A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Mavorixafor in patients with WHIM Syndrome with Open-Label Extension

WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is
a rare, autosomal dominant, combined primary immunodeficiency syndrome caused
by inherited gain of function (GOF) mutations altering the C-X-C chemokine
receptor type 4 (CXCR4) receptor carboxyl terminus. The disease is associated
with significant morbidity and mortality, primarily due to bacterial, viral and
fungal infections, susceptibility to human papilloma virus (HPV) disease and an
increased risk of malignancies.

The immune defects in WHIM syndrome arise from the inappropriate retention of
otherwise sufficiently functional white blood cells (WBCs) in the bone marrow,
including neutrophil retention and impaired interactions among T cells and B
cells. These deficiencies underpin the WHIM syndrome symptomatology and can
lead to life-threatening complications.

The precise incidence of WHIM syndrome is unknown but estimated to be less than
1 in a million.

WHIM syndrome typically manifests in early childhood, marked by frequent and
severe bacterial infections and the appearance of warts. However, the diagnosis
of WHIM syndrome is often delayed: about half of the patients were diagnosed in
adulthood.

There are no approved treatments directed at the primary pathophysiology of the
syndrome. Current therapeutic options for WHIM patients include parenteral
immunoglobulin (Ig) therapy, granulocyte-colony stimulating factor (G-CSF),
antibiotic prophylaxis, and hematopoietic stem cell transplantation. In
addition, plerixafor, a parenteral CXCR4 inhibitor, is being investigated in
patients with WHIM syndrome.
G-CSF and prophylactic Ig therapy are the most commonly prescribed treatments.
However, both are nonspecific, difficult to administer, do not address the
primary underlying defect, and have limited effectiveness in mitigating
hematological defects and preventing infection. Neither treatment addresses the
increased susceptibility to HPV-related disease.
The challenges and limitations of the currently available treatment options
illustrate that the primary underlying drivers of morbidity in WHIM syndrome
remain unaddressed, namely patient quality-of-life (QoL) and vulnerability to
life-limiting infection and malignancy.

Mavorixafor is a second-generation, small-molecule, non competitive, allosteric
antagonist of CXCR4 that acts by binding to extracellular domains of the
receptor, resulting in specific and reversible inhibition of receptor signaling
in response to its ligand CXCL12. Mavorixafor is currently in clinical
development in patients with oncology (renal cell carcinoma and melanoma) and
WHIM syndrome.
The Phase 2 data showed clear evidence of the expected effect of mavorixafor in
inducing sustained increase in ANC and ALC at doses >=300 and >=100 mg,
respectively.
The preliminary data in 2 patients suggest an overall decrease in non-genital
wart burden. There were no changes in Ig levels, and there were too few
revaccinations to enable any conclusions.
Mavorixafor appeared to be well tolerated. The most common SOC (system organ
class) for TEAEs (treatment-emergent adverse event) was infections and
infestations. . There were no SAEs reported, and there was no clinically
relevant finding in clinical laboratory values, vital signs, or ECGs.
A dose of 400 mg QD was required to achieve both AUCANC and AUCALC above the
levels considered clinically relevant. Given the overall safety profile and the
recommendation of the Data Review Committee (DRC), 400 mg QD has been selected
as the dose for further investigation in the Phase 3 portion of this study.

This study has been transitioned to CTIS with ID 2024-518461-10-00 check the CTIS register for the current data.

• Randomized Placebo-Controlled Period:

Primary:
- to demonstrate the efficacy of mavorixafor in patients with Warts,
Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome as
assessed by increasing levels of circulating neutrophils compared with placebo,
and relative to a clinically meaningful threshold.

Key Secondary:
- To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome
as assessed by increasing levels of circulating lymphocytes compared with
placebo and relative to a clinically meaningful threshold.
- To demonstrate the clinical efficacy of mavorixafor in participants with WHIM
syndrome as assessed by a composite endpoint of infections and warts.
- To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome
as assessed by improvement in warts.
- To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome
as assessed by reduction in infections.

Other Secondary:
- To demonstrate the efficacy of mavorixafor in participants with WHIM syndrome
including as assessed by participant-reported outcomes.
- To evaluate the safety and tolerability of mavorixafor in participants with
WHIM syndrome.
-To evaluate pharmacokinetics (PK) of mavorixafor in participants with WHIM
syndrome.

