Bryostatin for Multiple Sclerosis

Overseen By Sarah M Planchon Pope, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Robert Fox

Must be taking: Disease modifying therapy

Must not be taking: Valproic acid, Lithium, Carbamazepine, others

Disqualifiers: Seizures, Unstable cardiovascular, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 14

Duration: 26 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test the safety of a new treatment called bryostatin for people with multiple sclerosis (MS) who are on stable medication. Researchers are studying bryostatin to understand its interaction with MS and its symptoms. Individuals who have managed their MS with consistent treatment for at least a year and can participate in study assessments may be suitable candidates. As a Phase 1 trial, this research focuses on understanding how bryostatin works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for this trial?

The trial requires that participants be off a DMT or on a stable dose of a DMT for at least 1 year before joining, and the dose should not change during the study unless necessary. Some specific medications must be stopped before screening, such as vitamin E, valproic acid, lithium, carbamazepine, teriflunomide, dalfampridine, acetaminophen, ciprofloxacin, trimethoprim/sulfamethoxazole, and St. John's Wort. Other medications will be reviewed on a case-by-case basis.

Do I need to stop my current medications to join the trial?

You may need to stop certain medications before joining the trial. Specifically, you should not use vitamin E, valproic acid, lithium, carbamazepine, teriflunomide, dalfampridine, acetaminophen, ciprofloxacin, trimethoprim/sulfamethoxazole, St. John's Wort, or any potent/moderate inhibitors or inducers of certain enzymes. Additionally, you should not consume grapefruit juice during the study.

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

Research has shown that bryostatin-1 is generally safe for humans, with past studies indicating good tolerance. It has been studied for several brain-related conditions, such as Alzheimer's disease and multiple sclerosis.

Although specific safety data for bryostatin-1 in multiple sclerosis is not available, its use in other conditions has been promising without major safety issues. This is a Phase 1 trial, aimed at determining the safety of bryostatin-1 for people with multiple sclerosis. Phase 1 trials are the initial step in testing a new treatment in humans, so while detailed safety data for MS is not yet available, the trial will closely monitor for any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Bryostatin is unique because it offers a new approach to treating multiple sclerosis (MS). Unlike standard MS treatments, which often focus on modulating the immune system, Bryostatin works by activating protein kinase C, a pathway that might promote nerve repair and prevent further damage. Researchers are excited about Bryostatin because it may not only slow disease progression but also help repair damaged nerves, which is a potential game-changer for MS patients.

What evidence suggests that bryostatin might be an effective treatment for multiple sclerosis?

Research has shown that bryostatin-1 may help treat neurological disorders like multiple sclerosis (MS). In mouse studies, bryostatin-1 successfully prevented and reversed MS symptoms, possibly due to its effect on a protein called PKC, which is crucial for nerve cell health. Bryostatin-1 also shows promise for other brain-related conditions, suggesting potential benefits for overall neurological health. These findings indicate that bryostatin-1 might aid people with MS. Participants in this trial will receive treatment with bryostatin-1 to evaluate its potential benefits for MS. ^{1 2 3 4 6}

Who Is on the Research Team?

Robert Fox, MD

Principal Investigator

The Cleveland Clinic

Are You a Good Fit for This Trial?

This trial is for individuals with multiple sclerosis (MS) who are currently on any disease-modifying therapy. The study is focused on understanding the safety of a single dose of Bryostatin in this specific patient population.

Inclusion Criteria

Hospital Anxiety and Depression Scale <11

English-speaking

I have been in good health for the past 6 months and any chronic illness I have is under control.

Exclusion Criteria

My kidney function is reduced with a creatinine clearance below 45ml/min.

I haven't had serious health issues in the last 6 months and have been cancer-free for 2 years, except for certain skin cancers.

My diabetes is not well-managed according to my doctor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive bryostatin treatment over a 26-week period, with 14 doses administered. Doses 1, 2, 8, and 9 are loading doses 20% higher than the fixed dose.

26 weeks

14 visits (in-person)

Safety and Exploratory Outcomes Evaluation

Evaluation of safety and exploratory outcomes, including various cognitive and MRI assessments.

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including long-term follow-up assessments.

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Bryostatin

Trial Overview The trial is testing the safety profile of a medication called Bryostatin in patients with MS. It's a phase 1 study, which means it's an early-stage trial to assess how safe the drug is and how the body responds to it.

How Is the Trial Designed?

Group I: Bryostatin 1 Experimental Treatment 1 Intervention

Participants in this arm will receive treatment with Bryostatin 1

Who Is Running the Clinical Trial?

Robert Fox

Lead Sponsor

Trials

2

Recruited

20+

Synaptogenix, Inc.

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

Corticosteroid therapy, particularly high-dose intravenous methylprednisolone, is the primary treatment for acute exacerbations of multiple sclerosis, indicating its efficacy in managing sudden clinical changes.

