Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: GlaxoSmithKline Trading Services Limited, 12 Riverwalk, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
Momelotinib and its major human circulating metabolite (M21), are inhibitors of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F, which contribute to signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. JAK1 and JAK2 recruit and activate STAT (signal transducer and activator of transcription) proteins that control gene transcription impacting inflammation, haematopoiesis, and immune regulation. Myelofibrosis is a myeloproliferative neoplasm associated with constitutive activation and dysregulated JAK signalling that contributes to elevated inflammation and hyperactivation of activin A receptor type 1 (ACVR1), also known as activin receptor-like kinase 2 (ALK-2). Additionally, momelotinib and M21 are direct inhibitors of 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 kinase (IKK), interleukin-1 receptor-associated kinase 1 (IRAK1), and others.
Momelotinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis and inhibits hepcidin. Maximal inhibition of STAT3 phosphorylation occurred 2 hours after momelotinib dosing with inhibition persisting for at least 6 hours. An acute and sustained reduction of circulating hepcidin was observed for the duration of the 24-week study, associated with increased iron levels and haemoglobin, following administration of momelotinib to patients with myelofibrosis.
The efficacy of momelotinib in the treatment of patients with myelofibrosis was evaluated in two randomised Phase 3 trials, MOMENTUM and SIMPLIFY-1.
MOMENTUM was a double-blind, 2:1 randomised, active-controlled Phase 3 study in 195 symptomatic and anaemic patients with myelofibrosis who had previously received a JAK inhibitor. All patients had received ruxolitinib and 3.6% of patients had also received fedratinib; prior JAK inhibitor treatment was for ≥90 days or ≥28 days if therapy was interrupted by the need for red blood cell transfusions or due to Grade 3 or 4 thrombocytopenia, anaemia, or haematoma. Patients were treated with Omjjara 200 mg once daily or danazol 300 mg twice daily for 24 weeks, followed by open-label treatment with Omjjara. The two primary efficacy endpoints were percentage of patients with total symptom score (TSS) reduction of 50% or greater from baseline to week 24 (as measured by the Myelofibrosis Symptom Assessment Form [MFSAF] v4.0), and the percentage of patients who were transfusion independent (TI) at week 24 (defined as no transfusions and all haemoglobin values ≥8 g/dL in the 12 weeks prior to week 24). A key secondary endpoint measured the percentage of subjects with ≥35% reduction in spleen volume from baseline at week 24.
Per eligibility criteria, patients were symptomatic with a MFSAF TSS of ≥10 points at screening (mean MFSAF TSS 27 at baseline), and anaemic with haemoglobin (Hgb) values <10 g/dL. The MFSAF daily diary captured the core symptoms of MF: night sweats, abdominal discomfort, pain under the left rib, fatigue, early satiety, pruritus, and bone pain. The inactivity item was excluded from the TSS calculation. Each of the symptoms of the MFSAF v.4.0 were measured on a scale of 0 (absent) to 10 (worst imaginable). Eligible patients were also required to have an enlarged spleen at baseline and a minimum baseline platelet count of 25 × 109/L.
Patients had received prior JAK inhibitor therapy for a median duration of 99 weeks. The median age was 71 years (range 38 to 86 years); 79% were 65 years or older, and 31% were aged 75 years or older, and 63% were male. Sixty-four percent (64%) of patients had primary myelofibrosis, 19% had post-PV myelofibrosis, and 17% had post-ET myelofibrosis. Five percent (5%) of patients had intermediate-1 risk, and 57% had intermediate-2 risk, and 35% had high-risk disease, determined by the Dynamic International Prognostic Scoring System (DIPSS). Sixteen percent (16%) of patients had severe thrombocytopenia (defined as platelet values of less than 50 × 109/L). Forty-eight percent (48%) of patients had severe anaemia (defined as baseline Hgb values <8 g/dL). Within the 8 weeks prior to enrolment, 79% had red blood cell transfusions. At baseline, 13% and 15% of patients treated with Omjjara and danazol, respectively, were transfusion independent (no transfusions and all haemoglobin values ≥8 g/dL in the 12 weeks prior to dosing). The baseline median Hgb value was 8.0 g/dL (range 3.8 g/dL to 10.7 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 spleen volume (measured by magnetic resonance imaging [MRI] or computed tomography [CT])] was 2105 cm³ (range 609 to 9717 cm³).
At week 24, a significantly higher percentage of patients treated with Omjjara achieved a TSS reduction of 50% or greater from baseline (superiority, one of the primary endpoints) and a spleen volume reduction by 35% or greater from baseline (superiority, one of the secondary endpoints) (table 3).
Table 3. Percent of patients achieving symptom reduction and spleen volume reduction at week 24 (MOMENTUM):
| Omjjara n=130 | Danazol n=65 | |
|---|---|---|
| Patients with TSS reduction of 50% or greater, n (%) | 32 (25%) | 6 (9%) |
| Treatment differencea (95% CI) | 16% (6, 26) | |
| p-value (superiority) | 0.0095 | |
| Patients with spleen volume reduction by 35% or greater, n (%) | 29 (22%) | 2 (3%) |
| Treatment differencea (95% CI) | 18% (10, 27) | |
| p-value (superiority) | 0.0011 | |
TSS = total symptom score; CI = confidence interval.
a Superiority based on a stratified Cochran-Mantel-Haenszel test.
