Selumetinib (Koselugo®): A Comprehensive Monograph on the First-in-Class MEK Inhibitor for Neurofibromatosis Type 1

[Executive Summary]

Selumetinib, marketed under the brand name Koselugo®, represents a landmark achievement in targeted cancer therapy and the treatment of rare genetic disorders. It is a first-in-class, orally active, and highly selective inhibitor of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2), key components of the RAS/RAF/MEK/ERK signaling pathway.[1] The development and approval of selumetinib have fundamentally altered the therapeutic landscape for neurofibromatosis type 1 (NF1), a debilitating genetic condition.

The core indication for selumetinib is the treatment of pediatric patients with NF1 who have symptomatic, inoperable plexiform neurofibromas (PN).[1] In the United States, it is approved for patients aged two years and older, while in the European Union, the approval is for patients aged three years and older.[5] Prior to selumetinib, the only management option for these often disfiguring and painful tumors was surgery, which was frequently not feasible due to the tumors' invasive nature and proximity to vital structures.

The approval of selumetinib was based on the robust and compelling results of the National Cancer Institute (NCI)-sponsored SPRINT trial. In this pivotal study, selumetinib demonstrated a confirmed Objective Response Rate (ORR) of 66%, signifying a volumetric reduction of at least 20% in PN size.[7] These responses were not only statistically significant but also durable and clinically meaningful, leading to notable improvements in patient-reported outcomes, including pain reduction, enhanced physical function, and better overall quality of life.[9]

The safety profile of selumetinib is significant and consistent with its mechanism of action, but it has been shown to be manageable in the target pediatric population. The most common adverse reactions are gastrointestinal (vomiting, diarrhea, nausea) and dermatologic (rash, dry skin) toxicities.[5] While these often necessitate dose interruptions or reductions, permanent discontinuation is less common. More serious, though less frequent, risks include cardiomyopathy (decreased left ventricular ejection fraction), ocular toxicity, and elevated creatine phosphokinase (CPK), which mandate a rigorous, multidisciplinary monitoring and management strategy.[5]

Selumetinib's journey to market was facilitated by a strategic co-development and co-commercialization partnership between AstraZeneca and Merck (known as MSD outside the US and Canada).[5] Its clinical importance was recognized by regulatory agencies worldwide, which granted multiple expedited review designations, leading to rapid approvals by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).[8]

In conclusion, selumetinib stands as a paradigm-shifting therapy that has filled a critical unmet medical need for children with NF1 and inoperable PN. Its success is a testament to decades of foundational public research, effective public-private collaboration, and the power of targeted therapy to address the genetic drivers of disease.[9] It not only provides a vital treatment option but also serves as a model for future drug development in rare diseases.

[Molecular Profile and Physicochemical Properties]

A precise understanding of the chemical and physical characteristics of selumetinib is fundamental to its pharmacology, formulation, and clinical application. This section details its nomenclature, structural data, and key identifiers.

Chemical Identity and Nomenclature

Selumetinib is a small molecule drug belonging to the benzimidazole class of chemical compounds.[1] Its complex structure also classifies it as a hydroxamic acid ester, a member of monochlorobenzenes and bromobenzenes, and an organofluorine compound.[2]

• Generic Name: The universally recognized generic name is Selumetinib. International nonproprietary names include the French spelling, Sélumétinib, and the Latin, Selumetinibum.[1]
• Brand Name: The sole brand name under which selumetinib is marketed is Koselugo®.[4]
• Systematic (IUPAC) Name: The formal chemical name according to IUPAC nomenclature is 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide.[2] An alternative, equally valid systematic name is 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide.[18]
• Synonyms and Development Codes: Throughout its development, selumetinib was widely known by several codes. Its journey began at Array BioPharma Inc., where it was designated ARRY-142886.[12] After being licensed by AstraZeneca, it was assigned the code AZD6244.[12] These two codes are frequently used in early scientific literature. Other identifiers include NSC 741078 and CL 1,040.[2] This nomenclature history reflects the drug's progression from an investigational compound at a biotechnology company to a major pharmaceutical asset.

Structural and Formulaic Data

The molecular composition and structure of selumetinib define its interactions with biological targets.

• Chemical Formula: The empirical formula for the selumetinib free base is C17​H15​BrClFN4​O3​.[1]
• Molecular Weight: The average molecular weight is calculated to be 457.68 g/mol.[1]
• Monoisotopic Mass: The precise monoisotopic mass is 456.000009 Da.[1]
• Structural Identifiers: For computational and database purposes, selumetinib is uniquely identified by its:
• Canonical SMILES (Simplified Molecular-Input Line-Entry System): CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)Cl)C(=O)NOCCO.[2]
• InChIKey (International Chemical Identifier Key): CYOHGALHFOKKQC-UHFFFAOYSA-N.[2]
• Visual Structure: Two-dimensional and three-dimensional representations of the selumetinib molecule are publicly available for visualization in chemical databases such as PubChem, under the compound identifier (CID) 10127622.[2]

Selumetinib Sulfate - The Clinical Formulation

For clinical use, selumetinib is formulated as a sulfate salt to enhance its physicochemical properties, such as stability and solubility.[24] This is a critical distinction for precise pharmacological and formulation documentation.

• Description: Selumetinib sulfate is the hydrogen sulfate salt of the active selumetinib base.[24]
• Chemical Formula (Sulfate Salt): The addition of sulfuric acid results in the formula C17​H17​BrClFN4​O7​S.[25]
• Molecular Weight (Sulfate Salt): The molecular weight of the salt form is 555.77 g/mol.[25]
• CAS Number (Sulfate Salt): The unique CAS registry number for selumetinib sulfate is 943332-08-9.[25]

Key Database Identifiers

Cross-referencing across scientific and regulatory databases is essential for research and clinical practice. The key identifiers for selumetinib and its sulfate salt are consolidated in Table 2.1.

Table 2.1: Selumetinib Key Identifiers and Properties

Attribute	Value for Selumetinib (Base)	Value for Selumetinib Sulfate
Generic Name	Selumetinib	Selumetinib Sulfate
Brand Name	Koselugo®	Koselugo®
CAS Number	606143-52-6 1	943332-08-9 25
Molecular Formula	C17​H15​BrClFN4​O3​ 1	C17​H17​BrClFN4​O7​S 25
Molecular Weight	457.68 g/mol 1	555.77 g/mol 26
DrugBank ID	DB11689 1	DBSALT002048 22
PubChem CID	10127622 22	16214875 25
ChEMBL ID	CHEMBL1614701 2	CHEMBL2105684 26
UNII	6UH91I579U 2	807ME4B7IJ 25
KEGG ID	D09666 2	D10024 25

[Mechanism of Action and Cellular Pharmacology]

The clinical efficacy of selumetinib is rooted in its precise molecular mechanism, which targets a fundamental signaling pathway that is aberrantly activated in neurofibromatosis type 1 and various cancers.

