Summary Basis of Decision for Inrebic

 

Clinical Pharmacology

The medicinal ingredient in Inrebic, fedratinib, is an oral kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3, and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.

Fedratinib inhibits cytokine-induced phosphorylation of the signal transducer and activator of transcription (STAT3) protein in whole blood from patients with myelofibrosis.

Following oral administration, fedratinib is rapidly absorbed, achieving maximum plasma concentration within 0.5 to 4 hours. Steady-state plasma levels of fedratinib are reached within 15 days of once daily dosing, with an approximately threefold accumulation.

Fedratinib is metabolized by multiple cytochrome P450 (CYP) enzymes in vitro, with the predominant contribution from CYP3A4 and with a lesser contribution from CYP2D6, CYP2C19, and flavin-containing monooxygenases. Concomitant administration of Inrebic with strong and moderate CYP3A4 inhibitors may increase fedratinib exposure leading to an increased risk of adverse reactions. Therefore, a starting dose reduction is recommended when administering Inrebic with strong and moderate CYP3A4 inhibitors. The effect of concomitant administration with strong or moderate CYP3A4 inducers is unknown.

No clinically meaningful effect on the pharmacokinetics of fedratinib was observed in subjects with mild hepatic impairment compared to that in subjects with normal hepatic function. The pharmacokinetics of fedratinib has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).

Following a single 300 mg dose of fedratinib, the area under plasma concentration versus time curve (AUC) from time zero to infinity (AUC_inf) increased by 1.5-fold in subjects with moderate renal impairment and by 1.9-fold in subjects with severe renal impairment compared to that in subjects with normal renal function. Accordingly, dose reduction of Inrebic is recommended in patients with severe renal impairment (creatinine clearance 15 mL/min to 29 mL/min as estimated by Cockcroft-Gault equation).

A dedicated drug-food interaction study demonstrated that the exposure to Inrebic was not affected by food. However, a high-fat, high-calorie meal significantly decreased nausea and vomiting associated with Inrebic.

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

Clinical Efficacy

The efficacy of Inrebic in the treatment of intermediate‑2 or high-risk myelofibrosis, including patients previously exposed to ruxolitinib, is supported by the results of two pivotal studies: one Phase III (JAKARTA) and one Phase II clinical trial (JAKARTA-2).

The JAKARTA trial was a randomized, double-blind, placebo-controlled, 3-arm Phase III study in patients with intermediate‑2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly and a platelet count greater than or equal to 50 x 10⁹/L. The patients had not been previously treated with Janus kinase (JAK) inhibitors. The study randomized 289 patients in a ratio of 1:1:1 to receive Inrebic 400 mg (number of patients [n] = 96), Inrebic 500 mg (n = 97) or placebo (n = 96) once daily for at least six consecutive 28-day cycles.

In the intention-to-treat population (all randomized patients), the median age was 65 years (range of 27 to 86 years), 47% of patients were older than 65 years, and 59% of patients were male. Most patients (64%) had primary myelofibrosis, 26% had post-polycythemia vera myelofibrosis, and 10% had post-essential thrombocythemia myelofibrosis. Fifty-two percent of patients had intermediate‑2 risk and 48% had high-risk disease. At baseline, patients had a median palpable spleen length of 15 cm and a median spleen volume of 2,568 mL (range of 316 mL to 8,244 mL) as measured by magnetic resonance imaging (MRI) or computed tomography (CT) in patients with contraindications for MRI. The median normal spleen volume is approximately 215 mL. Most patients (73.7%) had constitutional symptoms (weight loss greater than 10% over a year before screening, fever persisting for more than one month, or sweats persisting for more than one month). Overall, 67% of patients presented with V617F mutations of JAK2 gene. Per the study criteria, no patients had received prior treatment with a JAK2 inhibitor. However, most patients (73%) had received at least one prior therapy for myelofibrosis.

The primary efficacy endpoint was the spleen response rate defined as the proportion of patients with a 35% or greater reduction in spleen volume (measured by MRI or CT) from baseline to the end of cycle 6 (at week 24) and confirmed 4 weeks later. An Independent Review Committee conducted a blinded review of the MRI/CT images.

The key secondary endpoint was the proportion of patients with a 50% or greater reduction in total symptom score from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The MFSAF v2.0 diary captures the six core symptoms of myelofibrosis: night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. Patients completed the diary daily during the week prior to day 1 of each treatment cycle and at the end of cycle 6. Symptom scores ranged from 0 ("absent") to 10 ("worst imaginable"). The reductions in total symptom score from baseline suggest an improvement in symptom burden.

