A Phase 3, External Placebo-Controlled, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Patients with Neuromyelitis Optica Spectrum Disorder (NMOSD)

Neuromyelitis optica spectrum disorder is a severe disabling autoimmune
inflammatory disorder of the CNS that predominately affects the optic nerves
and spinal cord, and less commonly the brain. The disorder is ultra-rare,
affecting 0.5 to 4.4 per 100,000 worldwide inhabitants (Pandit L, 2015).
The most common manifestations of NMOSD are characterized by recurrent, severe
relapses of optic neuritis or transverse myelitis, which result in a stepwise
accumulation of relapse-related neurologic disability that can be irreversible
(Wingerchuk DM, 2006). The annualized relapse rate (ARR) for patients with
NMOSD is estimated to be about 1 relapse per year per patient, with the vast
majority of patients experiencing relapse (Flanagan EP, 2016; Ghezzi A, 2004;
Jarius S, 2012).
In a study of AQP4-Ab positive neuromyelitis optica (NMO) patients, morbidity
was significant with 18% experiencing permanent visual disability, 34%
experiencing permanent motor disability, and 23% experiencing wheelchair
dependency during the follow-up period (Kitley J, 2012)


SOLIRIS® (eculizumab), the first-in-class complement component C5 inhibitor, is
the only therapy approved by the U.S. FDA for the treatment of NMOSD in adult
patients who are anti-AQP4 Ab positive. Supportive treatments, including
corticosteroids and other immunosuppressive therapies (ISTs), have been used
based on clinical experience and consensus (Trebst C, 2014). Despite the use of
ISTs as supportive therapy, a significant number of patients (> 50%) continued
to experience disease relapses that resulted in incremental and permanent
neurologic deficits and disability (Bichuetti DB, 2010; Jacob A, 2009).
Eculizumab has been demonstrated to be effective in reducing relapse risk.
After the initial induction dose, eculizumab is administered every 2 weeks
(q2w) to maintain adequate complement suppression. Neuromyelitis optica
spectrum disorder is a chronic disease, and a frequent dosage regimen may
impose a significant burden on patients, many of whom are disabled and require
assistance with transportation.
Ravulizumab has a longer serum terminal elimination half-life and corresponding
duration of pharmacologic activity relative to eculizumab. Ravulizumab was
designed based on comprehensive modelling and simulation analyses to maintain
efficacious concentrations across a longer dosing interval. The q8w dosage
regimen is less burdensome for patients and has 4-fold fewer pharmacokinetic
(PK) troughs, leading to fewer opportunities for achieving incomplete
complement inhibition associated with sub-therapeutic exposure. The reduction
in infusion frequency offers the potential to provide patients and physicians
with an additional option for effective treatment of NMOSD while also improving
quality of life (QoL) through fewer missed days of work, better treatment
adherence, and improved accessibility.

Complement activation is a major determinant of disease pathogenesis in
patients with NMOSD (Hinson SR, 2009; Nytrova P, 2014; Papadopoulos MC, 2012;
Verkman, 2012). Binding of AQP4 IgG to the AQP4 water channel, which is highly
expressed on astrocytic surfaces in the CNS, has been shown to lead to
hexameric assembly of immunoglobulin G (IgG). This in turn recruits and
activates complement C1, the first step in activation of the complement cascade
(Diebolder CA, 2014). Complement activation initiates an inflammatory cascade
that induces permeabilization of the blood brain barrier and astrocyte
necrosis. Lesions that form during this process are indicative of NMOSD and are
positive for anti-AQP4 Abs and complement (Papadopoulos MC, 2012).
The therapeutic role of inhibition of terminal complement activation was
demonstrated with eculizumab in Study ECU-NMO-301. Study ECU-NMO-301 was a
randomized, double-blind, placebo-controlled, multicenter study that evaluated
the safety and efficacy of eculizumab in patients with relapsing NMOSD. A
significant effect on the time to first adjudicated On-trial Relapse was
observed for eculizumab compared with placebo (p<0.0001). An approximately
94.2% reduction in the risk of relapse was observed in patients who received
eculizumab compared with placebo (Pittock SJ, 2019). In conjunction with the
efficacy results, the serum free C5 results indicated that immediate, complete,
and sustained terminal complement inhibition was achieved.

