Summary Basis of Decision for Ojjaara

Clinical Pharmacology

Momelotinib and its major human circulating metabolite M21, are inhibitors of wild type Janus kinase 1 and 2 (JAK1 and JAK2) and mutant JAK2^V617F, which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Janus kinase 1 and JAK2 recruit and activate signal transducer and activator of transcription (STAT) proteins that control gene transcription impacting inflammation, hematopoiesis, and immune regulation.

Myelofibrosis is a myeloproliferative neoplasm associated with constitutive activation and dysregulated Janus kinase signaling that contributes to elevated inflammation and hyperactivation of activin A receptor type 1 (ACVR1), also known as activin receptor‑like kinase 2 (ALK‑2). Momelotinib and M21 additionally inhibit ACVR1, which further down regulates liver hepcidin expression resulting in increased iron availability and red blood cell production. Momelotinib and M21 potentially inhibit additional kinases, such as other JAK family members, inhibitor of κB kinases, or interleukin-1 receptor-associated kinase 1, among others.

Pharmacodynamics

Momelotinib inhibits cytokine‑induced STAT3 phosphorylation in whole blood from subjects with myelofibrosis with maximal inhibition occurring 2 hours after momelotinib dosing and inhibition persisting for at least 6 hours. Momelotinib did not prolong the QT interval to any clinically relevant extent at a clinical dose of 800 mg (4 times the highest recommended clinical dosage of 200 mg).

Pharmacokinetics

At a dose of 200 mg once daily at steady‑state, the mean maximum concentration of momelotinib in plasma was 479 ng/mL (61%) and the area under the concentration‑time curve (AUC) was 3,288 ng·h/mL (60%) in subjects with myelofibrosis. Momelotinib was rapidly absorbed with a median time to maximum plasma concentration of 1.8 hours. Momelotinib steady‑state apparent volume of distribution was 984 L (118%). Momelotinib plasma protein binding was approximately 91% in healthy volunteers. The elimination half‑life of momelotinib and M21 was 4 to 7 hours. Momelotinib clearance was 103 L/h (87%).

Drug-Drug Interactions

Effect of drugs on momelotinib

Coadministration of momelotinib with strong inducers of cytochrome P450 (CYP) 3A4 (CYP3A4) enzymes may lead to a decreased momelotinib exposure and consequently a risk of reduced efficacy. Monitoring of the clinical signs and symptoms of myelofibrosis is recommended.

Coadministration of momelotinib with inhibitors of the organic anion transporting polypeptides OATP1B1 or OATP1B3, increases momelotinib exposure, which may increase the risk of adverse reactions. As such, additional monitoring is advised and dose modifications of Ojjaara should be considered based on adverse reactions.

Effect of momelotinib on other drugs

Momelotinib may increase the exposure of sensitive breast cancer resistance protein (BCRP) substrates, which may increase the risk of adverse reactions to these drugs. Additional monitoring is advised and dose modifications of sensitive BCRP substrates should be considered, based on adverse reactions. Whenever possible, alternative medications to sensitive BCRP substrate should be considered.

Given uncertainties whether momelotinib may reduce the effectiveness of hormonal contraceptives, women using hormonal contraceptives should add a barrier method during treatment and for at least one week after the last dose of Ojjaara.

Special Populations

Dose modification is recommended for patients with severe hepatic impairment (Child‑Pugh Class C) as momelotinib AUC is increased by 97% compared with subjects with normal hepatic function. The recommended starting dose of momelotinib is 150 mg once daily in patients with severe hepatic impairment. Dose modification is not needed for patients with moderate or severe renal impairment (estimated glomerular filtration rate 15 to 59 mL/min/1.73 m²). There are no data in patients with end‑stage renal disease receiving dialysis.

For further details, please refer to the Ojjaara Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The market authorization of Ojjaara for the treatment of patients with myelofibrosis was based on two pivotal Phase III studies, SIMPLIFY 1 and MOMENTUM. Efficacy data from the two pivotal studies were not integrated due to differences in prior Janus kinase inhibitor treatment and the comparators studied. The MOMENTUM study provided the pivotal efficacy data to support the use of Ojjaara in patients with moderate to severe anemia who had previously been treated with a Janus kinase inhibitor. The supporting evidence for Ojjaara in the Janus kinase inhibitor‑naïve setting was derived from post‑hoc analysis in the anemic subpopulation (hemoglobin less than 10 g/dL) in the SIMPLIFY-1 study.

