A study to investigate efficacy, safety, and tolerability of mavorixafor in participants with congenital and acquired primary autoimmune and idiopathic chronic neutropenic disorders experiencing recurrent and/or serious infections

Overview

Sponsor-declared trial summary

Key facts

Sponsor

X4 Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Immune System Diseases [C20]

Trial duration

22 Jul 2024 → ongoing

Decision date (initial)

2025-10-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

X4 Pharmaceuticals, Inc

External identifiers

EU CT number

2023-508482-32-00

ClinicalTrials.gov

NCT06056297

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Therapy, Efficacy

To evaluate the efficacy of mavorixafor regarding infection rate and ANC in participants with CN who are not receiving chronic G-CSF treatment and in the overall population regardless of background therapy

Secondary objectives 5

1. To evaluate severity of infections (over 52 weeks)
2. To evaluate duration of infections (over 52 weeks)
3. To evaluate incidence of antibiotic use (over 52 weeks)
4. To evaluate incidence of oral ulcers (over 52 weeks)
5. To evaluate QoL via PROs (change from baseline to 52 weeks) – PROMIS SF Fatigue

Conditions and MedDRA coding

Neutropenias

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participants must be at least 12 years of age, at the time of signing the informed consent/assent, as per the local regulations and guidelines.
2. Bone marrow aspirate ± biopsy during the screening visit (or prior documentation of bone marrow aspirate ± biopsy within previous 9 months submitted for review and considered adequate for type of CN by central review hematopathologist) does not demonstrate evidence of hematologic malignancy or high risk for transformation by central review hematopathologist.
3. Body weight of ≥ 15 kg (inclusive).
4. Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male Participants: • A male participant must agree to use highly effective contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 3 weeks after the last dose for participants early terminating the study or until EOS visit for participants completing the Week 52/Day 365 visit and refrain from donating sperm during this period. Female Participants: • A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:  Not a woman of childbearing potential (WOCBP) as defined in Appendix 3. OR  A WOCBP who agrees to follow the contraceptive guidance, as mentioned in Appendix 3 during the treatment period and for at least 3 weeks after the last dose of study drug for participants early terminating the study or until EOS visit for participants completing the Week 52/Day 365 visit.
5. Participant, parent, and/or appropriate legally designated representative is capable of giving signed ICF and/or assent as described in Appendix 1, Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
6. Diagnosis of congenital or acquired primary autoimmune and idiopathic chronic neutropenic disorder ≥ 6 months prior to the screening visit that is NOT attributable to medications, active or recent infections or malignancy. • Congenital Neutropenia, including but not limited to these classifications: a. Isolated with a permanent (non-cyclic) presentation, e.g., ELANE, CSF3R, CXCR2, WAS b. Associated with extra-hematologic manifestations, e.g., Barth syndrome, Cohen syndrome, G6PC3, Kostmann disease c. Associated with metabolic disorders, e.g., glycogen storage disease 1b (GSD1b) d. Shwachman-Diamond syndrome • Acquired Primary Neutropenia a. Chronic idiopathic neutropenia b. Primary autoimmune neutropenia Other CN disorders that may be eligible for enrollment can be clarified and approved upon discussion with the study Medical Monitor
7. Have an ANC < 1000 cells/µL during screening (single ANC value from hematology) and confirmed trough mean ANC (mean value of multiple ANC measurements over 6 hours) at baseline visit, with no clinical evidence of systemic infection. Note: In the event of a systemic infection during the screening visit that may, in the opinion of the Investigator, have an effect on ANC, the baseline visit may be postponed or repeated, as deemed appropriate by the Investigator, to confirm trough ANC < 1000 cells/μL. Repeat measures should be justified with reason to believe the measure would change and should be limited to 3 times for any single type of event.
8. Prior history of recurrent and/or serious infections during the 12 months preceding the screening visit (i.e., suffering sequelae of CN), as defined by having at least 2 infections in the last 12 months that meet the following criteria: • Infection requiring the use of antibiotics (intravenous [IV]/oral); OR • Infection requiring a visit to healthcare facility (including but not limited to emergency room visit, urgent care facility, primary care physician’s office, or in-patient hospitalization); AND for all potential participants: • Infections considered by the Investigator to be likely related to the potential participant’s CN disorder. Note: Although oral ulcers (i.e., canker sores, aphthous ulcers) are sequelae of CN, they are not considered as de novo infections for the purpose of eligibility. If the finding of the oral ulcer(s) and/or oral mucositis are either thought to be exacerbated by or as a result of an infection, e.g., fungal etiology, then they can be considered an infection. Recurrent herpes simplex virus (HSV) or human papillomavirus (HPV) oral or genital lesions are NOT classified for the purpose of this study as infections. If such lesions have signs of secondary bacterial or fungal etiology, they can be considered infections. Gingivitis is NOT to be considered an infection. Periodontitis can be considered an infection.
9. Participants who are on G-CSF or other active background therapy must have been receiving these therapies during the previous 12 months while continuing to suffer from infections, be on a stable dose and dosing schedule for ≥ 4 weeks prior to screening visit, and remain on this dose and dosing schedule throughout the study (Note: for participants receiving chronic G-CSF treatment, dosing modifications may be considered for safety reasons [e.g., if ANC > 10,000 cells/µL for ≥ 4 weeks; refer to Section 6.1.2]).
10. Participants must be willing to keep their G-CSF or other background therapy doses/regimens stable (other than for safety reasons) for the duration of the study.