The RAS/RAF/MEK/ERK Signaling Pathway and its Role in NF1

The mitogen-activated protein kinase (MAPK) cascade, specifically the RAS/RAF/MEK/ERK pathway, is a central signaling axis in human cells. It transduces signals from cell surface receptors to the nucleus, regulating critical cellular processes including proliferation, differentiation, survival, and apoptosis.[1]

In the context of neurofibromatosis type 1, this pathway is constitutively hyperactivated. NF1 is an autosomal dominant genetic disorder caused by mutations in the NF1 gene.[1] This gene encodes neurofibromin, a tumor suppressor protein that functions as a GTPase-activating protein (GAP). Neurofibromin accelerates the conversion of the active, GTP-bound form of RAS to its inactive, GDP-bound state, effectively acting as a brake on the signaling cascade.[1] In individuals with NF1, the loss-of-function mutations in neurofibromin lead to an accumulation of active RAS-GTP. This results in unchecked, persistent downstream signaling through RAF, MEK, and ERK, which drives the uncontrolled cell growth and survival that manifests as plexiform neurofibromas and other tumors.[1] This clear genetic and biochemical lesion makes the RAS/RAF/MEK/ERK pathway an ideal therapeutic target for treating NF1-related pathologies.

Selumetinib's Molecular Target and Binding Mechanism

Selumetinib was specifically designed to intercept this aberrant signaling cascade at a critical juncture.

• Primary Targets: Selumetinib is a potent and highly selective inhibitor of the dual specificity kinases MEK1 (mitogen-activated protein kinase kinase 1) and MEK2.[1] These kinases are positioned directly downstream of RAF and are the sole known activators of ERK1/2.
• Binding Mechanism: A crucial feature of selumetinib is its mechanism of inhibition. It is a non-ATP-competitive, or allosteric, inhibitor.[1] Unlike many kinase inhibitors that compete with adenosine triphosphate (ATP) for the enzyme's active site, selumetinib binds to a distinct pocket adjacent to the ATP binding site. This allosteric binding induces a conformational change that locks the enzyme in an inactive state, preventing it from phosphorylating its substrate, ERK. This mechanism confers a significant advantage; since selumetinib does not have to compete with the high and variable intracellular concentrations of ATP, it can achieve more potent and sustained inhibition.
• Selectivity and Potency: Selumetinib demonstrates remarkable potency and selectivity. It inhibits MEK1 with a half-maximal inhibitory concentration (IC50​) of 14 nM and MEK2 with a dissociation constant (Kd​) of 530 nM.[18] Importantly, comprehensive kinase profiling has shown that selumetinib has minimal activity against a wide panel of over 40 other kinases, including those structurally similar or in related pathways like EGFR, p38α, and even its direct downstream target, ERK2.[18] This high degree of selectivity is a direct result of its unique allosteric binding mechanism and is instrumental in minimizing off-target effects, a property that is particularly vital for a drug intended for chronic administration in a pediatric population.

Pharmacodynamic Effects

By inhibiting MEK1/2, selumetinib produces profound downstream pharmacodynamic effects that counter the consequences of pathway hyperactivation.

• Downstream Inhibition: The primary pharmacodynamic effect of selumetinib is the prevention of MEK-mediated phosphorylation and activation of ERK1 and ERK2.[3] This effectively silences the final effector kinase in the cascade, blocking the transmission of oncogenic signals to the nucleus.
• Cellular Consequences: The blockade of ERK signaling leads to desirable anti-tumor cellular outcomes.[1] These include:
• Inhibition of Cell Proliferation: Selumetinib effectively suppresses the growth of tumor cell lines that harbor activating mutations in upstream components like B-Raf and Ras, which are dependent on the MEK/ERK pathway for their growth.[19]
• Induction of Apoptosis: Beyond simply halting growth (cytostasis), selumetinib actively promotes programmed cell death (apoptosis) in cancer cells by disrupting the pro-survival signals normally transmitted by the pathway.[18]
• In Vivo Evidence: The therapeutic hypothesis was strongly validated in preclinical models. In genetically engineered mouse models that recapitulate human NF1, treatment with selumetinib led to a marked inhibition of ERK phosphorylation within neurofibromas. This biochemical effect translated directly into therapeutic benefit, with significant reductions in neurofibroma number, volume, and proliferation rates.[29] This provided the compelling preclinical proof-of-concept that paved the way for clinical trials.

The mechanism of action also provides a clear rationale for the drug's characteristic safety profile. The MEK/ERK pathway is not exclusive to tumors; it plays a vital role in the normal physiology and turnover of highly proliferative tissues such as the skin, gastrointestinal epithelium, and hair follicles. Therefore, systemic inhibition of this pathway logically results in the most commonly observed on-target adverse events, including acneiform rash, diarrhea, stomatitis, and paronychia.[5] This direct link between the intended mechanism and the side effects is a critical concept for clinicians, as it explains why these toxicities are expected and informs strategies for their management through supportive care and dose modification, rather than being viewed as unexpected or off-target events.

[Comprehensive Pharmacokinetic Profile (ADME)]

The pharmacokinetic (PK) profile of selumetinib, which describes its absorption, distribution, metabolism, and excretion (ADME), governs its dosing regimen, potential for drug interactions, and overall clinical utility. Its properties have been well-characterized in both adult and pediatric populations.

Absorption

Selumetinib is formulated for oral administration and exhibits rapid absorption.

• Bioavailability and Tmax: Following oral administration, selumetinib reaches its maximum plasma concentration (Tmax) quickly, typically within 1 to 1.5 hours.[1] The mean absolute oral bioavailability in healthy adults has been determined to be 62%, indicating good absorption from the gastrointestinal tract.[1]
• Food Effect: The absorption of selumetinib is notably influenced by food. Initial clinical trials and prescribing information mandated a strict fasting schedule, requiring patients to avoid food for 2 hours before and 1 hour after each dose.[31] This was based on early studies in adults showing that a high-fat meal could decrease the peak concentration (Cmax) by 50% and a low-fat meal could decrease Cmax by 60% and the total exposure (Area Under the Curve, AUC) by 38%.[31] This fasting requirement imposed a significant daily burden, totaling six hours, which was particularly challenging for pediatric patients. However, a subsequent dedicated study in the pediatric population demonstrated that while food affected initial absorption rates, it did not have a clinically relevant impact on steady-state drug exposure.[31] This crucial finding led to a label revision by both the FDA and EMA, which now allows Koselugo® to be taken with or without food, representing a major improvement in convenience and quality of life for patients and their families.[31]

Distribution

Once absorbed into the bloodstream, selumetinib distributes extensively throughout the body.