The MOMENTUM Study

This trial was a double‑blind, randomized, active‑controlled study conducted in 195 symptomatic myelofibrosis subjects with anemia who had previously been treated with an approved Janus kinase inhibitor agent. Eligible subjects were required to have enlarged spleen at baseline, a Myelofibrosis Symptom Assessment Form [MFSAF] total symptom score of 10 units or higher, hemoglobin values less than 10 g/dL, and a minimum baseline platelet count of 25 × 10⁹/L. Subjects with an active uncontrolled infection were excluded from the study.

Subjects were randomized in a 2:1 ratio to receive either Ojjaara 200 mg once daily (number of subjects [n] = 130) or danazol 300 mg twice daily (n = 65) for 24 weeks. After 24 weeks, subjects on the danazol arm were permitted to switch to momelotinib; all subjects who entered the open‑label treatment period received Ojjaara. Randomization was stratified by baseline MFSAF total symptom score (less than 22 versus [vs.] 22 or higher), baseline palpable spleen length below the left costal margin (less than 12 cm vs. 12 cm or larger), and baseline red blood cell or whole blood units transfused in the 8‑weeks before randomization (0, 1 to 4, or 5 or more units).

The co‑primary efficacy endpoints were the proportion of subjects achieving a 50% or greater reduction from baseline in MFSAF total symptom score at Week 24 (MFSAF total symptom score response rate) and the proportion of subjects with transfusion independence at Week 24. The main secondary endpoint was the splenic response rate (SRR) at Week 24 defined as the proportion of subjects who had a spleen volume reduction of 25% or greater from baseline to Week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT) scan.

Symptoms were assessed using an MFSAF diary, which captured the core symptoms of myelofibrosis such as fatigue, night sweats, pruritus, abdominal discomfort, pain under ribs on left side, early satiety, and bone pain. Prior to randomization (baseline and during the randomized treatment period, each subject maintained a daily MFSAF diary in which the subject assigned a score ranging from 0 (absent) to 10 (worst imaginable) to each core symptom. Then, each symptom score was added together to yield a daily total symptom score with a maximum score of 70. At baseline, the mean MFSAF total symptom score was 28 in the Ojjaara group and 26 in the danazol group.

All recruited subjects previously received Janus kinase inhibitor therapy; the median duration of treatment in the total population (N = 165) was 99 weeks. The median age was 71 years (age range: 38 to 86 years), with 79% of the subjects aged 65 years and older. Most subjects were white (81%) and 63% were male. Sixty-four percent (64%) of subjects had primary myelofibrosis, 19% had post‑polycythemia vera myelofibrosis, and 17% had post‑essential thrombocythemia myelofibrosis. Five percent (5%) of subjects had intermediate‑1 risk, 57% had intermediate‑2 risk, and 35% had high‑risk disease as defined by the Dynamic International Prognostic Scoring System for myelofibrosis. Within the 8 weeks prior to treatment, 79% of subjects had red blood cell transfusions. At baseline, 13% and 15% of subjects were transfusion independent (defined as no red blood cell transfusions in the 12 weeks before the first dose and hemoglobin 8 g/dL or higher) in the Ojjaara and danazol groups, respectively. The baseline median hemoglobin score was 8 g/dL and the median platelet count was 96 × 10⁹/L (range: 24 × 10⁹/L to 733 × 10⁹/L). The baseline median palpable spleen length was 11.0 cm below the left costal margin; the median central spleen volume (measured by MRI or CT) was 2,105 cm³ (range: 610 cm³ to 9,717 cm³).

