A randomized, double-blind, placebo-controlled, multi-center study to evaluate the safety and efficacy of eculizumab in subjects with refractory generalized myasthenia gravis (gMG)

Myasthenia Gravis is a rare, debilitating, acquired autoimmune disease of the
neuromuscular junction (NMJ), caused by the failure of neuromuscular
transmission, which results from the binding of auto-antibodies (Abs) to
proteins involved in signaling at the neuromuscular junction (NMJ). Myasthenia
Gravis is clinically characterized by weakness and fatigability of skeletal
muscles. The prevalence of MG is estimated to be between 14-20 per
100,000 people in the United States. In the MG patient population, there is a
wide range of disease severity. Although many patients with MG can be managed
with anticholinesterase inhibitor therapy and immunosuppressants, there is a
cohort of patients who continue to have marked generalized weakness and bulbar
signs and symptoms of the disease despite adequate dosing of immunosuppressant
therapy. For these patients,
there is a medical need for alternative treatment strategies targeting
different pathophysiological aspects of the disease. Since complement
activation plays a pivotal role in the pathophysiology of MG, eculizumab, a
terminal complement inhibitor, as such may benefit patients who continue to
have generalized weakness and bulbar signs and symptoms despite current
standard of care. Alexion has completed a phase II, randomized, double-blind,
placebo-controlled, pilot trial (cross-over design), protocol number C08-001,
to establish safety and efficacy of eculizumab in 14 subjects with refractory
gMG. In this phase 2 clinical trial, 86% (6/7) subjects in the eculizumab arm
had >=3-point reduction in the Quantitative MG (QMG) score vs. 57% (4/7) in
placebo arm, 86% (6/7) had >=2-point change in the MG activities of the
Activities of Daily Living profile (MG-ADL) vs 57% (4/7) in the placebo arm and
the mean change from baseline in MG-ADL was -4.1 points. The data from the
pilot trial (C08-001) provide preliminary evidence of the safety and efficacy
of eculizumab in the treatment of refractory gMG and warrants further
investigation.

Main Objective:
Assess the efficacy of eculizumab as compared with placebo in the treatment of
refractory gMG based on the improvement in the MG specific Activities of Daily
Living profile (MG-ADL).

Secondary Objectives:
- Safety and tolerability of eculizumab as compared with placebo in gMG subjects
- Efficacy of eculizumab compared with placebo
- Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of eculizumab
- Characterize the effect of eculizumab as compared with placebo on Quality of
Life measures

This is a randomized, double-blind, parallel-group, placebo-controlled,
multicenter trial to evaluate the safety and efficacy of eculizumab for the
treatment in subjects with refractory gMG. Approximately 92 eligible subjects
will be randomized on Day 1 on a 1:1 ratio to one of two treatment arms, (1)
eculizumab infusion or (2) placebo infusion. Subjects may continue to receive
stable dose/type of supportive immunosuppressive therapy (IST), but no new ISTs
and no increase in IST dosage are permitted during the trial. There will be 3
periods in this study: Screening Period, Study Period, and Follow-up Period
(for subjects who withdraw from this trial or who do not enter the extension
trial). Subjects may be provided the opportunity to participate in an extension
trial (separate protocol) to receive eculizumab after completion of this trial.

Investigational Product (IP), eculizumab or placebo, will be intravenously
administered according to the following regimen:

Induction Phase:
eculizumab or placebo; 3 vials of IP (placebo or equivalent to 900 mg of
eculizumab) weekly x 4 (every 7 days ±2 days) followed by 4 vials of IP
(placebo or equivalent to 1200 mg of eculizumab) one week later for the fifth
dose.

Maintenance Phase: eculizumab or placebo: 4 vials of IP (placebo or equivalent
to 1200 mg of eculizumab) every two weeks (every 14 days ±2 days).

Supplemental Doses:
If PE is administered due to a clinical deterioration (as defined by this
protocol), supplemental IP (2 vials) will be administered within 60 minutes
after the end of each PE session. Per-protocol, scheduled IP administration
will be continued according to the specified dose-administration schedule for
the subject. If the subject is scheduled to receive the protocol-scheduled dose
on the day of a PE session, then the scheduled dose should be administered
within 60 minutes after the end of the PE session.

The proposed phase III clinical trial includes only patients with refractory
generalized MG. The inclusion criteria are designed to select patients who
continue to have clinical symptoms, including oropharyngeal/respiratory
symptoms despite treatment with immunosuppressive agents or chronic use of IVIG
or Plasma Exchange to maintain clinical stability. This is a small subset of
the broader MG population, but is the population with greatest unmet medical
need.

The lack of effective treatment, the new and targeted mechanism of action of
eculizumab and the promising efficacy data achieved in clinical Phase II study
support the potential benefit of eculizumab in this population.

This clinical development program is designed to assess the efficacy of
eculizumab as compared with placebo in the treatment of refractory gMG based on
the improvement in the MG-specific Activities of Daily Living profile (MG-ADL).

The safety profile of eculizumab has been extensively characterized in PNH and
aHUS patients. The most significant risk associated with the use of eculizumab
is the risk of meningococcal infection and key mitigation measures have been
put in place. The risk of meningococcal infection observed to date in Soliris®
(eculizumab) treated patients is less than 0.5 events/100 patient years of
treatment.

In addition, strict requirements for contraception are also mandated to
minimize the risk of unintended pregnancies during the study period and in the
5 months following the last dose of study drug as per currently approved
Soliris® (eculizumab) SmPC.

In summary, the benefit-to-risk balance is considered as favorable.