Mavorixafor (Xolremdi®): A Comprehensive Monograph on a First-in-Class CXCR4 Antagonist for WHIM Syndrome and Beyond

1.0 Executive Summary

Mavorixafor, marketed as Xolremdi®, represents a landmark achievement in the field of precision medicine for rare immunological disorders. It is a first-in-class, orally administered, selective antagonist of the C-X-C chemokine receptor 4 (CXCR4). The drug's development and approval are founded on a sophisticated understanding of the pathophysiology of WHIM (Warts, Hypogammoglobulinemia, Infections, and Myelokathexis) syndrome, a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. By directly targeting the underlying genetic defect, Mavorixafor corrects the pathological retention of neutrophils and lymphocytes in the bone marrow, a mechanism that distinguishes it from previous supportive therapies.

The United States Food and Drug Administration (FDA) granted approval for Mavorixafor in April 2024 for the treatment of WHIM syndrome in patients aged 12 years and older. This decision was based on the robust and clinically meaningful results of the pivotal 4WHIM Phase 3 trial. The study unequivocally met its primary and key secondary endpoints, demonstrating a highly statistically significant increase in the time that absolute neutrophil counts (TATANC) and absolute lymphocyte counts (TATALC) were maintained above clinically relevant thresholds. More importantly, this hematologic correction translated into tangible clinical benefits, including a 60% reduction in the annualized infection rate and a 40% reduction in a composite score of infection severity and frequency compared to placebo.

While Mavorixafor's efficacy is clear, its clinical use requires careful management of a complex safety and pharmacokinetic profile. The drug exhibits a concentration-dependent risk of QTc interval prolongation, necessitating baseline and periodic monitoring in at-risk individuals. Furthermore, Mavorixafor is a potent inhibitor of the CYP2D6 metabolic enzyme and interacts with the CYP3A4 and P-glycoprotein pathways, leading to a significant potential for drug-drug interactions that require strict contraindications and dose adjustments. Its absorption is also profoundly reduced by food, mandating a rigid dosing schedule in a fasted state to ensure therapeutic efficacy.

Beyond WHIM syndrome, Mavorixafor is being actively investigated for other conditions where CXCR4 dysregulation is implicated. Promising Phase 2 data in chronic neutropenia have shown that Mavorixafor can durably increase neutrophil counts and, critically, allow for a significant reduction in the use of injectable granulocyte colony-stimulating factor (G-CSF), suggesting a potential paradigm shift in the management of these disorders. Early-stage trials in oncology, including melanoma and Waldenström's macroglobulinemia, are exploring its potential to modulate the tumor microenvironment and enhance the efficacy of other cancer therapies.

In conclusion, Mavorixafor is a transformative therapy that has established a new standard of care for WHIM syndrome. Its approval validates the CXCR4 pathway as a critical therapeutic target and highlights the success of a mechanistically driven drug development strategy. Its future potential in chronic neutropenia and oncology is substantial, though contingent on the outcomes of ongoing pivotal trials and the successful navigation of its intricate safety and drug interaction profile in broader patient populations.

2.0 Introduction and Drug Identification

Mavorixafor is a novel, small-molecule therapeutic agent that signifies a major advancement in the targeted treatment of rare primary immunodeficiencies.[1] As the first and only therapy specifically developed and approved for WHIM syndrome (Warts, Hypogammoglobulinemia, Infections, and Myelokathexis), it addresses a long-standing unmet medical need for a patient population previously reliant on supportive care.[2] Its mechanism, which directly counteracts the genetic defect underlying the disease, positions it as a paradigm of modern precision medicine.

2.1 Nomenclature and Classification

The drug is identified through a standardized set of names and codes used across clinical, regulatory, and research domains.

• Generic Name: The internationally recognized nonproprietary name for the active substance is Mavorixafor.[5]
• Brand Name: In the United States, Mavorixafor is marketed under the proprietary brand name Xolremdi®.[5]
• Developmental Codes: Throughout its research and development history, Mavorixafor has been referred to by several codes, including X4P-001, AMD-070, and AMD-11070.[5]
• Therapeutic Category: Mavorixafor is classified as a CXC Chemokine Receptor 4 (CXCR4) Antagonist.[3] The U.S. FDA considers it to be a first-in-class medication, highlighting its novel mechanism of action.[5] Its Anatomical Therapeutic Chemical (ATC) classification code, as assigned by the World Health Organization (WHO), is L03AX24.[5]

2.2 Historical Context and Development

The clinical development pathway of Mavorixafor is a compelling example of strategic drug repurposing driven by an evolving understanding of molecular biology. The compound was originally synthesized and investigated by AnorMED, with its initial therapeutic focus being the treatment of Human Immunodeficiency Virus (HIV) infections.[6] This initial direction was based on the well-established role of the CXCR4 receptor as a critical co-receptor for the entry of certain strains of HIV into T-cells.[11]

Subsequently, the asset was acquired and its development was advanced by X4 Pharmaceuticals, a company headquartered in Boston, Massachusetts, with a research center of excellence in Vienna, Austria.[2] X4 Pharmaceuticals strategically pivoted the development program away from the competitive and complex HIV market towards rare diseases and oncology.[1] This decision was predicated on the seminal discovery that gain-of-function mutations in the

CXCR4 gene are the direct monogenic cause of WHIM syndrome.[2]

This strategic reorientation from a broad, pathogen-focused application to a highly specific, host-focused genetic target represents a sophisticated approach to modern drug development. By targeting the fundamental cause of a rare disease, the company could pursue a more streamlined clinical and regulatory path, often benefiting from programs like Orphan Drug Designation. This pivot required a deep mechanistic understanding of the CXCR4 signaling axis and its dysregulation in disease. The ultimate success of this strategy, culminating in the first-ever FDA approval for a WHIM syndrome therapy, validates the value of mechanistically driven repurposing and precision targeting in drug development.[3]

3.0 Chemical Profile and Properties

A comprehensive understanding of Mavorixafor's chemical and physical properties is fundamental to its pharmacological characterization, formulation development, and analytical identification. The molecule is a synthetic organic compound belonging to the benzimidazole class.[3]

3.1 Chemical Structure

The two-dimensional chemical structure of Mavorixafor is depicted below.