• Volume of Distribution (Vd): The mean apparent volume of distribution at steady state is large, ranging from 78 L to 171 L in pediatric patients.[1] A Vd of this magnitude, far exceeding the volume of total body water, indicates that the drug does not remain confined to the bloodstream but distributes widely into peripheral tissues, which is necessary for it to reach the site of the plexiform neurofibromas.
• Plasma Protein Binding: Selumetinib is highly bound to plasma proteins, with a bound fraction of 98.4%.[1] It binds primarily to serum albumin (96%) and, to a lesser extent, to alpha-1 acid glycoprotein (<35%).[1] This high degree of protein binding has a significant clinical implication: in the event of an overdose, dialysis is unlikely to be an effective method for removing the drug from the body, as only the small unbound fraction is available for clearance by such methods.[1]

Metabolism

Selumetinib is extensively metabolized, primarily in the liver, into numerous metabolites.

• Primary Site and Enzymes: The liver is the main site of selumetinib metabolism.[1] The biotransformation is complex and involves multiple enzymatic pathways. It is a major substrate of the cytochrome P450 enzyme CYP3A4, which accounts for a significant portion of its clearance. To a lesser extent, it is also metabolized by CYP2C19, CYP1A2, CYP2C9, and CYP2E1.[29] In addition to oxidation by CYP enzymes, selumetinib also undergoes direct phase II conjugation via glucuronidation, mediated by UGT1A1 and UGT1A3.[29] This heavy reliance on CYP3A4 is the basis for the clinically significant drug-drug interactions observed with strong inhibitors or inducers of this enzyme.
• Metabolic Pathways and Key Metabolites: The metabolism of selumetinib is intricate. A key pathway involves N-demethylation, primarily via CYP2C19 and CYP1A2, to form the metabolite M8 (N-desmethyl selumetinib).[1] This metabolite is noteworthy because it is also pharmacologically active, retaining MEK inhibitory properties. Although M8 accounts for less than 10% of the circulating parent drug concentration, it is estimated to contribute approximately 21-35% of the overall observed pharmacological effect, making it a significant contributor to the drug's efficacy.[1] Other major pathways include hydrolysis of the amide group and glucuronidation, leading to major circulating metabolites like M2 (an amide glucuronide) and M15 (a carboxylic acid).[1]

Excretion

Metabolized and unchanged selumetinib are cleared from the body through multiple routes.

• Route of Elimination: The primary route of elimination for selumetinib and its metabolites is hepatobiliary, with approximately 59% of an administered dose recovered in the feces. A smaller but substantial portion, around 33%, is eliminated via the kidneys in the urine.[1]
• Half-Life (t1/2​): Selumetinib has a relatively short elimination half-life. In pediatric patients receiving the recommended dose of 25 mg/m², the mean half-life is approximately 6.2 hours.[1] Studies in adults have reported similar values, ranging from 7.5 to 13 hours.[1] This pharmacokinetic property necessitates twice-daily dosing to maintain plasma concentrations within the therapeutic window and ensure continuous inhibition of the MEK pathway.
• Clearance (CL/F): The typical apparent oral clearance of selumetinib, based on a population PK model that included pediatric patients, is 11.6 L/h.[35] A population PK analysis found that body surface area (BSA) was the only covariate with a clinically relevant impact on drug exposure, which provides the rationale for the BSA-based dosing strategy used in children.[35]

Table 4.1: Summary of Selumetinib Pharmacokinetic Parameters

Parameter	Value / Description	Source(s)
Time to Peak (Tmax)	1–1.5 hours	1
Oral Bioavailability	62% (in healthy adults)	1
Food Effect	Cmax and AUC reduced by food, but not clinically significant at steady state in pediatrics. Can be taken with or without food.	31
Volume of Distribution (Vd)	78–171 L (pediatric); indicates extensive tissue distribution.	29
Plasma Protein Binding	98.4% (primarily to albumin)	29
Metabolism Site	Extensive hepatic metabolism	1
Major Metabolizing Enzymes	CYP3A4 (major), CYP2C19, CYP1A2, UGT1A1, UGT1A3	29
Active Metabolite	M8 (N-desmethyl selumetinib); contributes 21-35% of activity.	1
Route of Elimination	~59% in feces, ~33% in urine	1
Elimination Half-Life (t1/2​)	~6.2 hours (pediatric); supports twice-daily dosing.	1
Clearance (CL/F)	~11.6 L/h (pediatric population model)	35

[Clinical Efficacy in Neurofibromatosis Type 1]

The clinical development of selumetinib for neurofibromatosis type 1 culminated in the pivotal SPRINT trial, which provided the definitive evidence of its efficacy and led to its landmark regulatory approvals.

The Pivotal SPRINT Trial (NCT01362803)

The SPRINT trial was the cornerstone of selumetinib's approval. It was a multi-phase study sponsored by the National Cancer Institute's (NCI) Cancer Therapy Evaluation Program (CTEP), a testament to the power of public-sector research in addressing rare diseases.[5]

• Study Design: The study was designed as an open-label, multicenter, Phase I/II trial.[36] The Phase I portion established the recommended Phase II dose, and the Phase II portion (Stratum 1) was designed to evaluate efficacy and served as the primary basis for regulatory approval.[38]
• Patient Population: The Phase II trial enrolled 50 pediatric patients with a median age of 10.2 years (range: 3.5 to 17.4 years).[10] A key eligibility criterion was the presence of NF1 with symptomatic, inoperable plexiform neurofibromas. Inoperability was strictly defined as a PN that could not be completely removed by surgery without a high risk of substantial morbidity (e.g., nerve damage, major disfigurement, organ dysfunction), highlighting the severe unmet medical need of this population.[37]
• Baseline Morbidities: The trial population was heavily affected by their disease. All 50 patients had at least one significant PN-related morbidity at baseline, with a median of three per patient. The most common of these were disfigurement (present in 88% of patients), motor dysfunction (66%), pain (52%), airway dysfunction (32%), visual impairment (20%), and bladder/bowel dysfunction (20%).[37] This context is critical, as it establishes that the goal of therapy was not merely to shrink tumors, but to alleviate these debilitating symptoms.

Primary and Secondary Efficacy Outcomes

The SPRINT trial successfully met its primary and key secondary endpoints, demonstrating both objective tumor responses and tangible clinical benefits for patients.

