Mavorixafor

1 INDICATIONS AND USAGE XOLREMDI is indicated in patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lympocytes. XOLREMDI is a CXC chemokine receptor 4 antagonist indicated in patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage: Weight more than 50 kg: 400 mg orally once daily. ( 2 ) Weight less than or equal to 50 kg: 300 mg orally once daily. ( 2 ) Administer XOLREMDI on an empty stomach after an overnight fast, and at least 30 minutes before food. ( 2 ) 2.1 Recommended Dosage The recommended dosage of XOLREMDI is: Weight more than 50 kg: 400 mg orally once daily on an empty stomach after an overnight fast, and at least 30 minutes before food. Weight less than or equal to 50 kg: 300 mg orally once daily on an empty stomach after an overnight fast, and at least 30 minutes before food. Swallow the capsules whole. Do not open, break, or chew capsules. If a dose of XOLREMDI is missed, the next dose should be taken as scheduled. Do not take more than 1 XOLREMDI dose each day. 2.2 Dosage Modifications for Strong CYP3A4 inhibitors Reduce daily dosage of XOLREMDI to 200 mg when used concomitantly with strong CYP3A4 inhibitors [see Drug Interactions (7.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions (5.2) ] The most common adverse reactions (›10% and at a frequency higher than placebo) were: thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact X4 Pharmaceuticals, Inc. at 1-866-MED-X4MI (1-866-633-9464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of XOLREMDI was evaluated in Study 1, a randomized placebo-controlled trial of 31 adult and pediatric patients 12 years and older with WHIM syndrome [see Clinical Studies (14) ] . Patients received XOLREMDI 400 mg or 200 mg, based on age and body weight (N=14) or placebo (N=17). One patient received the 200 mg dose, and 13 patients received the 400 mg dose. Note that the 200 mg XOLREMDI daily dose is only recommended for use in patients receiving strong CYP3A4 inhibitors [see Dosage and Administration (2.1 , 2.2) ] . For all other patients, the recommended dosage is either 400 mg daily (if weighing more than 50 kg) or 300 mg daily (if weighing up to 50 kg), unless dose reductions are needed due to concomitant use with moderate CYP3A4 inhibitors or P-gp inhibitors [see Drug Interactions (7.1) ] . The data below are based on the 52-week, placebo-controlled portion of the study. Twelve patients received XOLREMDI for at least 6 months, and 10 patients received XOLREMDI for at least 1 year. Table 1 summarizes the most common adverse reactions (>10%) in Study 1, which were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness. Table 1: Adverse Reactions in ≥10% Patients with WHIM Syndrome Receiving XOLREMDI and More Frequently Reported than Placebo During Study 1 Number (N) and Percent (%) of Patients Adverse Reaction XOLREMDI (N=14) Placebo (N=17) Thrombocytopenia 3 (21%) 0 Pityriasis 2 (14%) 0 Rash 2 (14%) 0 Rhinitis 2 (14%) 0 Epistaxis 2 (14%) 1 (6%) Vomiting 2 (14%) 1 (6%) Dizziness 2 (14%) 1 (6%) Serious adverse reactions of thrombocytopenia occurred in 3 of the 14 patients who received XOLREMDI, 2 of which occurred in the setting of infection or febrile neutropenia.

12.3 Pharmacokinetics Mavorixafor pharmacokinetic parameters are presented as geometric mean (CV%) in adults with WHIM syndrome unless otherwise specified. Mavorixafor steady state C max is 3304 (58.6%) ng/mL and the AUC from 0 to 24 hours (AUC 0-24h ) is 13970 (58.4%) ng*h/mL following 400 mg once daily. Mavorixafor demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in C max and AUC 0-24 over a dose range of 50 mg (0.125 times the recommended dosage) to 400 mg. Mavorixafor steady state is reached after approximately 9 to 12 days at the highest approved recommended dosage in healthy subjects. Absorption Mavorixafor median (range) time to C max (T max ) is 2.8 hours (1.9 to 4 hours) at the highest approved recommended dosage. Effect of Food High Fat Meal: Mavorixafor C max decreased by 66% and AUC decreased by 55% following single-dose administration of XOLREMDI 400 mg with a high‑fat meal (1000 calories, 50% fat) to healthy subjects. Low Fat Meal: Mavorixafor C max decreased by 55% and AUC decreased by 51% following single-dose administration of XOLREMDI 400 mg with a low-fat meal (500 calories, 25% fat) to healthy subjects. In addition, a 14% higher mavorixafor C max and 18% lower AUC was observed following single-dose administration of XOLREMDI 400 mg with a low-fat meal to healthy subjects after an overnight fast compared to fasting for an additional 4 hours after the XOLREMDI dose. Distribution Mavorixafor volume of distribution is 768 L. Mavorixafor is >93% bound