dordaviprone 125 MG Oral Capsule

INDICATIONS AND USAGE MODEYSO is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). MODEYSO is a protease activator indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. ( 1 ) This indication is approved under accelerated approval based on response rate and duration of response [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

DOSAGE AND ADMINISTRATION • Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens. ( 2.1 ) • Monitor ECG and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated. ( 2.2 ) • The recommended dose in adult patients is 625 mg orally once weekly. ( 2.3 ) • The recommended dose in pediatric patients weighing ≥10 kg is based on body weight (see Table 1). ( 2.3 ) • Take MODEYSO orally once weekly on an empty stomach, at least 1 hour before or 3 hours after food intake. ( 2.3 ) • Continue MODEYSO until disease progression or unacceptable toxicity. ( 2.3 ) 2.1 Patient Selection Select patients for treatment with MODEYSO based on the presence of an H3 K27M mutation from tumor specimens [see Clinical Studies ( 14 )] . An FDA-approved test for the detection of this mutation is not currently available. 2.2 Recommended Testing Before Starting MODEYSO Monitor electrocardiograms (ECG) and electrolytes before starting MODEYSO and periodically during treatment as clinically indicated [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . 2.3 Recommended Dosage and Administration Take MODEYSO on an empty stomach, at least 1 hour before or 3 hours after food intake [see Clinical Pharmacology ( 12.3 )] . Adults The recommended dosage of MODEYSO is 625 mg orally once weekly. Pediatrics The recommended dosage of MODEYSO in pediatric patients aged 1 to <17 years who weigh at least 10 kg is based on body weight (Table 1). A recommended dosage of MODEYSO has not been established in pediatric patients who weigh less than 10 kg. Table 1: Recommended Body Weight-Based Dosage for Pediatric Patients Body Weight (kg) Recommended Dosage 10 kg to <12.5 kg 125 mg Once Weekly 12.5 kg to <27.5 kg 250 mg Once Weekly 27.5 kg to <42.5 kg 375 mg Once Weekly 42.5 kg to <52.5 kg 500 mg Once Weekly ≥52.5 kg 625 mg Once Weekly Continue MODEYSO until disease progression or unacceptable toxicity. Swallow capsules whole. For patients unable to swallow capsules whole, open each capsule, mix contents with approximately 15 to 30 mL of liquid (sports drink, apple juice, lemonade, or water) before administration, and administer orally as a liquid [see Patient Counseling Information ( 17 )] . Once mixed, administer within 2 hours of preparation, or discard and mix a new dose. Vomiting If vomiting occurs after taking a dose, do not take an additional dose and take the next dose at the regularly scheduled time. Missed Dose If a dose is missed within 2 days, take the missed dose as soon as possible. If a dose is missed by more than 2 days, skip the missed dose and take the next dose at the scheduled time. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage reductions for adverse reactions for MODEYSO are provided in Table 2. Table 2: Recommended Dosage Reductions for Adverse Reactions Patient’s Weight (kg) First Dosage Reduction Second Dosage Reduction Pediatric patients 10 kg to <12.5 kg Permanently discontinue N/A Pediatric patients 12.5 kg to <27.5 kg 125 mg once weekly Permanently discontinue Pediatric patients 27.5 kg to <42.5 kg 250 mg once weekly 125 mg once weekly Pediatric patients 42.5 kg to <52.5 kg 375 mg once weekly 250 mg once weekly Pediatric patients ≥52.5 kg and adult patients 500 mg once weekly 375 mg once weekly The recommended dosage modifications for adverse reactions are provided in Table 3. Table 3: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity a Dosage Modification b Hypersensitivity [see Warnings and Precautions ( 5.1 )] Any grade If hypersensitivity is suspected based on clinical judgement, interrupt MODEYSO until resolution of the event. Permanently discontinue MODEYSO in patients who develop serious hypersensitivity reactions. QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] QTc absolute value >500 ms or An increase of >60 ms from baseline Interrupt MODEYSO until QTc interval ≤480 ms or return to baseline. Resume MODEYSO at the next lower dose level. Torsades de pointes, polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening arrhythmia Permanently discontinue MODEYSO. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Interrupt MODEYSO until ≤Grade 1 or return to baseline. Resume MODEYSO at the next lower dose level. Recurrent Grade 4 Permanently discontinue MODEYSO. a. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. b. See Table 2 for recommended dosage reductions. 2.5 Dosage Modifications for CYP3A4 Inhibitors Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. • If concomitant use of a strong CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 375 mg once weekly. • If concomitant use of a moderate CYP3A4 inhibitor cannot be avoided for adult and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO from 625 mg to 500 mg once weekly. • The recommended dosage for pediatric patients weighing less than 52.5 kg who are receiving strong or moderate CYP3A4 inhibitors has not been established. Upon discontinuation of the CYP3A4 inhibitor, wait for 3 to 5 plasma half-lives of the CYP3A4 inhibitor, then increase MODEYSO to the dose that was taken before starting the CYP3A4 inhibitor [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

