OJJAARA- momelotinib_tablet

Momelotinib is an inhibitor of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2 V617F Momelotinib inhibited STAT3 phosphorylation in whole blood from patients with MF. Maximal inhibition of STAT3 phosphorylation occurred 2 hours after momelotinib dosing and inhibition persisted for at least 6 hours [see Clinical Pharmacology ( 12. 1 [see Clinical Pharmacology ( 12. 1 Cardiac Electrophysiology Momelotinib did not prolong the QT interval to any clinically relevant extent at 4 times the highest recommended dosage of 200 mg. Momelotinib pharmacokinetic parameters are presented as mean (%CV) and were derived in patients with MF unless otherwise specified. The momelotinib steady-state C max max Absorption Median time to momelotinib C max max Effect of Food No clinically significant differences in momelotinib pharmacokinetics were observed following administration of either a high-fat meal (800 kcal; 50% fat) or low-fat meal (400 kcal; 20% fat) in healthy subjects. Distribution Momelotinib steady state apparent volume of distribution is 984 L (118%). Momelotinib plasma protein binding is approximately 91% in healthy volunteers. Elimination The elimination half-life of momelotinib and the M21 metabolite is 4 to 8 hours. Momelotinib clearance is 103 L/h (87%). Metabolism: M21 is an active human metabolite that has approximately 40% of the pharmacological activity of the parent. M21 is formed by CYP followed by aldehyde oxidase metabolism of momelotinib. The mean M21 to momelotinib ratio for AUC ranged from 1. Excretion: Specific Populations No clinically significant differences in momelotinib and M21 pharmacokinetics were observed based on age (range: 28 to 92 years), race (83% White, 6% Asian, 2% Black), sex (60% male), weight (range: 34 kg to 138 kg), renal impairment (eGFR: 16. 73 m 2 2 Patients with Hepatic Impairment: max max Drug Interaction Studies Clinical Studies OATP1B1/1B3 Inhibitors: max max BCRP Substrates: max Other Drugs: No clinically significant differences in the pharmacokinetics of a CYP3A4 substrate (midazolam) were observed when used concomitantly with momelotinib. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Momelotinib is a weak, reversible, time-independent inhibitor of CYP2B6 but does not inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, or 3A4/5. The M21 metabolite does not inhibit any of these CYP enzymes. Momelotinib and M21 do not induce CYP3A4, CYP2C8, CYP2C9, or P-glycoprotein (P-gp). Uridine diphosphate-glucuronosyltransferase (UGT): Momelotinib is an inhibitor of UGT1A1 and UGT1A9. The M21 metabolite is an inducer of UGT1A1. Transporter Systems: Momelotinib and M21 are substrates in vitro for efflux transporters, P-gp and BCRP, and hepatic uptake transporters, OATP1B1/1B3. Momelotinib is an inhibitor of BCRP.

OJJAARA is indicated for the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia. OJJAARA is a kinase inhibitor indicated for the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia.

3 The recommended dosage of OJJAARA is 200 mg orally once daily. OJJAARA may be taken with or without food. Swallow OJJAARA tablets whole. Do not cut, crush, or chew tablets. If a dose of OJJAARA is missed, the next scheduled dose should be taken the following day. Obtain the following blood tests prior to starting treatment with OJJAARA, periodically during treatment, and as clinically indicated: [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 The recommended starting dosage in patients with severe hepatic impairment (Child-Pugh Class C) is 150 mg orally once daily [see Use in Specific Populations ( 8. 6 Manage hematologic and non-hematologic adverse reactions as described in Table 1 Table 1: Dose Modifications for OJJAARA-Related Adverse Reactions ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal. a b c d e Thrombocytopenia Dose Modification a Baseline Platelet Count Platelet Count >=100 × 10 9 20 × 10 9 9 Reduce daily dose by 50 mg from the last given dose <20 × 10 9 Interrupt treatment until platelets recover to 50 × 10 9 Restart OJJAARA at a daily dose of 50 mg below the last given dose b >=50 × 10 9 9 <20 × 10 9 Interrupt treatment until platelets recover to 50 × 10 9 Restart OJJAARA at a daily dose of 50 mg below the last given dose b <50 × 10 9 <20 × 10 9 Interrupt treatment until platelets recover to baseline Restart OJJAARA at a daily dose of 50 mg below the last given dose b Neutropenia Dose Modification a Absolute neutrophil count (ANC) <0. 5 × 10 9 Interrupt treatment until ANC >=0. 75 × 10 9 Restart OJJAARA at a daily dose of 50 mg below the last given dose b Hepatotoxicity (unless other apparent causes) Dose Modification a ALT and/or AST >5 × ULN (or >5 × baseline, if baseline is abnormal) and/or total bilirubin >2 × ULN (or >2 × baseline, if baseline is abnormal) Interrupt treatment until AST and ALT <=2 × ULN or baseline c d Restart OJJAARA at a daily dose of 50 mg below the last given dose b If reoccurrence of ALT or AST elevations >5 × ULN, permanently discontinue OJJAARA Other Non-Hematologic Dose Modification a Grade 3 or higher e Interrupt treatment until the toxicity resolves to Grade 1 or lower (or baseline) Restart OJJAARA at a daily dose of 50 mg below the last given dose b Discontinue OJJAARA in patients unable to tolerate 100 mg once daily.