3.2 Systematic Name and Key Identifiers

Mavorixafor is systematically named according to IUPAC nomenclature as N'-(1H-benzimidazol-2-ylmethyl)-N'-butane-1,4-diamine.[3] The "(8S)" designation specifies the stereochemistry at the chiral center of the tetrahydroquinoline ring, which is critical for its biological activity. A comprehensive list of its key chemical and database identifiers is provided in Table 3.1.

3.3 Molecular Formula and Weight

The molecular composition and mass of Mavorixafor are precisely defined:

• Molecular Formula: C21​H27​N5​.[3]
• Average Molecular Weight: 349.482 g·mol⁻¹.[5] Other sources report this value rounded to 349.5 g/mol.[3]
• Monoisotopic Mass: 349.226645889 Da, representing the mass of the molecule with the most common isotopes of its constituent atoms.[15]

3.4 Structural Codes

For computational chemistry and database informatics, Mavorixafor is represented by several standardized structural codes:

• SMILES (Simplified Molecular-Input Line-Entry System): C1C[C@@H](C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3.[3] The @@ notation specifies the (S)-stereochemistry at the chiral carbon.
• InChI (International Chemical Identifier): InChI=1S/C21H27N5/c22-12-3-4-14-26(15-20-24-17-9-1-2-10-18(17)25-20)19-11-5-7-16-8-6-13-23-21(16)19/h1-2,6,8-10,13,19H,3-5,7,11-12,14-15,22H2,(H,24,25)/t19-/m0/s1.[3]
• InChIKey: WVLHHLRVNDMIAR-IBGZPJMESA-N.[3] This hashed version of the InChI is used for database lookups.

3.5 Physicochemical Properties

• Physical Form and Formulation: Mavorixafor is a crystalline solid in its pure form.[9] For clinical use, it is formulated into 100 mg opaque hard gelatin capsules. These capsules have a white body imprinted with "100 mg" and a light blue cap imprinted with "MX4" for oral administration.[18] The inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium lauryl sulfate, and sodium stearyl fumarate.[19]
• Solubility: The compound is reported to be soluble in dimethyl sulfoxide (DMSO), a common solvent for in vitro biological assays.[9]
• Stability: Under appropriate storage conditions (-20°C for research-grade material), Mavorixafor is stable for at least four years.[9]

Table 3.1: Chemical Identifiers and Properties of Mavorixafor

Property	Identifier / Value	Source(s)
Generic Name	Mavorixafor	5
Brand Name	Xolremdi®	5
Drug Class	CXC Chemokine Receptor 4 (CXCR4) Antagonist	3
IUPAC Name	N'-(1H-benzimidazol-2-ylmethyl)-N'-butane-1,4-diamine	3
Molecular Formula	C21​H27​N5​	3
Molar Mass (Average)	349.482 g·mol⁻¹	5
CAS Number	558447-26-0	3
DrugBank ID	DB05501	3
PubChem CID	11256587	5
SMILES String	C1C[C@@H](C2=C(C1)C=CC=N2)N(CCCCN)CC3=NC4=CC=CC=C4N3	3
InChIKey	WVLHHLRVNDMIAR-IBGZPJMESA-N	3

4.0 Mechanism of Action and Pharmacodynamics

The therapeutic effect of Mavorixafor is rooted in its precise and potent modulation of the CXCR4/CXCL12 signaling axis, a fundamental pathway in immunology and hematology. Its mechanism of action directly addresses the molecular pathology of WHIM syndrome, making it a quintessential example of a targeted therapy.

4.1 The CXCR4/CXCL12 Signaling Axis and its Dysregulation in WHIM Syndrome

4.1.1 Normal Physiology

The C-X-C chemokine receptor type 4 (CXCR4) is a seven-transmembrane G protein-coupled receptor (GPCR) that is widely expressed on various cell types, including hematopoietic stem cells, mature lymphocytes, neutrophils, and fibroblasts.[13] Its sole identified endogenous ligand is the chemokine CXCL12, also known as Stromal Cell-Derived Factor-1α (SDF-1α).[7] The interaction between CXCR4 and CXCL12, which is highly expressed by bone marrow stromal cells, governs a multitude of physiological processes. Most critically, this axis regulates the trafficking, homing, and retention of leukocytes within the bone marrow microenvironment, ensuring a proper balance between the bone marrow reserve and the pool of circulating immune cells.[1]

4.1.2 Pathophysiology in WHIM Syndrome

WHIM syndrome is a rare, autosomal dominant primary immunodeficiency directly caused by heterozygous gain-of-function mutations in the CXCR4 gene.[2] The majority of these mutations are nonsense or frameshift variants that lead to the truncation of the receptor's cytoplasmic C-terminal tail.[16] This region of the receptor is crucial for initiating the normal processes of desensitization and internalization following ligand binding. Without it, the mutated CXCR4 receptor fails to properly downregulate its signaling upon stimulation by CXCL12.[15]

This genetic defect results in a state of receptor hyperactivation. The mutated CXCR4 exhibits an exaggerated and prolonged response to CXCL12, leading to the overactivation of downstream signaling pathways, including the ERK and AKT pathways.[15] The primary clinical consequence of this unchecked signaling is the pathological retention of mature neutrophils and lymphocytes within the bone marrow.[1] This phenomenon, termed myelokathexis for neutrophils, results in severe chronic neutropenia and lymphopenia in the peripheral blood, rendering patients highly susceptible to recurrent bacterial and viral infections.[1]

4.2 Mavorixafor's Antagonistic Action on the CXCR4 Receptor

4.2.1 Molecular Interaction and Selectivity

Mavorixafor is a potent, selective, and orally bioavailable allosteric antagonist of the CXCR4 receptor.[3] It functions by selectively binding to the CXCR4 receptor, thereby physically blocking the binding of its ligand, CXCL12.[1] This competitive inhibition prevents the activation of the receptor and the subsequent initiation of downstream intracellular signaling cascades that are pathologically amplified in WHIM syndrome.[13]

The potency of Mavorixafor is high, with a half-maximal inhibitory concentration (IC50​) of 13 nM in radioligand binding assays.[9] Its selectivity is a key attribute for a favorable safety profile. Mavorixafor shows negligible activity against a panel of other related chemokine receptors, including CCR1, CCR2b, CCR4, CCR5, CXCR1, and CXCR2, with

IC50​ values for these receptors all exceeding 10 µM.[9] This high degree of selectivity ensures that its pharmacological effects are confined to the intended CXCR4 target, minimizing the potential for off-target adverse events.