After 24 weeks of treatment, study results showed that Ojjaara was superior to danazol in reducing MFSAF total symptom score by at least 50% (25% Ojjaara vs. 9% danazol, p = 0.0095), and non‑inferior in improving the transfusion independence rate (30% Ojjaara vs. 20% danazol, p = 0.012). Ojjaara was also superior to danazol in terms of the splenic response rate, with 39% of Ojjaara‑treated subjects showing a spleen volume reduction of 25% or greater compared to 6% of danazol‑treated subjects (p <0.0001).

The SIMPLIFY-1 Study

The SIMPLIFY‑1 trial was a double‑blind, randomized, active‑controlled study. A total of 432 adult subjects who were Janus kinase inhibitor‑naïve were randomly assigned in a 1:1 ratio to receive either Ojjaara 200 mg once daily (n = 215) or ruxolitinib (adjusted dose) twice daily (n = 217) for 24 weeks. Upon completion of the double‑blind treatment phase, subjects in the ruxolitinib group were allowed to switch to Ojjaara during an open‑label period. Eligible subjects were required to have an enlarged spleen at baseline and, a minimum baseline platelet count of 50 × 10⁹/L. Subjects with active uncontrolled infection, or previously treated with JAK inhibitors were excluded from the study. Randomization was stratified by transfusion dependence (yes or no) and platelet count (<100 × 10⁹/L, ≥100 × 10⁹/L and ≤200 × 10⁹/L, or >200 × 10⁹/L). Post‑hoc analyses were conducted in a subgroup of 181 subjects with anemia (hemoglobin less than 10 g/dL).

The primary efficacy endpoint was the percentage of subjects who had a spleen volume reduction of 35% or greater from baseline to Week 24. Secondary endpoints included modified MFSAF total symptom score response rate at Week 24 (defined as the percentage of subjects with total symptom score reduction of 50% or greater from baseline to Week 24) and transfusion independence at Week 24 (defined as no transfusions and all hemoglobin values 8 g/dL or higher in the 12 weeks prior to Week 24).

The subject’s total symptom score response was measured by having subjects maintain an MFSAF total symptom score diary. The inactivity item was excluded from the total symptom score calculation.

In the anemic subgroup, the median age was 68 years (age range: 25 to 86 years) with 67% of subjects 65 years and older. Eighty‑one percent of subjects were white and 59% of subjects were male. Sixty‑three percent of subjects had primary myelofibrosis, 13% had post‑polycythemia vera myelofibrosis, and 24% had post‑essential thrombocythemia myelofibrosis. Four percent (4%) of subjects had intermediate‑1 risk, 25% had intermediate‑2 risk, and 71% had high‑risk disease, determined by the International Prognostic Scoring System. In this study, 42% of subjects had moderate to severe anemia (defined as baseline hemoglobin values less than 10 g/dL). Within the 8 weeks prior to enrollment, 55% of subjects had red blood cell transfusions. At baseline, 29% and 44% of subjects treated with Ojjaara or ruxolitinib, respectively, were transfusion independent. The baseline median hemoglobin measurement was 8.8 g/dL (range 6 g/dL to 10 g/dL) and the median platelet count was 193 × 10⁹/L (range 54 × 10⁹/L to 2,865 × 10⁹/L). At baseline, the median spleen volume at baseline (measured by MRI or CT) was 1,843 cm³ (range: 352 cm³ to 9,022 cm³). The baseline characteristics of the overall population were similar to the anemic subgroup, with the exception of anemia severity and transfusion requirements.

The results from the SIMPLIFY‑1 study demonstrated that Ojjaara was non‑inferior to ruxolitinib for splenic response rate in the overall population, with 26.5% of subjects in the Ojjaara group having a spleen volume reduction of 35% or greater at Week 24 compared to 29.5% in the ruxolitinib group (p = 0.014). Likewise, in the anemic subpopulation a similar proportion of subjects achieved a spleen volume reduction by 35% or more (31% Ojjaara versus 33% ruxolitinib). In this subgroup, Ojjaara was also nominally superior in transfusion independence rate over the 24 week period, with 47% of subjects treated with Ojjaara achieving or maintaining transfusion independence compared to 27% of subjects treated with ruxolitinib. However, a lower percent of anemic subjects treated with Ojjaara (25%) achieved a reduction of 50% or greater in total symptom score at Week 24, compared with ruxolitinib (36%).