• Primary Endpoint - Objective Response Rate (ORR): The primary measure of efficacy was the ORR. This was rigorously defined as the percentage of patients who achieved a partial response, specified as a decrease in PN volume of at least 20% from baseline, as measured by volumetric magnetic resonance imaging (MRI).[8] To be counted, this response had to be confirmed on a subsequent MRI scan performed 3-6 months later. The use of volumetric MRI was itself an innovation driven by NCI researchers, as traditional two-dimensional measurements were found to be unreliable for tracking the complex, irregular growth of PNs.[15]
• ORR Results: The trial yielded a remarkably high ORR. According to the NCI investigator assessment, 66% of patients (33 out of 50) had a confirmed partial response.[6] An independent central review of the imaging data, a standard practice for regulatory submission, confirmed an ORR of 44%.[8] All observed responses were partial; no patients experienced complete disappearance of their tumors.[8]
• Duration of Response (DoR): The tumor responses were not transient but were impressively durable. Among the patients who responded, 82% had a sustained response that lasted for at least 12 months.[7] At the time of the primary analysis, the median duration of response had not been reached, indicating that the majority of responders were maintaining their benefit over a long period.[7]
• Secondary Endpoints - Clinical Benefit: The trial's success extended beyond radiographic measurements. Selumetinib treatment led to clinically meaningful improvements in the symptoms and functional impairments caused by the PNs.[9] Key secondary endpoints demonstrated:
• Pain Reduction: After one year of treatment, there was a mean decrease of 2 points on the 11-point Numeric Rating Scale for pain as reported by the children themselves, a change that is widely considered to be clinically meaningful.
• Improved Function and Quality of Life (QoL): Clinically significant improvements were observed in both child- and parent-reported interference of pain with daily functioning (in 38% and 50% of patients, respectively) and in overall health-related QoL (in 48% and 58%, respectively). Furthermore, objective functional outcomes improved, with 56% of patients showing gains in strength and range of motion.[10]

The demonstration of benefit across this spectrum of outcomes—from tumor volume to patient-reported pain and function—was a critical factor in the drug's approval. It showed that the radiographic shrinkage of the tumor translated into a tangible, positive impact on patients' lives. This holistic evidence base, combining objective imaging with patient-centered endpoints, reflects a modern approach to drug evaluation, where the patient's experience is central to defining therapeutic success.

Long-Term Follow-Up and Progression-Free Survival (PFS)

Follow-up data has continued to reinforce the long-term benefits of selumetinib.

• Sustained Benefit: In a long-term follow-up of the SPRINT cohort with a median of 4.4 years of treatment, 74% of the original 50 patients continued to experience either further tumor shrinkage or disease stability, underscoring the durability of the treatment effect.[16]
• Progression-Free Survival (PFS): Because the SPRINT trial was a single-arm study, researchers performed a comparative analysis against a matched control group of patients from an NCI-led NF1 Natural History (NH) study.[43] This analysis showed that treatment with selumetinib dramatically reduced the risk of PN progression. The adjusted hazard ratio for progression was approximately 0.11-0.12, indicating an almost 90% reduction in the risk of tumor growth compared to the natural history of the disease.[43]

Efficacy in Other Populations and Investigational Uses

The success in pediatric NF1 has spurred investigation into other areas.

• Adults with NF1 PN (KOMET Trial): A Phase III, placebo-controlled trial (KOMET) evaluated selumetinib in adults with NF1 and inoperable PN. The study met its primary endpoint, showing a statistically significant ORR of 20% for selumetinib compared to 5% for placebo by cycle 16.[40] While this response rate is lower than that seen in the pediatric population, it still demonstrates activity.
• Other Cancers: As a MEK inhibitor, selumetinib has biological rationale for use in any cancer driven by the MAPK pathway. It has been investigated, both as a monotherapy and in combination, in clinical trials for various solid tumors, including renal cancer, colon cancer, and optic nerve glioma.[45]

Table 5.1: SPRINT Phase II Trial - Key Efficacy Outcomes

Endpoint	Metric / Definition	Result	Source(s)
Primary Endpoint	Objective Response Rate (ORR): ≥20% decrease in PN volume, confirmed	66% (33/50 patients) per NCI assessment	7
Durability	Duration of Response (DoR)	Median DoR not reached; 82% of responders had DoR ≥12 months	7
Pain	Change in Child-Reported Pain Intensity (NRS-11)	Mean decrease of 2 points (clinically meaningful)	10
Quality of Life	Improvement in Child-Reported Overall QoL	48% of patients showed clinically meaningful improvement	10
Function	Improvement in Strength / Range of Motion	56% of patients showed clinically meaningful improvement	10
Progression	Progression-Free Survival (PFS) vs. Natural History Cohort	Adjusted Hazard Ratio ~0.11 (approx. 89% risk reduction)	43

[Safety, Tolerability, and Risk Management]

While selumetinib offers profound efficacy, its use is associated with a significant and predictable spectrum of adverse events that require proactive monitoring and management. The safety profile is consistent with the on-target effects of MEK inhibition and has been characterized extensively in the SPRINT trial and other studies.[7]

Overview of Adverse Event Profile

The overall safety profile is characterized by frequent, mostly low-grade toxicities that are manageable for most patients.

• Dose Modifications: The high frequency of adverse events makes dose adjustments a standard part of therapy. In the pivotal SPRINT trial, a remarkable 80% of patients required at least one temporary dose interruption, and 24% required a permanent dose reduction due to adverse reactions.[5] This indicates that side effect management is not an exception but the norm. However, the rate of permanent discontinuation of the drug due to an adverse event was much lower, at 12%.[5] This discrepancy between the high rate of interruption and the low rate of discontinuation is a crucial finding. It suggests that while side effects are common and often require a treatment break, they are generally manageable to a degree that allows most patients to continue therapy and derive benefit. This underscores a favorable benefit-risk assessment as determined by clinicians and families in a real-world setting.

Common Adverse Reactions (≥40%)

The most common adverse reactions are primarily gastrointestinal and dermatologic, reflecting the role of the MEK pathway in the turnover of these tissues. The following were reported in ≥40% of pediatric patients in SPRINT [5]:

• Gastrointestinal: Vomiting (82%), abdominal pain (76%), diarrhea (77%), nausea (66%), and stomatitis (inflammation of the mouth, 50%).
• Dermatologic: Rash of any type (91%), with the most frequent being dermatitis acneiform (an acne-like rash, 54%), dry skin (60%), paronychia (inflammation of the skin around the nails, 48%), and pruritus (itching, 46%).
• Constitutional/General: Fatigue (56%), pyrexia (fever, 56%), and headache (48%).
• Musculoskeletal: Musculoskeletal pain (58%).

Serious Adverse Reactions and Key Toxicities

Beyond the common side effects, selumetinib carries risks of more serious toxicities that mandate specific monitoring and management protocols. The safety profile necessitates a proactive, multidisciplinary management approach, often involving specialists in cardiology, ophthalmology, and dermatology.