• Open-Label Period:

Primary:
- To evaluate the safety and tolerability of mavorixafor in patients with WHIM
syndrome.

Secondary:
- To evaluate the long-term efficacy of mavorixafor in participants with WHIM
syndrome.

This is a Phase 3, 2-period study, with an initial 12-month, randomized,
double-blind, placebo-controlled period (referred to as the Randomized
Placebo-Controlled Period) followed by an open-label extension (referred to as
the Open-Label Period hereafter).

To be eligible for the study, participants must have a diagnosis of WHIM
syndrome and a genotype-confirmed mutation of C-X-C chemokine receptor type 4
(CXCR4), be at least 12 years of age, and have a confirmed absolute neutrophil
count (ANC) or total white blood cell (WBC) count <= 400 cells/µL at screening,
as well as meet all other eligibility criteria.

The Randomized Placebo-Controlled Period comprises a 12 months (52-week)
treatment period. Approximately 18 to 28 participants will be randomized 1:1
to mavorixafor or matching placebo and stratified according to the use of
immunoglobulin (Ig) therapy, irrespective of the mode of administration
(inlcuding subcutaneous or intravebous). The 2 strata are defined as (1) have
received any Ig treatment within 5 months prior to screening visit/signing of
the informed consent form (ICF), or (2) have not received any Ig treatment
within 5 months prior to screening visit/signing of the ICF.

Both the baseline assessments for eligible participants and the administration
of the first dose of study drug or placebo will occur during a time period of
approximately 28 hours from Day -1 to Day 1. Specifically, the baseline
assessments, including an electrocardiogram (ECG) and serial samples for ANC
and absolute lymphocyte count (ALC), as well as total WBC count and absolute
monocyte count (AMC), will be conducted over 24 hours prior to study drug
administration. In the case of systemic infection between screening and
baseline, the baseline visit may be postponed for up to 4 weeks or until the
ANC has been confirmed to be <= 400 cells/µL. Systemic infections must be
resolved prior to first study drug administration. If an infection occurs any
time between the screening and the baseline visits, this event will be
considered medical history, and the Investigator should record the event via
the clinician-reported outcome (ClinRO) mechanism as well as record the event
on the Medical History form of the electronic case report form (eCRF).
Participants will be treated with oral mavorixafor 400 mg once daily (QD)
except for adolescents weighing <= 50 kg, who will be treated with mavorixafor
200 mg QD.
Participants stratified to the no prior Ig stratum will not be treated with Ig
during the duration of the study (including in the Open-Label Period).
Participants in the prior Ig therapy stratum will continue on the same Ig
treatment (ie, same dose, mode of administration, and frequency) as
administered prior to joining the study. During the study, administration of Ig
must not occur within 4 days prior to each visit.
The first dose of study drug will be administered on the morning of Day 1,
followed by an ECG at 2 hours postdose (± 30 minutes) and blood draws at 2
hours and 4 hours postdose (each ± 15 minutes) (prior to discharge).
At Weeks 1 and 4 (± 3 days), participants will have a telephone call from the
Investigator or designee to evaluate safety and discuss study compliance,
followed by scheduled study visits every 13 weeks (ie, Weeks 13, 26, 39, and 52
[± 14 days for all of these visits]). In order to avoid multiple needle sticks,
blood sampling for pharmacokinetics (PK), ALC, AMC, ANC, and WBC count may
require an indwelling catheter.

Participants will be contacted by phone approximately 72 to 24 hours prior to
each scheduled study visit to check if the participants feels that he/she may
have an ongoing infection, and to remind the participant not to take his/her
study medication at home on the day of the visit, as the study medication will
be administered during the visit. In the event of symptoms consistent with
infection, the visits may be delayed until the symptoms of infection are
cleared.