4.2.2 Efficacy on Mutated Receptors

A critical feature of Mavorixafor's mechanism is its ability to act effectively on both wild-type and the mutated CXCR4 variants that cause WHIM syndrome.[7] By inhibiting the aberrant response to CXCL12 regardless of the receptor's mutational status, Mavorixafor directly addresses the core genetic defect of the disease, rather than merely managing its downstream consequences.

4.3 Pharmacodynamic Effects: Mobilization of Neutrophils and Lymphocytes

The primary pharmacodynamic effect of Mavorixafor is the direct result of its CXCR4 antagonism. By disrupting the pathological signaling that tethers leukocytes to the bone marrow, Mavorixafor promotes the mobilization and trafficking of mature neutrophils and lymphocytes from the marrow into the peripheral circulation.[1] This leads to a rapid and substantial increase in the absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) in the bloodstream.

Clinical data have characterized the temporal profile of this effect. Following a single oral dose, the mobilization is rapid, with ANC and ALC levels reaching their peak concentration approximately 4 hours after administration. The effect is transient, with cell counts returning toward baseline within the 24-hour dosing interval.[7] This dynamic response profile necessitates a consistent, once-daily dosing regimen to maintain therapeutically effective cell counts over time and provide continuous immune surveillance.

4.4 Cardiac Electrophysiology: Analysis of QTc Interval Prolongation

A significant and clinically important pharmacodynamic effect of Mavorixafor is its ability to cause concentration-dependent prolongation of the QTc interval on an electrocardiogram (ECG).[7] This effect on cardiac repolarization is a critical safety consideration that requires careful risk management.

A dedicated thorough QT (TQT) study conducted in healthy volunteers provided definitive data on this risk. At a supratherapeutic dose of 800 mg (twice the maximum recommended dose), Mavorixafor produced a maximum mean increase in the QTc interval of 15.6 ms.[18] This magnitude of QTc prolongation is considered clinically significant and underscores the need for the warnings and precautions outlined in the drug's prescribing information.

The direct link between the genetic cause of WHIM syndrome and Mavorixafor's mechanism makes it a model of precision medicine. However, the drug's potent activity on the fundamental CXCR4/CXCL12 axis creates a delicate therapeutic balance. While the drug is highly selective for CXCR4, this receptor is expressed in various tissues, including the heart. The observed QTc prolongation is therefore likely an on-target effect stemming from the modulation of CXCR4 signaling in cardiac myocytes, rather than an unrelated off-target interaction. This creates a therapeutic challenge: the dose must be sufficient to overcome the pathological leukocyte retention in the bone marrow but must remain below a threshold that would induce clinically dangerous cardiac arrhythmias. This narrow therapeutic window is the reason for the complex dosing adjustments and contraindications related to drug interactions. The warnings against co-administration with strong CYP3A4 inhibitors or CYP2D6 substrates are not routine precautions; they are critical risk mitigation strategies directly tied to Mavorixafor's intrinsic pharmacodynamic properties and the need to tightly control its plasma concentrations to maintain safety.[18]

5.0 Comprehensive Pharmacokinetic Profile

The pharmacokinetic (PK) profile of Mavorixafor, which describes its absorption, distribution, metabolism, and excretion (ADME), is complex and has significant implications for its clinical use. These properties dictate the drug's dosing regimen, its potential for drug-drug interactions, and its suitability for use in specific patient populations.

5.1 Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Mavorixafor is an orally bioavailable small molecule.[6] Following oral administration in a fasted state, it is absorbed with a median time to reach peak plasma concentration (Tmax) of 2.8 hours, with a range of 1.9 to 4 hours.[7] With once-daily dosing, the drug reaches steady-state plasma concentrations after approximately 9 to 12 days.[15]
• Distribution: Mavorixafor distributes extensively throughout the body, as indicated by its large apparent volume of distribution (Vd) of 768 L.[7] It is highly bound to plasma proteins (>93%), which typically limits the amount of free drug available to exert pharmacological effects and can be a source of drug interactions with other highly protein-bound medications.[7]
• Metabolism: The metabolism of Mavorixafor is primarily mediated by the cytochrome P450 (CYP) enzyme system. It is a major substrate of CYP3A4 and, to a lesser extent, a substrate of CYP2D6.[7] It is also a minor substrate of CYP2C19 and the efflux transporter P-glycoprotein (P-gp).[7] Critically, Mavorixafor is not only a substrate but also an inhibitor of these pathways. It is classified as a strong inhibitor of CYP2D6, a weak inhibitor of CYP3A4, and an inhibitor of P-gp.[3] This dual role as both a "victim" and a "perpetrator" in metabolic interactions is the foundation of its complex drug-drug interaction profile.
• Excretion: Mavorixafor is eliminated from the body primarily through the feces, with 61% of an administered dose recovered in feces. A smaller portion (13.2%) is excreted in the urine, with only 3% of that being the unchanged parent drug, indicating that metabolism is the main route of clearance.[7] The drug has a long terminal elimination half-life ( t1/2​) of approximately 82 hours, which supports a once-daily dosing regimen.[7] The apparent clearance (CL/F) is 62 L/hour.[7]

5.2 Analysis of Nonlinear Kinetics and Food-Drug Interactions

Mavorixafor's pharmacokinetics are characterized by two clinically important features: nonlinearity and a significant food effect.

