PMN310 for Alzheimer's Disease

Recruiting at 21 trial locations

Overseen By Wendy Luca

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: ProMis Neurosciences, Inc

Must be taking: Acetylcholinesterase inhibitors, Memantine

Must not be taking: Anti-amyloid treatments

Disqualifiers: Parkinson's, Huntington's, Stroke, others

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

Compensation: Varies

Number of Visits: 12

Duration: 48 weeks

128 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This Phase 1b study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple IV infusions of PMN310 in patients with early Alzheimer's disease.

Will I have to stop taking my current medications?

The trial allows patients to continue taking FDA-approved acetylcholinesterase inhibitors or memantine as long as the dose has been stable for at least 3 months before screening. However, if you are currently receiving anti-amyloid treatments, you must stop them at least 9 months before screening.

How does the drug PMN310 for Alzheimer's disease differ from other treatments?

PMN310 is unique because it targets the p38 MAPK pathway, which is involved in regulating inflammation in the brain associated with Alzheimer's disease. This approach aims to reduce neuroinflammation and amyloid beta accumulation, which are key factors in the progression of Alzheimer's. ^{1 2 3 4 5}

What data supports the effectiveness of the drug PMN310 for Alzheimer's Disease?

There is no direct data on PMN310, but research on similar treatments suggests that targeting specific pathways in Alzheimer's, like the calcineurin-Pin1 signaling cascade, has shown promise in reducing disease prevalence in other contexts. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with early Alzheimer's disease. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be required to have a particular stage or severity of Alzheimer's.

Inclusion Criteria

Patient and caregiver provide written informed consent

I am 50 or older and can see and hear well enough to do tests.

I've been on a stable dose of medication for Alzheimer's for at least 3 months.

Exclusion Criteria

Pregnant or breastfeeding

Living in a continuous care or long-term care nursing facility

Negative PET scan with any amyloid-targeting ligand within 6 months of Screening or during Screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive PMN310 or placebo once every 28 days for a total of 12 infusions

48 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PMN310

Trial Overview The study is testing PMN310, which is given through IV infusions to see if it's safe and can help patients with early Alzheimer's. It will also compare results against a placebo group that receives no active drug.

How Is the Trial Designed?

Group I: Cohort 3 PMN310 1400 mg or placebo Experimental Treatment 2 Interventions

PMN310 1400 mg or placebo administered as a 60-minute infusion.

Group II: Cohort 2 PMN310 700 mg or placebo Experimental Treatment 2 Interventions

PMN310 700 mg or placebo administered as a 60-minute infusion.

Group III: Cohort 1 PMN310 350 mg or placebo Experimental Treatment 2 Interventions

PMN310 350 mg or placebo administered as a 60-minute infusion.

Who Is Running the Clinical Trial?

ProMis Neurosciences, Inc

Lead Sponsor

Trials

2

Recruited

170+

Published Research Related to This Trial

In a study involving 41 Alzheimer disease patients, acupuncture alone showed a significant improvement in cognitive function (measured by MMSE) compared to a combination of acupuncture and music therapy.

While both treatments improved patient outcomes, acupuncture alone was found to be more effective than the combination therapy, suggesting that acupuncture may be a stronger intervention for enhancing therapeutic effects in Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical observation on acupuncture combined with music for treatment of Alzheimer disease]. Liu, G., Yuan, LX.[2018]

In a preliminary study of 16 patients with early Alzheimer's disease, the p38α kinase inhibitor neflamapimod showed potential to improve episodic memory function, with significant increases in memory scores observed at 28 and 84 days.

While there were no overall group effects on brain amyloid plaque load, a responder analysis indicated that some patients experienced a reduction in amyloid signal, suggesting a possible impact on β-amyloid production that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease. Scheltens, P., Prins, N., Lammertsma, A., et al.[2022]

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 24-week open-label extension study involving 175 patients previously treated with placebo, those who switched to memantine showed significant improvements in functional, global, and cognitive assessments compared to their decline while on placebo.

The safety profile of memantine remained favorable, with a high completion rate of 78%, reinforcing its efficacy and safety for treating moderate to severe Alzheimer disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Reisberg, B., Doody, R., Stöffler, A., et al.[2022]

Despite over 50 drug candidates passing phase II trials for Alzheimer's disease, none have successfully completed phase III trials, highlighting the challenges in developing effective treatments.

Current trends in Alzheimer's drug discovery include the development of disease-modifying agents that aim to slow disease progression, multitargeted drugs addressing multiple pathways, and the repositioning of existing medications for new therapeutic uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends. Bachurin, SO., Bovina, EV., Ustyugov, AA.[2018]

Aβ1-40 oligomers stimulate the production of interleukin-6 (IL-6) in human microglial cells, indicating a link between amyloid beta accumulation and neuroinflammation in Alzheimer's disease.

The activation of p38 MAPK is crucial for the increase in IL-6 secretion, suggesting that targeting this pathway could be a potential therapeutic strategy to reduce neuroinflammation associated with Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

p38 MAPK Is a Major Regulator of Amyloid Beta-Induced IL-6 Expression in Human Microglia. Lin, H., Dixon, SG., Hu, W., et al.[2023]

APP-C31, a peptide produced from the cleavage of amyloid precursor protein, enhances the aggregation and toxicity of amyloid-β40 (Aβ40) peptides, which are implicated in Alzheimer's disease pathology.

The study reveals that APP-C31 promotes the formation of large Aβ40 deposits in neurons, leading to increased cell damage and apoptosis, suggesting it could be a novel target for Alzheimer's disease treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β40 Aggregation and Toxicity in Alzheimer's Disease. Nam, E., Lin, Y., Park, J., et al.[2023]

Inhibiting microglial p38α in a mouse model of Alzheimer's disease did not lead to changes in behavior, inflammation levels, or overall amyloid plaque burden, suggesting that targeting this pathway may not have harmful effects in early-stage Alzheimer's.

The study found that while microglial p38α inhibition altered microglia-plaque interactions, it increased levels of soluble Aβ42, indicating a complex role of p38α in neuroinflammatory responses that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early chronic suppression of microglial p38α in a model of Alzheimer's disease does not significantly alter amyloid-associated neuropathology. Braun, DJ., Frazier, HN., Davis, VA., et al.[2023]

The study identified a novel PSEN1 variant (p.E318G) that is significantly associated with high levels of tau and phosphorylated tau in cerebrospinal fluid, indicating its potential role as a biomarker for Alzheimer's disease (AD).

Individuals carrying the p.E318G variant, especially those with the APOE-ε4 allele, face a significantly increased risk of developing AD, with a risk level comparable to that of APOE-ε4 homozygous individuals, highlighting the variant's importance in AD susceptibility and progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers. Benitez, BA., Karch, CM., Cai, Y., et al.[2022]

Citations

1. China pubmed.ncbi.nlm.nih.gov

[Clinical observation on acupuncture combined with music for treatment of Alzheimer disease]. [2018]

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

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease. [2022]

3. 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]

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

A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. [2022]

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

Drugs in Clinical Trials for Alzheimer's Disease: The Major Trends. [2018]

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

p38 MAPK Is a Major Regulator of Amyloid Beta-Induced IL-6 Expression in Human Microglia. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β40 Aggregation and Toxicity in Alzheimer's Disease. [2023]

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

Early chronic suppression of microglial p38α in a model of Alzheimer's disease does not significantly alter amyloid-associated neuropathology. [2023]

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

The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers. [2022]