• Cardiomyopathy: A decrease in left ventricular ejection fraction (LVEF), a measure of the heart's pumping function, is a known risk. An asymptomatic decrease in LVEF of ≥10% from baseline occurred in 23% of pediatric patients.[5] While these events were mostly asymptomatic and resolved in 71% of cases, they require diligent monitoring. The prescribing information mandates assessment of LVEF by echocardiogram or cardiac MRI prior to starting treatment, every 3 months during the first year of therapy, and every 6 months thereafter.[5]
• Ocular Toxicity: A range of eye problems can occur, including blurred vision, photophobia, and cataracts.[5] More serious events, though less common, include retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO). RVO is a sight-threatening condition that requires permanent discontinuation of selumetinib. Baseline and regular ophthalmic assessments are required during treatment to detect these changes early.[5]
• Severe Skin and Gastrointestinal Toxicity: While common, rash and diarrhea can become severe. Grade 3 rash occurred in 8% of patients, and Grade 3 diarrhea occurred in 15%.[5] Severe diarrhea requires prompt intervention with anti-diarrheal agents (e.g., loperamide) and increased fluid intake to prevent dehydration.[5]
• Increased Creatinine Phosphokinase (CPK): Elevation of the muscle enzyme CPK is very common, occurring in 76% of patients, with Grade 3 or 4 elevations in 9%.[5] This can be associated with myalgia (muscle pain) and carries a risk of rhabdomyolysis (severe muscle breakdown). Regular monitoring of serum CPK levels is required before and during treatment.[5]
• Increased Vitamin E Levels and Bleeding Risk: The selumetinib capsules contain D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), a form of vitamin E, as an excipient.[5] Vitamin E can inhibit platelet aggregation and antagonize vitamin K, potentially increasing the risk of bleeding, particularly in patients also taking anticoagulants or antiplatelet agents. Supplemental vitamin E is not recommended, and coagulation parameters should be monitored more frequently in patients on vitamin K antagonists.[5]
• Embryo-Fetal Toxicity: Based on animal studies, selumetinib can cause fetal harm. Therefore, it is contraindicated in pregnancy. Females of reproductive potential must have a negative pregnancy test before starting therapy and use effective contraception during treatment and for 1 week after the last dose. Males with female partners of reproductive potential must also use effective contraception during the same period.[5]

Drug-Drug Interactions

Selumetinib's heavy reliance on CYP3A4 for metabolism makes it highly susceptible to clinically significant drug-drug interactions.

• CYP3A4 and CYP2C19 Inhibitors: Co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, clarithromycin) or the dual CYP2C19/3A4 inhibitor fluconazole can significantly increase selumetinib plasma concentrations, thereby increasing the risk of toxicity. If concomitant use cannot be avoided, a dose reduction of selumetinib is required.[5]
• CYP3A4 Inducers: Conversely, co-administration with strong or moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John's Wort) can significantly decrease selumetinib concentrations, potentially reducing its efficacy. Concomitant use of these agents with selumetinib should be avoided.[5]

Table 6.1: Adverse Reactions Reported in ≥40% of Pediatric Patients Treated with Koselugo® in the SPRINT Trial

System Organ Class	Adverse Reaction	Frequency (All Grades)	Frequency (Grade ≥3)
Gastrointestinal Disorders	Vomiting	82%	6%
	Abdominal Pain	76%	2%
	Diarrhea	77%	16%
	Nausea	66%	2%
	Stomatitis	50%	2%
Skin and Subcutaneous Tissue Disorders	Rash (all types)	91%	8%
	Dermatitis acneiform	54%	4%
	Dry Skin	60%	0%
	Paronychia	48%	6%
	Pruritus	46%	0%
General Disorders	Fatigue	56%	4%
	Pyrexia (Fever)	56%	8%
Nervous System Disorders	Headache	48%	2%
Musculoskeletal Disorders	Musculoskeletal Pain	58%	4%
Data derived from SPRINT trial safety population as reported in prescribing information.5

[Dosing, Administration, and Special Populations]

The safe and effective use of selumetinib requires strict adherence to dosing guidelines that are tailored to the individual patient, with specific protocols for administration, dose modification, and use in special populations.

Recommended Dosing Regimen

Selumetinib dosing is individualized to account for differences in patient size, a standard practice in pediatric oncology.

• Dosage: The recommended dose of Koselugo® is 25 mg/m² of body surface area (BSA), administered orally twice daily.[8] The two doses should be taken approximately 12 hours apart to maintain steady therapeutic concentrations.
• BSA-Based Dosing and Formulation: Dosing is calculated based on the patient's BSA and then rounded to the nearest achievable 5 mg or 10 mg increment. Koselugo® is available as 10 mg and 25 mg hard capsules, which can be used in combination to achieve the prescribed dose.[33] The maximum recommended single dose is 50 mg. Because a child's BSA changes with growth, it is important for clinicians to periodically reassess BSA and adjust the dose accordingly. Table 7.1 outlines the specific dosing based on BSA ranges as per the European prescribing information.

Method of Administration

Proper administration is crucial to ensure consistent drug absorption and efficacy.

• Capsule Integrity: Patients must be instructed to swallow the capsules whole with water. The capsules should not be chewed, dissolved, or opened.[6] This is because the capsule formulation is designed for a specific release profile, and altering it could impair drug absorption and performance. This requirement can pose a significant challenge for very young children or patients with swallowing difficulties, and the ability to swallow capsules should be assessed before prescribing.
• Food Intake: As a result of updated clinical data, Koselugo® can be administered with or without food.[31] This represents a significant change from the initial protocol, which required a strict fasting period, and greatly improves the convenience and feasibility of the twice-daily regimen for patients and their families.

Dose Modifications for Adverse Reactions

Given the high frequency of adverse events, a clear, structured plan for dose modification is a cornerstone of selumetinib therapy.

• General Dose Reduction Schedule: The prescribing information provides a two-step dose reduction schedule. For a Grade 2 (intolerable) or Grade 3/4 adverse reaction, treatment should be interrupted until the toxicity resolves to Grade 1 or better. Therapy can then be resumed at the next lower dose level. If a patient is unable to tolerate the dose after two reductions, Koselugo® should be permanently discontinued.[33]
• Specific Toxicity Management: Detailed guidance is provided for managing key serious toxicities. For example, in the case of asymptomatic LVEF reduction, treatment is interrupted, and cardiac function is monitored frequently. For RPED, treatment is withheld until resolution and then resumed at a reduced dose. For RVO, treatment must be permanently discontinued.[5]

Use in Special Populations

Dose adjustments are required for certain patient populations.