• Nonlinear Pharmacokinetics: The drug exhibits nonlinear, or greater than dose-proportional, pharmacokinetics across the clinically relevant dose range of 50 mg to 400 mg.[15] This means that an increase in the dose leads to a disproportionately larger increase in plasma exposure (Cmax and AUC). For instance, doubling the dose will more than double the plasma concentration. This property makes precise dosing and avoidance of factors that alter absorption particularly important, as small changes in the absorbed amount can lead to large, potentially toxic, changes in systemic exposure. The drug also shows at least partial nonlinear apparent clearance, although this is not considered to be clinically significant at the approved dosage.[15]
• Significant Food Effect: The absorption of Mavorixafor is dramatically and negatively impacted by the presence of food.
• Administration with a high-fat meal (approximately 1,000 calories, 50% fat) was found to decrease the peak plasma concentration (Cmax) by 66% and the total drug exposure (AUC) by 55%.[7]
• Similarly, a low-fat meal (approximately 500 calories, 25% fat) decreased Cmax by 55% and AUC by 51%.[7]

This profound negative food effect has led to strict administration guidelines. To ensure adequate and consistent absorption, Mavorixafor must be administered on an empty stomach after an overnight fast, and patients must wait at least 30 minutes after taking the dose before consuming food.[8] The combination of a long half-life, nonlinear kinetics, and a strong food effect creates a challenging PK profile. While the 82-hour half-life is advantageous for once-daily dosing and adherence, the other factors introduce significant potential for variability. The nonlinear kinetics amplify the consequences of any change in absorption. Given that a meal can reduce exposure by more than half, a patient who fails to follow the fasting instructions could experience a much greater than 50% reduction in peak drug levels, potentially rendering the dose sub-therapeutic and ineffective at mobilizing a sufficient number of immune cells. Therefore, patient education on the critical importance of the fasting administration schedule is paramount to achieving the desired clinical outcomes observed in trials.

5.3 Pharmacokinetics in Special Populations

• Pediatric Use: The pharmacokinetics of Mavorixafor in adolescent patients (aged 12 to <17 years) were found to be comparable to those in adults after accounting for differences in body weight. This finding supports the approved indication for this age group without requiring a distinct pediatric dosing algorithm beyond the weight-based stratification.[7]
• Renal Impairment: For patients with mild-to-moderate renal impairment (creatinine clearance [CrCl] 30-89 mL/min), no dosage adjustment is recommended. However, Mavorixafor has not been studied in patients with severe renal impairment (CrCl <30 mL/min) or end-stage renal disease (ESRD), and its use is therefore not recommended in these populations.[22]
• Hepatic Impairment: Similarly, no dosage adjustment is necessary for patients with mild hepatic impairment. Due to a lack of clinical data, Mavorixafor is not recommended for use in patients with moderate-to-severe hepatic impairment.[22] To address this data gap, a Phase 1 clinical trial (NCT06858696) has been initiated to specifically investigate the pharmacokinetics and safety of Mavorixafor in participants with hepatic impairment.[25]

Table 5.1: Summary of Mavorixafor Pharmacokinetic Parameters (Adults, 400 mg Dose)

Parameter	Value	Source(s)
Time to Peak (Tmax)	2.8 hours (median)	7
Peak Concentration (Cmax)	3,304 ng/mL	22
Total Exposure (AUC₀₋₂₄hr)	13,970 ng·hr/mL	22
Volume of Distribution (Vd)	768 L	7
Protein Binding	>93%	7
Half-life (t1/2​)	82 hours	7
Clearance (CL/F)	62 L/hour	7
Primary Metabolism Route	CYP3A4, CYP2D6	7
Primary Excretion Route	Feces (61%)	7
Effect of High-Fat Meal	↓ 66% Cmax, ↓ 55% AUC	7

6.0 Clinical Efficacy in WHIM Syndrome

The clinical efficacy of Mavorixafor for the treatment of WHIM syndrome was definitively established in the 4WHIM trial, a global, pivotal Phase 3 study. The trial was designed to the highest standards of clinical evidence to assess the drug's impact on both hematologic parameters and key clinical outcomes.

6.1 The Pivotal 4WHIM Phase 3 Trial (NCT03995108): Design and Demographics

• Trial Design: The 4WHIM study was a 52-week, randomized, double-blind, placebo-controlled, multicenter trial.[2] This design is considered the gold standard for minimizing bias and providing robust evidence of a drug's efficacy and safety. Following the 52-week blinded period, eligible participants could enroll in an open-label extension (OLE) phase, during which all patients received Mavorixafor, allowing for the assessment of long-term outcomes.[29]
• Patient Population: The trial enrolled 31 participants aged 12 years and older who had a genetically confirmed diagnosis of WHIM syndrome.[5] The participants were randomized in a 1:1 ratio, with 14 assigned to the Mavorixafor group and 17 to the placebo group.[2] The study population was representative of the known WHIM patient population, including 48% adolescents (aged 12-17) and patients with both nonsense (81%) and frameshift (19%) CXCR4 mutations.[27] As expected, baseline hematologic parameters were severely depressed, with a median screening absolute neutrophil count (ANC) of 150-200 cells/µL and a median absolute lymphocyte count (ALC) of 420-520 cells/µL, confirming the severe cytopenias characteristic of the disease.[27]
• Dosing Regimen: Participants in the active arm received Mavorixafor 400 mg orally once daily, while the control arm received a matching placebo.[4]

6.2 Analysis of Primary and Key Secondary Endpoints: TATANC and TATALC

The trial successfully met its primary and key secondary endpoints, which were designed to quantify the drug's pharmacodynamic effect on circulating neutrophil and lymphocyte levels over a 24-hour period.