A numerically higher percent of patients treated with Omjjara (30%; 39/130) achieved transfusion independence (defined as no transfusions and all Hgb values ≥8 g/dL in the 12 weeks prior to week 24) compared with 20% (13/65) for danazol at week 24.
SIMPLIFY-1 was a double-blind, randomised, active-controlled study in 432 patients with myelofibrosis who had not previously received a JAK inhibitor. Post-hoc analyses were conducted in a subgroup of 181 patients with moderate to severe anaemia (Hgb <10 g/dL). The baseline characteristics and efficacy results are provided for this subgroup.
In the overall population, the primary efficacy endpoint was percentage of patients with spleen volume response (reduction by 35% or greater) at week 24. Secondary endpoints included modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) TSS response rate at week 24 (defined as the percentage of patients with TSS reduction of 50% or greater from baseline to week 24) and transfusion independence at week 24 (defined as no transfusions and all Hgb values ≥8 g/dL in the 12 weeks prior to week 24).
Per eligibility criteria, patient TSS response was measured by the modified MPN-SAF v2.0 diary (mean MPN-SAF TSS 19 at baseline). The inactivity item was excluded from the TSS calculation. Eligible patients were also required to have an enlarged spleen at baseline and a minimum baseline platelet count of 50 × 109/L.
In the anaemic subgroup, the median age was 68 years (range 25 to 86 years) with 67% of patients older than 65 years, and 19% were aged 75 years or older, and 59% male. Sixty-three percent (63%) of patients had primary myelofibrosis, 13% had post-PV myelofibrosis, and 24% had post-ET myelofibrosis. Four percent (4%) of patients had intermediate-1 risk, and 25% had intermediate-2 risk, and 71% had high-risk disease, determined by the International Prognostic Scoring System (IPSS). In this study, 42% of patients had moderate to severe anaemia (defined as baseline Hgb values <10 g/dL). Within the 8 weeks prior to enrolment, 55% of patients had red blood cell transfusions. At baseline, 29% and 44% of patients treated with Omjjara and ruxolitinib, respectively, were transfusion independent (no transfusions and all haemoglobin values ≥8 g/dL in the 12 weeks prior to dosing). The baseline median Hgb value was 8.8 g/dL (range 6 g/dL to 10 g/dL), and the median platelet count was 193 × 109/L at baseline (range 54 × 109/L to 2865 × 109/L). The baseline median palpable spleen length was 12.0 cm below the left costal margin; the median spleen volume (measured by MRI or CT) was 1843 cm³ (range 352 to 9022 cm³). The baseline characteristics of the overall population were similar to the anaemic subgroup, with the exception of anaemia severity and transfusion requirements.
Patients were treated with Omjjara 200 mg daily or ruxolitinib adjusted dose twice daily for 24 weeks, followed by open-label treatment with Omjjara without tapering of ruxolitinib. The efficacy of Omjjara in SIMPLIFY-1 was based on post-hoc analysis of spleen volume response (reduction by 35% or greater) in the subgroup of patients with anaemia (Hgb values <10 g/dL) (table 4). In this subgroup, a numerically lower percent of patients treated with Omjjara (25%) achieved a TSS reduction of 50% or greater at week 24 compared with ruxolitinib (36%).
Table 4. Percent of patients achieving spleen volume reduction at week 24 in the anaemic subgroup (SIMPLIFY-1):
| Omjjara n=86 | Ruxolitinib n=95 | |
|---|---|---|
| Patients with spleen volume reduction by 35% or greater, n (%) (95% CI) | 27 (31%) (22, 42) | 31 (33%) (23, 43) |
In the overall population, the percent of patients achieving 35% or greater reduction from baseline in spleen volume (non-inferiority, primary endpoint) at week 24 was 27% for Omjjara and 29% for ruxolitinib (treatment difference 9%; 95% CI: 2, 16, p-value: 0.014).
The European Medicines Agency has waived the obligation to submit the results of studies with Omjjara in all subsets of the paediatric population in the treatment of myelofibrosis (see 4.2 for information on paediatric use).
Momelotinib is rapidly absorbed after oral administration with the maximal plasma concentration (Cmax) achieved within 3 hours post-dose, with plasma exposures increased in a less than dose-proportional manner, especially at doses above 200 mg. In a clinical study, at the dose of 200 mg once daily at steady state, the mean momelotinib Cmax (% CV) is 479 ng/mL (61%) and AUCtau is 3288 ng×h/mL (60%) in patients with myelofibrosis.
Following low-fat and high-fat meals in healthy volunteers, the Cmax of momelotinib was 38% and 28% higher, respectively, and the AUC was 16% and 28% higher, respectively, as compared with those under fasted conditions. These changes in exposure were not clinically meaningful.