• Pediatric Use: Selumetinib is approved for pediatric patients aged 2 years and older in the US and 3 years and older in the EU.[5] Its safety and efficacy have not been established in children younger than 2 years of age.[11] Recognizing the challenge of capsule administration in the youngest patients, an age-appropriate granule formulation is under development to improve access for this group.[14]
• Hepatic Impairment: The liver is the primary site of selumetinib metabolism. No dose adjustment is necessary for patients with mild hepatic impairment (Child-Pugh A). However, for patients with moderate hepatic impairment (Child-Pugh B), the starting dose should be reduced to 20 mg/m² twice daily.[32] The drug is not recommended for patients with severe hepatic impairment (Child-Pugh C), as its safety in this group has not been established.[32]
• Pregnancy and Lactation: Selumetinib is contraindicated during pregnancy due to the risk of embryo-fetal harm. Due to the potential for adverse reactions in a breastfed child, women are advised not to breastfeed during treatment and for 1 week after the final dose.[5]

Table 7.1: Recommended Dosing and Dose Adjustments for Koselugo® (Based on EMA Prescribing Information)

Part A: Initial Dosing Based on Body Surface Area (BSA)

BSA Range (m2)	Initial Koselugo® Dose (Twice Daily)
0.55 – 0.69	20 mg morning, 10 mg evening
0.70 – 0.89	20 mg twice daily
0.90 – 1.09	25 mg twice daily
1.10 – 1.29	30 mg twice daily
1.30 – 1.49	35 mg twice daily
1.50 – 1.69	40 mg twice daily
1.70 – 1.89	45 mg twice daily
≥ 1.90	50 mg twice daily

Part B: Dose Reduction Schedule for Adverse Reactions

Initial Dose (mg/twice daily)	First Dose Reduction (mg/twice daily)	Second Dose Reduction (mg/twice daily)
25 mg	20 mg	15 mg (or 20 mg morning, 10 mg evening)
20 mg	15 mg (or 20 mg morning, 10 mg evening)	10 mg
Specific dose reductions vary by initial BSA-based dose. Permanently discontinue if unable to tolerate after two reductions. Refer to full prescribing information for complete tables.33

Part C: Dose Adjustments for Special Conditions

Condition	Recommended Dose Adjustment
Moderate Hepatic Impairment (Child-Pugh B)	Reduce starting dose to 20 mg/m² twice daily.
Coadministration with Strong/Moderate CYP3A4/2C19 Inhibitors	Reduce dose (e.g., from 25 mg/m² to 20 mg/m²). Avoid if possible.

[Regulatory and Commercial Trajectory]

The path of selumetinib from an investigational compound to a globally approved therapy is a compelling story of strategic partnership, scientific rigor, and efficient regulatory navigation, driven by the profound unmet need in the NF1 community.

Development and Commercialization

Selumetinib's development involved key collaborations that were essential to its success.

• Origin: The compound, originally known as ARRY-142886, was discovered and initially developed by Array BioPharma Inc. It was subsequently licensed by AstraZeneca in 2003, where it was given the development code AZD6244.[12]
• Strategic Collaboration: A pivotal moment in its commercial trajectory occurred in July 2017, when AstraZeneca and Merck & Co., Inc. (known as MSD outside the United States and Canada) entered into a global strategic oncology collaboration. This agreement included the co-development and co-commercialization of selumetinib for multiple cancer types.[5] This partnership combined the resources and expertise of two pharmaceutical giants to advance the drug through late-stage clinical trials and global regulatory submissions. Under the terms of the agreement, AstraZeneca is responsible for manufacturing and booking product sales, with profits being shared with Merck.[5]

Regulatory Milestones and Expedited Approvals

The compelling data from the SPRINT trial and the serious, life-altering nature of inoperable PN in children prompted regulatory agencies to grant selumetinib access to their most rapid review pathways. The sequential granting of these designations illustrates the drug's perceived importance and the strength of its clinical data.

• Orphan Drug Designation: Recognizing NF1 as a rare disease, both the U.S. FDA (in February 2018) and the European Medicines Agency (EMA) (in August 2018) granted selumetinib Orphan Drug Designation. This status provides incentives to encourage the development of drugs for rare conditions.[6]
• Breakthrough Therapy Designation: In April 2019, the FDA granted selumetinib Breakthrough Therapy Designation. This is reserved for drugs intended to treat a serious condition where preliminary clinical evidence indicates a substantial improvement over available therapies on a clinically significant endpoint.[9]
• Priority Review: The FDA also granted Priority Review, which shortens the target review timeline from the standard 10 months to 6 months. This is granted to drugs that, if approved, would offer significant improvements in the safety or effectiveness of the treatment of serious conditions.[8]

The combination of these expedited pathways demonstrates a highly functional regulatory system working to accelerate patient access to a transformative therapy. The journey from the New Drug Application submission in November 2019 to full approval in April 2020 took less than six months, a testament to the urgency and clarity of the clinical evidence.[13]

Global Marketing Authorizations

Following the successful clinical trials, selumetinib achieved landmark approvals in major markets around the world.

• U.S. FDA Approval: On April 10, 2020, the FDA approved Koselugo® for the treatment of pediatric patients aged 2 years and older with NF1 who have symptomatic, inoperable PN.[1] This was a historic moment, as selumetinib became the first-ever medical therapy approved by the FDA for this debilitating condition.[8]
• EU EMA Approval: The EMA followed suit, granting a conditional marketing authorisation on June 17, 2021, based on a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in April 2021. The European approval is for pediatric patients aged 3 years and above.[6] The "conditional" status means the approval is based on a positive benefit-risk balance from the available data, but the company is required to provide additional, comprehensive long-term data from ongoing studies to confirm its safety and efficacy over time.[6]
• Other Approvals: Selumetinib has also secured approvals in numerous other regions, including in Canada by Health Canada on August 23, 2022, solidifying its status as the global standard of care for this indication.[1]

[Synthesis and Future Perspectives]

The approval and clinical integration of selumetinib mark a watershed moment for patients with neurofibromatosis type 1 and a significant milestone in the field of targeted therapy. Its story offers a blueprint for rare disease drug development and opens new avenues for future research.

Concluding Synthesis of Benefit-Risk Profile

Selumetinib presents a clear and highly favorable benefit-risk profile for its approved indication. It offers unprecedented, durable efficacy in a patient population that previously had no approved medical therapies. The primary benefit is the objective, radiographically confirmed shrinkage of inoperable plexiform neurofibromas in a majority of pediatric patients. Crucially, this tumor reduction translates into clinically meaningful improvements in pain, motor function, and overall quality of life. This profound benefit is balanced against a safety profile characterized by frequent, predictable, and largely manageable on-target toxicities. While the high rate of adverse events necessitates a rigorous and proactive multidisciplinary management strategy involving dose modifications and specialized monitoring, the low rate of permanent treatment discontinuation demonstrates that, for most patients, the therapeutic gains substantially outweigh the challenges of treatment.