The study met its primary endpoint. A spleen response rate of 36.5% was demonstrated in the Inrebic 400 mg group as compared to 1.0% in the placebo group (p<0.0001). The spleen response rate at the end of cycle 3 was 42.7% in the Inrebic 400 mg group versus 1.0% in the placebo group, indicating an early spleen response to treatment. Overall, 49.0% of patients receiving Inrebic 400 mg versus 2.1% of placebo-treated patients (p<0.0001) achieved a 25% or greater reduction in spleen volume. Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the Inrebic 400 mg group. The proportions of patients with a reduction of at least 50% in the total symptom score were 40.4% and 34.8% in the Inrebic 400 mg and 500 mg groups, respectively, versus 8.6% in the placebo group. Both doses of Inrebic demonstrated a significant meaningful clinical benefit over the placebo. However, the study results did not establish any significant benefit of the 500 mg dose over the 400 mg dose. Therefore, the recommended dose of Inrebic is 400 mg daily. An early termination of JAKARTA precluded sufficient follow-up to determine progression-free survival, overall survival, and long-term safety outcomes. The median duration of exposure to Inrebic 400 mg was 62 weeks (range of 1 to 91.9 weeks).

The JAKARTA-2 trial was a Phase II, multicentre, open-label, single-arm study in patients previously exposed to ruxolitinib with a diagnosis of intermediate-1 with symptoms, intermediate‑2 or high-risk myelofibrosis with splenomegaly and a platelet count greater than or equal to 50 x 10⁹/L. The primary efficacy endpoint was the spleen response rate at the end of cycle 6 as measured by MRI/CT. Of note, the JAKARTA-2 study did not require a confirmatory MRI/CT scan 4 weeks later. The key secondary endpoint was the symptom response rate, defined as the proportion of patients with a 50% or greater reduction in total symptom score from baseline to the end of cycle 6 as measured by the MFSAF v2.0 diary. Ninety-seven patients previously exposed to ruxolitinib were enrolled in the study and received a starting dose of Inrebic 400 mg once daily. The median age was 67 years (range of 38 to 83 years), 58% of patients were older than 65 years and 55% of patients were male. The majority (55%) of patients had primary myelofibrosis, 26% had post-polycythemia vera myelofibrosis, and 19% had post-essential thrombocythemia myelofibrosis. Sixteen percent of patients had intermediate-1 disease with symptoms, 49% had intermediate‑2 disease, and 35% had high-risk disease. Patients had a median palpable spleen length of 18 cm and a median spleen volume of 2,893.5 mL (range of 737 mL to 7,815 mL). The median duration of prior exposure to ruxolitinib was 10.7 months (range of 0.1 months to 62.4 months).

The study met its primary endpoint demonstrating a spleen response rate of 30.9% at the end of cycle 6 (40.2% at the end of cycle 3). These data suggest an early spleen response. The proportion of patients achieving a 50% or greater reduction in total symptom score from baseline to the end of cycle 6 was 26.7%. The median percent change in total symptom score at the end of cycle 6 was -44.3%, indicating an improvement of approximately 44% in myelofibrosis-related symptoms. Most patients in the MFSAF analysis population had a decrease in the total symptom score at the end of cycle 6. All key symptoms assessed showed an improvement at the end of cycle 6, with a median reduction of -22.2% in bone or muscle pain, -44.1% in itching, -46.2% in abdominal discomfort, -51.3% in early satiety, -76.0% in night sweats, and -83.3% in pain under ribs on left side. An exploratory analysis of the patients' responses to the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) also showed a numerical improvement at the end of cycle 6 relative to baseline across global health status (mean improvement of +8.7). All functional domain scores for cognitive, emotional, physical, role, and social functioning showed respective mean improvements (+4.4, +4.2, +7.8, +9.1, and +7.2).

To confirm the robustness of the results from the single-arm JAKARTA-2 study, the sponsor conducted five supportive analyses for the primary endpoint using different methods and applying new, more stringent criteria for analysis populations. The intention-to-treat population consisted of 97 patients, while cohort 1 (n = 79) included patients who met newly defined criteria for patients with relapsed/refractory disease to ruxolitinib or patients intolerant to ruxolitinib. Cohort 1a (n = 66), a subgroup of cohort 1, included patients who had received cycle 6 of Inrebic treatment or who had discontinued Inrebic treatment for reasons other than "study terminated by sponsor". Results for cohort 1 and cohort 1a (spleen response rates of 30.4% and 36.4%, respectively) were consistent with the primary analysis results. Subgroup analyses consistently showed clinically significant improvements in the splenomegaly and myelofibrosis-associated symptoms, thus further supporting the overall robustness of the data. Assessments of long-term effects of Inrebic were limited due to early termination of the study. The median duration of exposure to Inrebic 400 mg was 24 weeks (range of 0.7 to 79.4 weeks).

