Fedratinib (Inrebic®): A Comprehensive Pharmacological and Clinical Monograph

Section 1: Executive Summary and Drug Profile

Fedratinib is an orally bioavailable, small-molecule kinase inhibitor developed as a targeted therapy for myeloproliferative neoplasms (MPNs).[1] Pharmacologically, it is classified as a potent and selective inhibitor of Janus Associated Kinase 2 (JAK2) and, to a lesser extent, FMS-like tyrosine kinase 3 (FLT3).[3] Its primary, globally approved indication is for the treatment of adult patients with intermediate-2 or high-risk primary myelofibrosis (MF) or secondary myelofibrosis (post-polycythemia vera or post-essential thrombocythemia).[5] The approval of Fedratinib marked a significant development in the therapeutic landscape for this rare and debilitating bone marrow disorder, as it was the second such therapy to receive U.S. Food and Drug Administration (FDA) approval, following a nearly decade-long interval after the approval of ruxolitinib. This addressed a substantial unmet medical need for patients with limited treatment options.[7]

The clinical value of Fedratinib is substantiated by robust evidence from pivotal clinical trials, most notably the JAKARTA and JAKARTA2 studies. These trials demonstrated that Fedratinib provides statistically significant and clinically meaningful reductions in both spleen volume and the debilitating symptom burden associated with myelofibrosis, in both treatment-naïve and previously treated patient populations.[9] However, this pronounced efficacy is counterbalanced by a significant and unique safety concern. Fedratinib carries a boxed warning for serious and potentially fatal encephalopathy, including Wernicke's encephalopathy (WE), a neurological emergency stemming from thiamine (Vitamin B1) deficiency. This risk necessitates stringent and proactive risk management protocols, including baseline and periodic thiamine level assessment and mandatory daily thiamine supplementation for all patients.[6]

The trajectory of Fedratinib's development is as notable as its clinical profile. The program was placed on a clinical hold by the FDA in 2013 due to the suspected cases of WE, an event that typically terminates a drug's development.[10] Its subsequent revival, re-evaluation, and eventual approval by major regulatory bodies is a testament to its perceived efficacy and the profound unmet need in the myelofibrosis patient population. This journey from clinical hold to market approval exemplifies a complex regulatory and clinical decision-making process where the substantial benefits of a therapy for a severe disease were determined to outweigh its serious, but manageable, risks. The entire narrative of Fedratinib is thus defined by this intricate balance between high efficacy and a specific, high-impact toxicity, making its successful clinical use contingent upon rigorous physician oversight and patient adherence to safety protocols.

Section 2: Physicochemical and Structural Properties

This section provides the foundational chemical data for Fedratinib, establishing its identity as a small molecule and detailing the properties that influence its formulation, biological activity, and analytical characterization.

Chemical Identity and Nomenclature

Fedratinib is known by its generic name and is marketed under the brand name Inrebic®.[1] During its development, it was identified by the codenames SAR302503 and TG101348.[2] Chemically, it is classified as a sulfonamide and is structurally derived from an anilinopyrimidine scaffold.[1] The approved drug product is often in the form of fedratinib hydrochloride or fedratinib dihydrochloride monohydrate.[2]

Structural and Molecular Data

The definitive chemical structure of Fedratinib is described by its International Union of Pure and Applied Chemistry (IUPAC) name: N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide.[2] For computational chemistry and database cross-referencing, its structure is represented by the following identifiers:

• Canonical SMILES: Cc1cnc(nc1Nc1cccc(c1)S(=O)(=O)NC(C)(C)C)Nc1ccc(cc1)OCCN1CCCC1 [3]
• InChIKey: JOOXLOJCABQBSG-UHFFFAOYSA-N [14]

Physicochemical Properties

Fedratinib's physicochemical properties are consistent with those of an orally administered small-molecule drug. Its chemical formula is C27​H36​N6​O3​S, corresponding to a molecular weight of approximately 524.7 g/mol.[1] It is a synthetic organic compound with a topological polar surface area of 116.86 Ų and is soluble in organic solvents such as dimethyl sulfoxide (DMSO) at concentrations up to 50 mg/mL.[14] Its calculated properties, including 8 hydrogen bond acceptors and 3 hydrogen bond donors, are relevant for its interaction with biological targets and its overall pharmacokinetic profile.[16]