The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 The most common adverse reactions (>=20% in either study) are thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea. 1 To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OJJAARA was evaluated in 215 patients in 2 clinical trials (MOMENTUM and SIMPLIFY-1 anemic subgroup [hemoglobin (Hb) <10 g/dL]) [see Clinical Studies ( 14 MOMENTUM Patients in the MOMENTUM trial had been previously treated with a JAK inhibitor and were randomly assigned 2:1 to receive double-blind OJJAARA 200 mg orally once daily (n = 130) or danazol 300 mg orally twice daily (n = 65) for 24 weeks, after which they were eligible to receive open-label OJJAARA in an extended treatment phase. Among patients who received OJJAARA, 72% were exposed for 24 weeks or longer and 52% were exposed for 48 weeks or longer [see Clinical Studies ( 14 Serious adverse reactions occurred in 35% of patients who received OJJAARA during the randomized treatment period of the MOMENTUM trial; the most common serious adverse reactions (>=2%) included bacterial infection (8%), viral infection (5%), hemorrhage (4%), acute kidney injury (3%), pneumonia (3%), pyrexia (3%), thrombosis (3%), syncope (2%), thrombocytopenia (2%), and renal and urinary tract infection (2%). Fatal adverse reactions occurred in 12% of patients who received OJJAARA; the most common (>=2%) fatal adverse reaction was viral infection (5%). Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 18% of patients during the randomized treatment period of the MOMENTUM trial. Adverse reactions that resulted in permanent discontinuation (>=2%) included viral infection (2%) and thrombocytopenia (2%). Dosage reduction or treatment interruption due to an adverse reaction occurred in 34% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (>=2%) included thrombocytopenia (13%), bacterial infection (2%), diarrhea (2%), and neutropenia (2%). Among the 130 patients treated with OJJAARA during the randomized treatment period of MOMENTUM, the most common adverse reactions (>=20%) were thrombocytopenia, diarrhea, hemorrhage, and fatigue ( Table 2 Table 2: Adverse Reactions Occurring in >=5% of Patients Receiving OJJAARA during Randomized Treatment in MOMENTUM a b c d Adverse Reaction OJJAARA n = 130 Danazol a n = 65 All Grades b % Grade >=3 % All Grades % Grade >=3 % Thrombocytopenia c 28 22 17 12 Diarrhea c 22 0 9 2 Hemorrhage c 22 2 18 8 Fatigue c 21 2 20 5 Nausea c 16 2 9 3 Bacterial infection c,d 15 8 18 8 Abdominal pain c 13 1 18 3 Viral infection c,d 12 5 3 0 Pruritus c 11 2 11 0 Elevated liver enzymes c 10 2 9 3 Pyrexia c 10 2 8 0 Cough c 8 0 5 0 Paresthesia c 8 1 2 0 Dizziness c 8 2 2 0 Vomiting c 8 1 0 0 Rash c 6 0 11 0 Renal and urinary tract infection c,d 6 2 11 5 Arrhythmia c 5 1 6 2 Neutropenia 5 5 3 3 SIMPLIFY-1 Patients in the SIMPLIFY-1 trial were JAK inhibitor naïve and randomly assigned 1:1 to receive double-blind OJJAARA 200 mg orally once daily (n = 215) or ruxolitinib 5 to 20 mg orally twice daily (n = 217). Upon completion of the double-blind treatment phase, all patients were eligible to receive OJJAARA during the open-label phase. The safety of OJJAARA was evaluated in the population of patients with MF who were anemic at study entry. SIMPLIFY-1 enrolled 180 anemic patients who received OJJAARA (n = 85) or ruxolitinib (n = 95). Among these anemic patients who received OJJAARA, 78% were exposed for 24 weeks or longer and 61% were exposed for 48 weeks or longer [see Clinical Studies ( 14 Serious adverse reactions occurred in 28% of the anemic patients who received OJJAARA during the randomized treatment period of the SIMPLIFY-1 trial; the most common serious adverse reactions (>=2%) included bacterial infection (7%), pneumonia (6%), heart failure (4%) arrhythmia (2%), and respiratory failure (2%). A fatal adverse reaction (bacterial infection) occurred in 1 patient who received OJJAARA. Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 19% of the anemic patients during the randomized treatment period of the SIMPLIFY-1 trial. Adverse reactions that resulted in permanent discontinuation of OJJAARA (>=2%) included bacterial infection (2%), dizziness (2%), fatigue (2%), hypotension (2%), and thrombocytopenia (2%). Dosage reductions or treatment interruptions of OJJAARA due to an adverse reaction occurred in 21% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (>=2%) were thrombocytopenia (8%), pneumonia (4%), bacterial infection (2%), abdominal pain (2%), elevated liver enzymes (2%), and hypotension (2%). Among the 85 anemic patients treated with OJJAARA during the randomized treatment period of SIMPLIFY-1, the most common adverse reactions (>=20%) were dizziness, fatigue, bacterial infection, hemorrhage, thrombocytopenia, diarrhea, and nausea (). Table 3: Adverse Reactions Occurring in >=5% of Anemic Patients Receiving OJJAARA during Randomized Treatment in SIMPLIFY-1 a b c d Adverse Reactions OJJAARA n = 85 Baseline Hb <10 g/dL Ruxolitinib a n = 95 Baseline Hb <10 g/dL All Grades b % Grade >=3 % All Grades % Grade >=3 % Dizziness c 24 1 15 2 Fatigue c 22 0 25 1 Bacterial infection c,d 21 8 12 2 Hemorrhage c 21 1 18 2 Thrombocytopenia c 21 11 34 6 Diarrhea c 20 1 20 1 Nausea c 20 0 3 1 Abdominal pain c 18 1 14 1 Cough c 14 0 11 0 Hypotension c 14 2 0 0 Pain in extremity 12 0 5 0 Pyrexia c 12 1 11 0 Rash c 12 0 3 0 Renal and urinary tract infection c,d 12 1 4 0 Elevated liver enzymes c 11 4 9 0 Headache c 11 0 16 0 Peripheral edema 11 0 8 0 Arrhythmia c 8 2 2 1 Paresthesia c 8 0 3 0 Pneumonia c 8 8 5 3 Vomiting c 8 0 5 0 Back pain 7 1 2 0 Viral infection c,d 6 0 13 2 Vitamin B1 deficiency 6 0 7 0 Other Adverse Reactions Clinically relevant adverse reactions occurring in <5% of anemic patients in the MOMENTUM and SIMPLIFY-1 studies include: Eye Disorders: Infections and Infestations: Nervous System Disorders: Vascular Disorders:.

2 Risk Summary Available data on the use of OJJAARA in pregnant women are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. Based on animal reproduction studies conducted in rats and rabbits, momelotinib may cause embryo-fetal toxicity at exposures lower than the expected exposure in patients receiving 200 mg once daily (see ) The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 embryofetal developmental study, pregnant rabbits received momelotinib at 7. 5, 30 or 60 mg/kg/day orally during the period of organogenesis (Gestation Day 7 to 20). Momelotinib was associated with maternal toxicity at 60 mg/kg/day, which resulted in reduced mean fetal weight, delayed bone ossification, and an abortion at less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC). No developmental toxicity was observed at lower doses tested in rabbits. In a pre- and post-natal development study, pregnant rats received momelotinib 2, 6 or 12 mg/kg/day orally from organogenesis through lactation (Gestation Day 6 to lactation Day 20). Decreased pup body weights and embryo-lethality were observed in the dams administered 6 and 12 mg/kg/day. Pup survival was significantly reduced in the 12 mg/kg/day group from birth to Day 4 of lactation. Momelotinib exposure in dams at 12 mg/kg and 6 mg/kg were approximately 2 times the exposure at the recommended dose (based on combined momelotinib and M21 AUC). The exposure in dams at the No Observed Adverse Effect Level (NOAEL) dose of 2 mg/kg was less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC). Risk Summary There are no data on the presence of momelotinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether OJJAARA is excreted in human milk. Momelotinib was present in rat pups following nursing from treated dams with adverse effects observed in the offspring. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in a breastfed child, patients should not breastfeed during treatment with OJJAARA, and for at least 1 week after the last dose of OJJAARA. Data Animal Data: Contraception Advise females of reproductive potential who are not pregnant to use highly effective contraception during therapy and for at least 1 week after the last dose of OJJAARA. The safety and effectiveness of OJJAARA in pediatric patients have not been established. There were 275 patients aged 65 years and older in the clinical studies for MF [see Clinical Studies ( 14 The recommended starting dose of OJJAARA in patients with severe hepatic impairment (Child-Pugh C) is 150 mg orally once daily [see Dosage and Administration ( 2. 3 Momelotinib is extensively metabolized [see Clinical Pharmacology ( 12. 3 [see Clinical Pharmacology ( 12.