Current immune-modulating agents have not shown enough clinical benefit to be routinely used for disease progression, highlighting the need for more targeted future treatments aimed at disease prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The current therapy of multiple sclerosis. Francis, DA.[2019]

In a study involving 43 patients with progressive multiple sclerosis, high dose biotin (300 mg/day) was found to be safe and well tolerated, with no evidence of toxicity or new brain lesions after one year.

Despite its safety, high dose biotin did not improve neurological function, and over one-third of patients experienced worsening symptoms, suggesting that while biotin is safe, it may not provide the expected benefits for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose biotin as treatment for progressive multiple sclerosis. Birnbaum, G., Stulc, J.[2018]

There is a critical need for effective treatment options for progressive multiple sclerosis (MS), and ongoing research is exploring new pathways and molecules that may offer reparative, remyelinating, or neuroprotective effects.

The review emphasizes the importance of standardized clinical outcome measures, including the Expanded Disability Status Scale and patient-reported outcomes, to effectively evaluate and demonstrate the benefits of new treatments in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome measures for progressive MS trials. Ontaneda, D., Cohen, JA., Amato, MP.[2018]

In two Phase II trials involving advanced Alzheimer's disease patients, bryostatin treatment led to significant improvements in cognitive function, as measured by the Severe Impairment Battery (SIB), with increases of 4.1 and 4.2 points above baseline at 13 weeks.

The pooled analysis of 95 patients confirmed that bryostatin treatment resulted in a statistically significant improvement in SIB scores over time compared to placebo, indicating its potential efficacy in enhancing cognitive function in Alzheimer's patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bryostatin Placebo-Controlled Trials Indicate Cognitive Restoration Above Baseline for Advanced Alzheimer's Disease in the Absence of Memantine1. Thompson, RE., Tuchman, AJ., Alkon, DL.[2022]

The REGIMS registry is a multicenter observational study in Germany that collects data on the side effects of immunotherapies for multiple sclerosis, providing valuable insights into the long-term safety of these treatments.

By the end of 2019, REGIMS had recruited 1000 patients, primarily women with relapse-remitting MS, demonstrating the registry's ability to gather high-quality, real-world data despite facing logistical challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chances and Challenges of Registry-Based Pharmacovigilance in Multiple Sclerosis: Lessons Learnt from the Implementation of the Multicenter REGIMS Registry. Simbrich, A., Thibaut, J., Khil, L., et al.[2022]

Nanoparticle-encapsulated Bryostatin-1 shows equal or greater efficacy than unmodified Bryostatin-1 in activating key proteins involved in neuroprotection, suggesting enhanced therapeutic potential for Alzheimer's disease.

In an Alzheimer's mouse model, treatment with nanoparticle-encapsulated Bryostatin-1 improved spatial learning and memory retention, indicating its potential as a cognitive enhancer in neurodegenerative conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoparticle-Encapsulated Bryostatin-1 Activates α-Secretase and PKC Isoforms In vitro and Facilitates Acquisition and Retention of Spatial Learning in an Alzheimer's Disease Mouse Model. Schrott, L., Yi, P., Jackson, K., et al.[2021]

Dimethyl fumarate has been shown to significantly reduce relapse rates in patients with relapsing-remitting multiple sclerosis (MS), with a reduction of 34% to 49% in the proportion of patients experiencing relapses over two years, based on two phase III trials (DEFINE and CONFIRM).

The safety profile of dimethyl fumarate is comparable to placebo, with serious adverse effects occurring at similar rates; however, some patients experienced intolerable flushing and gastrointestinal issues, leading to discontinuation in 3% and 4% of cases, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis. Venci, JV., Gandhi, MA.[2015]

Biologic immunotherapies, including monoclonal antibodies like natalizumab and ocrelizumab, have significantly improved treatment for multiple sclerosis, particularly during its inflammatory phase.

However, these therapies can lead to serious immunological side effects, such as secondary autoimmunity and immunodeficiency, which can complicate their safety and efficacy, exemplified by the market withdrawal of daclizumab due to severe adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Established and Emerging Immunological Complications of Biological Therapeutics in Multiple Sclerosis. Soleimani, B., Murray, K., Hunt, D.[2020]

Alemtuzumab, natalizumab, and fingolimod are the most effective immunotherapies for preventing relapses in patients with relapsing-remitting multiple sclerosis, although their impact on preventing disability worsening is uncertain.

Fingolimod carries a high risk of treatment discontinuation due to adverse events, highlighting the importance of monitoring for side effects in patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis. Tramacere, I., Del Giovane, C., Filippini, G.[2016]

In a study of 257 patients with relapsing-remitting multiple sclerosis, BG00012 at a dose of 240 mg three times daily significantly reduced the mean total number of new gadolinium-enhancing lesions by 69% compared to placebo, indicating strong efficacy in reducing disease activity.