Table 2.1: Fedratinib Identification and Chemical Properties
Parameter	Value
Generic Name	Fedratinib 1
Brand Name	Inrebic® 1
DrugBank ID	DB12500 1
CAS Number	936091-26-8 2
IUPAC Name	N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide 2
Developmental Codes	SAR302503, TG101348 2
Chemical Formula	C27​H36​N6​O3​S 3
Molar Mass	524.68 g·mol⁻¹ 2
InChIKey	JOOXLOJCABQBSG-UHFFFAOYSA-N 14
Canonical SMILES	Cc1cnc(nc1Nc1cccc(c1)S(=O)(=O)NC(C)(C)C)Nc1ccc(cc1)OCCN1CCCC1 16
Solubility	Soluble in DMSO (45-50 mg/mL) 14

Section 3: Preclinical and Clinical Pharmacology

This section delineates the biological activity of Fedratinib, detailing its molecular mechanism of action, its physiological effects on the body, and its pharmacokinetic profile, which collectively define its therapeutic utility and potential for adverse events.

Mechanism of Action (MoA)

Primary Target - JAK2 Inhibition

The primary mechanism of action of Fedratinib is the potent and selective inhibition of Janus Associated Kinase 2 (JAK2).[2] It functions as an ATP-competitive inhibitor, binding to the kinase domain of JAK2 and preventing its phosphorylation and activation.[4] This inhibition is highly potent against both wild-type JAK2 and the constitutively active JAK2V617F mutant, which is a key pathogenic driver in a majority of patients with myeloproliferative neoplasms, including myelofibrosis.[2] The half-maximal inhibitory concentration (

IC50​) for both forms of the enzyme is in the low nanomolar range, reported as approximately 3 to 6 nM.[2]

Kinase Selectivity Profile

A defining feature of Fedratinib's pharmacology is its selectivity for JAK2 over other members of the JAK family of kinases. Preclinical data demonstrate that it is approximately 35-fold more selective for JAK2 over JAK1 and over 334-fold more selective for JAK2 over JAK3.[14] This selectivity profile was a key design feature, distinguishing it from the first-generation JAK inhibitor ruxolitinib, which inhibits JAK1 and JAK2 with roughly equal potency.[19] This was likely intended to create a more targeted therapeutic effect and potentially mitigate side effects associated with broader JAK inhibition. However, the most common and dose-limiting toxicities of Fedratinib, namely anemia and thrombocytopenia, are direct consequences of inhibiting JAK2, which is essential for normal erythropoiesis and megakaryopoiesis. This demonstrates that the potent on-target inhibition of JAK2 is responsible for both the desired therapeutic effect in myelofibrosis and the most significant on-target toxicities. This inherent link suggests that separating the drug's efficacy from its common hematologic adverse effects may be fundamentally challenging.

Secondary Targets - FLT3 and RET

In addition to its primary activity against JAK2, Fedratinib also exhibits inhibitory activity against other clinically relevant tyrosine kinases. Notably, it inhibits FMS-like tyrosine kinase 3 (FLT3) and the RET proto-oncogene, with IC50​ values of approximately 25 nM and 17–48 nM, respectively.[1] Mutations and overexpression of FLT3 are implicated in the pathogenesis of certain hematologic malignancies, particularly acute myeloid leukemia (AML).[4] While the clinical relevance of this secondary activity in the context of myelofibrosis is not fully elucidated, it represents a component of the drug's broader kinome profile that may contribute to its overall biological effects.

Downstream Signaling Pathway

The functional consequence of JAK2 inhibition by Fedratinib is the disruption of the canonical JAK-STAT signaling pathway. In myelofibrosis, the hyperactive JAK2V617F mutant leads to the constitutive phosphorylation and activation of downstream Signal Transducer and Activator of Transcription (STAT) proteins, primarily STAT3 and STAT5.[1] These activated STAT proteins translocate to the nucleus and drive the transcription of genes involved in cell proliferation, differentiation, and survival. By blocking the initial phosphorylation step, Fedratinib effectively shuts down this entire signaling cascade. This interruption prevents the uncontrolled proliferation of malignant hematopoietic progenitor cells and ultimately induces apoptosis (programmed cell death), thereby reducing the disease burden.[1]

Pharmacodynamics (PD)

The relationship between Fedratinib concentration in the body and its clinical effects has been formally evaluated. Pooled analyses of data from Phase 2 and 3 clinical trials revealed a statistically significant positive exposure-response relationship for efficacy.[20] Higher drug exposure was directly associated with a greater likelihood of achieving the primary efficacy endpoints: a spleen volume reduction of 35% or more (SVR35) and a 50% or greater reduction in total symptom score (TSS).[20] This finding provides strong validation for the drug's mechanism of action and supports the 400 mg once-daily dose as being within a therapeutically effective range.

