Effective Date

Date of Origin 

01-01-2025            

01-01-2025

Xolremdi™

(mavorixafor)

Capsule

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

WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) Syndrome

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. CXCR4 normally promotes homing of circulating senescent neutrophils to bone marrow and inhibits egress of nascent bone marrow neutrophils to blood. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia.(2,4) It is estimated to occur in about 1 in 5 million live births. Approximately 60 cases have been reported in the medical literature.(3)

While symptoms vary, patients with WHIM syndrome can have serious and/or frequent infections, including pneumonia, sinusitis, and skin infections and are at risk for life-threatening bacterial and viral infections.(2,4,5)

Xolremdi is a selective CXCR4 antagonist and is the first therapy specifically indicated in patients with WHIM syndrome. Mavorixafor is a selective allosteric antagonist of the CXCR4 receptor that increases mobilization and trafficking of leukocytes from the bone marrow.(5)

Efficacy

The efficacy of Xolremdi in patients aged 12 years and older with WHIM syndrome was demonstrated in the 52-week, randomized, double-blind, placebo-controlled portion of Study 1 (NCT03995108). Enrolled patients had a genotype-confirmed variant of CXCR4 consistent with WHIM syndrome, and a confirmed absolute neutrophil count (ANC) less than or equal to 400 cells/microliter (or total white blood cell [WBC] count less than or equal to 400 cells/microliter if ANC was below the lower limit of detection) obtained during no clinical evidence of infection.(1,6) Patients were permitted to continue (but not initiate) immunoglobulin therapy at the same dose. Use of other CXCR4 antagonists was not permitted. Thirty-one patients were randomized 1:1 to receive either placebo (N=17) or Xolremdi (N=14) once daily for 52 weeks.(1)

The efficacy of Xolremdi in the treatment of patients with WHIM syndrome was based on improvement in absolute neutrophil counts (ANC), improvement in absolute lymphocyte counts (ALC), and a reduction in infections. For ANC, the mean time (hours) above ANC threshold (TATANC) of 500 cells/microliter over a 24-hour period was assessed 4 times throughout the study (every 3 months for 12 months). The results over the 52-week period showed that TATANC was statistically significantly greater in patients treated with Xolremdi (LS mean [SE] 15.0 [1.89] hours) compared with placebo (2.8 [1.52] hours) (p value <0.0001).(1)

For ALC, the mean time (hours) above ALC threshold (TATALC) of 1,000 cells/microliter over a 24-hour period was assessed 4 times throughout the study (every 3 months for 12 months). The results over the 52-week period showed that TATALC was statistically significantly greater in patients treated with Xolremdi (LS mean [SE] 15.8 [1.39] hours) compared with placebo (4.6 [1.15] hours) (p value <0.0001).(1)

The efficacy of Xolremdi was further assessed in a composite endpoint consisting of total infection score and total wart change score using a Win-Ratio method. The Win-Ratio of 2.76 is the number of pairs of Xolremdi-treated patient “wins” divided by the number of pairs of placebo patient “wins.” Analyses of the individual components of this composite endpoint showed an approximately 40% reduction of total infection score, weighted by infection severity, in Xolremdi-treated patients compared with placebo-treated patients. The annualized infection rate was reduced approximately 60% in Xolremdi-treated patients [LS mean (SE) 1.7(0.5)] compared with placebo-treated patients [LS mean (SE) 4.2 (0.7)]. There was no difference in total wart change scores between the Xolremdi and placebo treatment arms over the 52-week period.(1)

Safety

Xolremdi has no boxed warnings, and is contraindicated with use of drugs that are highly dependent on CYP2D6 for clearance.(1) 

1

Xolremdi prescribing information. X4 Pharmaceuticals, Inc. April 2024.

2

Heusinkveld LE, Yim E, Yang A, Azani AB, et al. Pathogenesis, Diagnosis, and Therapeutic Strategies in WHIM Syndrome Immunodeficiency. Expert Opin Orphan Drugs. 2017;5(10):813-825.