Primary
• To evaluate the effect of ravulizumab on adjudicated On-Trial Relapses in
adult patients with NMOSD

Secondary
• To evaluate the safety of ravulizumab in adult patients with NMOSD
• To evaluate the effect of ravulizumab on adjudicated annualized relapse rate
(ARR) in adult patients with NMOSD
• To evaluate the effect of ravulizumab on disease-related disability in adult
patients with NMOSD
• To evaluate the effect of ravulizumab on quality of life (QoL) in adult
patients with NMOSD
• To evaluate the effect of ravulizumab on neurologic function in adult
patients with NMOSD
• To characterize the pharmacokinetics (PK) of ravulizumab in adult patients
with NMOSD
• To characterize the pharmacodynamics (PD) of ravulizumab in adult patients
with NMOSD
• To characterize the immunogenicity of ravulizumab in adult patients with
NMOSD

Study ALXN1210-NMO-307 is a Phase 3, external placebo-controlled, open-label,
multicenter study to evaluate the efficacy and safety of ravulizumab in adult
patients with NMOSD.
Approximately 55 eligible adult patients with NMOSD will be enrolled.

This study will employ a single-arm treatment design, utilizing the placebo
group from Study ECU-NMO-301 (conducted 2014 to 2018) as a contemporaneous
external placebo control. This will allow for a robust assessment of
ravulizumab as a treatment option for NMOSD.

There are 4 periods in this study: Screening Period, Primary Treatment Period,
Long-Term Extension Period, and Safety Follow-up Period. Patients will be
screened for eligibility for up to 6 weeks during the Screening Period. The
Primary Treatment Period ends and the Long-Term Extension Period starts when
the last patient completes the End of Primary Treatment (EOPT) Period Visit,
which is initiated when all patients have completed the Week 26 Visit. All
patients will continue to receive ravulizumab during the Long-Term Extension
Period for up to 2 years, or until ravulizumab is approved and/or available (in
accordance with country-specific regulations), whichever occurs first. The
total treatment duration for each patient will be up to 4 years. After the last
dose of study drug or early discontinuation (ED), patients will be followed for
8 weeks.

This is a single-arm treatment study with no masking.

Eligible patients will enroll into the study to receive intravenous infusions
of ravulizumab.
The ravulizumab dose for each patient will be based on body weight.

The dosing regimen consists of a loading dose followed by maintenance dosing
administered every 8 weeks (q8w).
The maintenance dosing should be initiated 2 weeks after the loading dose
administration.

For each patient, the total duration of study participation will be up to 4
years and 14 weeks, including the Screening Period (up to 6 weeks), the Primary
Treatment Period (between 26 weeks and 2 years), the Long-Term Extension Period
(up to 2 years), and the Safety Follow-up Period (8 weeks).

Patients are asked to undergo procedures as described in the protocol table '
schedule of events', 1-4 on pages 16-24.
The study consists of a screening period up to 6 weeks, a primary treatment
period of at least 26 weeks, a long-term extension period up to 2 years and a
safety follow- up period of 8 weeks.
These procedures include:
- Physical exam, vital signs, demographic and medical history
- Ophthalmological exam
- Neurologic exam
- ECG
- OCT
- MRI
- Meningococcol vaccination
- Questionnaires: EQ-5D, SF-36, EDSS (including FSS)
- Blood and urine tests (including HIV)
- Optional blood test for DNA and RNA
- Optional Cerebrospinal fluid test for DNS and RNA
- Pregnancy tests in women of childbearing potential
- Female patients: no breastfeeding allowed. Effective methods of birth control
must be used from the time of signing the ICF, throughout the entire study and
for 8 months following the last dose of the study drug.
- Male patients: due to the potential risk of the effect on the sperm
appropriate method of contraception must be used starting at screening and
continuing for at least 8 months following the last dose of study drug.

The study medication as well performing the study-related procedures, may cause
discomforts and risks. Ravulizumab may also have discomforts and risks that are
still unknown. These may be mild or serious and may be very serious,
long-lasting, or may never go away. There is also a risk of death.