• Primary Endpoint: The primary endpoint was the mean time above threshold for absolute neutrophil count (TATANC), where the threshold was set at a clinically meaningful level of 500 cells/µL.[4]
• Result: The Mavorixafor group demonstrated a least squares (LS) mean TATANC of 15.0 hours. In stark contrast, the placebo group's LS mean TATANC was only 2.8 hours. This substantial difference of 12.2 hours was highly statistically significant (P<.001), unequivocally demonstrating Mavorixafor's ability to correct neutropenia for a majority of the dosing interval.[5]
• Key Secondary Endpoint: The key secondary endpoint was the mean time above threshold for absolute lymphocyte count (TATALC), with the threshold set at 1,000 cells/µL.[4]
• Result: Mavorixafor was also highly effective in correcting lymphopenia. The LS mean TATALC for the Mavorixafor group was 15.8 hours, compared to 4.6 hours for the placebo group. This 11.2-hour difference was also highly statistically significant (P<.001).[5]

These results show that Mavorixafor treatment led to a sustained elevation of both neutrophil and lymphocyte counts into or toward the normal range. These increases were observed at each assessment point throughout the entire 52-week treatment period, confirming the durability of the drug's hematologic effect.[4]

6.3 Impact on Clinical Outcomes: Infection Rates, Severity, and Duration

Crucially, the robust hematologic improvements observed with Mavorixafor translated into meaningful clinical benefits for patients, particularly in reducing the burden of infections, which is the primary source of morbidity in WHIM syndrome.

• Reduction in Infection Frequency and Severity:
• Annualized Infection Rate: Treatment with Mavorixafor resulted in a 60% lower annualized infection rate compared to placebo (LS mean of 1.7 infections/year vs. 4.2 infections/year; nominal P=.007).[4]
• Total Infection Score: A composite endpoint that combines the number and severity of infections was 40% lower in the Mavorixafor group, indicating that infections were not only less frequent but also less severe.[4]
• Severe Infections: Mavorixafor treatment led to a 75% reduction in the number of participants experiencing severe (Grade 3 or higher) infections. Only one patient (7%) in the Mavorixafor arm experienced a severe infection, compared to five patients (29%) in the placebo arm.[32]
• Reduction in Infection Duration and Antibiotic Use:
• The total duration of time patients experienced infections was reduced by over 70%. Patients on placebo had a mean of 7 weeks (49.1 days) with infections over the 52-week trial, whereas patients on Mavorixafor had a mean of only 2 weeks (14.1 days).[32]
• This reduction in infection burden was accompanied by a corresponding decrease in the need for medical interventions, including the use of antibiotics.[26]

6.4 Long-Term Data and Post-Hoc Analysis of Cutaneous Manifestations (Warts)

While the benefits on infection were clear within the 52-week trial period, the effect on the chronic cutaneous manifestations of WHIM syndrome, specifically warts caused by human papillomavirus (HPV), required a longer observation period.

• 52-Week Results: The primary analysis at the end of the 52-week randomized period did not show a statistically significant difference in the total wart change score between the Mavorixafor and placebo arms.[8]
• Long-Term Open-Label Extension Data: A post-hoc analysis of participants who continued treatment in the OLE for a total of two years revealed a significant and positive effect on warts. Among participants with baseline warts who received Mavorixafor for two years, 4 out of 6 (66.7%) showed improvement, and 2 of those (33.3%) achieved complete remission. Similarly, among patients who initially received placebo and then switched to Mavorixafor in the OLE, 6 of 8 (75.0%) showed improvement and 4 (50.0%) experienced complete remission during the OLE period.[30]

These findings reveal a clear temporal disconnect between the different clinical benefits of Mavorixafor. The hematologic response is nearly immediate, occurring within hours of the first dose. The reduction in acute infections becomes statistically significant over several months, with the effect strengthening in the latter half of the first year of treatment. This suggests that while immune cell numbers are restored quickly, a sustained period of immune reconstitution is necessary to effectively reduce the frequency of clinical infections. The effect on chronic, persistent viral infections like warts is even more delayed, taking over a year to become apparent. This is biologically plausible, as clearing established HPV lesions requires a complex, coordinated, and persistent T-cell mediated immune response to be mounted within the skin. This insight is critical for managing patient and physician expectations, emphasizing that Mavorixafor is a chronic, disease-modifying therapy whose full spectrum of benefits may take years to manifest.

Table 6.1: Key Efficacy Outcomes from the 4WHIM Phase 3 Trial

Endpoint	Mavorixafor (N=14)	Placebo (N=17)	P-value / Difference	Source(s)
Primary Endpoint: LS Mean TATANC (hours)	15.0	2.8	P<.001	26
Key Secondary Endpoint: LS Mean TATALC (hours)	15.8	4.6	P<.001	26
Annualized Infection Rate (LS Mean)	1.7	4.2	60% reduction (P=.007)	26
Total Infection Score	7.41	12.27	40% reduction	26
Severe (Grade ≥3) Infections (% of patients)	7% (1/14)	29% (5/17)	75% reduction	32

7.0 Investigational Pipeline and Future Indications

The therapeutic principle behind Mavorixafor—mobilizing leukocytes from the bone marrow by antagonizing CXCR4—has potential applications beyond WHIM syndrome. X4 Pharmaceuticals is actively pursuing a pipeline of additional indications where this mechanism may address significant unmet medical needs.

7.1 Chronic Neutropenia (CN)

• Scientific Rationale: The CXCR4/CXCL12 signaling axis is the central regulator of neutrophil retention in and release from the bone marrow. In various forms of chronic neutropenia (CN), including congenital, idiopathic, and cyclic neutropenia, patients suffer from low circulating neutrophil counts despite having adequate reserves in the marrow. Antagonizing CXCR4 with Mavorixafor offers a logical strategy to mobilize these reserves and increase peripheral ANC, thereby reducing infection risk.[34]
• Phase 1b/2 Trial (NCT04154488): A completed open-label Phase 1b/2 trial provided strong proof-of-concept for this indication.[37]
• Results: The six-month study demonstrated that once-daily oral Mavorixafor led to durable and clinically meaningful increases in mean ANC. This effect was observed both when Mavorixafor was used as a monotherapy and when it was added to a stable regimen of granulocyte colony-stimulating factor (G-CSF).[34]
• G-CSF Sparing Effect: A particularly compelling finding was the G-CSF-sparing effect. In the combination therapy cohort, physicians were able to substantially reduce the dose of injectable G-CSF in 9 of 12 eligible participants. The mean G-CSF dose reduction was 70% by the six-month mark, and three participants were able to discontinue G-CSF entirely, all while maintaining ANC levels in the normal range.[34] This outcome is highly significant, as it suggests Mavorixafor could reduce the burden of frequent injections and the side effects associated with long-term G-CSF therapy, such as bone pain. This positions Mavorixafor not only as a potential new monotherapy but also as a synergistic agent capable of optimizing the existing standard of care, which could be a powerful value driver from both a clinical and commercial perspective.
• Phase 3 4WARD Trial (NCT06056297): Based on the strength of the Phase 2 data, X4 has initiated a global, pivotal Phase 3 trial named 4WARD. This randomized, double-blind, placebo-controlled study is currently enrolling patients with congenital, autoimmune, or idiopathic CN and a history of recurrent infections. The trial will evaluate Mavorixafor as a monotherapy or in combination with G-CSF.[14] In recognition of the unmet need in this population, the FDA has granted Fast Track designation to Mavorixafor for the treatment of CN.[35]