Conversely, and somewhat counterintuitively, the same analyses found no statistically significant association between Fedratinib exposure and the incidence of key safety endpoints, including grade ≥3 anemia, grade ≥3 thrombocytopenia, or any-grade gastrointestinal toxicities (nausea, vomiting, diarrhea).[20] This lack of a clear exposure-safety correlation suggests that these adverse events are not simply a function of overexposure within the therapeutic window. Instead, it lends further support to the idea that the primary toxicities are a direct result of the on-target inhibition of JAK2 required to achieve a therapeutic effect. The level of JAK2 inhibition necessary for efficacy appears to be sufficient to cause myelosuppression and other side effects in susceptible individuals, independent of minor variations in drug concentration.

Pharmacokinetics (PK)

Absorption

Fedratinib is administered orally. Following a single 400 mg dose, it is absorbed with a median time to peak plasma concentration (Tmax​) ranging from 1.75 to 3 hours.[1] At this dose, the peak plasma concentration (

Cmax​) is approximately 1804 ng/mL.[1] The administration of Fedratinib with a high-fat meal does not have a clinically significant effect on its overall absorption (AUC) but may help reduce the incidence of nausea and vomiting, making co-administration with food a recommended practical option for improving tolerability.[1]

Distribution

Fedratinib exhibits extensive distribution throughout the body, as evidenced by a large apparent volume of distribution (Vd​) of 1770 L.[1] In systemic circulation, it is highly bound to plasma proteins, with a protein binding of 92% or greater.[1]

Metabolism

Fedratinib undergoes hepatic metabolism, primarily mediated by the Cytochrome P450 (CYP) enzyme system. The main enzymes responsible for its metabolism are CYP3A4 and CYP2C19, with a minor contribution from flavin-containing monooxygenase 3 (FMO3).[1] This reliance on the CYP3A4 pathway is the basis for several clinically significant drug-drug interactions, which require careful management and dose adjustments.

Excretion

The elimination of Fedratinib and its metabolites occurs predominantly via the fecal route. Approximately 77% of an administered oral dose is recovered in the feces, of which 23% is unchanged parent drug.[1] Renal excretion plays a minor role, accounting for only 5% of the dose, with 3% excreted as unchanged drug in the urine.[1] Fedratinib has a long elimination half-life of approximately 41 hours and a terminal half-life of 114 hours, which supports a convenient once-daily dosing regimen.[1] The systemic clearance of the drug is approximately 13 L/h.[1]

Section 4: Clinical Efficacy in Myelofibrosis

The clinical efficacy of Fedratinib in myelofibrosis is supported by two pivotal trials, JAKARTA and JAKARTA2, which established its role in both the first-line (JAK-inhibitor naïve) and second-line (post-ruxolitinib) treatment settings. These studies provide the foundational evidence for its regulatory approvals and its position in the clinical management of the disease.

The JAKARTA Trial: Efficacy in the First-Line (JAK-Inhibitor Naïve) Setting

Study Design

The JAKARTA trial (NCT01437787) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Fedratinib in patients with intermediate-2 or high-risk primary or secondary myelofibrosis who had not previously been treated with a JAK inhibitor.[7] A total of 289 patients were randomized in a 1:1:1 ratio to receive either Fedratinib 400 mg once daily, Fedratinib 500 mg once daily, or a matched placebo.[22] The primary analysis focused on the comparison between the approved 400 mg dose arm (n=96) and the placebo arm (n=96) over six 28-day treatment cycles.[24]

Primary Endpoint - Spleen Volume Response

The primary efficacy endpoint of the JAKARTA trial was the spleen volume response rate (SVRR), defined as the proportion of patients who achieved a reduction in spleen volume of 35% or more from baseline at the end of cycle 6 (week 24), as measured by magnetic resonance imaging (MRI) or computed tomography (CT), with a confirmatory scan performed 4 weeks later.[7] The results for this primary endpoint were both statistically and clinically significant. In the intent-to-treat population, 37% of patients receiving Fedratinib 400 mg achieved a spleen volume response, compared to only 1% of patients in the placebo group (

p<0.0001).[7] In an updated, post-hoc analysis that assessed spleen response at week 24 without the requirement for a 4-week confirmation scan—a methodology consistent with other pivotal trials in myelofibrosis—the SVRR for the Fedratinib 400 mg arm was even higher at 47%.[10]