Paradigm Shift in NF1 Management

The advent of selumetinib has fundamentally transformed the management of NF1-related plexiform neurofibromas. It has moved the clinical paradigm away from a passive "watch and wait" approach or a reliance on high-risk surgery, to a new era of proactive, targeted medical intervention. For the first time, clinicians can offer a therapy that directly targets the underlying molecular driver of tumor growth. This has not only provided a vital new treatment option but has also brought a new sense of hope and empowerment to a patient community long underserved by medical innovation.[9]

A Model for Rare Disease Drug Development

The successful development of selumetinib serves as an exemplary case study for navigating the complexities of rare disease research. Several key factors contributed to its success and offer lessons for future endeavors:

1. Foundational Public Research: The entire clinical development program was built upon a bedrock of over 30 years of research into NF1 biology conducted and supported by the National Cancer Institute. This long-term public investment was indispensable.[15]
2. Development of Novel Clinical Endpoints: The NCI's development and validation of volumetric MRI as a sensitive and reliable method for measuring PN tumor volume was a critical enabling technology. Without this tool, accurately assessing the primary endpoint of the SPRINT trial would have been impossible.[15]
3. Effective Collaboration: The journey involved seamless collaboration between government (NCI), academia, patient advocacy groups (e.g., Children's Tumor Foundation), and industry (AstraZeneca/Merck). This synergistic model leveraged the strengths of each partner.[14]
4. Efficient Regulatory Strategy: The effective use of the full suite of expedited regulatory pathways (Orphan Drug, Breakthrough Therapy, Priority Review) ensured that this transformative therapy reached patients in the shortest possible time frame once its benefits were clear.[8]

Future Perspectives and Unanswered Questions

While selumetinib is a major advance, its success raises new questions and defines the next frontier of research in NF1 and MEK inhibition.

• Ongoing Research: The field continues to move forward with several key initiatives:
• Improved Formulations: An age-appropriate granule formulation is being developed to improve administration and access for the youngest children who cannot swallow capsules.[49]
• Adult Population: The KOMET trial has established efficacy in adults, and further data will refine its role in this population.[40]
• Long-Term Outcomes: Continued follow-up of the SPRINT cohort is essential to understand the ultimate duration of benefit, the evolution of the safety profile over many years, and whether early treatment can alter the natural history of the disease.
• Expanded Indications: Research is ongoing to explore selumetinib's utility for other NF1-related complications, such as optic nerve gliomas, and in other cancers driven by the MAPK pathway.[46]
• Key Unanswered Questions: The future research agenda will be shaped by several critical questions:
• What is the optimal duration of therapy? Is lifelong treatment necessary, or can therapy be stopped after a maximal response is achieved?
• Can selumetinib prevent the malignant transformation of benign PNs into highly aggressive malignant peripheral nerve sheath tumors (MPNST), a major cause of mortality in NF1?
• Can selumetinib be combined with other targeted agents or treatment modalities to enhance efficacy, overcome resistance, or reduce toxicity?

Answering these questions will be essential to fully realizing the potential of MEK inhibition and continuing to improve the lives of individuals affected by neurofibromatosis type 1.

