOVO) for the treatment of relapsed or refractory acute myeloid leukemia (R/R AML) with an IDH1 mutation. This stand-alone trial is designed to evaluate the efficacy, safety and pharmacokinetics of ivosidenib in Chinese patients with IDH1 mutant R/R AML.

AML is the most common type of acute leukemia in adults and is characterized by rapid disease progression. There are approximately 20,000 new cases of AML in the U.S. each year, with a five-year survival rate of approximately 27%, as compared to 30,000 new cases in China annually and a five-year survival rate of below 20%. The majority of AML patients develop tolerance to treatments or eventually relapse, leading to R/R AML which has a poor prognosis. With an increasing life expectancy and aging population in China, the incidence of AML may rise significantly in the country. Interruption to the differentiation of hematopoietic stem cells due to IDH1 mutation is associated with around 6%-10% of all AML cases. Among the currently approved treatments for AML in China, there is no effective therapy for this patient population.

Discovered and developed by CStone's partner Agios Pharmaceuticals, ivosidenib was approved by the U.S. FDA in July 2018 for the treatment of adult R/R AML patients with an IDH1 mutation as detected by an FDA-approved test.

"Ivosidenib is the first and only approved precision therapy in the U.S. that targets IDH1 mutation in R/R AML and the only asset in CStone's pipeline that has obtained a marketing authorization. This approval for the registrational study in China marks a big milestone for us," commented Dr. Frank Jiang, Chairman and CEO of CStone. "Through precision therapies, patients can potentially benefit from treatments targeting the specific genetic mutations that drive the cancer. CStone remains committed to advancing precision therapies and bringing more targeted treatment options to patients."

"Ivosidenib was first approved as a treatment for IDH1 mutant R/R AML. The U.S. FDA recently approved a supplemental NDA for ivosidenib to include newly diagnosed AML patients with an IDH1 mutation who are ≥ 75 years old or have comorbidities that preclude the use of intensive induction chemotherapy. In March 2019, the U.S. FDA granted Breakthrough Therapy designation for ivosidenib in combination with azacitidine for the treatment of the same newly diagnosed AML patients. These milestones demonstrate ivosidenib's promising clinical utility. We are poised to rapidly roll out this trial for ivosidenib as a monotherapy for R/R AML in China. We hope the study will generate favorable clinical data, paving the way for the drug to quickly enter the China market," noted Dr. Jason Yang, CStone's Chief Medical Officer.

*About TIBSOVO (ivosidenib)*

In the United States, TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

· Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
· Adult patients with relapsed or refractory AML.

*IMPORTANT SAFETY INFORMATION*

*WARNING: **DIFFERENTIATION SYNDROME*

*Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.*

*WARNINGS AND PRECAUTIONS*

*Differentiation Syndrome: See Boxed WARNING. *In the clinical trial, 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. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. 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 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. One patient developed ventricular fibrillation attributed to TIBSOVO^®. Concomitant use of TIBSOVO^® with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT[3] 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 occurred in
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