Exclusion criteria 26

1. Participant is incapacitated and unable to comply with protocol-specific requirements
2. Grapefruit-containing products, which are variable inhibitors of CYP3A4, are prohibited from the day the first dose of study drug is given and during the study.
3. A diagnosis of secondary neutropenia including those due to: a. Hypersplenism b. Infection c. Malignancy d. Autoimmune disease, e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, graft-versus-host disease, thyroid disease e. Nutritional deficiency, e.g., vitamin B12, folic acid, copper, caloric malnutrition f. Drug-induced cause, e.g., chemotherapy, clozapine, antiretrovirals, antibiotics, monoclonal antibodies.
4. Positive hepatitis C virus (HCV) antibodies with confirmation by HCV ribonucleic acid polymerase chain reaction reflex testing.
5. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). If the participant tests HBsAg negative, HBcAb positive, and hepatitis B surface antibody positive upon reflex testing, the participant would be considered eligible.
6. A diagnosis of any of the following: • Aplastic anemia • WHIM syndrome • Certain CNs, including but not limited to these classifications, are excluded: a. Isolated with a cyclic presentation, e.g., ELANE b. Associated with immune dysregulation, e.g., CVID, ALPS, familial hemophagocytic lymphohistiocytosis, Chédiak-Higashi syndrome, GATA2 deficiency syndrome c. Associated with bone marrow failure, e.g., Fanconi anemia, Diamond-Blackfan anemia • Neutropenia associated with a Duffy-null phenotype (formerly known as benign ethnic neutropenia). However, a participant with an autosomal dominant pathogenic variant in a gene associated with CN on a Duffy-null background may be eligible for inclusion.
7. A history of HIV and an acquired immunodeficiency syndrome-defining condition other than CD4+ count < 200 cells/µL. Participants with HIV may be enrolled if viral load as determined by routinely used tests has been undetectable for at least 6 months prior to the screening visit; if the participant is taking effective antiretroviral therapy (ART), regimen must have been stable for > 4 weeks prior to the screening visit.
8. Known active COVID 19 infection or a positive test within the local accepted clinical and governmental guidelines for a communicable window. Note: Participants with prior COVID 19 exposure are permitted to enroll if they have a negative test and conform with local guidelines.
9. Major surgery (defined as any invasive procedure that involves penetrating or exposing a body cavity) ≤ 6 weeks before the baseline visit requiring general anesthesia or which, in the opinion of the Investigator, may compromise the safety of the participant.
10. A medical or personal condition that may potentially compromise the safety of the participant, may preclude the participant’s successful completion of the clinical study, or could, in the opinion of the Investigator or the Medical Monitor, interfere with the objectives of the study.
11. Participants who are awaiting HSCT due to somatic variants in genes associated with high risk for clonal proliferation.
12. An active malignancy or history (≤ 5 years prior to enrollment in the study) of solid or hematologic malignancy.
13. Exception: Adequately treated basal cell or squamous cell skin cancer, localized prostate cancer, carcinoma in situ of the cervix, , in situ ductal or lobular carcinoma of the breast, or stage 1, low-grade colon cancer after surgical treatment. Participants with a prior or concurrent solid tumor whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen, in the opinion of the Medical Monitor, may be eligible