7.2 Oncology

• Scientific Rationale: The CXCR4/CXCL12 axis is increasingly recognized as a key player in cancer biology. It is implicated in promoting tumor growth, angiogenesis, metastasis to CXCL12-rich environments (like lymph nodes, lung, and liver), and the creation of an immunosuppressive tumor microenvironment (TME) by recruiting regulatory T-cells and myeloid-derived suppressor cells.[11] By blocking CXCR4, Mavorixafor has the potential to inhibit tumor cell migration and, perhaps more importantly, remodel the TME to be more permissive to an anti-tumor immune response, potentially synergizing with immunotherapies like checkpoint inhibitors.[13]
• Melanoma: A Phase 1b biomarker-driven study (NCT02823405) in patients with melanoma provided early evidence for this hypothesis. Serial tumor biopsies showed that Mavorixafor monotherapy increased the infiltration of cytotoxic CD8+ T-cells and upregulated gene expression signatures associated with inflammation (TIS and IFNγ) within the TME. The combination of Mavorixafor with the PD-1 inhibitor pembrolizumab was found to be safe and further increased serum levels of key T-cell-attracting chemokines (CXCL9 and CXCL10). These findings suggest Mavorixafor could potentially sensitize "cold" tumors to checkpoint inhibitors.[20]
• Waldenström's Macroglobulinemia (WM): Mavorixafor has also been investigated in WM, a rare B-cell lymphoma, in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib.[2] A Phase 1b trial demonstrated that this combination was well-tolerated and led to robust decreases in serum IgM (a marker of tumor burden) and meaningful increases in hemoglobin levels, suggesting clinical activity.[40]

7.3 Other Potential Applications

• HIV Infection: The original development focus for Mavorixafor (then AMD-070) was as an HIV entry inhibitor, owing to CXCR4's role as a co-receptor for T-tropic HIV-1 strains.[6] In vitro studies confirmed its potent anti-viral activity, with IC50​ values as low as 2 nM in cell lines and 9 nM in primary human peripheral blood mononuclear cells (PBMCs).[9] While clinical development for this indication was ultimately discontinued, this potent activity remains a notable pharmacological feature of the molecule.[12]

8.0 Safety, Tolerability, and Risk Management

A thorough understanding of Mavorixafor's safety profile is essential for its appropriate and safe clinical use. Data from the pivotal 4WHIM trial and other studies have characterized its adverse reaction profile, identified key risks, and established a framework for risk management through contraindications, warnings, and management of drug-drug interactions.

8.1 Profile of Adverse Reactions from Clinical Trials

In the 52-week, placebo-controlled 4WHIM trial, Mavorixafor was generally well-tolerated. No participants discontinued the study due to treatment-emergent adverse events (TEAEs), and no serious TEAEs were considered related to the study drug.[4]

• Common Adverse Reactions: The most frequently reported adverse reactions (occurring in ≥10% of patients and at a higher rate than in the placebo group) are summarized in Table 8.1. These include thrombocytopenia, various skin rashes (pityriasis, rash), respiratory symptoms (rhinitis, epistaxis), and gastrointestinal or neurological effects (vomiting, dizziness).[7]
• Serious Adverse Reactions: The most notable serious adverse reaction was thrombocytopenia (low platelet count). Serious cases occurred in 3 of the 14 patients (21%) who received Mavorixafor. It is important to note that two of these serious events occurred in the context of an ongoing infection or febrile neutropenia, suggesting that the underlying clinical status may be a contributing factor.[23]

Table 8.1: Common Adverse Reactions (≥10%) Reported in the 4WHIM Trial

Adverse Reaction	XOLREMDI (N=14) %	Placebo (N=17) %	Source(s)
Thrombocytopenia	21%	0%	23
Pityriasis	14%	0%	23
Rash	14%	0%	23
Rhinitis	14%	0%	23
Epistaxis	14%	6%	23
Vomiting	14%	6%	23
Dizziness	14%	6%	23

8.2 In-depth Review of Warnings, Precautions, and Contraindications

The prescribing information for Mavorixafor includes several critical safety warnings that require careful clinical management.

• Contraindications: The use of Mavorixafor is strictly contraindicated with drugs that are highly dependent on the CYP2D6 enzyme for their clearance.[7] Mavorixafor is a strong inhibitor of CYP2D6, and co-administration could lead to dangerously high levels of the substrate drug. A common example of such a drug is the over-the-counter cough suppressant dextromethorphan.[44]
• Warnings and Precautions:
• Embryo-Fetal Toxicity: Based on its mechanism of action, Mavorixafor is expected to cause fetal harm. The CXCR4/SDF-1 signaling pathway is known to be essential for normal embryo-fetal and placental development. Although animal reproduction studies have not been conducted, the mechanistic risk is considered high.[5] Consequently, the pregnancy status of females of reproductive potential must be verified before initiating therapy. These patients must be advised to use an effective method of contraception during treatment and for three weeks following the final dose.[18]
• QTc Interval Prolongation: As detailed previously, Mavorixafor causes concentration-dependent prolongation of the QTc interval.[7] Before starting therapy, any modifiable risk factors for QTc prolongation, such as hypokalemia or other electrolyte abnormalities, should be corrected. A baseline ECG is recommended, and periodic monitoring during treatment is advised for patients with risk factors, such as those taking concomitant medications that increase Mavorixafor exposure or other drugs known to prolong the QT interval.[7] Dose reduction or discontinuation may be necessary if significant prolongation occurs.[23]

8.3 Comprehensive Drug-Drug Interaction Analysis

Mavorixafor's complex metabolic profile as both a substrate and an inhibitor of major drug-metabolizing enzymes and transporters results in a high potential for clinically significant drug-drug interactions (DDIs). These interactions are bidirectional.

