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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether Siponimod, a drug used in multiple sclerosis, can slow brain atrophy in people with mild Alzheimer's disease. Participants will receive either Siponimod or a placebo for 12 months, followed by a six-month follow-up. The study will assess the safety and tolerability of Siponimod, its effects on brain shrinkage, and any changes in cognitive function. Suitable candidates have mild Alzheimer's, can take oral medication daily, and have someone to assist them regularly. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to advancements in Alzheimer's treatment.

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.

Is there any evidence suggesting that Siponimod is likely to be safe for humans?

Research has shown that Siponimod, also known as Mayzent, is generally safe for people. The FDA has approved it for treating multiple sclerosis, indicating it has passed strict safety tests for that condition. While currently under testing for Alzheimer's, this background provides some confidence about its safety.

These studies focus on safety and how well people tolerate the drug. Previous patients demonstrated that it can reduce certain risks without major side effects. The trial employs careful dosing to ensure safety, as the drug has shown benefits in conditions like multiple sclerosis.

However, since this is a Phase 2 trial for Alzheimer's, the treatment's safety remains under close monitoring. This phase ensures the treatment does not cause harm and is well-tolerated by participants. Always consult a doctor to determine if joining a trial is appropriate. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Most treatments for Alzheimer's disease focus on managing symptoms or slowing down disease progression, often by targeting amyloid plaques or neurotransmitter activity. But Siponimod works differently, targeting the S1P1 receptor, which plays a role in immune system regulation and inflammation. This unique mechanism could potentially address Alzheimer's disease from a novel angle, offering hope for a more effective treatment. Researchers are excited about Siponimod because it could modify the disease process itself, rather than just alleviating symptoms, which is a significant step forward in Alzheimer's treatment.

What evidence suggests that Siponimod might be an effective treatment for Alzheimer's?

This trial will compare Siponimod with a placebo to evaluate its potential effects on Alzheimer's disease. Research has shown that Siponimod may help treat multiple sclerosis (MS) by reducing the risk of worsening disability and slowing memory and thinking problems. Specifically, studies found that Siponimod reduced the risk of worsening disability in MS by 21% compared to a placebo and slowed memory and thinking problems by 27% in patients with active MS. While Siponimod is not yet proven effective for Alzheimer's disease, its ability to slow brain shrinkage in MS suggests it might also benefit Alzheimer's. The hope is that Siponimod could slow brain damage in Alzheimer's, similar to its effects in MS. ^{1 2 3 4 6}

Who Is on the 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

Are You a Good Fit for This Trial?

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

Prior to dosing all randomized study subjects must show proof they have received immunization to varicella (VZV IgG)

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06639282?term=SIPONIMOD&rank=1

Repurposing Siponimod for Alzheimer's Disease

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 ...

2.

reporter.nih.gov

reporter.nih.gov/project-details/10671526

Repurposing Siponimod for Alzheimer's Disease

The secondary objective is to determine drug effect on relative annual brain atrophy rates in the two groups by comparing pre- and post- exposure volumetric MRI ...

3.

mscare.org

mscare.org/novartis-receives-fda-approval-for-mayzent-siponimod/

Novartis receives FDA approval for MAYZENT (Siponimod)

Mayzent significantly reduced the risk of three-month confirmed disability progression (CDP) (primary endpoint; 21% reduction versus placebo, p=0.013; 33% ...

4.

neurologylive.com

neurologylive.com/view/siponimod-approved-spms-avp786-phase-3-results-treatment-agitation-alzheimerrelated-dementia-mobile-technology-care-parkinson-disease

Siponimod Approved for SPMS, AVP-786 Phase 3 Results ...

The approval was granted based on data from the EXPAND trial, which ultimately showed that 3-month confirmed disability progression was reduced by 21% with the ...

5.

novartis.com

novartis.com/us-en/news/media-releases/novartis-presents-data-actrims-ectrims-effects-treatment-mayzent-siponimod-studied-disability-progression-and-cognitive-processing-speed-patients-progressing-relapsing-multiple-sclerosis

Novartis presents data at ACTRIMS-ECTRIMS on the ...

The analysis reported that in patients with active SPMS, siponimod reduced the risk of 6-month cognitive worsening by 27% and improved the ...

6.

novartis.gcs-web.com

novartis.gcs-web.com/static-files/d239e8c0-d7c0-4108-a312-08100c851f25

Novartis receives FDA approval for Mayzent® (siponimod), the ...

Additionally, Mayzent meaningfully delayed the risk of six-month CDP (26% versus placebo, p=0.0058) and reduced the annualized relapse rate (ARR) ...