2 Organic Anion Transporting Polypeptide (OATP)1B1/B3 Inhibitors Momelotinib is an OATP1B1/B3 substrate. Concomitant use with an OATP1B1/B3 inhibitor increases momelotinib maximal concentrations (C max [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 4 Breast Cancer Resistance Protein (BCRP) Substrates Momelotinib is a BCRP inhibitor. OJJAARA may increase exposure of BCRP substrates , [see Clinical Pharmacology ( 12.

OVERDOSAGE
There is no known antidote for overdose with OJJAARA. If overdose is suspected, the patient should be monitored for signs or symptoms of adverse reactions or effects, and appropriate supportive treatment should be instituted immediately. Further management should be as clinically indicated. Hemodialysis is not expected to enhance the elimination of momelotinib.
NONCLINICAL TOXICOLOGY
The carcinogenicity potential of momelotinib was assessed in rasH2 Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay. In fertility studies in rats, momelotinib was administered for at least 70 days (males) and 14 days (females) prior to cohabitation and up to the implantation day (gestation Day 7) at doses of 5, 25, and 68 mg/kg/day. Momelotinib reduced sperm concentration and motility and reduced testes and seminal vesicle weights at 25 mg/kg/day or greater (approximately 13 times the recommended dose based on combined momelotinib and M21 AUC) leading to reduced fertility at 68 mg/kg/day. In females, momelotinib reduced ovarian function (reproductive cycles and ovulation) at 68 mg/kg/day and decreased the number of pregnant females and increased pre- and post-implantation loss with most pregnant rats having total litter loss at 25 mg/kg/day or greater. Exposures at the NOAEL in male and female rats at 5 mg/kg/day are approximately 3-times the recommended dose (based on combined momelotinib and M21 AUC).
CLINICAL STUDIES
The efficacy of OJJAARA in the treatment of adults with intermediate 1, intermediate 2, or high-risk MF, including primary MF, post-PV MF or post-ET MF, as defined by the Dynamic International Prognostic Scoring System (DIPSS) or International Prognostic Scoring System (IPSS) for MF, was established in the MOMENTUM trial and in a subpopulation of adults with anemia in the SIMPLIFY-1 trial. All patients received a starting dosage of OJJAARA 200 mg once daily. Eligible patients had baseline platelet count of >=25 × 10 9 9 MOMENTUM MOMENTUM (NCT04173494) was a double-blind, 2:1 randomized, active-controlled trial in 195 symptomatic and anemic adults with MF who had previously received an approved JAK inhibitor therapy. Patients were treated with OJJAARA 200 mg once daily or danazol 300 mg twice daily for 24 weeks, then switched to open-label treatment with OJJAARA. The median age was 71 years (range 38 to 86 years) with 79% of patients aged 65 years and older, and 63% of patients were male. Overall, 81% of patients were White, 9% of patients were Asian, 2% of patients were Black, and 6% of patients were Hispanic or Latino. Sixty-four percent of patients had primary MF, 19% had post-PV MF, and 17% had post-ET MF. Five percent of patients had intermediate-1 risk, 57% had intermediate-2 risk, and 35% had high-risk disease. Within the 8 weeks prior to treatment, 79% of patients had received red blood cell (RBC) transfusions (median of 4 RBC units; interquartile range: 1-6). At baseline, 13% and 15% of patients were transfusion independent (defined as no red blood cell transfusions in the 12 weeks before the first dose and Hb >=8 g/dL) in the OJJAARA and danazol groups, respectively. The baseline median Hb count was 8 g/dL and the median platelet count was 96 × 10 9 9 9 3 3 3 Symptoms were measured using the Myelofibrosis Symptom Assessment Form (MFSAF v4. The MFSAF v4. 0 patient diary, completed throughout the randomized treatment period, captured the core symptoms of MF: fatigue (weariness and tiredness), night sweats (or feeling hot or flushed), itching, abdominal discomfort (feeling pressure or bloating), pain under ribs on left side, feeling of fullness after beginning to eat, and bone pain. For each item, symptom scores, ranging from 0 (absent) to 10 (worst imaginable), were added to create a daily Total Symptom Score (maximum score of 70). At baseline, the mean MFSAF v4. 