SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer’s Disease (AD): A Multi-center, Randomized, Double-Blind, Placebo-Controlled Safety and Biomarker Study of Pepinemab Anti-SEMA4D Antibody in Early-AD

1. Written informed consent from subject and legally acceptable representative (trial
partner).

2. Have a reliable and competent trial partner who must have a close relationship with
the subject, who has face to face contact at least three days a week for a minimum of
ten waking hours a week and is willing to accompany the subject to all trial visits.
The trial partner should understand the nature of the trial and adhere to trial
requirements (e.g., dose, visit schedules, receive phone calls, and evaluations).

3. Male and female subjects between the ages of 55 to 85 (inclusive).

4. If female, not be of childbearing potential as indicated by one of the following:

a) Has reached natural menopause defined as either: i) ≥ 12 months of spontaneous
amenorrhea or ii) ≥ 6 months of spontaneous amenorrhea with serum follicle stimulating
hormone (FSH) levels > 40 mIU/ml as determined by the central laboratory; b) Has had a
hysterectomy; or c) Has had a bilateral tubal ligation; or d) Has had a bilateral
oophorectomy (with or without a hysterectomy) and more than 6 weeks have passed since
the surgery.

5. If male must agree to use a reliable method of birth control (condoms with
contraceptive foams or sexual abstinence) during the study and for 6 months after the
last dose of study drug.

6. Must fulfill one of the following:

1. A documented amyloid PET scan (florbetaben F18, florbetapir F18, or flutametamol
F18) determined as positive by the investigator obtained prior to the Screening
visit.

2. A documented positive amyloid CSF result obtained prior to the Screening visit.

3. If documentation is not available in the subject’s record that states that the
subject has had a positive amyloid PET scan or positive amyloid CSF result prior
to the Screening visit, a positive amyloid CSF result is required at screening.
The cut-off value for CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio will be based on the
value established by the central CSF screening laboratory and specified in a
separate laboratory manual.

7. Evidence of cognitive impairment based on history and neuropsychological testing that
meet the diagnostic criteria for Mild Cognitive Impairment or probable Alzheimer’s
dementia.

8. Global Clinical Dementia Rating (CDR) of 0.5 or 1.0

9. MMSE score ≥22.

10. Adequate vision and motor function to comply with testing.

11. Use of AD medications (including but not limited to donepezil, rivastigmine,
galantamine, tacrine, and memantine) at doses that have been stable for at least 8
weeks prior to Screening Visit.

12. Subjects on stable doses of centrally-acting medications for 8 weeks prior to
Screening Visit.

13. In the opinion of the Investigator, subjects should be in reasonably good health over
the last 6 months and any chronic disease should be stable, based on medical history
and screening assessments.

Exclusion

1. Have participated in an investigational drug or device study within 30 days of the
Baseline Visit. If previous investigational drug was a monoclonal antibody,
antibody-drug conjugate or similar protein therapeutic, 180 or days or 5 half-lives,
whichever occurs first.

2. Have a known allergy to any ingredient in the study drug formulation.

3. Have a body weight greater than 125kg.

4. Are a suicide risk, as determined by meeting any of the following criteria:

1. suicide attempt within one year prior to Baseline.

2. suicidal ideation as defined by a positive response to question 4 and 5 on the
C-SSRS within 60 days of the Baseline Visit.

5. Have a history of substance abuse (based on DSMIV criteria) within the past 12 months
prior to Screening.

6. Significant acute or chronic infection at Screening. including, among others: Known
history of human immunodeficiency virus (HIV) or known acquired immunodeficiency
syndrome. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as,
HBV surface antigen positive or positive HCV antibody with reflex to positive HCV
RNA).

7. Have clinically significant laboratory or ECG abnormalities at Screening, in the
opinion of the Investigator.

8. Have clinically relevant hematologic, hepatic, cardiac, or renal disease.

9. Have a clinically significant medical, surgical, laboratory, or behavioral abnormality
which in the judgment of the site Investigator makes the subject unsuitable for the
study. as well as anyone with a history of malignancy of any type within 2 years of
Screening. Persons with a history of surgically-excised non-melanoma skin cancers,
superficial bladder or prostate cancer are permitted.

10. Subjects that have a diagnosis of a neurological condition causing cognitive
impairment other than sporadic MCI/mild dementia due to AD (e.g. Lewy body disease or
frontotemporal dementia), a primary psychiatric diagnosis (e.g. Cognitive Impairment
due to Schizophrenia, CIAS), or significant findings on brain MRI at screening
inconsistent with AD (e.g. cerebrovascular disease or tumor).

11. Have any of the following conditions (which would exclude MRI or PET participation):

1. Subjects deemed unable to cooperate due to claustrophobia, inability to lie on
scanner bed for 45 minutes, or inability to achieve venous access sufficient for
tracer or pepinemab administration.

2. An implant/device/condition that is contraindicated for MRI (e.g. pacemaker,
severe claustrophobia, prosthetic heart valve, any metal fragments in the eyes or
body–in some cases, an X-ray may be needed before an MRI scan, to ensure it is
safe to enter the scanner).

3. Body habitus that would impede completion of imaging scans.

12. Has an MRI scan obtained at Screening that shows evidence of a neurological disorder
other than early AD or > 4 cerebral microhemorrhages (regardless of their anatomical
location or diagnostic characterization as “possible” or “definite”), a single area of
superficial siderosis, or any other clinically significant finding (e.g., any lesion
that may account for their cognitive impairment, including but not limited to brain
tumor, severe white matter disease with a rating of 3 on the age-related white matter
changes (ARWMC) scale, arteriovenous malformation, cavernous hemangioma, or any
infarct in a strategic cortical or subcortical location). Are undergoing FDG-PET and
have received research-related radiation exposure that exceeds institutional
guidelines in the prior year if applicable.

13. Are undergoing a LP for CSF collection and have any of the following conditions:
uncorrected bleeding or clotting disorders, skin infections near the site of the LP,
suspicion of increased intracranial pressure, allergies to numbing medications (local
anesthetics), acute spinal trauma, history of migraines.

14. Are undergoing a LP for CSF collection and taking any of the following types of
anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, or thrombin
inhibitors.