A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With Optional Open-Label Extension in Subjects With Relapsing Multiple Sclerosis to Evaluate the Efficacy and Safety of BIIB033 as an Add-on Therapy to Anti-Inflammatory Disease-Modifying Therapies

BIIB033 is a first-in-class human monoclonal antibody directed against LINGO-1,
a negative regulator of oligodendrocyte progenitor cells (OPCs) differentiation
and myelination. Specifically, LINGO-1 expression is increased in OPCs from
demyelinated white matter of multiple sclerosis (MS) brain tissues. LINGO-1
negatively regulates oligodendrocyte differentiation and myelination, neuronal
survival, and axonal regeneration by activating ras homolog gene family member
A and inhibiting Protein kinase B phosphorylation signaling pathways BIIB033
enhances differentiation of primary rat, monkey, and human oligodendrocytes in
vitro and enhances axonal myelination in an in vitro rat dorsal root
ganglion/OPC co-culture bioassay. Additionally, BIIB033 enhances remyelination
and functional recovery in the rat lysophosphatidylcholine (LPC), cuprizone,
myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis
(MOG-EAE), and MOG-EAE optic neuritis models The therapeutic hypothesis is that
BIIB033 will act in the central nervous system (CNS) to block LINGO-1, which is
expressed on both oligodendrocytes and neurons. In turn, the inhibition of
LINGO-1 may promote remyelination via differentiation of OPCs normally present
in the CNS and promote axonal regeneration by blocking signaling from myelin
debris on the Nogo66 receptor 1 complex in neurons. Therefore, BIIB033
treatment in demyelinating diseases such as MS may lead to improved CNS repair
with corresponding beneficial effects on neurological function and disability.

Three Phase 1 studies and 2 Phase 2 studies have been completed. The Phase 1
studies included Studies 215HV101 (single-ascending dose study in healthy
volunteers), 215MS101 (multiple-ascending dose study in subjects with RRMS or
SPMS), and 215HV102 (single- and
multiple-dose study in healthy Japanese volunteers). The Phase 2 studies
included Study 215ON201 in subjects with acute optic neuritis (AON) and Study
215MS201 in subjects with relapsing form of MS. In the Phase 1 studies, BIIB033
exposure was dose proportional over the studied dose levels and dose ranges,
with doses ranging from 0.1 to 100 mg/kg. BIIB033 was well tolerated, and
laboratory findings revealed no clinically meaningful abnormalities. BIIB033
pharmacokinetics (PK) in subjects with MS was similar to that observed in
healthy adults, and BIIB033 PK doesnot appear to be altered by the concurrent
treatment of IFN* or GA. Additionally, the clinical study portions of an
additional Phase 1 study have been completed. Study 215HV103 is a single-dose
study in healthy volunteers using study drug from 2 different manufacturing
processes (referred to as BIIB033-A and BIIB033-B). Preliminary data indicate
that the PK parameters (area under the concentration-time curve from time 0 to
infinity [AUCinf] and maximum observed concentration [Cmax]) are very similar
for the BIIB033-A material and the
BIIB033-B material. The completed Phase 2 Study 215ON201 was a 24-week,
randomized study designed to assess the efficacy, safety, tolerability, and PK
of BIIB033 (100 mg/kg) versus placebo in 82 subjects with their first episode
of AON.
A trend in improvement was observed for the intent-to-treat (ITT) population in
fullfield visual evoked potential latency of the affected eye at both Weeks 24
and 32 with BIIB033 over placebo, compared with the baseline of the unaffected
fellow eye. This improvement reached statistical significance in the
per-protocol population at Week 32. These data provided proof-of-biology
evidence for CNS remyelination with
BIIB033 treatment. No treatment effects were observed in retinal thinning or
visual acuity tests with
BIIB033 over placebo. In this study, 100 mg/kg of BIIB033 infused IV every 4
weeks was well tolerated,
and the overall incidence of adverse events (AEs) was the same in the placebo
and BIIB033 groups (83%). Hypersensitivity reactions occurred in 2 subjects (5%
of BIIB033-treated subjects who received 100-mg/kg dose), and postbaseline
weight
gain was also observed.
The completed Phase 2 Study 215MS201 was a 72-week, multicenter, randomized,
double-blind, parallel-group, placebo-controlled, dose-ranging study to assess
the efficacy, safety, tolerability, and PK of BIIB033, when used concurrently
with Avonex, in subjects with relapsing forms of
MS. BIIB033 was evaluated at doses of 3, 10, 30, and 100 mg/kg. * The primary
endpoint was confirmed improvement in 1 or more assessments of a multicomponent
disability endpoint over 72 weeks. A statistically significant linear
dose-response on primary endpoint was not observed with BIIB033 treatment
versus placebo (p=0.9831). Analyses showed a non-monotonic, inverted U-shaped
dose response to BIIB033 with more favorable outcomes in the 10- and 30-mg/kg
groups. Prespecified univariate subgroup analyses suggested enhanced efficacy
in younger
subjects and in those with clinical and magnetic resonance imaging (MRI)
features suggestive of more preserved brain tissue integrity. Analyses of
individual functional assessments as well as the Overall Response Score also
suggested a more pronounced favorable effect of BIIB033 at the 10-mg/kg dose,
although there was a waning effect over time. Post hoc multivariate analysis
showed a greater and more durable efficacy in a
subpopulation (approximately 25% to 30% of the ITT population) defined by
shorter disease duration and baseline MRI characteristics consistent with lower
myelin content but higher tissue integrity in T2 lesions, especially in the
10-mg/kg group. BIIB033 was generally well tolerated, with hypersensitivity
reactions seen only at the 100-mg/kg dose (4 subjects [1% of BIIB033-treated
subjects]) and a trend for
dose-dependent weight gain over 72 weeks, with a mean increase between 0.9 and
1.9 kg in 4 BIIB033 dosing groups. The study showed no change in the PK profile
of BIIB033 and no new safety signals. The efficacy results observed in Study
215MS201, combined with the favorable safety profile demonstrated by the Phase
1 and Phase 2 studies as well as the proof of biology achieved in
Study 215ON201, support the continued evaluation of BIIB033.