Secondary Endpoint - Symptom Burden Reduction

A key secondary endpoint was the symptom response rate, defined as the proportion of patients achieving a 50% or greater reduction in their Total Symptom Score (TSS) from baseline to the end of cycle 6.[22] The TSS was calculated using the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary, which captures the severity of core disease-related symptoms such as night sweats, itching, abdominal discomfort, and bone pain.[22] The results for this endpoint mirrored the strong efficacy seen in spleen response. A total of 40% of patients treated with Fedratinib 400 mg achieved a symptom response, compared to just 9% of patients receiving placebo (

p<0.0001).[7]

Durability of Response

The median duration of the spleen response in the Fedratinib 400 mg arm was estimated to be 18.2 months.[7] However, this analysis was significantly impacted by extensive censoring of data due to the premature termination of the study following the FDA's clinical hold. As a result, this figure likely underestimates the true durability of response.[10]

The JAKARTA2 Trial: Efficacy in the Second-Line (Post-Ruxolitinib) Setting

Study Design and Patient Population

The JAKARTA2 trial (NCT01523171) was a critical Phase 2, single-arm, open-label study that evaluated Fedratinib 400 mg once daily in 97 patients with intermediate- or high-risk myelofibrosis who had previously been treated with ruxolitinib.[19] This study was designed to address the significant unmet medical need for patients whose disease progresses on, or who are intolerant to, the standard-of-care first-line therapy.

Updated Analysis with Stringent Criteria

The interpretation of the JAKARTA2 results evolved significantly over time. The initial analysis relied on broad, investigator-assessed definitions of ruxolitinib failure.[31] As clinical experience with ruxolitinib grew, the hematology community developed more rigorous, consensus-based criteria for defining resistance and intolerance. The subsequent re-analysis of the JAKARTA2 data using these more stringent criteria provides a much more robust and clinically meaningful assessment of Fedratinib's efficacy in a true second-line population.[11] This process of refining the endpoint definition was crucial. By applying objective criteria, the re-analysis confirmed that Fedratinib provides a meaningful benefit to patients who have genuinely failed the standard of care, rather than a mixed population that may have discontinued for less clinically urgent reasons. This strengthened evidence was likely instrumental in convincing regulators of its second-line utility, particularly in light of the drug's known safety risks.

Efficacy Outcomes

In the updated intention-to-treat (ITT) analysis of all 97 patients, the SVRR at the end of cycle 6 was 31% (95% CI 22%, 41%).[11] In the "Stringent Criteria Cohort" (n=79), which included only those patients who met the rigorous definitions for ruxolitinib failure, the SVRR was 30% (95% CI 21%, 42%).[11] The symptom response rate (≥50% reduction in TSS) in the evaluable population was 27%.[29] These results firmly established that Fedratinib possesses significant clinical activity in a difficult-to-treat, relapsed/refractory patient population, providing a much-needed therapeutic option after first-line JAK inhibitor failure.

Efficacy Across Key Patient Subgroups

Patients with Thrombocytopenia

Thrombocytopenia is a common and challenging complication of both myelofibrosis and its treatment. An important analysis of pooled data from the JAKARTA and JAKARTA2 trials assessed the efficacy of Fedratinib in patients with baseline thrombocytopenia (platelet counts of 50 to <100 × 10⁹/L). The results showed that Fedratinib maintained its efficacy in this higher-risk subgroup. Spleen response rates at 24 weeks were not statistically different between patients with low baseline platelets and those with higher baseline platelets (≥100 × 10⁹/L) in either the first-line or second-line setting.[28] This finding is clinically significant, as it demonstrates the utility of Fedratinib in a patient population that can be difficult to manage with other JAK inhibitors.

Table 4.1: Summary of Pivotal Clinical Trials (JAKARTA & JAKARTA2)
Feature	JAKARTA (NCT01437787)	JAKARTA2 (NCT01523171)
Phase	3 7	2 19
Study Design	Randomized, Double-Blind, Placebo-Controlled 7	Single-Arm, Open-Label 28
Patient Population	JAK-Inhibitor Naïve, Intermediate-2 or High-Risk MF 7	Previously Treated with Ruxolitinib, Intermediate- or High-Risk MF 30
Number of Patients (Analyzed)	96 (Fedratinib 400 mg) vs. 96 (Placebo) 22	97 (ITT Population); 79 (Stringent Criteria Cohort) 11
Primary Endpoint	Spleen Volume Response Rate (SVRR) at Week 24 7	Spleen Volume Response Rate (SVRR) at Week 24 11
Spleen Volume Response Rate (SVRR ≥35%)	37% (Fedratinib) vs. 1% (Placebo) (p<0.0001) 7	31% (ITT); 30% (Stringent Criteria Cohort) 11
Symptom Response Rate (TSS Reduction ≥50%)	40% (Fedratinib) vs. 9% (Placebo) (p<0.0001) 7	27% (Evaluable Population) 29