• Effect of Other Drugs on Mavorixafor (Mavorixafor as a "Victim"):
• Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, grapefruit products): These drugs block the primary metabolic pathway of Mavorixafor, leading to increased plasma concentrations and a higher risk of adverse reactions, particularly QTc prolongation. Co-administration requires a dose reduction of Mavorixafor.[18]
• Moderate CYP3A4 Inhibitors or P-gp Inhibitors: These may also increase Mavorixafor exposure. Clinical monitoring for adverse effects is required, with dose reduction of Mavorixafor as needed.[18]
• Strong CYP3A4 Inducers (e.g., rifampin, carbamazepine, St. John's Wort): These drugs accelerate the metabolism of Mavorixafor, which is predicted to decrease its plasma concentrations and potentially reduce its efficacy. Concomitant use should be avoided.[18]
• Effect of Mavorixafor on Other Drugs (Mavorixafor as a "Perpetrator"):
• CYP2D6 Substrates: As a strong inhibitor of CYP2D6, Mavorixafor can dramatically increase the exposure of drugs metabolized by this enzyme. This interaction is the basis for the formal contraindication with drugs that are highly dependent on this pathway for clearance.[7]
• Sensitive CYP3A4 or P-gp Substrates: As a weak CYP3A4 inhibitor and a P-gp inhibitor, Mavorixafor can increase the exposure of sensitive substrates of these pathways (e.g., certain statins, digoxin). More frequent monitoring for substrate-related toxicities is recommended when these drugs are used concomitantly.[18]

Table 8.2: Clinically Significant Drug-Drug Interactions with Mavorixafor

Interacting Drug Class	Effect on Mavorixafor or Substrate	Clinical Recommendation	Source(s)
Strong CYP3A4 Inhibitors	Increases Mavorixafor Cmax and AUC	Reduce Mavorixafor daily dose.	18
Strong CYP3A4 Inducers	Decreases Mavorixafor Cmax and AUC	Avoid concomitant use.	18
P-gp Inhibitors	Increases Mavorixafor Cmax and AUC	Monitor for adverse effects; reduce Mavorixafor dose if needed.	18
CYP2D6 Substrates	Mavorixafor increases substrate exposure	Contraindicated with drugs highly dependent on CYP2D6 for clearance.	7
Sensitive CYP3A4 Substrates	Mavorixafor may increase substrate exposure	Monitor more frequently for substrate-related adverse reactions.	22
P-gp Substrates	Mavorixafor may increase substrate exposure	Monitor more frequently for substrate-related adverse reactions.	22

9.0 Regulatory and Therapeutic Landscape

Mavorixafor's journey to market and its positioning within the treatment paradigm for WHIM syndrome are defined by its regulatory milestones and its distinct advantages over existing and alternative therapeutic strategies.

9.1 U.S. FDA Regulatory History and Approval

The regulatory process in the United States for Mavorixafor was efficient, reflecting the significant unmet need in WHIM syndrome.

• Submission and Review: X4 Pharmaceuticals submitted a New Drug Application (NDA) for Mavorixafor to the U.S. Food and Drug Administration (FDA) on September 5, 2023. On October 31, 2023, the FDA accepted the application for filing and granted it Priority Review status, a designation reserved for drugs that, if approved, would offer a significant improvement in the safety or effectiveness of the treatment of a serious condition.[8]
• Approval: The FDA approved Mavorixafor, under the brand name Xolremdi, on April 26, 2024.[8] Press releases and other reports may cite slightly different dates like April 29 or April 30, which typically reflect the dates of public announcement.[2]
• Approved Indication: Xolremdi is specifically indicated for use in patients aged 12 years and older with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.[3]

9.2 European Medicines Agency (EMA) Status and Pathway to Potential Approval

Efforts are underway to make Mavorixafor available to patients in Europe and other regions.

• Orphan Designation: Recognizing the rarity and severity of WHIM syndrome, the European Commission granted Mavorixafor orphan designation (EU/3/19/2183) on July 25, 2019. This decision was based on a positive opinion from the EMA's Committee for Orphan Medicinal Products (COMP) and provides incentives for the development of the drug.[3]
• Marketing Authorization Application (MAA): On January 24, 2025, X4 Pharmaceuticals announced that the EMA had validated its MAA for Mavorixafor for the treatment of WHIM syndrome.[14] This validation marks the beginning of the formal scientific review process by the EMA's Committee for Medicinal Products for Human Use (CHMP).[48]
• Anticipated Decision: A final decision from the European Commission on the MAA is anticipated in the first half of 2026.[14] If approved, Mavorixafor would become the first and only drug specifically indicated for WHIM syndrome in Europe. To facilitate its commercial launch, X4 has established a partnership with Norgine for the commercialization of Mavorixafor in Europe, Australia, and New Zealand.[14]

9.3 Comparative Analysis: Mavorixafor vs. Standard of Care and Alternative Therapies

Mavorixafor enters a therapeutic landscape where no targeted treatments previously existed. Its unique profile offers distinct advantages over the historical standard of care and other investigational approaches.

