Modeyso Drug Information

• The following potential clinically significant adverse reactions are described elsewhere in the labelling:
• Hypersensitivity [see Warnings and Precautions ( 5.1 )] .
• QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] . The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chimerix at toll-free phone # 1-866-662-2679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in WARNINGS AND PRECAUTIONS and below reflects exposure to MODEYSO at the recommended weight-based dose taken until disease progression or unacceptable toxicity in 376 adult and pediatric patients with glioma across four open-label clinical studies (ONC006, ONC013, ONC014, and ONC018) [see Clinical Studies ( 14 )] . Of the 376 patients who received MODEYSO, 35% were exposed for 6 months, and 17% were exposed for 1 year. The median age was 23 years (range: 3 to 80): 30% were 2 to 11 years old, 11% were 12 to 17 years old, 55% were 18 to 64 years old, and 3.7% were 65 years or older. Fifty-two percent (52%) were female; 74% White, 10% unknown race or race not reported, 9% Black or African American, 4% Asian, 2.9% other or multiple races; and 13% were of Hispanic or Latino ethnicity. Karnofsky/Lansky Performance Status (KPS/LPS) score was 80 to 100 in 66% of patients, 60 to 70 in 27%, and <60 in 7%. relevant disease characteristics included primary tumor locations in the midline (91%) and non‑midline regions (9%); 33% had diffuse intrinsic pontine glioma (dipg); 30% had multifocal disease; 79% had an h3 k27m mutation; 75% had recurrent disease. serious adverse reactions occurred in 33% of patients who received modeyso. serious adverse reactions in>2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%), and muscular weakness (2.1%). Fatal adverse reactions occurred in 1% of patients who received MODEYSO, including cardiac arrest (0.5%), intracranial hemorrhage (0.3%), and encephalopathy (0.3%). Permanent discontinuation of MODEYSO due to an adverse reaction occurred in 2.1% of patients. Adverse reactions which resulted in permanent discontinuation of MODEYSO in >1 patient included confusional state. Dosage interruptions of MODEYSO due to an adverse reaction occurred in 6% of patients. Adverse reactions which required dosage interruption in >1 patient included increased alanine aminotransferase, increased aspartate aminotransferase, decreased lymphocyte count, muscular weakness, and aspiration pneumonia. Dose reductions of MODEYSO due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dose reductions in >1 patient included decreased neutrophil count and increased alanine aminotransferase. The most common adverse reactions (≥20%) were fatigue, headache, vomiting, nausea, and musculoskeletal pain. The most common (≥2%) Grade 3 or 4 laboratory abnormalities were decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. Adverse reactions that occurred in at least 10% of patients treated with MODEYSO are presented in Table 4. Table 4: Adverse Reactions (≥10%) in Patients with Glioma Who Received MODEYSO in ONC006, ONC013, ONC014, and ONC018 Adverse Reaction MODEYSO (N=376) All Grades (%) Grade 3 or 4 (%) General Disorders Fatigue a 34 3.2 Gait disturbance 16 3.7 Nervous System Disorders Headache b 32 4.3 Cranial nerve disorders c 16 1.3 Hemiparesis 15 4.5 Dysarthria 13 2.7 Dizziness 13 0.5 Ataxia 10 1.3 Gastrointestinal Disorders Vomiting 24 2.7 Nausea 24 0.8 Dysphagia 13 2.1 Constipation 11 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain d 20 2.9 Muscular weakness 13 4.5 Metabolism and Nutrition Disorders Hyperglycemia 12 0.8 Skin and Subcutaneous Tissue Disorders Rash e 11 0.8 a. Includes asthenia. b. Includes head discomfort and sinus headache. c. Includes accessory nerve disorder, auditory nerve disorder, facial nerve disorder, facial paralysis, facial paresis, glossopharyngeal nerve disorder, hypoglossal nerve disorder, IIIrd nerve disorder, IIIrd nerve paralysis, IVth nerve disorder, IVth nerve paralysis, tongue paralysis, trigeminal nerve disorder, trigeminal neuralgia, VIth nerve disorder, VIth nerve paralysis, and VIth nerve paresis. d. Includes back pain, pain in extremity, arthralgia, neck pain, non-cardiac chest pain, myalgia, bone pain, musculoskeletal chest pain, musculoskeletal stiffness, and spinal pain. e. Includes dermatitis, dermatitis acneiform, dermatitis bullous, eczema, erythema multiforme, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular. Other clinically important adverse reactions observed in less than 10% of patients treated with MODEYSO were peripheral neuropathy, seizure, diarrhea, tremor, and venous thromboembolic events. Selected laboratory abnormalities that occurred in at least 10% of patients treated with MODEYSO are presented in Table 5. Table 5: Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with Glioma Receiving MODEYSO in ONC006, ONC013, ONC014, and ONC018 Laboratory Abnormality a MODEYSO b All Grades (%) Grade 3 or 4 (%) Chemistry Alanine aminotransferase increased 28 2.4 Aspartate aminotransferase increased 22 0.9 Calcium decreased 20 2.7 Sodium decreased 14 0.3 Potassium decreased 13 0.3 Glucose decreased 11 0 Alkaline phosphatase increased 11 0.3 Hematology Hemoglobin decreased 25 0.6 Neutrophils decreased 24 1.5 Lymphocytes decreased 19 7 a. Severity as defined by the National Cancer Institute CTCAE Version 5.0. b. The denominator for each laboratory parameter is based on the number of patients with a baseline and post‑treatment laboratory value available, which ranged from 325 to 330 patients.