WARNINGS AND PRECAUTIONS • Hypersensitivity: If clinically significant hypersensitivity or anaphylaxis occur, immediately discontinue MODEYSO and initiate appropriate medical treatment and supportive care. ( 5.1 ) • QTc Interval Prolongation: MODEYSO causes concentration dependent QTc interval prolongation. Interrupt or reduce the dose of MODEYSO in patients who develop QT prolongation, and permanently discontinue MODEYSO in patients with signs of life-threatening arrhythmias. ( 5.2 , 12.2 ) • Embryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Hypersensitivity MODEYSO can cause severe hypersensitivity reactions. In the pooled safety population [see Adverse Reactions ( 6.1 )], Grade 3 hypersensitivity reactions occurred in 0.3% of patients receiving MODEYSO. Signs and symptoms of hypersensitivity may include rash, hives, fever, low blood pressure, wheezing, or swelling of the face or throat. Inform patients about the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical attention if symptoms occur. If clinically significant hypersensitivity or anaphylaxis occur, immediately interrupt MODEYSO and initiate appropriate medical treatment and supportive care. Based on the severity of the adverse reaction, temporarily interrupt or permanently discontinue MODEYSO [see Dosage and Administration ( 2.4 )] . 5.2 QTc Interval Prolongation MODEYSO causes a concentration-dependent QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] , which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. In the pooled safety population [see Adverse Reactions ( 6.1 )] , of the 82 patients who underwent at least one post-baseline ECG assessment, 6% experienced an increase in QTc of >60 msec compared to baseline after receiving MODEYSO and 1.2% had an increase in QTc to >500 msec. Monitor ECGs and electrolytes prior to starting MODEYSO and then periodically during treatment as clinically indicated. Significant prolongation of the QT interval may occur when MODEYSO is taken concomitantly with other products that have a known potential to prolong the QT interval. Avoid concomitant use of MODEYSO with products known to prolong the QT interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.2 )] . Increase the frequency of monitoring when administering MODEYSO to patients taking other products that have a known potential to prolong the QT interval and in patients with congenital long QT syndrome, existing QTc prolongation, a history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or who are taking strong or moderate CYP3A4 inhibitors. Interrupt or reduce the dose of MODEYSO in patients who develop QT prolongation, and permanently discontinue MODEYSO in patients with signs of life-threatening arrhythmias [see Dosage and Administration ( 2.4 )] . 5.3 Embryo-fetal Toxicity Based on findings from animal studies and its mechanism of action, MODEYSO can cause fetal harm when administered to a pregnant woman. In embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with MODEYSO and for 1 month after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Dordaviprone is a protease activator of the mitochondrial caseinolytic protease P (ClpP). Dordaviprone also inhibits the dopamine D2 receptor. Diffuse midline gliomas harboring an H3 K27M mutation are associated with the loss of H3 K27 trimethylation. In-vitro, dordaviprone activated the integrated stress response, induced apoptosis, and altered mitochondrial metabolism leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma models. Dordaviprone exhibited antitumor activity in cell-based assays and in vivo models of H3 K27M-mutant diffuse glioma.