Open-label Extension of the ARGX-113-1802 Trial to Investigate the Long-term Safety, Tolerability, and Efficacy of Efgartigimod PH20 SC in Patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Efgartigimod (ARGX-113) is a human immunoglobulin (Ig) G1-derived Fc of the za
allotype that binds with nanomolar affinity to human neonatal Fc receptor
(FcRn). Efgartigimod encompasses IgG1 residues D221-K447 (European Union [EU]
numbering scheme) and has been modified with the so-called ABDEG* technology
(ABDEG* = antibody that enhances IgG degradation) to increase its affinity for
FcRn at both physiological and acidic pH. The increased affinity for FcRn of
efgartigimod at both acidic and physiological pH results in a blockage of FcRn
mediated recycling of IgGs.
Given the essential role of the FcRn receptor in IgG homeostasis, inhibiting
this FcRn function, as is achieved by efgartigimod, leads to rapid degradation
of all IgGs, including disease associated autoantibodies of the IgG isotype.
This approach is thought to result in alleviation of signs and symptoms in
IgG-driven autoimmune diseases.
The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of
intravenous (IV) administrations of efgartigimod have been investigated in the
first-in-human trial ARGX 113 1501 in healthy adult subjects. A second trial
ARGX-113-1702 in healthy adult subjects investigated the bioavailability,
safety, tolerability, immunogenicity, PK, and PD following SC administration of
efgartigimod and evaluated the reduction of the IV infusion time from 2 hours
to 1 hour.
Phase 2 trials in immune thrombocytopenia (ITP; ARGX 113 1603) and myasthenia
gravis (MG; ARGX 113 1602) have indicated that efgartigimod administered by IV
infusion is well tolerated, induces a specific, rapid PD effect (ie, reduction
in IgG levels, including autoantibody levels), and is associated with
improvement in clinical signs and symptoms in patients with ITP and MG,
separately.) Additionally, the safety and tolerability of efgartigimod is being
evaluated for the treatment of patients with pemphigus in the Phase 2 trial
ARGX 113 1701 and for the treatment of patients with MG in the Phase 3 trial
ARGX 113 1704.
For the Phase 2 trials in patients with CIDP, a fixed dose of 1,000 mg of
efgartigimod PH20 SC was selected based on the results of the Phase 1 trial
ARGX 113 1901 in healthy subjects that achieved a similar PD effect as that
observed in generalized myasthenia gravis (gMG) and ITP, ie, IgG reduction, at
steady state as achieved by weekly 10 mg/kg IV infusions. Doses of 10 mg/kg
efgartigimod IV have demonstrated a favorable safety and efficacy profile
across Phase 2 trials in MG and ITP patients. To select the fixed SC dose, an
open label, parallel group trial in healthy male subjects (ARGX-113-1901) has
been performed to investigate the PK, PD, safety, and tolerability of different
single fixed SC dose levels of efgartigimod co administered with rHuPH20.
In the current OLE trial, as well as in the main trial, efgartigimod is co
formulated with the permeation enhancer rHuPH20 (efgartigimod PH20 SC). rHuPH20
acts as a spreading factor that increases the dispersion and absorption of
other co administered drugs and allows SC dosing of greater volumes than
without rHuPH20. SC injections of rHuPH20 with fluids, small molecules,
peptides, and proteins (eg, IgG) were well-tolerated in all clinical trial
populations studied to date.

This study has been transitioned to CTIS with ID 2023-507885-21-00 check the CTIS register for the current data.

Primary objective:
- To assess the long-term safety and tolerability of efgartigimod PH20 SC
(efgartigimod co formulated with recombinant human hyaluronidase PH20 [rHuPH20]
for subcutaneous [SC] administration).

Secondary objectives:
- To determine the long-term efficacy.
- To evaluate the immunogenicity (anti-drug antibodies [ADA]) against
efgartigimod during the first 48-week treatment cycle [followed by a safety
follow-up period, if applicable]).
- To evaluate the pharmacokinetics (PK) of efgartigimod PH20 SC (during the
first 48-week treatment cycle
[followed by a safety follow-up period, if applicable]).
- To evaluate the pharmacodynamic (PD) effect of efgartigimod PH20 SC (ie,
total immunoglobulin G [IgG]
- To evaluate additional patient-reported outcomes (PROs) (including
patient-reported quality of life and
satisfaction with treatment).
- To explore self-administration of the treatment.
- To explore administration of the treatment by caregivers.
Note that there are other objectives for patients with less frequent than
weekly dosing of efgartigimod PH20 SC
which are described in a separate protocol appendix for a dosing frequency
substudy.

This is an open-label extension of the ARGX-113-1802 trial to investigate the
long-term safety, tolerability, and efficacy of efgartigimod PH20 SC in
patients aged 18 years and older with CIDP.
Patients will be given the opportunity to continue efgartigimod PH20 SC
treatment in this OLE trial in the event any of the following four conditions
are occurring, provided the patient has not permanently discontinued IMP:
• The patient experiences a clinical deterioration, (i.e., increase [worsening]
in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability
score in Stage B of ARGX-113-1802 as described in the ARGX-113-1802 protocol.
• The patient completes the Week 48 visit of Stage B of the ARGX-113-1802 trial
without any clinical deterioration.
• The patient is in Stage A or Stage B of the ARGX-113-1802 trial at the time
sufficient events for the primary endpoint analysis of that trial have been
reached and it is stopped.
• The patient completes the Week 48 visit of this OLE trial (Patients will be
offered the opportunity to continue in this trial until 2 years after marketing
authorization in apatient*s local country or until efgartigimod PH20 SC becomes
commercially available for patients with CIDP or
becomes available via continued access program, whichever comes first. ).
The OLE trial is planned in treatment cycles, each with a duration of 48 weeks.
In the OLE trial, 1,000 mg efgartigimod PH20 SC will be administered SC weekly,
ie, at the same dose and frequency as in the main ARGX 113 1802 trial.
The investigational medicinal product (IMP, ie, efgartigimod PH20 SC) will be
administered at the site at the scheduled visits. Other IMP administrations
will be administered by the patient (self-administration) or via a home nurse
or concierge service for visit at the trial site.

Optional Dosing Frequency Substudy: Note that after a minimum period of weekly
dosing in this OLE trial, as specified in Section 11.9 (Dosing Frequency
Substudy), patients who have a stable clinical condition for at least 12 weeks
will be offered to receive less frequent dosing to evaluate
the maintenance of the clinical condition by administration of efgartigimod
PH20 SC 1000 mg at 2 lower dosing frequencies.

Patients eligible for the extention study will receive open-label IMP as weekly
SC administrations of efgartigimod PH20 SC

Risks
No major safety findings have arisen in the ongoing and completed trials, nor
any pattern of adverse events (AEs)
which would raise concerns or alter the potential benefit-risk profile of
efgartigimod.
In clinical trials to date, efgartigimod has been well-tolerated in healthy
adult subjects and patients with gMG and ITP,
separately: the majority of treatment-emergent adverse events (TEAEs) were
considered to be mild (grade 1) in
severity. No TEAEs of grade >=3 have been reported. The most common TEAE
suspected to be related to efgartigimod
is headache; however, there is no evidence that headache occurs more frequently
in patients administered
efgartigimod than in patients administered placebo.