Indication

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

• Inrebic (fedratinib) is indicated for the treatment of splenomegaly and/or disease-related symptoms in adult patients with primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, including patients who have been previously exposed to ruxolitinib.

Health Canada revised the proposed indication to restrict the use of Inrebic only to patients with intermediate‑2 or high-risk myelofibrosis. Most patients (92%) in the clinical trials had intermediate‑2 or high-risk myelofibrosis. Moreover, the efficacy and safety of Inrebic have not been studied in patients with lower-risk categories of myelofibrosis. Accordingly, Health Canada approved the following indication:

• Inrebic (fedratinib) is indicated for the treatment of splenomegaly and/or disease-related symptoms in adult patients with intermediate‑2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis, including patients who have been previously exposed to ruxolitinib.

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

Clinical Safety

The safety of Inrebic was evaluated based on data from 608 patients receiving multiple doses of Inrebic in clinical trials, including patients with myeloproliferative neoplasms or solid tumours.

Serious cases of encephalopathy, including Wernicke's encephalopathy, a neurologic emergency resulting from thiamine (vitamin B1) deficiency, were reported in 1.3% (8/608) of the patients treated with Inrebic across clinical trials and 0.16% (1/608) of cases were fatal. Seven patients were taking Inrebic at a dose of 500 mg daily prior to the onset of neurologic findings and had predisposing factors such as gastrointestinal adverse events that could have led to thiamine deficiency. Most events resolved after Inrebic treatment cessation with some residual neurological symptoms including memory loss, cognitive impairment, and dizziness, except for one fatal outcome. Specific warnings, including a Serious Warnings and Precautions box are present in the Inrebic Product Monograph to highlight the risk of serious and fatal encephalopathy, including Wernicke's encephalopathy. The Inrebic Product Monograph contains recommendations for assessing thiamine levels in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated. It also warns that treatment with Inrebic should not be initiated in patients with thiamine deficiency.

During the clinical development of Inrebic, the most frequently reported treatment-emergent adverse events were gastrointestinal disorders (mainly diarrhea, nausea, and vomiting), for which study protocols had no specific instructions. Furthermore, dosing instructions for the pivotal trials advised that Inrebic should be taken on an empty stomach. In a food effect study, healthy subjects taking Inrebic with a high-fat, high-calorie meal had fewer gastrointestinal adverse events than those taking the drug under fasted conditions or with a low-fat meal. Accordingly, the Inrebic Product Monograph includes recommendations for the prophylactic use of antiemetics and starting antidiarrheal treatment at the first onset of symptoms. In addition, to enhance tolerability, it is recommended that Inrebic should be given with food, preferably with a high-fat, high-calorie evening meal.

Safety data from a pooled cohort of 203 patients with myelofibrosis treated with the recommended clinical dose of Inrebic 400 mg daily, including 97 patients previously exposed to ruxolitinib, support the use of Inrebic in the target patient population. Among the 203 patients, the median duration of exposure was 35.6 weeks (range of 0.7 to 114.6 weeks). For 95 patients treated with placebo until disease progression, after which these patients were allowed to crossover to active treatment, the median duration of exposure to Inrebic was up to 24.0 weeks (or 6 cycles). The safety and tolerability of Inrebic observed in patients previously exposed to ruxolitinib were consistent with the results obtained in JAK2-inhibitor-naïve patients and, generally, adverse events were manageable with dose reductions or dose interruptions and appropriate supportive care.

The most frequent non-hematologic adverse drug reactions in patients treated with Inrebic were diarrhea, nausea, and vomiting. Anemia and thrombocytopenia were the most frequent hematologic adverse reactions. The most frequent serious adverse events, regardless of causality, included pneumonia (4.4%), cardiac failure (3%), anemia (2.5%), atrial fibrillation, sepsis, pleural effusion, acute kidney injury, and diarrhea (1.5% each). Fatal adverse events not related to disease progression included cardiorespiratory arrest and sepsis (2 patients), cardiogenic shock, and hemorrhagic shock (in one patient, each).

Overall, 43.3% of patients treated with 400 mg of Inrebic developed grade 3 anemia, whereas no patients developed grade 4 anemia. Grade 3 and grade 4 thrombocytopenia occurred in 14.3% and 8.9% of patients, respectively. Anemia and thrombocytopenia were managed with supportive treatment, dose reduction or dose interruption. Elevations of liver enzymes, alanine aminotransferase (ALT) (51.7%) and aspartate aminotransferase (AST) (59.1%), were primarily grade 1 or 2 asymptomatic events. Grade 3 or 4 ALT, AST, and total bilirubin elevations occurred in 6.4% of patients and were generally reversible with dose modification or permanent treatment discontinuation.

Appropriate warnings and precautions are in place in the approved Inrebic Product Monograph to address the identified safety concerns.

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