The proposed study (215MS202) will further investigate the efficacy and safety
of BIIB033 as an add-on therapy in subjects with RMS who are on a stable dose
of an anti-inflammatory disease-modifying therapy (DMT) and with baseline
characteristics consistent with projected
enhanced treatment effect of BIIB033 as identified in the post hoc analysis
from Study 215MS201. To reduce variability and potential confounding factors
from different background DMTs while allowing for the evaluation of the effect
of BIIB033 across a range of background
therapies, 3 specific groups of background DMTs will be included in this study.
The DMTs are IFN* (Avonex, Plegridy, Betaferon/Betaseron, or Rebif), DMF
(Tecfidera), and natalizumab (Tysabri), representing different mechanisms of
action, anti-inflammatory activities, and routes of administration.
Randomization will be stratified by MS type (RRMS versus SPMS), background DMT
group, and baseline MTR/DTI characteristics.

Part 1: To evaluate the effects of BIIB033 versus placebo on disability
improvement over 72 weeks.
Part 2: evaluate long-term safety profile of BIIB033 as an add-on therapy in
subjects with MS.

Part 1 is a 72-week, multicenter, randomized, double-blind, placebo-controlled,
parallel-group, Phase 2 study to evaluate the efficacy and safety of BIIB033
(750 mg infused IV every 4 weeks) as an add-on therapy to a background DMT in
subjects with RMS.
Subjects who have completed study treatment (BIIB033 or placebo) in Part 1 will
have the option to take part in Part 2, which is a 96 week multicenter, OLE
phase that will evaluate BIIB033 treated subjects for long-term safety and
efficacy of BIIB033 treatment, and explore novel biomarkers and patient
reported outcomes (PROs) for remyelination/neurorepair MS therapies. Subjects
will continue the anti-inflammatory DMT used at the end of Part 1. DMT
treatment in Part 2 will continue to be managed by the Investigator. The study
will include clinical assessments every 24 weeks and 4 brain MRI measurements.

Part 1: The study treatment includes BIIB033 or placebo, administered once
every 4 weeks by IV infusion (at site) for a total of 19 doses over 72 weeks.
Part 2: All subjects will receive IV infusions of open-label BIIB033 750 mg
once every 4 weeks as an add-on therapy to anti inflammatory DMT.

Study (215MS202) will further investigate the efficacy and safety of BIIB033 as
an add-on therapy in subjects with RMS who are on a stable dose of an
anti-inflammatory disease-modifying therapy (DMT) and with baseline
characteristics consistent with projected enhanced treatment effect of BIIB033
as identified in the post hoc analysis from Study 215MS201. Another object of
the study is to learn more about side effects of the study drug. Like all
medicines, BIIB033 can cause side effects, although not everybody experiences
them. The most common side effects (which may or may not be related to BIIB033)
are: headache, urinary tract infection, upper respiratory tract infection,
common cold, stomach upset, fatigue, MS relapse, symptoms associated with
lumbar puncture (headache, nausea, neck pain, and double vision), a sensation
of tingling, numbness, or burning in arms or legs, flu-like illness, and fever.
Liver problems including jaundice (eyes and or skin turning yellow) along with
elevations in liver enzymes also occured. It is not known whether these
effects were related to BIIB033.
As with any new drug, there is a risk of rare or previously unknown side
effects, and/or a chance that BIIB033 might interact with other drugs.
If patients participate in this study, it will not mean that they suffer less
from RMS. RMS may get worse, improve, or stay the same. But patients will
contribute to increased knowledge about the treatment of RMS.