SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD)
SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD)
To investigate safety, tolerability, the effects on cognition and brain metabolism of
 pepinemab in early AD dementia (early AD) subjects.
This is a randomized double-blind, placebo-controlled, parallel-group study of pepinemab in
 early AD dementia defined as MCI and mild Alzheimer's dementia. The study is 40 weeks in
 duration, including a safety and efficacy evaluation 4 weeks after the last dose of study
 drug. Subjects with resolved adverse events at Week 36 will have a safety telephone call at
 Week 40. Subjects with unresolved adverse events at Week 36 will have a safety in-office
 visit at Week 40.

 The study protocol will include two sentinel subjects in each of the three blinded dose arms.
 Sentinel dosing will be implemented by randomly assigning one study subject to each of the
 three dose arms in a blinded manner, treating those subjects with study drug, and observing
 them for at least 48 hours after treatment. If no unexpected serious adverse events are
 observed within 48 hours after the third subject receives treatment, three additional
 subjects will be enrolled, with one subject each assigned randomly to each of the three dose
 arms. Again a 48-hour observation period will be observed following treatment to document any
 unexpected safety events that may occur. Should no unexpected serious adverse events occur
 within 48 hours after the sixth subject receives treatment, the remaining subjects will be
 assigned to the study dose cohorts according to the blinded randomization scheme and the
 1:1:1 randomization ratio.

 Subjects will be randomized to one of three treatment arms and will receive one dose of study
 drug every 4 weeks during the 32-week dosing period for a total of 9 doses of study drug. The
 primary objective is the safety and tolerability of study drug. A key secondary objective is
 the change in brain metabolism as assessed by [18F]fluorodeoxyglucose (FDG)-PET in the
 resting state.
Inclusion

 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.