A Randomized, Double-Blind, Placebo-Controlled Study, Followed by an Open-Label Extension, to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of Intrathecally Administered ISIS 814907 in Patients with Mild Alzheimer*s Disease

Part 1:
1. Patient is able to read, understand, and provide written informed consent
(signed and dated)
2. Male or female, aged 50-74 years, inclusive, at Screening
3. AD of mild severity (CDR Global score of 1 or CDR Global Score of 0.5 with a
Memory score of 1;; MMSE 20-27, inclusive) at Screening
4. Reduced CSF Aβ42 at Screening, consistent with a diagnosis of mild AD
5. Elevated CSF total tau and p-tau at Screening, consistent with a diagnosis
of mild AD
6. Diagnosis of probable AD dementia based on National Institute of
Aging-Alzheimer Association (NIA-AA) criteria (may be either amnestic or
nonamnestic [Global CDR score of 1.0] presentation) at Screening
7. Body Mass Index (BMI) >= 18 and <= 35 kg/m2
8. Total body weight > 50 kg (110 lbs)
9. Able and willing to meet all study requirements, including travel to Study
Center, procedures, measurements and visits, including:
a. Reside in a proximity to the Study Center that permits prompt appearance at
the facility if requested by the Investigator (maximum of 4-hour travel to
Study Center), unless neurological examination or admission, if needed, can be
arranged promptly at a suitably equipped and staffed alternative facility and
these arrangements have been discussed and agreed to by the Ionis Medical
Monitor
b. Adequately supportive psychosocial circumstances, in the opinion of the
Investigator
c. Caregiver/trial partner committed to facilitate patient*s involvement in the
study who is reliable, competent, at least 18 years of age, willing to
accompany the participant to select study visits and to be available to the
Study Center by phone if needed and who, in the opinion of the Investigator, is
and will remain sufficiently knowledgeable of the patient*s ongoing condition
to respond to Study Center inquiries about the patient, such as providing
information related to study outcome measures requiring caregiver input
d. Adequate visual and auditory acuity for neuropsychological testing
10. Able to read at a level necessary to complete study assessments
11. No evidence or prior diagnosis of general learning disability
12. Females must be non-pregnant, non-lactating and either surgically sterile
(e.g., bilateral tubal occlusion, hysterectomy, bilateral salpingectomy,
bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous
amenorrhea without an alternative medical cause and FSH levels in the
post-menopausal range for the laboratory involved)
13. Males must be surgically sterile, abstinent or, if engaged in sexual
relations with a female of child-bearing potential, must agree to use an
acceptable contraceptive method (refer to Section 6.3.1) from the time of
signing the informed consent form until at least 13 weeks after the last dose
of Study Drug (ISIS 814907 or placebo) or end of the study, whichever is
longer, Part 2:
1. Able to read, understand, and provide written informed consent (signed and
dated)
2. Able and willing to meet all study requirements in the opinion of the
Investigator, including:
a. Adequately supportive psychosocial circumstances
b. Caregiver/trial partner committed to facilitate patient's involvement in the
study who is reliable, competent, at least 18 years of age, willing to
accompany the participant to select study visits, and to be available to the
Study Center by phone if needed, and who, in the opinion of the Investigator,
is and will remain sufficiently knowledgeable of the patient's ongoing
condition to respond to Study Center inquiries about the patient, such as
providing information related to study outcome
measures requiring caregiver input
c. Adequate visual and auditory acuity for neuropsychological testing
d. Able to tolerate blood draws and lumbar punctures
3. Must have completed the Treatment Evaluation and Post-Treatment Periods in
MAD, Part 1 of the study
4. Females must be non-pregnant, non-lactating and either surgically sterile
(e.g. bilateral tubal occlusion, hysterectomy, bilateral salpingectomy,
bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous
amenorrhea without an alternative medical cause and FSH levels in the
post-menopausal range for the laboratory involved)
5. Males must be surgically sterile, abstinent, or if engaged in sexual
relations with a female of child-bearing potential, must agree to use and
acceptable contraceptive method (refer to Section 6.3.1) from the time of
signing the informed consent form until at least 13 weeks after the
last dose of ISIS 814907 or end of study, whichever is longer.

Part 1:
1. First or second degree family member among the investigational or Sponsor
staff directly involved in the trial
2. Any contraindication or unwillingness to undergo MRI scanning (e.g., metal
implants including MRI incompatible IUDs, claustrophobia, agitation or tremor
of a severity that precludes MRI scans)
3. Any contraindication or unwillingness to undergo LP
4. Patient receives daily nursing care due to cognitive condition
5. Evidence of clinically-relevant neurological disease other than the disease
being studied, including
a. Cerebrovascular disease (history of TIA, stroke, significant vascular
disease [large vessel stroke, diffuse white matter hyperintensities {WMHs},
multiple lacunes, bilateral thalamic lesions, and/or > 5 microhemorrhages on
brain MRI] or modified 8-item Hachinski Ischemia Scale score >= 4)
i. In addition to microhemorrhages, the degree of WMH severity will be
centrally rated on T2 FLAIR and GRE T2 star images using the Age Related White
Matter Changes (ARWMC) scale (e.g., WMHs > 5 mm, rated on a 4-point scale
ranging from 0 (no lesions) to 3 (diffuse involvement of the entire region),
within 5 regions in each hemisphere; a score of 3 in a region constitutes the
presence of diffuse WMH)
ii. Multiple lacunes are rated as the presence of at least 2 lacunes in the
basal ganglia and at least 2 lacunes in the frontal white matter. To meet the
criterion for the presence of bilateral thalamic lesions, at least 1 lesion
must to be present in each thalamus.
b. Current infectious/metabolic/systemic diseases affecting CNS
c. History of a serious infectious disease affecting the brain in the 5 years
prior to Screening
d. History of clinically-significant head trauma (i.e., any loss of
consciousness for > 5 minutes), including motor vehicle accident and/or
concussion in the 3 years prior to Screening
e. MRI scan at Screening shows evidence for a potential alternative etiology
for dementia (i.e., non-AD etiology)
f. History of generalized seizures in the 3 years prior to Screening
6. Psychiatric diagnosis/symptoms interfering with assessment of cognition
a. Attempted suicide, suicidal ideation with a plan that required hospital
admission and/or change in level of care within 6 months prior to Screening.
