XOLREMDI Hard capsule Ref.[116582] Active ingredients: Mavorixafor

Pharmacotherapeutic group: Immunostimulants, Other immunostimulants
ATC code: L03AX24

Mechanism of action

Mavorixafor is a CXC Chemokine Receptor 4 (CXCR4) antagonist that blocks the binding of the CXCR4 ligand, stromal-derived factor-1α (SDF-1α)/CXC Chemokine Ligand 12 (CXCL12). SDF-1/CXCR4 plays a role in trafficking and homing of leukocytes to and from the bone marrow compartment. Gain of function mutations in the CXCR4 receptor gene that occur in patients with WHIM syndrome lead to increased responsiveness to CXCL12 and retention of leukocytes in the bone marrow. Mavorixafor inhibits the response to CXCL12 in both wild‑type and mutated CXCR4 variants associated with WHIM syndrome. Treatment with mavorixafor results in increased mobilisation of neutrophils and lymphocytes and monocytes from the bone marrow into peripheral circulation.

Pharmacodynamic effects

Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) peaked at 4 hours after Xolremdi dosing and returned towards baseline within 24 h after dosing. Over mavorixafor doses of 50 mg (0.125 times the maximum recommended dose) to 400 mg once daily, higher mavorixafor exposure at steady state was associated with longer mean time (hours) above ANC threshold (TAT_ANC) of 500 cells/μL and longer mean time (hours) above ALC threshold (TAT_ALC) of 1 000 cells/μL over a 24-hour period.

Cardiac electrophysiology

In a QT study, the maximum mean increase in the QTc interval was 15.6 ms (upper bound of the 90% confidence interval = 19.8 ms) after administration of Xolremdi 800 mg (2 times the maximum recommended dose) in healthy volunteers. See section 4.4.

Clinical efficacy and safety

Xolremdi was assessed in two clinical studies. Study X4P-001-103 (hereafter, study 1) was a pivotal Phase 3 randomised, double-blind, placebo-controlled, multicentre clinical study in adult and adolescent (aged 12 years and older) patients with WHIM syndrome. Study X4P-001-MKKA (hereafter, study 2) was a supportive open-label Phase 2 study in adult patients with WHIM syndrome.

Phase 3 study (pivotal)

The efficacy of Xolremdi in adult and adolescent patients aged 12 to <18 years with WHIM syndrome was evaluated in the 52-week, randomised, double-blind, placebo-controlled period of study 1. All enrolled patients had a genotype-confirmed variant of CXCR4 consistent with WHIM syndrome, and a confirmed ANC ≤400 cells/μL. Mavorixafor 400 mg was administered orally once daily to adults and adolescents weighing >50 kg and 200 mg once daily to adolescents weighing ≤50 kg. Patients were permitted to continue (but not initiate) immunoglobulin therapy at the same dose. Use of other CXCR4 antagonists or granulocyte-colony stimulating factor (G-CSF) was not permitted.

Thirty-one patients were randomised 1:1 to receive either placebo (n=17) or mavorixafor (n=14) once daily for 52 weeks. Baseline patient demographics and disease characteristics are shown in Table 5.

Table 5. Baseline demographic and baseline characteristics in patients with WHIM syndrome (study 1):

Abbreviations: SD = standard deviation; Ig = immunoglobulin.
Note: Percentages are calculated based on the number of patients within each characteristic as denominator.

The primary efficacy endpoint was improvement in ANC as measured by the mean time (hours) above ANC threshold (TAT_ANC) of 500 cells/μL which was assessed over a 24-hour period 4 times throughout the study (every 3 months for 12 months). Over the 52-week period, TAT_ANC was statistically significantly greater in patients treated with mavorixafor compared with placebo. See Table 6 and Figure 1.

Table 6. Mean time (hours) above ANC threshold (TAT_ANC) in study 1:

Abbreviations: ANC = absolute neutrophil count; CI = confidence interval; LS = least squares; MMRM = mixed-model repeated measures; SD = standard deviation; SE = standard error; TAT = time above threshold of 500 cells/μL.
¹ The results are based on an MMRM analysis with time above threshold as a dependent variable; treatment, visit (weeks 13, 26, 39 and 52), treatment × visit, Ig use (randomisation strata), and baseline time above threshold as covariates; and patient as the repeated random effect.

Figure 1. TAT_ANC over time (hours) (LS Mean ± 95% CI) by treatment Group (study 1):

Abbreviations: ANC = absolute neutrophil count; CI = confidence interval; LS = least squares; TAT = total time (hours) above threshold (500 cells/μL) in 24 hours.
^* At week 52, 3 of 17 placebo patients were given mavorixafor in advance of their TAT measurement as they entered the open-label period of the study; one mavorixafor patient did not take mavorixafor. All data were included in the ITT analysis.

The key secondary efficacy endpoint was improvement in ALC as measured by the mean time (hours) above ALC threshold (TAT_ALC) of 1 000 cells/μL over a 24-hour period. Over the 52-week period, TAT_ALC was statistically significantly greater in patients treated with mavorixafor compared with placebo. See Table 7.

Table 7. Mean time (hours) above ALC threshold (TAT_ALC) in study 1:

Abbreviations: ALC = absolute lymphocyte count; CI = confidence interval; LS = least squares; MMRM = mixed-model repeated measures; SD = standard deviation; SE = standard error; TAT = time above threshold of 1 000 cells/μL.
¹ The results are based on an MMRM analysis with time above threshold as a dependent variable; treatment, visit (weeks 13, 26, 39 and 52), treatment × visit, Ig use (randomisation strata), and baseline time above threshold as covariates; and patient as the repeated random effect.

The efficacy of mavorixafor was further assessed on total infection score and total wart change score. Across the 52-week treatment period, the severity-weighted total infection score was numerically lower in mavorixafor-treated patients [LS mean (SE) 7.41 (2.805)] compared with placebo-treated patients [LS mean (SE) 12.27 (2.443)] with a mean difference of -4.85 [95% CI (-12.57, 2.86)]. Similarly, the annualised infection rate was numerically lower in mavorixafor-treated patients [LS mean (SE) 1.7 (0.5)] compared with placebo-treated patients [LS mean (SE) 4.2 (0.7)] with a rate ratio of 0.417 [95% CI (0.220, 0.789)]. There was no difference in total wart change scores between the mavorixafor and placebo treatment arms over the 52-week period.

Phase 2 study (supportive)

In an open-label Phase 2 (study 2) in 8 adult patients with WHIM syndrome, the pharmacodynamics of mavorixafor over the dose range 50 to 400 mg administered orally once daily, were evaluated. Doses of 300 to 400 mg achieved sustained increases in ANC ≥600 cells/μL and ALC ≥1 000 cells/μL.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Xolremdi in one or more subsets of the paediatric population for the treatment of WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome (see section 4.2 for information on paediatric use).

Other information

This medicinal product has been authorised under 'exceptional circumstances'. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.