Plasma protein binding of momelotinib is approximately 91% in humans. Based on population pharmacokinetics, the mean apparent volume of distribution of momelotinib at steady-state was 984 L in patients with myelofibrosis receiving momelotinib 200 mg once daily suggesting extensive tissue distribution.
Based on in vitro assessment, momelotinib is metabolised by multiple CYP enzymes (including CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP1A2). Generation of the active metabolite M21, involves biotransformation by CYP enzymes followed by metabolism by aldehyde oxidase.
Following an oral dose of momelotinib 200 mg, the mean terminal half-life (t½) of momelotinib was approximately 4 to 8 hours; the half-life of M21 was similar. Based on a clinical study, the apparent total clearance (CL/F) of momelotinib was 103 L/h in patients with myelofibrosis.
Momelotinib is mainly eliminated through metabolism and then excreted to faeces. Following a single oral dose of [14C]-labelled momelotinib in healthy male subjects, 69% of radioactivity was excreted in the faeces (13% of dose as unchanged momelotinib), and 28% in the urine (<1% of dose as unchanged momelotinib).
Effect of momelotinib on UDP-glucuronosyltransferase (UGT):
Momelotinib is an inhibitor of UGT1A1 and UGT1A9 at clinically relevant concentrations, but the clinical relevance is unknown. Momelotinib and its major circulating metabolite are not inhibitors of the other isoforms (UGT1A3/4/6 and 2B7) at clinically relevant concentrations.
Effect of momelotinib on CYP450 enzymes:
At clinically relevant concentrations neither momelotinib nor the major circulating metabolite, M21, represent a risk of inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.
Effect of momelotinib on drug transporters:
In vitro data indicates that momelotinib inhibits OCT1 and the active metabolite, M21, inhibits MATE1 at clinically relevant concentrations. Neither momelotinib nor M21 have been evaluated for MATE2-K inhibition.
In vitro data indicate that neither momelotinib nor its major metabolite, M21, inhibits the following transporters at clinically relevant concentrations: organic anion transporter 1 and 3 (OAT1, OAT3) and OCT2.
Effect of momelotinib on hormonal contraceptives:
Multiple doses of momelotinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. However, a risk for induction of other pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded and the effectiveness of concomitant administration of oral contraceptives may be reduced (see sections 4.4 and 4.5).
Gender and race (White vs Asian) do not have a clinically relevant effect on the pharmacokinetics of momelotinib based on exposure (AUC) data in healthy subjects. Exploratory results of population pharmacokinetics analysis in patients did not show any effects of age, weight, or gender on momelotinib pharmacokinetics.
Momelotinib AUC increased by 8% and 97% in subjects with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, respectively, compared to subjects with normal hepatic function (see section 4.2).
Momelotinib was not carcinogenic in mice and rats at exposures up to 12 and 17 times the clinical exposure level at 200 mg once daily based on combined momelotinib and the active major human metabolite, M21 (minimally produced in mice, rats and rabbits), AUC.
Momelotinib was not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for gene mutations and chromosomal aberrations.
In fertility studies, momelotinib was administered orally to male and female rats. In males, momelotinib reduced sperm concentration and motility and reduced testes and seminal vesicle weights at doses of 25 mg/kg/day and greater (exposures 13-times the recommended dose of 200 mg daily based on combined momelotinib and M21 AUC) resulting in reduced fertility at 68 mg/kg/day.
Observations in females included reduced ovarian function at 68 mg/kg/day and decreased number of pregnancies, increased pre- and post-implantation loss with total litter loss in most animals at 25 and 68 mg/kg/day. Exposures at the no adverse effect level in male and female rats at 5 mg/kg/day were approximately 3 times the recommended dose of 200 mg daily (based on combined momelotinib and M21 AUC).
In animal reproduction studies, oral administration of momelotinib to pregnant rats during the period of organogenesis caused maternal toxicity at 12 mg/kg/day and was associated with embryonic death, visceral malformation, and decreased foetal weights; skeletal variations were observed at 6 and 12 mg/kg/day and (approximately 3.5-fold the recommended dose of 200 mg daily based on combined momelotinib and M21 AUC). There were no developmental effects observed at 2 mg/kg/day at exposures equivalent to the recommended dose of 200 mg (based on combined momelotinib and M21 AUC).
In pregnant rabbits, oral administration of momelotinib during the period of organogenesis caused severe maternal toxicity and evidence of embryo-foetal toxicity (decreased foetal weight, delayed bone ossification, and abortion) at 60 mg/kg/day at less than the exposure equivalent to the recommended dose of 200 mg (based on combined momelotinib and M21 AUC).
In an oral pre- and post-natal development study, rats received oral administration of momelotinib from gestation to end of lactation. Evidence of maternal toxicity, embryo-lethality, and decreased birth weights were observed at 6 and 12 mg/kg/day. Pup survival was significantly reduced at 12 mg/kg/day from birth to Day 4 of lactation at exposures similar to or less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC) and was therefore considered a direct effect of momelotinib via exposure through the milk.
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