• CYP3A4 Inhibitors: Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO. If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the dose of MODEYSO as recommended. ( 2.5 , 7.1 )
• CYP3A4 Inducers: Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO. ( 7.1 )
• Drugs Known to Prolong QTc Interval: Avoid concomitant use of MODEYSO with products known to prolong the QTc interval. If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product. ( 5.2 , 7.2 , 12.2 ) 7.1 Effect of Other Drugs on MODEYSO Table 6 describes drug interactions where concomitant use of another drug affects MODEYSO. Table 6: Effect of Other Drugs on MODEYSO Strong and Moderate CYP3A4 Inhibitors Prevention or Management
• Avoid concomitant use of strong and moderate CYP3A4 inhibitors with MODEYSO.
• If concomitant use cannot be avoided for adults and pediatric patients who weigh at least 52.5 kg, reduce the MODEYSO dose as recommended [see Dosage and Administration ( 2.5 )] . Mechanism and Clinical Effects
• Dordaviprone is a CYP3A4 substrate.
• Strong and moderate CYP3A4 inhibitors increase dordaviprone exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of MODEYSO‑related adverse reactions [see Warnings and Precautions ( 5.2 )] . Strong or Moderate CYP3A4 Inducers Prevention or Management
• Avoid concomitant use of strong and moderate CYP3A4 inducers with MODEYSO . Mechanism and Clinical Effects
• Dordaviprone is a CYP3A4 substrate.
• Strong and moderate CYP3A4 inducers decrease dordaviprone exposure [see Clinical Pharmacology ( 12.3 )] , which may reduce the anti-tumor activity of MODEYSO. 7.2 Drugs Known to Prolong QTc Interval Table 7 describes drug interactions associated with QTc interval prolongation when used concomitantly with MODEYSO. Table 7: Products that Prolong QTc Interval Products that Prolong QTc Interval Prevention or Management
• Avoid concomitant use of MODEYSO with products known to prolong the QTc interval.
• If concomitant use cannot be avoided, separate administration of MODEYSO and the QT-prolonging product [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )] . Clinical Impact
• MODEYSO causes concentration dependent QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] .
• Concomitant use of MODEYSO with other QT-prolonging products may increase the risk of QTc-associated arrhythmias [see Warnings and Precautions ( 5.2 )] .

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action , MODEYSO can cause fetal harm when administered to a pregnant woman. There are no available data on MODEYSO use in pregnant women to inform a drug‑associated risk. In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose (see Data ). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, dordaviprone was administered orally to pregnant rats during the period of organogenesis from gestation day 7 to 17 at doses of 25, 62.5, and 125 mg/kg/day. Dordaviprone caused maternal mortality, pre-implantation loss, and embryo-fetal toxicity of absent eye and small renal papillae at the 125 mg/kg/day dose (≥2 times the human recommended doses based on body surface area). In an embryo-fetal development study, dordaviprone was administered orally to pregnant rabbits during the period of organogenesis from gestation days 7 to 19 at doses of 10, 25, 62.5, and 100 mg/kg/day.

Dordaviprone caused maternal mortality, embryo‑fetal mortality, lower fetal weights, and structural malformations of the face, limbs, vessels, brain, and heart at doses of ≥10 mg/kg/day (≥0.4 times the human exposure at the highest recommended dose based on C max ).

Pediatric Use The safety and effectiveness of MODEYSO has been established in pediatric patients aged 1 year and older for the treatment of diffuse midline glioma harboring an H3 K27M mutation . The efficacy of MODEYSO was evaluated in 4 pediatric patients aged 9 to 17 years with diffuse midline glioma harboring an H3 K27M mutation. Safety was evaluated in 154 pediatric patients with glioma aged 3 to 17 years who received MODEYSO at the recommended dose across four open‑label clinical studies (ONC006, ONC013, ONC014, and ONC018). Of these 154 patients, 73% were 3 to 11 years of age and 27% were 12 to 17 years of age. No additional safety signals were observed in pediatric patients . The exposure of dordaviprone in pediatric patients weighing 10 kg and higher is predicted to be within the range of exposures predicted in adults at the recommended dosage . The safety and effectiveness of MODEYSO have not been established in pediatric patients less than 1 year of age.