0 Total Symptom Score was 28 in the OJJAARA group and 26 in the danazol group. The efficacy of OJJAARA in the treatment of patients with primary or secondary MF and anemia was established based on a significantly higher percentage of patients treated with OJJAARA compared to danazol achieving a MFSAF v4. 0 Total Symptom Score reduction of 50% or more at Week 24 compared with their own baseline score ( Table 4 Table 4: Percent of Patients Achieving Symptom Reduction, Transfusion Independence, and Spleen Volume Reduction at Week 24 in MOMENTUM OJJAARA n = 130 Danazol n = 65 p-value a b c d Patients with MFSAF v4. 0 Total Symptom Score Reduction of 50% or more, n (%) 32 (25%) 6 (9%) <0. 01 Treatment difference a (95% CI) 16% (6, 26) Patients with Transfusion Independence (no transfusion or Hb <8 g/dL between Weeks 12 and 24), n (%) 39 (30%) 13 (20%) 0. 023 Non-inferiority treatment difference a, b (95% CI) 14% (2, 25) Patients with Spleen Volume Reduction by 25% or More, n (%) 51 (39%) 4 (6%) <0. 0001 Treatment difference a (95% CI) 33% (23, 44) MFSAF v4. 0 Total Symptom Score Change from Baseline b -9. 001 Treatment difference c (95% CI) -6. 4) Patients with Spleen Volume Reduction by 35% or More, n (%) 29 (22%) 2 (3%) 0. 001 Treatment difference a (95% CI) 18% (10, 27) Patients with No Transfusions c, d 46 (35%) 11 (17%) 0. 001 Treatment difference a (95% CI) 17% (8, 26) shows the percentage of patients treated with OJJAARA and danazol who achieved a 50% or greater reduction from baseline for each individual symptom in the MFSAF v4. Figure 1: Percent of Patients Achieving a 50% or Greater Reduction in Individual MFSAF v4. 0 Symptom Scores at Week 24 a QD = once daily; BID = twice a day. a SIMPLIFY-1 SIMPLIFY-1 (NCT01969838) was a double-blind, randomized, active-controlled trial in 432 adults with MF who had not previously received a JAK inhibitor. Patients were treated with OJJAARA 200 mg once daily or ruxolitinib adjusted dose twice daily for 24 weeks. Patients were eligible to switch to open-label OJJAARA after 24 weeks (without tapering of the JAK inhibitor received during the randomization period). The baseline characteristics and efficacy results provided are for the subset of patients who had anemia (Hb <10 g/dL) at baseline (n = 181). The median age was 68 years (range 25 to 86 years) with 67% of patients aged 65 years and older, and 59% of patients were male. Eighty-one percent of patients were White, 8% of patients were Asian, 1% of patients were Black, and 2% of patients were Hispanic or Latino. Sixty-three percent of patients had primary MF, 13% had post-PV MF, and 24% had post-ET MF. Four percent of patients had intermediate-1 risk, 25% had intermediate-2 risk, and 71% had high-risk disease. At baseline, 29% and 44% of patients were transfusion independent in the groups treated with OJJAARA or ruxolitinib, respectively. The baseline median Hb measurement was 8. 8 g/dL and the median platelet count was 193 × 10 9 9 9 3 3 3 The efficacy of OJJAARA in the treatment of patients with MF in SIMPLIFY-1 was based on spleen volume response (reduction by 35% or greater). A numerically lower percent of patients treated with OJJAARA (25%) achieved a Total Symptom Score reduction of 50% or more at Week 24 compared with ruxolitinib (36%). The spleen volume reduction results are presented in Table 5 Table 5: Percent of Patients a a OJJAARA n = 86 Ruxolitinib n = 95 Patients with Spleen Volume Reduction by 35% or More, n (%) (95% CI) 27 (31. 0) shows the percent change from baseline in spleen volume for each patient at Week 24 in SIMPLIFY-1. Figure 2: Percent Change from Baseline in Spleen Volume for Each Patient at Week 24 in SIMPLIFY-1 a, b a b Figure 1 Figure 2.

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