A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel, Multicenter Study to Evaluate the Safety and Efficacy of ALXN1720 in Adults with Generalized Myasthenia Gravis.

MG is a rare, debilitating disease characterized by the failure of
neuromuscular signal transmission. The estimated prevalence of MG is between
145 to 361 per million persons. MG can present at any age. However, female
incidence peaks in the third decade of life, whereas male incidence peaks in
the sixth or seventh decade. Major advances in the therapy of MG have reduced
its mortality to 1.5%, a level comparable to the general population. Despite
this improved overall prognosis, acute disease exacerbations with potentially
life-threatening hypoventilation still occur and remain a serious concern.
Voluntary muscle contraction requires the release of acetylcholine from nerve
endings at the NMJ. Patients with MG produce autoantibodies that target the
AChR or proteins involved in the formation of AChR clusters on the surface of
muscle fibers, eg, muscle-specific tyrosine kinase. Antibodies against AChR are
detected in most patients with MG (> 80%). Activation of the terminal
complement pathway contributes to the pathophysiology of MG in patients who
express autoantibodies against the AChR. The receptor is located at the NMJ of
muscle fibers. Its activation is essential for skeletal muscle movement.
Complement recruitment in the presence of antibodies against the AChR is
assumed to contribute to MG by damaging the NMJ through formation of the MAC.
Blocking terminal complement activity is an established treatment approach to
MG. Its efficacy has been demonstrated in independent pivotal trials of
eculizumab and ravulizumab, two monoclonal antibodies that inhibit the
enzymatic cleavage of C5. Both eculizumab and ravulizumab are approved by the
US Food and Drug Administration (FDA) for the treatment of gMG. C5 is a key
component of the terminal complement pathway. Like eculizumab and ravulizumab,
ALXN1720 inhibits C5 cleavage into the biologically active complement
components C5a and C5b. Based on the shared mechanism of action, ALXN1720 may
similarly show clinical efficacy in participants with gMG at doses that
accomplish an equivalent level of C5 inhibition. The proposed ALXN1720 dosage
regimen in this Phase 3 study is predicted to achieve complete terminal
complement inhibition, defined as free C5 < 0.5 µg/mL in the serum over the
entire treatment period in patients with gMG. Compared with conventional
antibodies, ALXN1720 has a low molecular weight, allowing it to be concentrated
in small volumes suitable for SC injection. Another benefit of ALXN1720 is its
long half-life, allowing convenient once weekly dosing intervals.

This study has been transitioned to CTIS with ID 2023-508284-77-00 check the CTIS register for the current data.

The purpose of this study is to evaluate the safety and efficacy of ALXN1720
for the treatment of gMG in adults with autoantibodies against AChR (AChR+).
The study will also evaluate the safety and performance of the administration
device (the PFS-SD).

ALXN1720-MG-301 is a Phase-3, randomized, double-blind, placebo-controlled,
parallel, multicenter study to evaluate the safety and efficacy of ALXN1720 in
adults with gMG.
The study comprises 3 periods: Screening (<= 4 weeks), randomized controlled
treatment (RCT; 26 weeks), and open label extension (96 weeks). Randomization
takes place in the RCT period 1:1 to either ALXN1720 or placebo.

Subjects will receive ALXN1720 or placebo, both administered through weekly
subcutaneous injection by using a prefilled syringe with safety device
(PFS-SD).

A weekly dose of study medication will be received via 1 or 2 subcutaneous
injection(s). In the first 5 weeks, the subject will come to the hospital every
week to receive the injection(s) and to be trained in self-administration of
the injection(s). After that, the subject can administer the injection(s) at
home (or have it administered by a caregiver). The subject should complete an
electronic diary after each administration of study medication. Remote and
hospital visits alternate, with the frequency of hospital visits decreasing
over the course of the study. In total there are 39 visits in about 2.5 years,
24 of which were in hospital and 15 remotely. The subject is asked to complete
several questionnaires one day before each hospital visit.
There is a small risk of serious meningococcal infection, therefore subjects
receive a vaccination during screening if they have not had it in the past 3
years. If the subject cannot wait more than 2 weeks after the vaccination, to
start the study medication, the subject will receive prophylactic antibiotics.

Acute disease exacerbations with potentially life-threatening hypoventilation
still occur and remain a serious concern.
The potential risks identified for participants in association with the
administration of ALXN1720 and the use of the PFS-SD are considered justified
because of the measures taken to minimize these risks and the anticipated
benefits that may be afforded to participants with gMG.