For patients with (i) a suicide ideation score >= 4 on the Columbia Suicide
Severity Rating Scale (C SSRS) within the last 6 months, or (ii) suicidal
behaviors within the last 6 months (as measured by the answer *Yes* on any of
the C-SSRS Suicidal Behavior Items, a risk assessment should be done by an
appropriately-qualified mental health professional (e.g., a Psychiatrist or
licensed Clinical Psychologist) to assess whether it is safe for the patient to
participate in the study. Patients deemed by the Investigator to be at
significant risk of suicide should be excluded
b. Major depressive episode within 6 months prior to Screening (with the
exception of patients in remission on allowed concomitant antidepressant
medication) or at risk for psychosis, confusional state or violent behavior in
the opinion of the Investigator
c. Geriatric Depression Scale Short Form > 6
d. History of alcohol or drug dependency/abuse within 3 years prior to Screening
7. Clinically-significant cardiac conditions including cardiac failure, angina
or previous acute coronary syndrome within 6 months of Screening
8. Ongoing or recent (within 12 weeks of Screening) uncontrolled,
clinically-significant medical condition including:
a. Hematological, hepatic, diabetes, hypertension, thyroid or endocrine
disease, gastrointestinal disease, dialysis, or abnormal renal function
b. Retinal impairment or disease that would interfere with the ability to
comply with study procedures
c. Peripheral vascular disease that would interfere with the ability to comply
with study procedures
d. Known history of or positive test for human immunodeficiency virus (HIV),
hepatitis C, chronic hepatitis B consistent with CDC interpretation of serology
panel or syphilis
9. History of bleeding diathesis or coagulopathy and/or platelet count < LLN at
Screening
10. A medical history of brain or spinal abnormalities by MRI/CT or history
that might interfere with the LP process, CSF circulation or safety assessment,
including subarachnoid hemorrhage, suggestions of raised intracranial pressure
on MRI or ophthalmic examination, spinal stenosis or curvature, spina bifida
occulta, chiari malformation, hydrocephalus, syringomyelia, tethered spinal
cord syndrome, frontotemporal brain sagging syndrome and connective tissue
disorders such as Ehlers-Danlos syndrome and Marfan syndrome
11. Any medical condition that increases risk of meningitis unless patient is
receiving appropriate prophylactic treatment
12. History of malignancy within 5 years prior to Screening, except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical
cancer, localized prostate carcinoma. Patients with other malignancies that
have been treated with potentially curative therapy with no evidence of
recurrence for >= 5 years post-therapy may also be eligible if approved by the
Sponsor Medical Monitor
13. Active infection requiring systemic antiviral or antimicrobial therapy that
will not be completed 3 days prior to Study Day -1
14. At Screening, have any condition such as medical, psychiatric or
neurological other than the tauopathy under study which, in the opinion of the
Investigator or Sponsor, would make the patient unsuitable for inclusion or
could interfere with the patient participating in or completing the study
15. Treatment with another investigational drug, biological agent, or device
within 1 month of Screening, or 5 half-lives of investigational agent,
whichever is longer
16. Use of a disallowed CNS-active or antipsychotic medication within 4 weeks
or 5 half-lives (whichever is greater) prior to the start of Screening
17. Change in dose regimen of an allowed CNS-active or antipsychotic medication
within 4 weeks or 5 half-lives (whichever is greater) prior to the start of
Screening
18. Change in dose regimen of a cholinesterase inhibitor or memantine within 8
weeks prior to the start of Screening
19. Change in dose regimen of estrogen replacement therapy within 4 weeks prior
to the start of Screening
20. Change in dose regimen of nutraceuticals or supplements within 4 weeks
prior to the start of Screening
21. Use of warfarin
22. Use of Neudexta (dextromethorphan and quinidine)
23. Prior treatment with an active immunotherapy agent targeting the CNS
24. Presence of an implanted shunt for the drainage of CSF or an implanted CNS
catheter
25. Any medical or surgical procedure involving general anesthesia within 12
weeks of Screening or planned during the study
26. Any history of gene therapy or cell transplantation or any experimental
brain surgery
27. Clinically-significant laboratory, vital sign or ECG abnormalities at
Screening (including HR < 45 bpm, SBP < 90 mmHg and confirmed BP readings >
170/105 mmHg)
28. Any hepatic, glucose, renal, hematology or thyroid laboratory tests above
or below the limits of normal that are considered to be clinically-significant
must be discussed with the Sponsor Medical Monitor
29. Clinically-significant B12 or folate deficiencies at Screening or previous
deficiencies that have not been corrected for at least 12 weeks prior to
Screening, Part 2:
1.Treatment with another IP within 1 month of Reg, or 5 half-lives of
investigation agent, whichever is longer
2.Use of a disallowed CNS-active or antipsychotic medication within 4 wks or 5
half-lives(whichever is greater) prior to Reg
3.Change in dosing regimen of an allowed CNS-active or antipsychotic medication
within 4 wks or 5 half-lives(whichever is greater) prior to Reg
4.Change in dose regimen of a cholinesterase inhibitor or memantine within 8
wks prior to Reg
5.Change in dose regimen of estrogen replacement therapy within 4 w