Section 5: Comprehensive Safety and Tolerability Profile

The safety and tolerability profile of Fedratinib is a critical component of its clinical use, defined by a significant boxed warning that mandates a proactive risk management strategy, as well as a predictable pattern of common adverse events that require diligent monitoring and management.

Boxed Warning: Encephalopathy Including Wernicke's (WE)

Risk Description

Fedratinib's prescribing information includes a boxed warning, the most stringent warning issued by the FDA, regarding the risk of serious and potentially fatal encephalopathy, including Wernicke's encephalopathy (WE).[6] WE is an acute neurological emergency caused by a deficiency in thiamine (Vitamin B1).[6] The classic triad of symptoms includes encephalopathy (confusion, memory problems, drowsiness), oculomotor dysfunction (abnormal eye movements, double vision), and gait ataxia (difficulty walking, problems with balance).[6]

Clinical Context and History

This specific risk is central to the history of Fedratinib. In November 2013, its clinical development was abruptly halted when the FDA placed all ongoing trials on a clinical hold due to reports of suspected cases of WE among study participants.[10] The subsequent re-evaluation of the complete safety data led to the implementation of a rigorous risk evaluation and mitigation strategy (REMS) that was deemed sufficient to allow for the drug's approval, given its demonstrated efficacy in a population with high unmet need.[10]

Mandatory Risk Management

To mitigate the risk of WE, the following proactive measures are mandatory for all patients being considered for or treated with Fedratinib:

• Assessment: Thiamine levels must be measured in all patients before initiating treatment. Levels should also be monitored periodically during therapy and at any time clinical signs or symptoms of WE are suspected.[6]
• Repletion: Fedratinib must not be initiated in any patient with a pre-existing thiamine deficiency. Thiamine levels must be repleted to within the normal range before the first dose of Fedratinib is administered.[6]
• Prophylaxis: All patients receiving Fedratinib should take daily oral thiamine supplementation (e.g., 100 mg) for the duration of treatment to prevent the development of deficiency.[33]
• Intervention: If WE is suspected at any point during treatment, Fedratinib must be discontinued immediately. The patient should be treated with parenteral (intravenous) thiamine, and Fedratinib should not be restarted until all symptoms have resolved or improved and thiamine levels have normalized.[6]

This comprehensive, proactive framework is a direct result of the lessons learned from the clinical hold. It represents a shift from a reactive approach to toxicity management to a preventative one, acknowledging that successful use of the drug is contingent on strict adherence to these safety protocols.

Common and Serious Adverse Reactions

Gastrointestinal Toxicity

The most frequently reported adverse reactions with Fedratinib are gastrointestinal in nature. In clinical trials, diarrhea (66%), nausea (62%), and vomiting (39%) were the most common side effects, affecting a majority of patients.[6] The onset of these symptoms is typically rapid, with a median time to onset of just one day, and 75% of cases occurring within the first two weeks of treatment.[6] While most cases are Grade 1 or 2, Grade 3 events can occur and may necessitate dose modification.

Hematologic Toxicity

Consistent with its potent on-target inhibition of JAK2-mediated hematopoiesis, the most common serious adverse reactions are hematologic. Anemia and thrombocytopenia are frequent, dose-limiting toxicities.[1] In clinical studies, new or worsening Grade 3 anemia occurred in 34% of patients, often requiring red blood cell transfusions (51% of patients).[6] New or worsening Grade ≥3 thrombocytopenia occurred in 12% of patients.[6] These events require regular monitoring of complete blood counts and may necessitate dose interruption, reduction, or supportive care.

Hepatic Toxicity

Elevations in liver transaminases (ALT and AST) are also common, with all-grade elevations occurring in over 40% of patients.[6] Grade 3 or 4 elevations are much less frequent (around 1%) but require intervention.[6] Liver function tests should be monitored at baseline and periodically throughout treatment.

