Study NOG112264, a Phase II Study of Ozanezumab (GSK1223249) versus Placebo in the Treatment of Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder characterised by
gradual degeneration and progressive loss of the upper and lower motor neurons
throughout the central nervous system, and is associated with severe neurologic
morbidity and death. The clinical course of the disease is highly variable
suggesting that multiple factors contribute to the pathogenesis of ALS. The
majority of patients (around 85%) die in the first 5 years following onset
mainly from complications of respiratory failure.
Palliative treatment for ALS prolongs survival and improves or maintains
quality of life. At present, riluzole is the only approved drug therapy for
ALS. Riluzole is thought to reduce the glutamate drive on motor neurons which
is considered to play an important role in the neurodegenerative process and
has demonstrated a marginal effect on functional decline with prolongation of
median survival by about 2 to 3 months. Thus, there remains a great unmet
medical need for a treatment that will be effective in slowing or halting the
decline of function and significantly prolonging survival in ALS.
Data suggest a role for Nogo-A in the pathophysiology of ALS, although it is
not clear to what extent Nogo-A may be involved in directly triggering the
pathology. GSK has developed a humanized immunoglobulinG1 (IgG1)-type
monoclonal antibody (mAb), ozanezumab (GSK1223249), against Nogo-A.
Study NOG112264 is a Phase II study intended to be considered as a registration
study, thus contributing efficacy, tolerability and safety data to the
registration package for ozanezumab.

Primary: to assess the effect of intravenous (IV) ozanezumab (15 mg/kg once
every 2 weeks) compared to placebo on the physical function and survival of ALS
patients over a treatment period of 48-weeks.
Secondary (major): other clinical outcomes, safety, tolerability, quality of
life, immunogenicity and PK.

Multicenter randomized double-blind placebo-controlled parallel group phase II
study.
Randomization (1:1) to:
1. Ozanezumab 15 mg/kg IV infusions once every 2 weeks
2. Placebo IV infusions once every 2 weeks
First 20 patients (part A) will be monitored very closely during the initial
part of the treatment period. Recruitment will halt temporarily once all Part A
subjects are randomized. Data from the first four dose administrations for
these subjects will be reviewed by an IDMC prior to continuing recruitment of
the remaining subjects (Part B). In part B the monitoring in the initial phase
will be less intense (2 visits less, no 6/24 h observations).
In Part B only, the randomization will be stratified by use of riluzole.
Study duration approx. 64 weeks, treatment period 48 weeks.
Individualized follow-up after leaving the study.
Approx 294 randomized patients.

Treatment with ozanezumab or placebo.

Risk: Adverse events of study medication.
Burden: 27 (part B0-29 (part A) visits in 64 weeks, incl. 2 24 h and 2 6 h
observation and PK days (group A during 1st 8 weeks).
IV infusions ozanezumab every 2 weeks, approx. 150 ml.
Blood tests every visit (15-40 ml, approx. 390 ml in total).
Optional pharmacogenetic research (10 ml blood).
Pulmonary function tests: 6x.
Muscle strength 5x.
ECG approx. 50% of visits.
Pregnancy test approx. 50% of visits.
Questionnaires every visit.