• Current Standard of Care (Supportive Therapy): Before Mavorixafor's approval, the management of WHIM syndrome was entirely supportive, aiming to manage the symptoms and complications of the disease without addressing its underlying cause.[2] This included:
• Granulocyte Colony-Stimulating Factor (G-CSF; Filgrastim): This injectable biologic stimulates the bone marrow to produce more neutrophils. However, it does not correct the fundamental trafficking defect of WHIM syndrome, nor does it address the associated lymphopenia or hypogammaglobulinemia.[52] Long-term use is burdensome and carries risks, including bone pain and, rarely, myelodysplasia.[54]
• Immunoglobulin Replacement Therapy (IVIG/SCIG): This therapy provides passive immunity by supplying exogenous antibodies, which helps to reduce the frequency of bacterial infections resulting from hypogammaglobulinemia. However, it is a costly and burdensome lifelong treatment that does not correct the underlying cellular immune defects.[16]
• Other Investigational CXCR4 Antagonists:
• Plerixafor (Mozobil): This is another potent CXCR4 antagonist, approved by the FDA for mobilizing hematopoietic stem cells for transplantation in cancer patients. It has been studied off-label in WHIM syndrome and has demonstrated efficacy in correcting cytopenias and improving warts.[16] However, its primary and significant disadvantage is its pharmacokinetic profile. Plerixafor has a short half-life, necessitating a burdensome regimen of twice-daily subcutaneous injections for chronic use, which is far less convenient than the once-daily oral administration of Mavorixafor.[52] A clinical trial comparing plerixafor to G-CSF found it to be non-inferior for preventing infections but not superior.[42]
• Curative-Intent Therapies:
• Hematopoietic Stem Cell Transplantation (HSCT): HSCT is the only potentially curative option for WHIM syndrome, as it replaces the patient's entire hematopoietic system with one from a healthy donor, thereby eliminating the defective CXCR4 gene from the immune cells.[16] Case series have shown that successful HSCT can lead to complete resolution of all disease symptoms.[55] However, HSCT is an aggressive, high-risk procedure associated with significant potential for life-threatening complications, including treatment-related mortality, graft rejection, graft-versus-host disease (GVHD), and severe infections during the period of immunosuppression. Due to these substantial risks, it is generally reserved only for the most severely affected patients.[57]

This comparative analysis places Mavorixafor in a uniquely advantageous position. It is the only available therapy that is simultaneously disease-modifying (targeting the root genetic cause), convenient (once-daily oral), and supported by robust Phase 3 efficacy and safety data. It is more effective and targeted than purely supportive care, vastly more convenient for chronic use than injectable plerixafor, and substantially safer and more broadly applicable than high-risk HSCT. This combination of attributes firmly establishes Mavorixafor as the new foundational standard of care for eligible patients with WHIM syndrome, fundamentally altering the treatment algorithm for this rare disease.

10.0 Expert Analysis and Concluding Remarks

Mavorixafor (Xolremdi®) is a transformative therapeutic agent whose approval marks a pivotal moment in the management of WHIM syndrome and a significant validation for the field of precision medicine. Its development and clinical profile demonstrate a sophisticated application of molecular biology to address the root cause of a rare genetic disease.

10.1 Benefit-Risk Profile Synthesis

The overall benefit-risk profile of Mavorixafor for its approved indication is highly favorable. The benefits are substantial and have been rigorously demonstrated. The pivotal 4WHIM trial showed not only a profound and statistically significant correction of the hallmark hematologic abnormalities of the disease—neutropenia and lymphopenia—but also translated this correction into a clinically meaningful reduction in the frequency, severity, and duration of infections. This dual impact on both surrogate biomarkers and hard clinical outcomes provides unequivocal evidence of its efficacy.

These established benefits are weighed against a set of manageable and well-characterized risks. The primary safety concerns are the potential for QTc interval prolongation and a complex profile of drug-drug interactions stemming from its effects on the CYP450 enzyme system, particularly its strong inhibition of CYP2D6. While significant, these risks are not insurmountable. They are predictable and can be effectively managed through careful patient selection, exclusion of contraindicated medications, baseline and periodic ECG monitoring in at-risk individuals, and systematic dose adjustments when co-administered with CYP3A4 inhibitors. The other reported adverse events, such as thrombocytopenia and rash, were generally manageable within the clinical trial setting. Thus, for a patient population facing a lifetime of recurrent, debilitating infections, the demonstrated benefits of Mavorixafor decisively outweigh its manageable risks.

10.2 Transformative Potential

The introduction of Mavorixafor fundamentally transforms the treatment paradigm for WHIM syndrome. It represents a shift away from the burdensome and incomplete solutions of supportive care—such as lifelong immunoglobulin infusions and G-CSF injections—to the first-ever targeted, oral, once-daily, disease-modifying therapy. This transition offers not only improved clinical outcomes but also a significant enhancement in quality of life by reducing the physical, logistical, and psychological burden of previous treatments. The success of Mavorixafor serves as a powerful validation of the CXCR4 signaling pathway as a druggable target in rare immunodeficiencies and provides a blueprint for developing targeted therapies for other monogenic disorders.

10.3 Future Outlook and Unanswered Questions

The future of Mavorixafor appears promising, with significant potential for label expansion. The ongoing investigation in chronic neutropenia is particularly compelling. The positive Phase 2 data, especially the G-CSF-sparing effect, suggest that Mavorixafor could address a major unmet need in this broader patient population by offering a more convenient, oral-based treatment regimen that reduces reliance on injectables. The early-stage signals in oncology, while preliminary, are intriguing. The potential for Mavorixafor to remodel the tumor microenvironment and sensitize tumors to immunotherapy could open up a vast new area of application, though this will require extensive further research to validate.

Despite the successes to date, several important questions remain. The long-term safety of chronic, lifelong CXCR4 antagonism is not yet fully understood and will require diligent post-marketing surveillance. The durability of the clinical response, especially the slow-to-emerge benefits on cutaneous warts, needs further characterization over many years of treatment. Finally, the efficacy and safety of Mavorixafor in populations excluded from the pivotal trial, such as patients with severe renal or hepatic impairment and children under 12, remain to be determined.

In conclusion, Mavorixafor is a landmark therapeutic achievement. It provides a highly effective and targeted treatment for patients with WHIM syndrome, establishing a new standard of care. Its ongoing development programs hold the promise of extending its benefits to other patient populations with significant unmet needs, solidifying its role as a key innovation in the treatment of diseases of the immune system.

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