Indication

The New Drug Submission for Ojjaara was filed by the sponsor with the following proposed indication:

Ojjaara is indicated for the treatment of disease‑related splenomegaly or symptoms, and anemia in adult subjects with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Kinase (JAK) inhibitor naïve or have been treated with a JAK inhibitor.

Health Canada approved the following indication:

Ojjaara (momelotinib) is indicated for the treatment of splenomegaly and/or disease related symptoms, in adult patients with intermediate or high‑risk: primary myelofibrosis, post‑polycythemia vera myelofibrosis or post‑essential thrombocythemia myelofibrosis, who have moderate to severe anemia.

The proposed indication was modified to reflect the patient population enrolled in the pivotal clinical trials, and the efficacy claims supported by the clinical data. In addition, the modified indication aligns with those of other JAK inhibitors used to treat myelofibrosis in Canada.

For more information, refer to the Ojjaara Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Ojjaara is based on pooled data from 448 subjects with myelofibrosis treated with Ojjaara during the randomized treatment period of the Phase III clinical studies SIMPLIFY‑1, MOMENTUM, and a supportive study SIMPLIFY‑2. Across these three studies, the median duration of Ojjaara exposure was 23.9 weeks, and the median dose was 187.5 mg (93.8% dose intensity).

The majority of subjects (94%) treated with Ojjaara reported a treatment‑emergent adverse event. However, one issue in the safety analysis is the overlap of several myelofibrosis signs and symptoms, such as thrombocytopenia, infections, and hemorrhage with adverse events reported in the studies. This complicated any causality assessment, especially in the absence of a placebo arm. Therefore, most adverse events with a frequency of 5% or higher were considered as possible adverse drug reactions, unless the event was also frequently observed in the comparator arm (suggesting it is common in the enrolled population) or not consistent with the mechanism of action of Ojjaara.

In general, the incidence of adverse events increased in subjects with worse prognostic factors (65 years and older, higher‑risk disease, low hemoglobin, or low platelet counts at baseline), but the differences were not clinically relevant.

The incidence of adverse drug reactions was reported after pooling similar terms to avoid diluting the true effect. The most frequent adverse drug reactions with an incidence rate of 15% or higher were: fatigue (25%), diarrhea (23%), thrombocytopenia (21%), abdominal pain (17%), bacterial infection (17%), dizziness (17%), and nausea (17%). In general, gastrointestinal toxicity was more frequent in Ojjaara‑treated subjects than subjects treated with either ruxolitinib or danazol.

Adverse events categorized as Grade 3 or higher were reported in 46.2% of the subjects, but only thrombocytopenia (12%) and bacterial infection (6.7%) showed a frequency higher than 5%. Severe cases of anemia were also reported in 8.5% of subjects, but anemia was not considered as an adverse drug reaction. Adverse events resulting in permanent discontinuation or treatment modification, occurred in 16.1% and 22.3% of the population. Thrombocytopenia was the most commonly reported severe adverse drug reaction leading to treatment cessation (2.5%), or modification (7.8%).

Serious adverse events were reported in 29% of subjects treated with Ojjaara. The most common serious adverse drug reactions were bacterial infection (6.0%) and pneumonia (3%). A total of 29 fatal events occurred during the randomized treatment period. For at least 8 fatal cases (6 of them coronavirus disease 19 [COVID‑19] related), a possible association with Ojjaara treatment could not be ruled out.

Conclusion

Overall, the safety profile of Ojjaara is comparable with that of other Janus kinase inhibitors, including the risk of serious infections, thrombocytopenia, neutropenia, and hepatotoxicity (mainly presented as transient increases in liver enzymes). Low grade peripheral neuropathy seems to be unique to Ojjaara and was included in the Ojjaara Product Monograph. Due to the short period of exposure or the lower number of cases reported during the randomized treatment period, the risk for major adverse cardiac events, thrombosis, and malignancies, risks reported for other Janus kinase inhibitors, cannot be ruled out.

