Collaboration with multiple sclerosis (MS) specialty colleagues led us to formulate the central hypothesis that Siponimod could lower the rate of brain atrophy in Alzheimer's disease (AD) subjects. To test our central hypothesis, we will carry out an 18-month Phase II, double-blind, randomized, twoarmed, placebo controlled, proof-of-concept clinical study in early AD subjects (i.e. mild AD) who will be receiving an escalating dose of Siponimod or placebo in the ratio 2:1 for 12 months, followed by a 6-month washout period. The primary outcome measures are safety and tolerability of Siponimod in mild AD subjects. The secondary outcome measures are the rates of brain atrophy derived from volumetric MRI (vMRI) as a proxy for neurodegeneration conducted at baseline, 6, 12, and 18 months. The tertiary outcome measures are the changes in cognition and the levels of AD-associated (e.g., Aβ and tau) and inflammatory biomarkers in CSF after Siponimod exposure. In an exploratory effort, we will also measure plasma inflammatory markers during the entire duration of the study to investigate whether one or more of these markers can be used as dynamic surrogate markers of treatment response. Using our unique experience with the repurposing of immunomodulatory drugs for AD (and NCT #04032626), in the present project we are using elements of clinical trial design that we believe were successful and made some adjustments to fit the pharmacologic and toxic properties of Siponimod.

Alzheimer's disease (AD) is a neurodegenerative disorder with several complex neuropathologies suspected to develop sequentially but that overlap over time as symptoms progress to dementia. Thus, to be effective, future intervention strategies will likely require combination therapies or pleiotropic agents to tackle several AD molecular pathogenic pathways simultaneously. For more than a decade, our group has been exploring the repurposing of immunomodulators for AD. Recent discussions with collaborators who specialize in multiple sclerosis suggest that sphingosine-1-phosphate receptor (S1PR) modulators are strong candidates for repurposing in AD. Indeed, S1PR modulators are blood brain barrier (BBB) penetrant and display pleiotropic actions, including immunomodulation and neuroprotective properties. S1P is a versatile endogenous molecule that regulates several signaling pathways by binding to five G-protein-coupled receptors, which are expressed in high levels in cardiac, vascular, immune, and brain cells. This widespread localization of S1PR was the historical basis for Novartis Pharmaceuticals, Inc, to develop oral formulations of S1PR modulators for multiple sclerosis (MS), which proved successful and resulted in two marketed oral compounds (i.e., fingolimod and Siponimod). In the present project, we intend to collaborate with Novartis to use the most recently FDA-approved S1PR modulator, Siponimod. Based on MS and animal experimentation literature, we hypothesize that Siponimod could alter the rate of neurodegeneration as measured by lowering the rate of brain atrophy in mild AD dementia subjects. In this Phase II, proof-of-concept, translational clinical study, mild AD dementia subjects will be randomized 2:1 and will receive gradual titration regimen of Siponimod starting at 0.25mg/day and increasing up to final dosage of 1 mg/day (N=70) or placebo (N=35) for 12 months. This will be followed by a 6-month washout period. Siponimod has demonstrated positive immunomodulatory and neuroprotective actions in MS patients, and because its toxicity profile is favorable for use in older individuals, Siponimod has a strong potential to alter markers of mild AD dementia pathology and disease trajectory.

Inclusion Criteria:

1. Male or female at least 50 years of age, but less than 85 (84 at time of screening)
2. Females must be of non-childbearing potential or have negative pregnancy test at time of screening. Women of non-childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for >12 months prior to the planned date of enrollment.
3. Must have a diagnosis of mild Alzheimer's Dementia determined by medical record review.
4. Vision and hearing must be sufficient to comply with study procedures.
5. Be able to take oral medications.
6. Must be able to attend all study visits indicated in the schedule of visits.
7. Must have a collateral informant/study partner who has significant direct contact with the patient at least 10 hours per week and who is willing to accompany the patient to specified clinic visits, supervise administration of all study medication, and be available for telephone visits/interviews.
8. Documented Mini Mental State Exam (MMSE) score between 20-26 at Screening Visit Day 1.
9. CT or MRI scan of the brain within 12 months of Screening Visit Day 1 showing no evidence of significant focal lesions or other pathology which could contribute to dementia. If neither a CT or a MRI scan is available from the past 12 months, a scan fulfilling the requirements must be obtained before randomization.
10. Hachinski ischemic score must be < 4.
11. Geriatric depression scale must be < 10.
12. Prior to dosing all randomized study subjects must show proof they have received immunization to varicella (VZV IgG).
13. Each patient must be assessed for capacity to consent by the principal or sub-investigators in order to provide informed consent. If the patient is deemed unable to provide informed consent, they must have a legally authorized representative (LAR), and the LAR must review and sign the informed consent form. If the patient does not have a LAR, the patient must appear able to provide informed consent and must review and sign the informed consent form. If the patient is deemed unable to provide informed consent and does not have a LAR, they cannot participate in the study. In addition, the patient's study partner/informant (as defined in the study inclusion criteria) must sign the informed consent form. If the LAR and the patient's study partner/informant are the same individual, he/she should sign under both.
14. No active suicidality identified on Columbia-Suicide Severity Rating Scale (C-SSRS).
15. Patients with stable prostate cancer may be included at the discretion of the Medical Monitor.
16. Patients who are on monoclonal antibody medication for the treatment of Alzheimer's (ex. lecanemab, donanemab) for > 6 months or have discontinued monoclonal antibody medication for the treatment of Alzheimer's for > 6 months may be included if all other criteria has been met.