Rescue use of granulocyte-colony stimulating factor (G-CSF) for up to
approximately 2 weeks is permitted after discussion with the Medical Monitor.
If an Investigator decides that a participant requires ongoing, regularly
scheduled treatment with G-CSF, then the participant must be discontinued from
study treatment or be considered for Early Release (Section 5.4.1.1) In the
event of rescue treatment with G-CSF or antibiotic therapy any time on or after
conducting the baseline visit, visits for ANC measures must be delayed for no
less than 14 days and no more than 28 days from the last dose of G-CSF, or no
less than 7 days (or 5 half-lives) for the antibiotic in consideration,
whichever is longer, and no more than 28 days from the last dose of
antibiotics.

Participants will be vaccinated with tetanus, diphtheria, and pertussis (Tdap)
and HPV 9-valent vaccine, recombinant (Gardasil®9) according to a predetermined
schedule starting at Week 13. Vaccination will be according to respective
vaccine schedules for all participants, unless not permitted per standard of
care. Revaccination for Gardasil®9 will be per vaccine schedule for
participants who have completed a full course of vaccination with Gardasil®9
prior to the study, unless not permitted per standard of care. Antibody
specific titers, including pertussis toxin, tetanus, human papillomavirus (HPV)
16, and HPV 18 will be collected in the Randomized Placebo-Controlled Period at
baseline, and Weeks 26, 39, 52, and EOS.
In the Randomized Placebo-Controlled Period, information about potential
infections will be collected via multiple sources: an electronic
participant-reported outcomes (PRO) questionnaire, the ClinRO questionnaire,
through information collected by the study team and entered into the Adverse
Event of Special Interest - Infections eCRF, and in documents uploaded in the
infection adjudication portal. Potential infection events will be evaluated by
a blinded, independent Adjudication Committee (AC) as outlined in the AC
Charter. The AC will evaluate all potential infection data and determine
whether an event is consistent with infection, the characteristics of the
infection, the severity of the infection, and whether a given participant may
qualify for Early Release from the Randomized Placebo-Controlled Period to the
Open-Label Period based on infection severity. The AC will be the final arbiter
of infections for the purpose of the efficacy analysis.
The warts Clinical Global Impression of Severity (CGI-S) and Clinical Global
Impression of Change (CGI-C), determined by blinded central review for the
target skin regions, will be used for the composite clinical endpoint analysis.
Electronic diaries that contain the PRO questionnaire will be distributed at
the baseline visit for the Randomized Placebo-Controlled Period and will
include a participant training session. The electronic diaries will be
completed daily during both the Randomized and Open-Label Periods.
Participants should continue to receive blinded study drug administration
through the Week 52 (ie, the End of Randomized Period [EoRP]) visit.
Participants completing the EoRP have 3 options:
• Roll over to the Open-Label Period: For these participants, the last day of
the EoRP visit is the last day of the Randomized Placebo-Controlled Period.
• End participation in the study: These participants and any participants who
discontinue study at any time during the Randomized Placebo-Controlled Period
will attend an End of Study (EOS) visit at 30 days (± 14 days) post-last dose
of study treatment.
• Roll over to long-term follow-up: These participants will have a safety
follow-up visit at 30 days (± 14 days) post-last dose of study treatment. The
safety follow-up visit will be identical to the EOS in terms of timing and
procedures performed.
For participants who discontinue study treatment during the Randomized
Placebo-Controll

Mavorixafor is a second-generation, small-molecule, non-competitive, allosteric
antagonist of the CXCR4 receptor.
The mavorixafor dose regimen for both the Randomized Period and the Open-Label
Period is 400 mg once daily (QD) for adults. For adolescents (12-17 years of
age) weighing >50 kg, the mavorixafor dose will also be 400 mg QD. Adolescents
weighing <=50 kg will receive mavorixafor 200 mg QD. Mavorixafor is administered
as 100-mg dose strength capsules.
Reference therapy, dosage, and mode of administration: placebo (equivalent
number of matching capsules).

WHIM syndrome is a disease of considerable morbidity and mortality, with no
currently available therapy directed against the underlying mechanism of
disease. Mavorixafor is an oral agent suitable for QD administration that
directly and specifically targets the molecular basis of the disease and is
expected to have efficacy at dose levels that will be safe and well tolerated.
For patients participating in this study, the potential clinical benefit of
mavorixafor, an orally bioavailable, investigational treatment that directly
targets the molecular pathogenesis of WHIM syndrome, outweighs its potential
risks when these risks are appropriately monitored and managed.