3

Geier CB, Ellison M, Cruz R, et al. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients. J Clin Immunol. 2022 Aug;42:1748-1765.

4

National Organization for Rare Disorders (NORD). WHIM Syndrome. Last updated 6/16/2024. Available at: https://rarediseases.org/rare-diseases/whim-syndrome/. 

5

Dale DC, Firkin F, Bolyard AA, et al. Results of a Phase 2 Trial of an Oral CXCR4 Antagonist, Mavorixafor, for Treatment of WHIM Syndrome. Blood. 2020;136(26):2994-3003.

6

Badolato R, Alsina L, Azar A, et al. A Phase 3 Randomized Trial of Mavorixafor, a CXCR4 Antagonis, for WHIM Syndrome. Blood. 2024 Jul;144(1):35-45.

Xolremdi

mavorixafor cap

100 MG

M ; N ; O ; Y

N

Xolremdi

mavorixafor cap

100 MG

120

Capsules

30

DAYS

Xolremdi

mavorixafor cap

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Xolremdi

mavorixafor cap

100 MG

Blue Partner ; Commercial ; GenPlus ; Health Insurance Marketplace ; NetResults A Series ; SourceRx

Initial Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. ONE of the following:
   1. The requested agent is eligible for continuation of therapy AND ONE of the following:

1. 1. 1. The patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days OR
      2. The prescriber states the patient has been treated with the requested agent (starting on samples is not approvable) within the past 90 days AND is at risk if therapy is changed OR
   2. BOTH of the following:
      1. ONE of the following:
         1. The patient has a diagnosis of WHIM (warts, hypogammaglobulinemia, infections and myelokathexis) syndrome AND ALL of the following:
            1. Genetic analysis confirms mutation in the CXC chemokine receptor 4 (CXCR4) gene AND
            2. Confirmed absolute neutrophil count (ANC) OR total white blood cell (WBC) count is less than or equal to 400 cells/microliter (prior to therapy with the requested agent AND during no clinical evidence of infection) AND
            3. The prescriber has assessed baseline status (prior to therapy with the requested agent) of the patient's symptoms (e.g., absolute neutrophil counts [ANC], absolute lymphocyte counts [ALC], number of infections) OR
         2. The patient has another FDA labeled indication for the requested agent and route of administration AND
      2. If the patient has an FDA labeled indication, then ONE of the following:
         1. The patient’s age is within FDA labeling for the requested indication for the requested agent OR
         2. There is support for using the requested agent for the patient’s age for the requested indication AND
2. The patient will NOT be using the requested agent in combination with any other CXCR4 antagonists (e.g., plerixafor) for the requested indication AND
3. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., geneticist, immunologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
4. The patient does NOT have any FDA labeled contraindications to the requested agent 

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Renewal Evaluation

Target Agent(s) will be approved when ALL of the following are met:

1. The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review] AND
2. The patient has had clinical benefit with the requested agent AND
3. The patient will NOT be using the requested agent in combination with any other CXCR4 antagonists (e.g., plerixafor) for the requested indication AND
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., geneticist, immunologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis AND
5. The patient does NOT have any FDA labeled contraindications to the requested agent

Length of Approval: 12 months

NOTE: If Quantity Limit applies, please refer to Quantity Limit Criteria.

Universal QL

Quantity limit for the Target Agent(s) will be approved when ONE of the following is met: 

1. The requested quantity (dose) does NOT exceed the program quantity limit OR
2. The requested quantity (dose) exceeds the program quantity limit AND ONE of the following:
   1. BOTH of the following:
      1. The requested agent does NOT have a maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication OR
   2. BOTH of the following:
      1. The requested quantity (dose) does NOT exceed the maximum FDA labeled dose for the requested indication AND
      2. There is support for why the requested quantity (dose) cannot be achieved with a lower quantity of a higher strength that does NOT exceed the program quantity limit OR
   3. BOTH of the following:
      1. The requested quantity (dose) exceeds the maximum FDA labeled dose for the requested indication AND
      2. There is support for therapy with a higher dose for the requested indication 

Length of Approval:  up to 12 months