Pancreatic Enzyme Elevation

Increases in serum amylase and lipase levels are observed in patients treated with Fedratinib. Grade 3 or higher elevations occurred in 2% and 10% of patients, respectively.[6] While clinical pancreatitis is rare, these laboratory abnormalities warrant monitoring at baseline and periodically, with dose modifications required for significant elevations.[6]

Other Potential Risks (Class Effects)

The prescribing information for Fedratinib also includes warnings about potential risks that have been associated with other drugs in the JAK inhibitor class, such as major adverse cardiac events (MACE), thrombosis (blood clots), and secondary malignancies.[6] While the rates of these events were not found to be increased with Fedratinib compared to placebo in its pivotal trials, clinicians are advised to consider these potential risks, particularly in patients with underlying cardiovascular risk factors or a history of smoking.[6]

Clinical Management of Adverse Events

The management of Fedratinib-related toxicities relies on a structured framework of dose modification and supportive care. The standard starting dose of 400 mg daily can be reduced in 100 mg decrements to manage adverse events. Treatment should be permanently discontinued if a patient is unable to tolerate a dose of 200 mg daily.[21]

Specific management strategies include:

• GI Toxicity: Prophylactic anti-emetic medications are recommended, particularly during the first 8 weeks of treatment. Diarrhea should be managed promptly with anti-diarrheal agents. For severe or persistent symptoms, dose interruption and reduction are necessary.[6]
• Hematologic Toxicity: Management is guided by regular monitoring of complete blood counts. Dose interruption is required for Grade 4 cytopenias or Grade 3 thrombocytopenia with bleeding. Upon resolution, the dose can be restarted at a reduced level. Supportive care, including blood or platelet transfusions, should be provided as clinically indicated.[6]

Section 6: Dosage, Administration, and Drug Interactions

This section provides practical clinical guidance on the appropriate use of Fedratinib, covering recommended dosing, administration procedures, necessary dose adjustments, and the management of clinically significant drug-drug and drug-food interactions.

Dosing and Administration

Recommended Dosage

The recommended starting dosage of Fedratinib is 400 mg taken orally once daily.[6] This dose is indicated for patients with a baseline platelet count of 50 × 10⁹/L or greater.[6] Treatment should continue for as long as the patient is deriving clinical benefit and is tolerating the medication. If a dose is missed, the patient should skip that dose and take the next scheduled dose at the regular time the following day; double doses should not be taken to make up for a missed dose.[33]

Method of Administration

Fedratinib is supplied as capsules that should be swallowed whole and should not be opened, broken, or chewed.[21] The medication may be taken with or without food. However, administration with a high-fat meal has been shown to potentially reduce the incidence of nausea and vomiting, making co-administration with food a practical recommendation to improve tolerability, especially during the initial phase of treatment.[6]

Dose Adjustments for Organ Impairment

Dose adjustments may be necessary for patients with pre-existing organ dysfunction:

• Renal Impairment: No initial dose adjustment is required for patients with mild to moderate renal impairment (Creatinine Clearance [CLcr] 30 to <90 mL/min). However, for patients with severe renal impairment (CLcr 15 to 29 mL/min), the dose of Fedratinib should be reduced to 200 mg once daily.[6]
• Hepatic Impairment: No dose adjustment is needed for patients with mild to moderate hepatic impairment. The use of Fedratinib in patients with severe hepatic impairment (Child-Pugh Class C) has not been studied and should be avoided.[21]

Clinically Significant Drug and Food Interactions

Fedratinib's metabolism via the CYP450 system makes it susceptible to a number of clinically important drug interactions. Careful review of concomitant medications is essential before initiating therapy.

CYP3A4-Mediated Interactions

Fedratinib is a substrate of CYP3A4, the enzyme responsible for the metabolism of a large number of drugs. Consequently, its plasma concentration and potential for toxicity can be significantly altered by CYP3A4 modulators.

• Strong CYP3A4 Inhibitors: Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin) significantly increases the exposure to Fedratinib. When concomitant use cannot be avoided, the dose of Fedratinib must be reduced to 200 mg once daily.[6]
• Strong and Moderate CYP3A4 Inducers: Co-administration with strong or moderate inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, St. John's Wort) is expected to decrease Fedratinib plasma concentrations, potentially compromising its efficacy. Therefore, the concomitant use of Fedratinib with these agents should be avoided.[6]

Fedratinib as an Inhibitor

Fedratinib itself is an inhibitor of several CYP enzymes, including CYP3A4, CYP2C19, and CYP2D6.[1] This means it can increase the plasma concentrations of other drugs that are metabolized by these enzymes (known as substrates). When Fedratinib is co-administered with substrates of these enzymes, particularly those with a narrow therapeutic index, patients should be monitored closely for signs of increased toxicity from the concomitant medication, and dose adjustments of the other drug may be necessary.[1]

