Siponimod for Alzheimer's Disease

(SIPO1-AD Trial)

Overseen By Marwan N Sabbagh, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Joseph's Hospital and Medical Center, Phoenix

Must not be taking: Cancer drugs, Amiodarone, Sulfa drugs, others

Disqualifiers: Infections, Neurological illness, Hypertension, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 24

Duration: 12 months

105 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, including those for cancer treatment, immune system suppression, and several specific drugs like Amiodarone and Fluconazole. If you're on any of these, you'll need to stop them to participate.

What data supports the effectiveness of the drug Siponimod for Alzheimer's Disease?

Siponimod has been shown to be effective in reducing disability progression and brain inflammation in patients with secondary progressive multiple sclerosis, which suggests it may have potential benefits for other neurological conditions like Alzheimer's Disease. ^{1 2 3 4 5}

How does the drug Siponimod differ from other Alzheimer's treatments?

Siponimod is unique because it is primarily used for multiple sclerosis and works by modulating the immune system, which is different from most Alzheimer's drugs that target neurotransmitters or amyloid plaques. This novel approach could offer a new way to address Alzheimer's disease by potentially reducing inflammation in the brain. ^{6 7 8 9 10}

Research Team

Marwan N Sabbagh, MD

Principal Investigator

St. Joseph's Hospital and Medical Center, Phoenix

Boris Decourt, PhD

Principal Investigator

Texas Tech University Health Sciences Center

Eligibility Criteria

This trial is for early-stage Alzheimer's disease patients, specifically those with mild cognitive impairment. Participants should be able to undergo MRI scans and willing to take an escalating dose of Siponimod or a placebo. The study excludes details on specific inclusion and exclusion criteria.

Inclusion Criteria

Must have a collateral informant/study partner with significant direct contact with the patient at least 10 hours per week

Documented Mini Mental State Exam (MMSE) score between 21-26 at Screening Visit

I am not able to become pregnant or I have a negative pregnancy test.

Exclusion Criteria

I do not have any active infections, including cold sores, shingles, bronchitis, sinus infections, colds, or fungal skin infections.

Meets DSM IV criteria for any major psychiatric disorder including psychosis, major depression, and bipolar disorder

I have had a brain or mental health condition in the last 3 years that could lead to memory loss.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an escalating dose of Siponimod or placebo for 12 months

12 months

Visits at baseline, 6, and 12 months

Washout

Participants undergo a 6-month washout period after treatment

6 months

Visit at 18 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Siponimod

Trial Overview The study tests if Siponimod can slow down brain shrinkage in Alzheimer's patients over an 18-month period, compared to a placebo. Patients are randomly assigned to receive either the drug or placebo in a 2:1 ratio for one year, followed by six months without treatment.

Participant Groups

Group I: Drug Arm Experimental Treatment 1 Intervention

Randomly assigned subjects who will receive an escalating dose of Siponimod (0.25-1 mg/day) for 12 months.

Group II: Placebo Arm Placebo Group 1 Intervention

Randomly assigned subjects who will receive a placebo daily for 12 months.

Siponimod is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Mayzent for:

• Relapsing forms of multiple sclerosis in adults

Approved in Canada as Mayzent for:

• Relapsing forms of multiple sclerosis in adults

Approved in European Union as Mayzent for:

• Active secondary progressive multiple sclerosis

Who Is Running the Clinical Trial?

St. Joseph's Hospital and Medical Center, Phoenix

Lead Sponsor

Trials

69

Recruited

17,400+

Arizona State University

Collaborator

Trials

311

Recruited

109,000+

Texas Tech University Health Sciences Center

Collaborator

Trials

107

Recruited

11,500+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Laboratory Corporation of America

Industry Sponsor

Trials

32

Recruited

18,800+

Findings from Research

Intravenous (IV) siponimod was found to be well tolerated in healthy subjects, with no significant effects on heart rate and similar safety profiles to oral siponimod, indicating its potential for safe use in clinical settings.

The pharmacokinetics showed that IV siponimod resulted in higher peak exposure compared to oral dosing, supporting the development of a rapid IV titration regimen for patients, particularly those with conditions like intracerebral hemorrhage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized, Open-label Study in Healthy Subjects. Shakeri-Nejad, K., Gardin, A., Gray, C., et al.[2020]

Siponimod has been shown to be statistically significantly more effective than interferon beta-1a and interferon beta-1b in delaying confirmed disability progression in patients with secondary progressive multiple sclerosis, based on a matching-adjusted indirect comparison of individual patient data from the EXPAND trial.

While siponimod demonstrated numerical superiority in reducing annualized relapse rates compared to other disease-modifying treatments, it was not statistically significant except when compared to natalizumab, indicating its potential as a strong option for managing SPMS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect treatment comparison of siponimod and other disease modifying treatments in secondary progressive multiple sclerosis. Samjoo, IA., Worthington, E., Haltner, A., et al.[2021]

Alzhemed (tramiprosate) is a well-tolerated treatment for mild-to-moderate Alzheimer's disease that effectively reduces levels of the neurotoxic amyloid-beta peptide in the cerebrospinal fluid after 3 months of treatment.

While Alzhemed did not show immediate cognitive improvements after 3 months, long-term follow-up suggested stabilization of cognitive function, particularly in patients with mild Alzheimer's disease, indicating potential benefits over extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alzhemed: a potential treatment for Alzheimer's disease. Aisen, PS., Gauthier, S., Vellas, B., et al.[2019]

Tacrolimus (FK506), an FDA-approved calcineurin inhibitor, can be safely delivered to APP/PS1 mice using time-release pellets, leading to normalization of calcineurin activity and significant reduction of Alzheimer's disease (AD) pathologies such as synapse loss and neuroinflammation.

The treatment with FK506 not only alleviated cognitive impairment and neuroinflammation but also preserved normal immune responses, suggesting it could be a promising early intervention for Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. Stallings, NR., O'Neal, MA., Hu, J., et al.[2023]

In a study involving 1,052 patients with mild-to-moderate Alzheimer's disease, tramiprosate showed a significant reduction in hippocampus volume loss compared to placebo, suggesting potential disease-modifying effects.

While the primary analyses did not demonstrate a significant cognitive improvement, post-hoc analyses indicated a trend towards cognitive benefits, highlighting the need for further investigation into tramiprosate's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). Aisen, PS., Gauthier, S., Ferris, SH., et al.[2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study . [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Cost-effectiveness and budget impact analysis of siponimod in the treatment of secondary progressive multiple sclerosis in Italy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized, Open-label Study in Healthy Subjects. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect treatment comparison of siponimod and other disease modifying treatments in secondary progressive multiple sclerosis. [2021]

6. Canada pubmed.ncbi.nlm.nih.gov

Memantine for treatment of moderate to severe Alzheimer's disease. [2013]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Alzhemed: a potential treatment for Alzheimer's disease. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response. [2023]

9. Denmark pubmed.ncbi.nlm.nih.gov

[Medical treatment of Alzheimer's disease]. [2018]

10. Poland pubmed.ncbi.nlm.nih.gov

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study). [2021]