A Phase 2, Randomized, Double-Blinded, Placebo-Controlled, Parallel-Group, Multicenter Trial to Evaluate the Safety and Tolerability, Efficacy, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 2 Dose Regimens of ARGX-117 in Adults With Multifocal Motor Neuropathy

MMN is considered a rare chronic immune-mediated neuropathy involving
progressive muscle weakness of mainly the hands, forearms, and lower legs. It
is clinically characterized by progressive asymmetric weakness involving 2 or
more nerves and partial motor conduction block. The estimated prevalence of MMN
is between 0.6 to 2 per 100,000 people and typically presents as an
asymmetrical upper limb pure motor neuropathy. The hallmark of the disease is
the presence of multifocal motor conduction blocks, ie. impaired propagation of
action potentials
along the axon, and patients often show high serum levels of immunoglobulin M
(IgM) antibodies against the ganglioside GM1
(monosialotetrahexosylganglioside). GM1 is widely expressed in the nervous
system by neurons, particularly around the node of Ranvier, and
Schwann cells. The current prevailing view is that GM1 antibodies target the
axolemma at the node of Ranvier. This is thought to interfere with axon-Schwann
cell interactions, causing widening of the node, and direct damage to the axon.

The presence and titers of IgM anti-ganglioside GM1 (anti-GM1) antibodies and
their complement activating properties, correlate with clinical features such
as weakness and axonal damage. Moreover, the binding and subsequent classical
complement pathway activation of
anti-GM1 IgM from patients with MMN to motor neurons derived from induced
pluripotent stem cells causes disturbed calcium homeostasis and structural
damage to these pluripotent cells in vitro, resembling the changes that occur
in MMN.

Anti-GM1 (and other gangliosides) IgM antibodies are produced by a limited
number of activated B cells; however, the mechanism of this B cell activation
has not yet been established. Binding of these anti-GM1 antibodies to GM1 leads
to activation of the classical complement
pathway, and subsequent MAC deposition. Consequently, this MAC deposition leads
to disruption of Schwann cell-axolemma junctions, displacement of ion-channel
clustering, and the disturbance of membrane integrity at the (para)nodal
regions resulting in demyelination.
Anti-GM1 IgM antibodies are identified in at least 40% of patients with MMN.

These findings suggest that complements play an important role in the
pathogenesis of MMN, therefore, the inhibition of complement activation may
provide a new therapeutic option in this disease.

High dose IV immunoglobulin (IVIg) treatment is the only approved treatment for
MMN. IVIg treatment often improves muscle strength; however, the efficacy of
IVIg in reducing MMN symptoms declines after several years and many patients
report progressive neurological deficits. The mechanism of action of IVIg in
MMN is not well understood; however, IVIg may have effects on humoral immunity
beneficial to those with MMN. IVIg partially reduced complement activity in
sera13 and may interfere with anti-GM1 IgM-mediated complement nerve
deposition. Despite treatment with IVIg, MMN related disabilities will continue
to progress due to ongoing axonal degeneration. Complement-modulating treatment
was previously evaluated using eculizumab, a monoclonal antibody against
complement factor 5 (C5) preventing
formation of MAC. Results showed that eculizumab was well tolerated, however,
only a small improvement was seen in selected motor performance measurements.
Considering the high levels of CD59 expression, iPSC-derived motor neurons show
a high innate ability to inhibit the
terminal portion of the complement cascade. Thus, the use of a C5 inhibitor to
preserve motor neuron function may be limited Moreover, C5 is downstream of C3,
whereas the presence of C3aR on MNs suggest that complement activation upstream
of C5 may have functional
consequences for MNs.

There is an unmet medical need for an efficacious treatment option with a more
favorable safety and tolerability profile and lower duration of administration
than the current standard of care.

Rationale:
Multifocal motor neuropathy (MMN) is a rare neuropathy characterized by
progressive asymmetric weakness and atrophy without sensory abnormalities. MMN
is considered a chronic immune-mediated neuropathy driven by the classical
complement pathway related to the presence of anti-ganglioside GM1
(monosialotetrahexosylganglioside [anti-GM1]) (and other gangliosides)
immunoglobulin M (IgM) antibodies produced by a limited number of B cell
clones. These antibodies activate the complement system's classical pathway and
subsequently yield membrane attack complex (MAC) deposition leading to
disruption of Schwann cell-axolemma junctions, displacement of ion-channel
clustering, and disturbance of membrane integrity at the (para)nodal regions
that result in demyelination and motor nerve conduction block.

Patients with MMN initially respond to the standard of care, intravenous
immunoglobulin (IVIg); however, the disease will continue to progress despite
treatment. There is an unmet medical need for an efficacious treatment option
with a more favorable safety and tolerability profile and a lower duration of
administration than the current standard of care.

ARGX-117, a therapeutic complement-inhibiting antibody that targets complement
factor 2 (C2), is being developed to reduce tissue inflammation and attenuate
the adaptive immune response by blocking both the lectin and classical
complement pathways. Inhibition of C2 in complement-mediated neuronal damage is
a promising mechanism for preventing axonal and glial injury. In an ex vivo
mouse model of acute neuropathy, the use of a C2 blocking antibody (Bro2) in
GalNAcT-/--Tg (neuronal) mice prevented the loss of neurofilament staining at
the nerve terminal, thereby maintaining axonal integrity. Additionally, C2
inhibition by Bro2 in GalNAcT-/--Tg(glial) mice resulted in the preservation of
ankyrin B at the distal paranode. Using an in vitro model for MMN, ARGX-117
blocked IgM-mediated classical pathway complement activation on both motor
neurons and Schwann cells, providing further support for developing ARGX-117 in
patients with MMN.

The safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and
immunogenicity of single and multiple doses of ARGX-117 administered
intravenously (IV), and ARGX-117 comixed with recombinant human hyaluronidase
PH20 (rHuPH20) administered subcutaneously (SC), are being evaluated in the
ongoing, first-in-human (FIH), phase 1 study, ARGX-117-1901.

This phase 2 clinical trial serves to evaluate the safety and efficacy of
different dose regimens of ARGX-117 versus placebo, in participants with MMN
previously stabilized with IVIg.

ARGX-117-2002 is a randomized, double-blinded, placebo-controlled,
parallel-group, multicenter trial to evaluate the safety and tolerability,
efficacy, PK, PD, and immunogenicity of different dose regimens of ARGX-117 in
adults with MMN. Two cohorts of at least 24 participants each are planned for
enrollment.

This trial consists of a screening period, an IVIg dependency period (if
applicable), an IVIg monitoring period, a double-blinded treatment period
(DBTP), and a safety follow-up period.

All participants will begin with a screening period and the diagnosis of MMN
will be assessed by the MMN Confirmation Committee (MCC). The MCC will also
assess IVIg dependency. Participants whose IVIg dependency is uncertain will
enter an IVIg dependency period to assess the impact of a delayed IVIg
administration on grip strength (GS) and/or motor function. The IVIg criterion
is considered fulfilled in an individual stabilized to IVIg for longer than 3
months if a clinically meaningful deterioration from any of these 2 parameters
is established. The IVIg criterion is also considered fulfilled if an
individual stabilized to IVIg for less than 3 months demonstrates a clinical
improvement following the initiation of IVIg therapy.

After completing the screening period (including the IVIg dependency period, if
applicable), all participants will begin the IVIg monitoring period.
Participants will receive IVIg during the IVIg monitoring period at a
frequency, duration, and dose established by their medical history. The IVIg
monitoring period includes 3 IVIg treatment cycles, and will establish baseline
values for all clinical endpoints assessed during the DBTP.
Participants will be randomized on day 1 of the DBTP in:
- a 2:1 ratio to ARGX-117 or placebo in cohort 1, and for option 1 (dose
regimen 2: high dose ARGX-117) or option 2 (dose regimen 3: lower dose
ARGX-117) in cohort 2
- in a 2:2:1:1 ratio to ARGX-117 (high dose), ARGX-117 (lower dose), placebo
(high dose), or placebo (lower dose) for option 3 in cohort 2
Randomization will be stratified based on an individual*s IVIg dose frequency:
1. IVIg dosed every 2 or 3 weeks
2. IVIg dosed every 4 or 5 weeks

The dosing of ARGX-117 or placebo will begin on day 1 of the DBTP, 7 days after
the final IVIg administration of the IVIg monitoring period.
Participants will be retreated with IVIg during the DBTP if there is a
clinically meaningful deterioration in muscle strength and/or motor function.
Investigational medicinal product (IMP) administration will continue throughout
the DBTP. A clinically meaningful deterioration is defined as a >30% decline of
the GS of either hand observed for at least 2 consecutive days (based on the
3-day averaged calculations) and/or a decline of at least 2 points on the
modified Medical Research Council (mMRC)-10 sum score. Based on their clinical
judgment, the investigator may choose to not re-treat the participant with
IVIg. All trial participants can request IVIg retreatment anytime during the
DBTP.

End of Trial/Rollover
After completing the 16-week DBTP, participants may enroll in a long-term
extension (LTE) study and receive ARGX-117; otherwise, participants will enter
the 9-month safety follow-up period.
The following interim database locks will occur:
- After the completion of the 16-week DBTP by all participants included in
cohort 1.
- After the completion of the 16-week DBTP by all participants included in
cohort 2.
A final database lock will occur when all participants have completed the
safety follow-up period, or have rolled over to the LTE study, if applicable.

The first IMP administration will begin 7 days after the final IVIg
administration at the end of the IVIg monitoring period.

IMP includes:
• ARGX-117 administered by IV infusion
• Placebo administered by IV infusion

ARGX-117 and placebo will be administered by an IV infusion over approximately
2 hours at visit 1. ARGX-117 and placebo will be administered by an IV infusion
over approximately 1 hour for all subsequent administrations.

Dose regimen 1 will be assessed in cohort 1. Dose regimen 1 will include an
ARGX-117 dose of 30 mg/kg on day 1, followed by a dose of 10 mg/kg every 7 days
for 4 weeks (4 infusions total), and a dose of 10 mg/kg every 14 days (5
infusions total) until the end of the DBTP.

Three options are available as the dose regimen for cohort 2, of which 1 will
be assessed per the decision of the EDRT:
• Option 1*Dose regimen 2 (high dose): a single dose of 60 mg/kg ARGX--117 or
placebo on day 1, followed by 4 weekly doses of 30 mg/kg
ARGX--117 or placebo on days 8, 15, 22, and 29 (4 total infusions), and a dose
of 30 mg/kg ARGX-117 or placebo every 2 weeks until the end of the DBTP,
starting from day 43 (5 total infusions in total).).
• Option 2*Dose regimen 3 (lower dose): a single dose of 15 mg/kg ARGX-117 or
placebo on day 1, followed by 4 weekly doses of 5 mg/kg ARGX-117 or placebo on
days 8, 15, 22, and 29 (4 total infusions), and a dose of 5 mg/kg ARGX-117 or
placebo every 4 weeks, on days 57 and 85, until the end of the DBTP (2 total
infusions). Additionally, placebo will be given every 4 weeks, on days 43, 71,
and 99.
• Option 3*Dose regimens 2 and 3

There was 1 reported serious adverse event (SAE) of *abscess* which was
considered not related to IMP (ARGX-117 or placebo).

No SAEs considered related to blinded treatment have been reported.

No deaths or life-threatening events have been reported.