Drug-Food Interaction (Grapefruit)

Grapefruit and grapefruit juice are potent inhibitors of intestinal CYP3A4 and can significantly increase the bioavailability and plasma concentrations of drugs metabolized by this enzyme, including Fedratinib. To avoid unpredictable increases in drug exposure and the associated risk of adverse events, patients must be instructed to avoid consuming grapefruit or grapefruit juice throughout the duration of their treatment with Fedratinib.[37]

Table 6.1: Key Drug Interactions and Management Recommendations
Interacting Agent/Class	Effect on Fedratinib/Other Drug	Clinical Management Recommendation
Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)	Increases plasma concentration and exposure of Fedratinib, increasing risk of toxicity. 6	Reduce Fedratinib dose to 200 mg once daily. If the inhibitor is discontinued, increase Fedratinib dose to 300 mg daily for two weeks, then to 400 mg daily as tolerated. 6
Strong/Moderate CYP3A4 Inducers (e.g., rifampin, phenytoin, St. John's Wort)	Decreases plasma concentration and exposure of Fedratinib, potentially reducing efficacy. 6	Avoid concomitant use. 6
Substrates of CYP3A4, CYP2C19, or CYP2D6 (e.g., certain benzodiazepines, statins, beta-blockers)	Fedratinib increases the plasma concentration of these substrates, increasing their risk of toxicity. 1	Monitor for adverse reactions of the concomitant medication. Dose adjustment of the substrate drug may be necessary. 1
Grapefruit / Grapefruit Juice	Increases absorption and plasma concentration of Fedratinib via inhibition of intestinal CYP3A4. 40	Avoid consumption of grapefruit and grapefruit juice during treatment with Fedratinib. 37

Section 7: Regulatory History and Global Status

The path of Fedratinib to market was unconventional and arduous, marked by changes in corporate ownership, a significant regulatory setback, and a remarkable revival. This history provides crucial context for its current place in clinical practice and highlights the powerful interplay between clinical data, regulatory science, and unmet medical need.

Development Pathway and Corporate History

Fedratinib was originally discovered at TargeGen, a biotechnology company. In 2010, the asset was acquired by Sanofi-Aventis, which continued its clinical development for myelofibrosis.[2] However, following a major safety concern, Sanofi discontinued the program in 2013. In a rare turn of events, the rights to Fedratinib were acquired in 2016 by Impact Biomedicines, a new company founded by Dr. John Hood, one of the original inventors of the drug at TargeGen.[2] This effort was reportedly motivated by compelling feedback from patients and investigators who had witnessed profound clinical benefits during the halted trials.[12] Impact Biomedicines was subsequently acquired by Celgene in 2018, which was later acquired by Bristol Myers Squibb, the current marketing authorization holder.[2]

The 2013 Clinical Hold and Subsequent Re-evaluation

The pivotal event in Fedratinib's history occurred in November 2013, when the FDA placed all ongoing clinical trials on a full clinical hold.[10] This action was taken in response to several suspected cases of Wernicke's encephalopathy (WE) that had been reported in patients participating in the studies.[12] A clinical hold for a serious and potentially fatal neurological adverse event is often a terminal event for a drug's development. However, the compelling efficacy data from the JAKARTA trial, which had completed enrollment, and the clear unmet need for new treatments in myelofibrosis, provided a strong rationale for a second look.

After acquiring the drug, Impact Biomedicines compiled and submitted a comprehensive body of clinical and non-clinical data to the FDA, which included a thorough re-analysis of the safety database to better characterize the risk of WE and its relationship to thiamine deficiency.[10] This rigorous re-evaluation ultimately led the FDA to lift the clinical hold in August 2017, a rare occurrence that paved the way for the New Drug Application (NDA) submission.[10] This revival was not merely a data-driven exercise; it was fueled by a combination of scientific persistence and the powerful narrative of patient-reported benefits, which together created the impetus to challenge the initial regulatory setback and invest in the exhaustive work required to bring the drug back into development.