BG00012 also decreased the annualized relapse rate by 32%, although this result was not statistically significant, and it was associated with some adverse events like abdominal pain and flushing, suggesting a generally favorable safety profile that supports further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Kappos, L., Gold, R., Miller, DH., et al.[2022]

In a study of 178 patients with progressive multiple sclerosis, high-dose biotin supplementation did not show a significant improvement in disability progression after 12 months, with only 3.8% of patients experiencing an improved Expanded Disability Status Scale (EDSS) score.

While 47.4% of patients reported stability in their condition, a notable 25% experienced worsening symptoms, and 14% reported adverse events, indicating that high-dose biotin may not be an effective treatment in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose biotin in progressive multiple sclerosis: A prospective study of 178 patients in routine clinical practice. Couloume, L., Barbin, L., Leray, E., et al.[2022]

Bryostatin-1, a natural compound derived from marine invertebrates, shows significant therapeutic potential for various neurological disorders, including Alzheimer's disease and traumatic brain injury, by targeting protein kinase C (PKC) to improve cognitive functions and provide neuroprotection.

Preclinical studies and clinical trials indicate that bryostatin-1 can effectively rescue deficits in spatial learning and memory, making it a promising candidate for treating CNS-related disorders, although further research is needed before clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bryostatin-1: a promising compound for neurological disorders. Tian, Z., Lu, XT., Jiang, X., et al.[2023]

Bryostatin-1 shows promise as a multi-target treatment for multiple sclerosis (MS) due to its anti-inflammatory, antioxidant, and neuroprotective properties, which could address various aspects of the disease's pathology.

The drug not only reduces matrix metalloproteinases (MMPs) activity and blood-brain barrier damage but also promotes neurogenesis and the differentiation of oligodendrocyte progenitor stem cells, potentially aiding in remyelination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Inflammation, Suppression of Matrix Metalloproteinases, Induction of Neurogenesis, and Antioxidant Property Make Bryostatin-1 a Therapeutic Choice for Multiple Sclerosis. Safaeinejad, F., Bahrami, S., Redl, H., et al.[2020]

Bryostatin-1 (bryo-1) has shown significant benefits in a mouse model of multiple sclerosis (EAE), preventing the onset of neurological deficits and even reversing them after they have started, indicating its potential as a treatment for MS.

Bryo-1 promotes an anti-inflammatory response in immune cells, which could be particularly beneficial for treating the progressive phase of MS, a stage that currently lacks effective therapies, while also having a favorable safety profile in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bryostatin-1 alleviates experimental multiple sclerosis. Kornberg, MD., Smith, MD., Shirazi, HA., et al.[2021]

In a study of 48 patients with progressive multiple sclerosis treated with high-dose biotin (MD1003) for one year, 27% showed significant clinical improvement as measured by the Expanded Disability Status Scale and other functional tests.

The treatment was also associated with increases in brain and cervical spinal cord volume in some patients, suggesting that MD1003 may have neuroprotective effects, particularly in less disabled individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003). Collongues, N., Kuhle, J., Tsagkas, C., et al.[2022]

Citations

1. pnas.org pnas.org/doi/10.1073/pnas.1719902115

Bryostatin-1 alleviates experimental multiple sclerosis We show that bryostatin-1 potently prevents disease and reverses neurologic deficits in the major mouse model of MS, experimental autoimmune encephalomyelitis ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06190912

NCT06190912 | Safety of Bryostatin in Patients With MS The study is 42 weeks in duration, including safety and exploratory outcomes evaluation at 30 days after the last full assessment (Week 28) and long-term ...

3. consultqd.clevelandclinic.org consultqd.clevelandclinic.org/a-case-study-in-neurotherapeutic-clinical-trial-design-and-conduct

A Case Study in Neurotherapeutic Clinical Trial Design Bryostatin-1 is a potent modulator of protein kinase C (PKC), a property that AD-focused studies showed reduces levels of soluble β amyloid ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10282138/

Bryostatin-1: a promising compound for neurological disorders Bryostatin-1 is shown to have great therapeutic potential for Alzheimer's disease, multiple sclerosis, fragile X syndrome, stroke, traumatic brain injury, and ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06190912?term=bryostatin&viewType=Table&rank=7

NCT06190912 | Safety of Bryostatin in Patients With MS The study is 42 weeks in duration, including safety and exploratory outcomes evaluation at 30 days after the last full assessment (Week 28) and long-term ...

6. withpower.com withpower.com/trial/phase-1-multiple-sclerosis-1-2024-7c54a

Bryostatin for Multiple Sclerosis · Info for Participants The provided research articles do not contain specific safety data for Bryostatin in the treatment of Multiple Sclerosis. They focus on other immunotherapies ...