14. Laboratory test results meeting ≥ 1 of the following criteria at the screening visit: • Hemoglobin < 9.0 g/dL • Platelets < 30,000/μL • Estimated glomerular filtration rate < 30 mL/min/1.73 m2, as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (age ≥ 18 years) or Schwartz equation (age 12-17 years). • Serum aspartate transaminase > 2.5 × upper limit of normal (ULN) • Serum alanine transaminase > 2.5 × ULN • Total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome, in which case total bilirubin ≥ 3.0 × ULN and direct bilirubin > 1.5 × ULN)
15. Prolonged corrected QT interval > 450 ms using Fridericia’s formula at the screening visit.
16. Participant is currently taking or has taken an investigational drug < 30 days prior to the screening visit, or 5 half-lives, whichever is longer.
17. Participant is pregnant or breastfeeding.
18. Unable and/or unwilling to swallow capsules.
19. Known systemic hypersensitivity to the mavorixafor drug substance, its inactive ingredients, or the placebo.
20. Diagnosed or suspected congenital long QT syndrome or any history of clinically significant (CS) ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes). Any history of arrhythmia will be discussed with the Medical Monitor before the participant’s entry into the study.
21. Receiving or requiring any medication/therapy that is prohibited (see Section 6.6.2.3).
22. Received more than 1 dose of mavorixafor in the past.
23. Received a CXCR4 antagonist (other than mavorixafor) in the past 6 months.
24. Participants taking pegylated-G-CSF unless they have a diagnosis of congenital neutropenia confirmed at the screening visit.
25. Unless a published drug metabolism exception is otherwise indicated by the Investigator following review, drugs which are (a) highly dependent on CYP2D6 for clearance are prohibited for a period starting 14 days or 5 half-lives, whichever is longer, prior to administration of study drug and during the study and (b) which are strong CYP3A4 inducers are prohibited for a period starting 7 days or 5 half-lives, whichever is longer, prior to the administration of study drug and during the study (see Appendix 5).
26. Systemic glucocorticoids (> 5 mg prednisone equivalent per day) are prohibited for a period starting 14 days or 5 half-lives, whichever is longer, prior to administration of study drug and during the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Annualized infection rate based on infections adjudicated by a BIAC during the 52-week treatment period
2. 2a: Proportion of ANC responders. An ANC responder is a participant meeting the definition of a positive ANC response for at least 3 out of 6 visits [Weeks 4, 8, 13, 26, 39, and 52] during the 52-week treatment period, where a positive ANC response is defined as: (please see next "ID 3")
3. 2b: (continued from ID 2) • ANC ≥ 1500 cells/µL, with the exception of participants with baseline ANC < 500 cells/µL • ≥ 2-fold increase in ANC from baseline, for participants with baseline ANC < 500 cells/µL

Secondary endpoints 5

1. Infection severity based on CTCAE grading, adjudicated by a BIAC during the 52-week treatment period
2. Infection duration based on duration of infections adjudicated by a BIAC during the 52-week treatment period
3. Antibiotic use due to infection, characterized by the frequency of antibiotic use during the 52-week treatment period
4. Oral ulcers, as assessed by presence or absence of ulcers, during the 52-week treatment period
5. Change from baseline to Week 52/Day 365 in PROMIS SF Fatigue Questionnaire total score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

X4 Pharmaceuticals Inc.

Sponsor organisation

X4 Pharmaceuticals Inc.

Address

61 North Beacon Street

City

Boston

Postcode

02134-1912

Country

United States

Scientific contact point

Organisation

X4 Pharmaceuticals Inc.

Contact name

Deb Steiner

Public contact point

Organisation

X4 Pharmaceuticals Inc.

Contact name

Deb Steiner

Third parties 21

Locations

12 EU/EEA countries · 49 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 195 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

34 submissions — initial application plus substantial / non-substantial modifications