The risks associated with Ojjaara treatment can be mitigated with frequent monitoring (e.g., laboratory assessments performed before initiating treatment with Ojjaara, periodically during treatment, and as clinically indicated), dose modifications or treatment interruption. These risks are acceptable in the context of this serious and life‑threatening disease.

For more information, refer to the Ojjaara Product Monograph, approved by Health Canada and available through the Drug Product Database.

Momelotinib is an inhibitor of both Janus kinase 1 and 2 (JAK1 and JAK2), the myeloproliferative neoplasm-associated JAK2^V617F mutant, and activin A receptor type 1 (ACVR1). Compared with momelotinib, the major human circulating metabolite, M21, was active but less potent on JAK1, JAK2, and ACVR1, whereas the minor human circulating metabolite, M19, was relatively inactive.

Momelotinib was metabolized by multiple cytochrome P450 (CYP) enzymes (including CYP3A4, CYP2C8, CYP2C19, CYP2C9, and CYP1A2). The M21 metabolite has approximately 40% of the pharmacological activity of the parent drug; it is formed by CYP followed by aldehyde oxidase metabolism of momelotinib. The mean M21 to momelotinib ratio based on the area under the concentration‑time curve (AUC) was 1.4 to 2.1. Momelotinib was mainly eliminated through metabolism and then excreted via feces. Following a single oral dose of radiolabeled momelotinib, 69% (13% unchanged) of radioactivity was excreted via feces and 28% (less than 1% unchanged) in urine. Approximately 12% of the administered dose was excreted in urine as M21.

Toxicologic findings in repeat‑dose rat (up to 26 weeks) and dog (up to 39 weeks) studies included reduced red cell mass and lower white blood cell count correlated with dose related cellular depletion in the bone marrow and lymphoid depletion in the spleen, lymph node, thymus, and/or gut‑associated lymphoid tissue. Recovery was noted but incomplete upon cessation of dosing. During ophthalmoscopic examination in dogs, non‑reversible cataracts (unilateral or bilateral) were observed after 39 weeks at an exposure 2.8‑times the anticipated human exposure at the recommended dose of 200 mg administered once daily (QD). Momelotinib affected cardiovascular parameters in dogs (decreased mean arterial blood pressure and increased heart rate) at exposure approximately 4‑fold above the estimated free drug maximum concentration (C_max) in humans receiving the recommended dose of 200 mg QD.

No evidence of tumorigenicity in rasH2 transgenic mice that received momelotinib at doses up to 100 mg/kg/day for 26 weeks. In a two‑year oral carcinogenicity study in Sprague‑Dawley rats, momelotinib caused benign Leydig cell tumors at an exposure 17‑times the recommended dose of 200 mg QD; however, it was considered related to a rat‑specific phenomenon. Momelotinib was not mutagenic or clastogenic. Momelotinib is not considered to be phototoxic.

In male rats, momelotinib reduced sperm concentration and motility and reduced testes and seminal vesicle weight. In female rats, momelotinib reduced ovarian function, decreased the number of pregnant females and increased pre‑ and post‑implantation loss. Exposures at the no‑observed‑adverse‑effect level (NOAEL) in male and female rats were approximately three‑times the exposure at the recommended dose of 200 mg QD. The administration of momelotinib to rats and rabbits during organogenesis caused maternal toxicity and was associated with increased embryonic death, reduced fetal weight, and an increased incidence of fetal anomalies. No development toxicity was observed in rats at exposures equivalent to the human recommended dose of 200 mg QD and in rabbits at exposures less than the recommended dose of 200 mg QD. In a development study in rats, pup survival was significantly reduced from birth to Day 4 of lactation at an exposure approximately two times the exposure of the recommended dose of 200 mg QD and considered a direct effect of momelotinib via exposure through the milk.

For more information, refer to the Ojjaara Product Monograph, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Ojjaara has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at 15 ºC to 30 ºC in the original bottle and protected from moisture.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy.)

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

One excipient in the drug product, lactose monohydrate, is of animal origin. The milk used in the manufacture of the lactose monohydrate component is sourced from healthy animals under the same conditions as those used to collect milk for human consumption. A statement confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this drug product indicating that it is considered to be safe for human use.