Global Regulatory Approvals

U.S. Food and Drug Administration (FDA)

On August 16, 2019, the FDA approved Fedratinib (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.[2] In recognition of the serious nature of the disease and the unmet need, the FDA had granted the application for Fedratinib both Priority Review and Orphan Drug designations.[2]

European Medicines Agency (EMA)

Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in December 2020, the European Commission granted a full marketing authorization for Fedratinib (Inrebic) on February 8, 2021.[3]

Comparison of Indications

While the core indication is similar across jurisdictions, there is a nuance in the approved labeling. The EU indication explicitly states that Fedratinib is for the treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis "who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib".[2] This language directly reflects the evidence base from both the JAKARTA (JAK-inhibitor naïve) and JAKARTA2 (post-ruxolitinib) trials, providing clear regulatory endorsement for its use in both the first- and second-line settings. The US indication is for intermediate-2 or high-risk MF without explicitly segmenting by prior JAK inhibitor status, though its use in the post-ruxolitinib setting is well-established based on the JAKARTA2 data and is a key part of its clinical utility.[6]

Section 8: Expert Synthesis and Conclusion

Fedratinib represents a significant and complex therapeutic advancement in the management of myelofibrosis. Its clinical profile is characterized by a compelling duality: robust, rapid, and clinically meaningful efficacy set against a backdrop of a serious and specific safety risk that demands unwavering clinical vigilance. A comprehensive assessment of its value requires a synthesized view of its benefits, risks, and its unique place in the evolving treatment paradigm for this challenging disease.

Integrated Risk-Benefit Assessment

The primary benefit of Fedratinib is its proven ability to produce deep and durable responses in patients with myelofibrosis. The pivotal JAKARTA and JAKARTA2 trials unequivocally demonstrated its capacity to significantly reduce splenomegaly and alleviate the profound symptom burden that defines the clinical course of the disease. This efficacy is observed in both treatment-naïve patients and, critically, in those who have failed prior therapy with ruxolitinib, addressing a major unmet medical need. The drug's benefits are therefore substantial and can be transformative for appropriately selected patients.

This efficacy must be weighed against its significant safety profile. The boxed warning for Wernicke's encephalopathy is a serious consideration that fundamentally shapes how the drug must be prescribed and monitored. However, this risk, along with the more common toxicities of gastrointestinal distress and myelosuppression, is now well-characterized. The key determinant of a favorable risk-benefit balance lies in the implementation of the mandatory and proactive risk management strategies outlined in the prescribing information. With strict adherence to thiamine assessment and supplementation, along with diligent monitoring and management of hematologic and other toxicities, the risks associated with Fedratinib can be effectively mitigated. The conclusion is that while the toxicities are considerable, they are largely predictable and manageable, allowing the drug's potent benefits to be realized.

Positioning in the Myelofibrosis Treatment Algorithm

Fedratinib has secured a vital and versatile position within the myelofibrosis treatment algorithm. Based on the robust, placebo-controlled data from the JAKARTA trial, it stands as a potent first-line option for JAK-inhibitor naïve patients with intermediate-2 or high-risk disease. Perhaps more importantly, the evidence from the JAKARTA2 trial establishes it as an essential and proven second-line therapy for the significant population of patients who experience treatment failure with, or intolerance to, ruxolitinib.[19] Its demonstrated efficacy in patients with baseline thrombocytopenia further carves out a specific clinical niche for patients who may be challenging to treat with other agents.[28] It is no longer just an alternative, but a necessary component of the therapeutic armamentarium, offering a validated pathway for patients after progression on first-line therapy.

Future Directions and Unanswered Questions

While its role in myelofibrosis is now well-defined, research continues to explore the full potential of Fedratinib. Ongoing studies are investigating its utility in other myeloproliferative neoplasms and its potential use in combination with other novel agents, which may further enhance efficacy or mitigate toxicity.[45] A key remaining question is the long-term impact of Fedratinib on overall survival. While early data are favorable, the maturation of long-term survival outcomes was inevitably disrupted by the clinical hold, and further follow-up will be required to fully elucidate its effect on the natural history of the disease.

Final Expert Conclusion

In conclusion, Fedratinib is a critical therapeutic agent for the treatment of intermediate- to high-risk myelofibrosis. Its turbulent development journey, from discovery to clinical hold and eventual resurrection and approval, is a powerful illustration of the delicate balance between profound therapeutic benefit and significant, but manageable, risk. It offers a vital treatment option capable of producing deep and durable responses in a disease with a poor prognosis and limited therapeutic alternatives. For the appropriate patient, under the care of an experienced hematologist who is fully committed to the principles of proactive monitoring and risk mitigation, Fedratinib provides a much-needed and effective tool to combat the debilitating progression of myelofibrosis.

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