Works cited

1. Selumetinib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 3, 2025, https://go.drugbank.com/drugs/DB11689
2. Selumetinib | C17H15BrClFN4O3 | CID 10127622 - PubChem, accessed August 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Selumetinib
3. Selumetinib (AZD6244) | MEK1/2 Inhibitor | MedChemExpress, accessed August 3, 2025, https://www.medchemexpress.com/Selumetinib.html
4. Selumetinib (oral route) - Side effects & dosage - Mayo Clinic, accessed August 3, 2025, https://www.mayoclinic.org/drugs-supplements/selumetinib-oral-route/description/drg-20488206
5. KOSELUGO® (selumetinib) Approved by FDA for Pediatric Patients ..., accessed August 3, 2025, https://www.merck.com/news/koselugo-selumetinib-approved-by-fda-for-pediatric-patients-two-years-and-older-with-neurofibromatosis-type-1-and-symptomatic-inoperable-plexiform-neurofibromas/
6. Koselugo | European Medicines Agency (EMA), accessed August 3, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/koselugo
7. FDA Approval Summary: Selumetinib for Plexiform Neurofibroma - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/33712511/
8. FDA approves selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas, accessed August 3, 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-neurofibromatosis-type-1-symptomatic-inoperable-plexiform-neurofibromas
9. Selumetinib Approved by FDA to Treat Children with NF1 - NCI, accessed August 3, 2025, https://www.cancer.gov/news-events/cancer-currents-blog/2020/selumetinib-nf1-fda-approval
10. Selumetinib in Children with Inoperable Plexiform Neurofibromas - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/32187457/
11. Koselugo® (selumetinib) | Official Caregiver Website, accessed August 3, 2025, https://koselugo.com/
12. Selumetinib granted US Breakthrough Therapy Designation in neurofibromatosis type 1 - AstraZeneca, accessed August 3, 2025, https://www.astrazeneca.com/media-centre/press-releases/2019/selumetinib-granted-us-breakthrough-therapy-designation-in-neurofibromatosis-type-1-01042019.html
13. Koselugo (selumetinib) FDA Approval History - Drugs.com, accessed August 3, 2025, https://www.drugs.com/history/koselugo.html
14. Koselugo approved in the EU for children with neurofibromatosis ..., accessed August 3, 2025, https://www.astrazeneca.com/media-centre/press-releases/2021/koselugo-approved-in-the-eu-for-children-with-neurofibromatosis-type-1-and-plexiform-neurofibromas.html
15. The Discovery of Selumetinib for Kids with NF1 - NCI, accessed August 3, 2025, https://www.cancer.gov/research/progress/discovery/selumetinib-plexiform-neurofibromas
16. Why Koselugo, accessed August 3, 2025, https://koselugo.com/why-koselugo
17. koselugo.com, accessed August 3, 2025, https://koselugo.com/why-koselugo#:~:text=KOSELUGO%C2%AE%20(selumetinib)%20is%20the,the%20brand%20name%20for%20selumetinib.
18. AZD 6244 (CAS 606143-52-6) - Cayman Chemical, accessed August 3, 2025, https://www.caymanchem.com/product/11599/azd-6244
19. Selumetinib | Megalin/LRP2 - R&D Systems, accessed August 3, 2025, https://www.rndsystems.com/products/selumetinib_6815
20. Selumetinib | CAS 606143-52-6 | SCBT - Santa Cruz Biotechnology, accessed August 3, 2025, https://www.scbt.com/p/selumetinib-606143-52-6
21. Selumetinib, 606143-52-6, 98 (HPLC) Sigma-Aldrich, accessed August 3, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sml3800
22. Selumetinib - Wikipedia, accessed August 3, 2025, https://en.wikipedia.org/wiki/Selumetinib
23. selumetinib | Ligand page | IUPHAR/BPS Guide to, accessed August 3, 2025, https://www.guidetoimmunopharmacology.org/GRAC/LigandDisplayForward?ligandId=5665
24. Definition of selumetinib sulfate - NCI Drug Dictionary, accessed August 3, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/selumetinib-sulfate
25. Selumetinib Sulfate | C17H17BrClFN4O7S | CID 16214875 - PubChem, accessed August 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/16214875
26. Compound: SELUMETINIB SULFATE (CHEMBL2105684) - ChEMBL - EMBL-EBI, accessed August 3, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL2105684
27. go.drugbank.com, accessed August 3, 2025, https://go.drugbank.com/drugs/DB11689#:~:text=Selumetinib%20exerts%20its%20effects%20by,Raf%2DMEK%2DERK%20cascade.&text=By%20inhibiting%20this%20oncogenic%20pathway,promotes%20pro%2Dapoptotic%20signal%20transduction.
28. What is the mechanism of Selumetinib? - Patsnap Synapse, accessed August 3, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-selumetinib
29. Selumetinib | Drug Lookup | Pediatric Care Online - AAP Publications, accessed August 3, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/6262/Selumetinib
30. Clinical Pharmacokinetics and Pharmacodynamics of Selumetinib - PMC - PubMed Central, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7935771/
31. Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas | Neuro-Oncology Advances | Oxford Academic, accessed August 3, 2025, https://academic.oup.com/noa/article/6/1/vdae036/7630392
32. FDA News: Issue 6, Apri 2020 - ASCPT, accessed August 3, 2025, [https://www.ascpt.org/Resources/ASCPT-News/View/articleid/24858?dnnprintmode=true&mid=16095&SkinSrc=[G]Skins%2F_default%2FNo+Skin&ContainerSrc=[G]Containers%2F_default%2FNo+Container](https://www.google.com/url?q=https://www.ascpt.org/Resources/ASCPT-News/View/articleid/24858?dnnprintmode%3Dtrue%26mid%3D16095%26SkinSrc%3D%255BG%255DSkins/_default/No%2BSkin%26ContainerSrc%3D%255BG%255DContainers/_default/No%2BContainer&sa=D&source=editors&ust=1754211741543090&usg=AOvVaw07L5k2oi7LKfnBAC36SU6L)
33. Koselugo, INN-selumetinib - EMA, accessed August 3, 2025, https://www.ema.europa.eu/en/documents/product-information/koselugo-epar-product-information_en.pdf
34. Events and resources to help you stay informed - Koselugo® (selumetinib), accessed August 3, 2025, https://koselugo.com/resources
35. Population pharmacokinetics and exposure-response of selumetinib and its N-desmethyl metabolite in pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/33903938/
36. Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas | Neuro-Oncology | Oxford Academic, accessed August 3, 2025, https://academic.oup.com/neuro-oncology/article/25/10/1883/7146403
37. SPRINT: a landmark study in the treatment of NF1 PN 1,2 - Koselugo HCP, accessed August 3, 2025, https://koselugohcp.com/study-design-moa
38. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/28029918/
39. (PDF) Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT - ResearchGate, accessed August 3, 2025, https://www.researchgate.net/publication/378394328_Selumetinib_for_children_with_neurofibromatosis_type_1_and_plexiform_neurofibromas_A_plain_language_summary_of_SPRINT
40. Efficacy of Selumetinib in Reducing Plexiform Neurofibroma Volume in Adults with Neurofibromatosis Type 1 | ESMO, accessed August 3, 2025, https://www.esmo.org/oncology-news/efficacy-of-selumetinib-in-reducing-plexiform-neurofibroma-volume-in-adults-with-neurofibromatosis-type-1
41. LESS MORE - Koselugo® (selumetinib), accessed August 3, 2025, https://koselugo.com/Content/koselugo_com/content/dam/open-digital/koselugo-dtc/en/pdfs/Koselugo-Patient-Caregiver-Brochure.pdf
42. Koselugo® (selumetinib) | Official HCP Website, accessed August 3, 2025, https://koselugohcp.com/
43. Selumetinib in pediatric patients with neurofibromatosis ... - ISPOR, accessed August 3, 2025, https://www.ispor.org/docs/default-source/intl2023/ispor23adeyemiposter-pdf.pdf?sfvrsn=edbeeb5c_0
44. Selumetinib in pediatric patients with neurofibromatosis type 1 and plexiform neurofibroma: Propensity score analysis of SPRINT vs. natural history control arm | Neuro-Oncology Advances | Oxford Academic, accessed August 3, 2025, https://academic.oup.com/noa/advance-article/doi/10.1093/noajnl/vdaf101/8134166
45. Selumetinib Active Not Recruiting Phase 1 Trials for Renal Cancer / Colon Neoplasm / Colon Cancer Treatment | DrugBank Online, accessed August 3, 2025, https://go.drugbank.com/drugs/DB11689/clinical_trials?conditions=DBCOND0029029%2CDBCOND0032053%2CDBCOND0032584&phase=1&purpose=treatment&status=active_not_recruiting
46. Selumetinib Completed Phase 2 Trials for Neurofibromatosis Type 1 / Neurofibromas, Cutaneous / Optic Nerve Glioma Treatment - DrugBank, accessed August 3, 2025, https://go.drugbank.com/drugs/DB11689/clinical_trials?conditions=DBCOND0164397%2CDBCOND0029664%2CDBCOND0001189&phase=2&purpose=treatment&status=completed
47. Pediatric Cancer Recruiting Phase 1 / 2 Trials for Selumetinib (DB11689) | DrugBank Online, accessed August 3, 2025, https://go.drugbank.com/indications/DBCOND0028140/clinical_trials/DB11689?phase=1%2C2&status=recruiting
48. Koselugo® (selumetinib) | Dosing - Koselugo HCP, accessed August 3, 2025, https://koselugohcp.com/dosing
49. Study Results | Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With NF1-related Symptomatic, Inoperable PN | ClinicalTrials.gov, accessed August 3, 2025, https://clinicaltrials.gov/study/NCT05309668?term=NCT02407405%20NCT04495127%20NCT05101148%20NCT05253131%20NCT05309668&rank=1&tab=results
50. Selumetinib recommended for approval in the EU by CHMP as the first medicine for paediatric patients with neurofibromatosis type 1 and plexiform neurofibromas - AstraZeneca, accessed August 3, 2025, https://www.astrazeneca.com/media-centre/press-releases/2021/selumetinib-recommended-for-eu-approval-in-nf1.html
51. Human medicines European public assessment report (EPAR): Koselugo, selumetinib, Date of authorisation: 17/06/2021, Revision: 6, Status, accessed August 3, 2025, https://efim.org/node/140609
52. Full article: Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT - Taylor & Francis Online, accessed August 3, 2025, https://www.tandfonline.com/doi/full/10.2217/fon-2023-0565
53. Selumetinib for children with neurofibromatosis type 1 and plexiform neurofibromas: A plain language summary of SPRINT - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/38869947/