to human plasma proteins in vitro . Elimination Mavorixafor's terminal half-life is 82 h (34%) with an apparent clearance of 62 L/h (40%) following single-dose administration of XOLREMDI 400 mg in health subjects. Mavorixafor exhibits at least partial nonlinear apparent clearance; however, this is not clinically significant at the approved recommended dosage. Metabolism CYP3A4 and, to a lesser extent, CYP2D6 are primarily responsible for mavorixafor metabolism. Excretion After a single oral dose of radiolabeled mavorixafor, 74.2% of the administered dose was recovered out of which 61.0% of administered radioactivity was recovered in feces and 13.2% (3% unchanged) was recovered in the urine over the 240-hour collection period in healthy subjects. Specific Populations No clinically significant differences in the pharmacokinetics of mavorixafor were observed based on age (12 to 58 years), sex, or mild to moderate renal impairment (CLcr 30 to <90 mL/min as estimated by the Cockcroft-Gault formula). The effects of severe renal impairment (CLcr 15 to <30 mL/min), end-stage renal disease (CLcr <15 mL/min), and moderate to severe hepatic impairment on the pharmacokinetics of mavorixafor are unknown. Lower body weight was associated with lower mavorixafor clearance. Mavorixafor exposures in patients with WHIM syndrome are comparable between those weighing 50 kg or less who receive 300 mg once daily and those weighing greater than 50 kg who receive 400 mg once daily. Following 400 mg once daily, median C max and AUC is 22% and 30% lower, respectively, in patients with higher body weight (85 kg and above) compared to patients with average body weight (50 to less than 85 kg). The difference in exposure between patients with average body weight and patients with higher body weight is not expected to have a clinically significant impact on patient outcomes. Pediatric Patients No clinically significant differences in the pharmacokinetics of mavorixafor were identified in pediatric patients aged 12 to <17 years with WHIM syndrome compared to adult patients after accounting for differences in body weight. Drug Interaction Studies Clinical Studies Strong CYP3A4 Inhibitors: The systemic exposures of mavorixafor following concomitant administration of a single dose of XOLREMDI 200 mg (0.5 times the recommended dosage for adult and adolescent patients 12 years and older weighing over 50 kg) with 200 mg itraconazole (strong CYP3A4 inhibitor and P-gp inhibitor) dosed to steady state was similar to the mavorixafor systemic exposure from a single dose of XOLREMDI 400 mg administered alone in healthy subjects. These results suggest an approximate increase in mavorixafor exposure by 2-fold due to itraconazole. CYP2D6 Substrates: Dextromethorphan (CYP2D6 substrate) C max increased by 6-fold (CI 90% : 5.1 to 8.3) and AUC by 9-fold (CI 90% : 6.5 to 12.3) following concomitant use with XOLREMDI 400 mg in healthy subjects. CYP3A4 Substrates: Midazolam (CYP3A4 substrate) C max increased by 1.1-fold (CI 90% : 1.0 to 1.3) and AUC by 1.7-fold (CI 90% : 1.4 to 2.1) following concomitant use with XOLREMDI 400 mg in healthy subjects. P-gp Substrates: Digoxin: Digoxin C max increased by 1.5-fold (CI 90% : 1.3 to 1.8) and AUC increased by 1.6-fold (CI 90% : 1.4 to 1.9) following concomitant use of a single oral dose of a transporter cocktail containing 0.25 mg of digoxin with XOLREMDI dosed to steady state (400 mg/day) in healthy subjects. Metformin: Metformin C max decreased by 35% (CI 90% : 17 to 49%) and AUC decreased by 35% (CI 90% : 20 to 47%) following concomitant use of a single oral dose of a transporter cocktail containing 10 mg of metformin with XOLREMDI dosed to steady state (400 mg/day) in healthy subjects. Other Drugs : No clinically significant differences in the pharmacokinetics of caffeine (CYP1A2 substrate), losartan (CYP2C9 substrate), omeprazole (CYP2C19 substrate), furosemide (OAT1 and OAT3 substrate) and oral contraceptives were observed following concomitant use with mavorixafor. In Vitro Studies CYP450 Enzymes: Mavorixafor is a substrate of CYP3A4, CYP2D6, CYP3A5, and CYP2C19, but is not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, and CYP4A11. Mavorixafor is an inhibitor of CYP3A4 (time dependent), CYP3A5, CYP2D6, CYP2B6, CYP1A2, CYP2C8, CYP2C9, and CYP2C19. Mavorixafor is an inducer of CYP1A2, but not an inducer of CYP2B6, CYP2C8, CYP2C9 and CYP3A4. Transporter Systems: Mavorixafor is a substrate of P-gp, but not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 or MATE2-K. Mavorixafor is an inhibitor of P-gp, OCT2, and MATE1, but is not an inhibitor of BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and MATE2-K.