Following side effects have been reported based on the clinical experience in
patients using Ravulizumab:
Meningococcal infection: patients receiving Ravulizumab, even after a single
dose, are at increased risk for the development of serious infections caused by
Neisseria meningitis. This is a bacterial infection that can hit the brain
(menignococcal meningitsi) or be present in the blood (meningococcal sepsis).
Meningococcal infections can rapidly become life-treating or fatal especially
if not reorganized and treated early. Subjects will receive a vaccination
against meningococcal infections. Vaccination alone may not be sufficient to
prevent infection with Neissara meningitis.
Due to similar mechanism of action there is also a risk for the infection
caused by the bacteria 'Neisseria gonorrhea' causing a gonococcal infection.

Side effects of Ravulizumab:
Very common side effects (seen in more than 10% of patients); diarrhea, nausea,
vomitting, nasopharyngitis, headache.
Common side effects (seen in 1 to 10% of patients); abdominal pain,
indigestion, flu-like illness, fever, chills, tiredness, muscle pain & spasm,
back-pain, joint-pain, dizziness, rash & itchness.
Uncommon side effects ( seen in less than 1% of patients); chills, upper
respiratory tract infection (common cold)

There is a risk of a reaction occurring when receiving ravulizumab. Symptoms
that may show that you are having a reaction include:
Headache, Lightheadedness, Itching, Muscle aches, Nausea, Vomiting, Sleepiness,
Skin redness, Abdominal discomfort, Excessive sweating
Tight feeling in chest, Fever, Chills or shivers, Shortness of breath, High or
low blood pressure, Swelling of tissue (all or parts of your body), Hives
Flushing, Rash, Heart palpitations (abnormal heart beat).

With any medication there is a risk of allergic reactions. Some symptoms of
allergic reactions and/or anaphylaxis are:
Rash such as hives; may also include itching, Difficulty breathing, shortness
of breath, tightness in the chest, and wheezing (noises while breathing)
Dizziness or feeling faint, Tingling and swelling around the mouth, in your
throat, or eyes, Fast pulse Very low blood pressure, Sweating, Seizures
(convulsions), Loss of consciousness, Flushing or temporary reddening of the
skin, (usually on the face), Possibly death.

Side effects and risks related to the study procedures:
• Blood draws
You may experience pain, bruising, or bleeding at the point where the blood was
drawn. There is also the possibility of infection, but this is rare. Although
the total amount of blood drawn over time is predicted to be well-tolerated,
anemia (low levels of red blood cells) may occur.
• Intravenous (IV) infusions
An IV line is placed in your vein to administer the study drug. There may be
discomfort during IV placement. Rarely, some people experience pain, bleeding,
bruising, swelling, clotting of the vein, leakage of the IV fluid into their
surrounding tissues, or infection at the location where the IV was placed.
Meningococcal vaccination before start the study. If so, the vaccine will be
injected into the arm. The vaccine can cause temporary swelling in the area
where the vaccine was injected.
• ECG
The electrocardiogram is a painless procedure,it requires lying still in on
examination table, which may be uncomfortable for some persons.
• MRI
MRI uses a large magnet to take images of the and spinal cord. An injection of
a contrast dye (gadolinium) through a needle in the arm is given before the MRI
scan. The main side effect associated with gadolinium, although rare, is an
allergic reaction. The MRI scan does not hurt, but it requires the patient to
be lying still for ca 45 minute to one hour.
• OCT
OCT is to examine the nerves in the back in the eyes. The procedure is
painless. Eye drops prior to the procedure. These drops will cause light glare
and make your vision blurry. These effects will go away after a few hours.
• Lumbar puncture
Lumbar puncture a procedure. A needle is inserted into the lower back and into
the spinal canal, the fluid filled space around the spinal cord, to collect
spinal fluid. Headache can occur following this procedure. Serious
complications are extremely rare and include bleeding into the spinal canal,
infection, injury to the spinal cord resulting in weakness and loss of
sensation or paralysis in the legs, spinal cord compression, and brain
herniation.

Ravulizumab provides patients and physicians with an option for less frequent
dosing, which allows greater access to care for those patients who may not
initiate treatment on eculizumab, may discontinue eculizumab due to frequency
of dosing, or who are currently receiving eculizumab every 2 weeks.