Exclusion Criteria:

1. Taking one of the following medications: Medications for treatment of cancer or other drugs that weaken the immune system (ex. Natalizumab and Rituximab), Amiodarone, Bishydroxycoumarin, Chloramphenicol, Cimetidine, Fluconazole, Fluvastatin, Miconazole, Phenylbutazone, Sulphinpyrazone, Sulphadiazine, Sulphamethizole, Sulfamethoxazole, Sulphaphenazole, Trimethoprim, and Zafirlukast.
2. Current active infection in participants including, but not limited to, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection and fungal skin infection. Siponimod may increase the risk in participants with active infections.
3. If participant received mRNA COVID-19 vaccination, must have received last dose at least 3 months prior to first dose of study drug/placebo.
4. Current evidence or history within the last 3 years of a neurological or psychiatric illness that could contribute to dementia, including (but not limited to) epilepsy, focal brain lesion, Parkinson's disease, seizure disorder, or head injury with loss of consciousness.
5. Meets DSM IV criteria for any major psychiatric disorder including psychosis, major depression and bipolar disorder.
6. Known history of or self-reported active alcohol and/ or substance abuse within the past three years.
7. Isolated living circumstances which would prohibit a study partner from providing sufficient and credible information about the participant.
8. Poorly controlled hypertension
9. Known Atrioventricular heart block, known heart block type I-III.
10. History of myocardial infarction or signs or symptoms of unstable coronary artery disease within the last year (including revascularization procedure/angioplasty).
11. Severe pulmonary disease (including chronic obstructive pulmonary disease) requiring more than 2 hospitalizations within the past year.
12. Untreated obstructive sleep apnea.
13. Any thyroid disease (unless euthyroid on treatment for at least 6 months prior to screening).
14. Active neoplastic disease (except for skin tumors other than melanoma) within five years.
15. Absolute lymphocytopenia of <1,000/mm3, or a history of lymphocytopenia within the past two years.
16. Absolute neutropenia of <1,000/mm3, or a history of neutropenia within the past two years.
17. History of/ or current thromboembolism (including deep venous thrombosis).
18. Any clinically significant hepatic or renal disease (including presence of Hepatitis B or C surface antigen or an elevated transaminase levels of greater than 2x the upper limit of normal (ULN) or creatinine greater than 1.5 x upper limit of normal (ULN)).
19. Clinically significant hematologic or coagulation disorder including any unexplained anemia, or a platelet count less than 100,000/µL at screening.
20. Use of any investigational drug within 30 days or within five half-lives of the investigational agent, whichever is longer.
21. Unwilling or unable to undergo CT or MRI imaging.
22. In the opinion of the investigator, participation would not be in the best interest of the subject.
23. Subjects with CYP2C9*3/*3 genotyping

Information from the study such as SAEs, the study protocol, case report forms, study results, Statistical Analysis Plan, Informed Consent Form, and findings that might alter the current benefit-risk profile of the Study Drug or that would be sufficient to consider changes in the Study Drug's administration or in the overall conduct of the Study, and the Clinical Study Report, will be shared with the drug manufacturer Novartis, and the subaward institutions, Arizona State University and Texas Tech, and the members of the Data Safety and Monitoring Board, who are associated with University of Indiana, Pentara Corporation, and Texas Tech, and the internal medical monitor and clinical monitoring team who are part of Barrow Neurological Institute (BNI).

From 03/08/2023 to 07/31/2027

Dr. Jeffrey Wilson at Arizona State University will be given study data directly from Barrow Neurological Institute (BNI) staff to perform biostatistical analysis. Dr. Boris Decourt at Texas Tech will be given blood and saliva samples from BNI to process, store, and analyze. Dr. Mirla Avila at Texas Tech, Dr. Martin Farlow at University of Indiana, and Dr. Craig Mallinckrodt at Pentara Corporation will receive case report forms from BNI staff such as the project manager and SAE information from Dr. Sabbagh. There are current data use and material transfer agreements in place with the respective institutions. Dr. Sabbagh and Dr. Decourt also plan to present study findings in the form of peer-reviewed manuscripts and presentations at scientific meetings.

The clinical research coordinator, the psychometrist, the co-investigators (Dr. Boris Decourt and Dr. Karl Golnik) will be masked. Everyone who is patient-facing will be masked.