Immunosuppression in Amyotrophic Lateral Sclerosis (ALS)

In an ongoing safety trial of neural stem cell injections into the spinal cord of patients
with ALS at Emory University, Atlanta, Georgia, one patient has demonstrated clear
improvement by objective clinical and electrophysiological measures, a finding that is
unheard of in patients with ALS.

This patient had an improvement in ALSFRS-R by 1.4 points per month. In 826 historical
controls from the Northeast ALS Consortium (NEALS) and the Western ALS Consortium (WALS)
database where ALSFRS-R was documented at 2 or more visits, there have been no patients that
have shown improvement in ALSFRS as seen in this case. Additionally, 5 patients in the stem
cell trial who were not on mechanical ventilators at the time of surgery seem to have very
slow disease progression as compared to the expectation from current understanding of typical
disease course. This observation raises consideration for a disease-modifying effect of the
novel immunosuppression regimen used in this trial. Also, given that ALS is clinically an
extraordinarily heterogeneous disease, the diagnosis of ALS may represent a group of
phenotypically similar but pathogenically variable disorders. It is possible that there
exists a subset of patients with an immune-responsive ALS subtype that has not been
previously recognized.

Recent studies have furthered the understanding of the immune mechanisms that contribute to
ALS progression. Microglia and lymphocytes have both neurotoxic and neuroprotective functions
depending on activation states and physiologic conditions within the nervous system.
Therefore, targeted immunotherapies that proportionally suppress neurotoxic immune elements,
while sparing or promoting protective elements, seemingly have more potential to modify
disease course in ALS than previously tested regimens. It is postulated that the
immunosuppression treatment given to the stem cell patients may have exhibited
neuroprotective effects by favorably promoting the ratio of regulatory T cells and other
protective immune mediators in relation to neurotoxic immune modulators. It is hoped that
this trial will optimize the chance of replicating these findings and advance knowledge about
the complex changes that occur within the immune system in patients with ALS before and after
treatment with an immunosuppression regimen.

The primary outcome measure will be rate of change of ALSFRS-R. A clinical response will be
defined as a rate of change of ALSFRS-R of +6 points over a 6 month period (mean of change of
+1 point per month).

Secondary outcome measures will include slow vital capacity (SVC), grip strength, and hand
held dynamometry (HHD). The change in rate of progression in clinical measures will be
monitored to look for a potential disease-modifying effect of the immunosuppression regimen.
Blood and cerebrospinal fluid immune system markers will be also be studied.

If a clinical response is seen among study participants following treatment, further analyses
will be conducted to explore any differential effects of immunosuppression in participants
with early-stage disease and later-stage disease. To ensure adequate numbers of participants
for conditional analyses stratifying by symptom onset date, participants will be enrolled
based on symptom onset within 24 months of the screening visit or more than 24 months before
screening. All participants will have the same treatment and will be treated as a single
group for the analyses of the main study outcomes.

Inclusion Criteria for participants with symptom onset within the past 24 months:

- Male or female patients 18-65 years of age.

- ALS diagnosed as possible, laboratory-supported probable, probable, or definite as
defined by revised El Escorial Criteria.

- Symptom onset ≤ 24 months from screening visit.

- A score of ≥38 on the Revised ALS Functional Rating Scale.

- Slow vital capacity (SVC) measure >80% of predicted for gender, height and age at
screening.

- Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of
riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects
are permitted in the study).

- Negative tuberculosis (TB) test within 3 months of Screening Visit.

- Subjects medically able to undergo lumbar puncture (LP) as determined by the
investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin
infection at or near the LP site).

- Capable of providing informed consent and following study procedures.

- Women must not be able to become pregnant (e.g. post menopausal, surgically sterile,
or using adequate birth control methods) for the duration of the study.

- Women of childbearing potential must have a negative pregnancy test at screening and
be non-lactating.

- Geographic accessibility to the study site.

Inclusion Criteria for participants with symptom onset greater than 24 months before
screening:

- Male or female patients age 18 or older.

- ALS diagnosed as possible, laboratory-supported probable, probable, or definite as
defined by revised El Escorial Criteria.

- Symptom onset >24 months from screening visit.

- Subjects must not have taken riluzole for at least 30 days, or be on a stable dose of
riluzole for at least 30 days, prior to the screening visit (riluzole-naïve subjects
are permitted in the study).

- Negative tuberculosis (TB) test within 3 months of Screening Visit.

- Subjects medically able to undergo lumbar puncture (LP) as determined by the
investigator (i.e., no bleeding disorder, allergy to local anesthetics, or a skin
infection at or near the LP site).

- Capable of providing informed consent and following study procedures.

- Geographic accessibility to the study site.

- Women must not be able to become pregnant (e.g. post menopausal, surgically sterile,
or using adequate birth control methods) for the duration of the study.

- Women of childbearing potential must have a negative pregnancy test at screening and
be non-lactating.

Exclusion Criteria

- Prior use of basiliximab, solumedrol, prednisone, tacrolimus or mycophenolate mofetil
within 30 days of the Screening Visit.

- Known allergy or sensitivity to basiliximab, solumedrol, prednisone, tacrolimus or
mycophenolate mofetil or a formulation of one of these drugs.

- Treatment with an immunosuppressant medication within 30 days of the Screening Visit.

- Active peptic ulcer disease.

- Any medical disorder that would make immunosuppression contraindicated including, but
not limited to, human immunodeficiency virus (HIV), tuberculosis, or evidence of
active cytomegalovirus (CMV) or infection.

- Subjects who have a diaphragm pacing system (DPS).

- Women who are pregnant, breastfeeding, or planning to become pregnant in the next 12
months.

- Active drug or alcohol use or dependence that, in the opinion of the site
investigator, would interfere with adherence to study requirements.

- Use of invasive or non-invasive mechanical ventilation (including Continuous Positive
Airway Pressure (CPAP) or Bi-level Positive Airway Pressure (BiPAP)) for any part of
the day or night prior to the Screening Visit (participants with symptom onset within
past 24 months only).

- Exposure to any other agent currently under investigation for the treatment of
patients with ALS (off-label use or investigational) within 30 days of the Screening
Visit.

- Inability to safely complete study activities based on the discretion of the site
investigator.