Neflamapimod for nonfluent variant primary progressive aphasia

A Phase 2a Clinical Study of the P38 Alpha Kinase Inhibitor Neflamapimod in Patients With Primary Progressive Aphasia (PPA)

This study tests whether neflamapimod can improve language symptoms and is safe for people with nonfluent variant primary progressive aphasia (nfvPPA).

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 40 Years to 85 Years
• Sex: All
• Sponsor: EIP Pharma Inc (industry)
• Locations: 7 sites (Chicago, Illinois and 6 other locations)
• Trial ID: NCT07033481 on ClinicalTrials.gov

What this trial studies

This Phase 2 randomized, placebo-controlled exploratory study gives participants with clinically diagnosed nonfluent variant PPA either neflamapimod or placebo to measure safety, pharmacokinetics, and clinical effects. Eligible participants are aged 40–85 and must meet consensus diagnostic criteria for nfvPPA with mild impairment on the CDR plus NACC FTLD scale. The trial collects drug level data and tracks language and functional measures over the treatment period to look for symptomatic benefit or slowing of decline. The multicenter study is sponsored by EIP Pharma and is being conducted at major U.S. academic sites.

Who should consider this trial

Good fit: Adults aged 40–85 with a consensus clinical diagnosis of nonfluent variant PPA, mild impairment on the CDR plus NACC FTLD scale, and the ability to provide informed consent (or have a legally authorized representative) are the intended participants.

Not a fit: People with other PPA variants, more advanced dementia than allowed by the entry criteria, or medical contraindications to the study drug are unlikely to benefit from this trial.

Why it matters

Potential benefit: If effective, neflamapimod could improve speech and language function or slow decline in people with nfvPPA.

How similar studies have performed: Early clinical work of neflamapimod and related p38 MAPK inhibitors has shown some encouraging signals in neurodegenerative conditions but remains inconclusive and experimental.

Eligibility criteria

Inclusion Criteria:

* Men and women aged 40-85 years at Screening.
* Participant or participant's legally authorized representative (where applicable) is willing and able to provide written informed consent.
* Clinical diagnosis of nfvPPA by consensus criteria \[Gorno-Tempini et al, 2011\].

  * At least one of the following core features must be present:

    1. Agrammatism in language production
    2. Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
  * At least 2 of 3 of the following other features must be present:

    1. Impaired comprehension of syntactically complex sentences
    2. Spared single-word comprehension
    3. Spared object knowledge
* Global CDR® plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration (NACC FTLD) score of 0.5 or 1 during Screening.
* CDR® plus NACC FTLD language domain score of 0.5, 1 or 2 during Screening.
* Normal or corrected eyesight and auditory abilities, sufficient to perform all aspects of the study scales and assessments.
* Fluent in English, per Investigator judgement.
* Must have reliable study partner that is able to attend all study visits with participant. Study partner must be able to read, write, and understand the English language.

Exclusion Criteria:

* Brain Magnetic Resonance Image (MRI) incompatible with a diagnosis of nfvPPA.
* History or evidence of a central nervous system (CNS) condition other than nfvPPA which may cause symptoms of aphasia or dementia, including but not limited to Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), inflammatory/demyelinating CNS conditions, Creutzfeldt Jakob disease, vascular dementia, post-stroke dementia, etc.
* Features or Parkinsonism, corticobasal syndrome or progressive supranuclear palsy that are as or more prominent than the language features of nfvPPA, and/or motor features which are sufficiently severe that they could significantly impact performance on any of the clinical or neuropsychological measures.
* Plasma pTau217 result with a high likelihood of the presence of amyloid pathology at Screening or documented evidence of positive biomarkers associated with Alzheimer's disease pathology (e.g., abnormal plasma Aβ42/40 ratio, abnormal CSF phospo-tau/amyloid ratio, or presence of amyloid tracer update on brain amyloid positron emission tomography \[PET\] imaging).
* Known progranulin (GRN) mutations.
* Ongoing major and active psychiatric disorder and/or other concurrent medical condition that, in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
* Metabolic or toxic encephalopathy or dementia due to a general medical condition.
* History of previous neurosurgery to the brain within the past five years.
* Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
* Clinically relevant intellectual impairment that may interfere with the ability to complete the study scales and assessments, at the discretion of the Investigator.
* Diagnosis of alcohol or drug abuse within the previous 2 years.
* Poorly controlled clinically significant medical illness, such as hypertension; myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would interfere with assessment of drug safety.
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2 × the upper limit of normal (ULN), total bilirubin \>1.5 × ULN, and/or International Normalized Ratio (INR) \>1.5.

  * If participant has a documented history of Gilbert's syndrome, criterion of total bilirubin \>1.5 x ULN is not applicable.
  * If participant is taking anticoagulants (e.g., warfarin), and has no known liver issues, INR \>3.
* Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
* Participated in a study of an investigational drug or transcranial direct current stimulation less than 6 weeks or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
* Male with female partner(s) of childbearing potential, unwilling or unable to adhere to contraception requirements specified in the protocol.
* Female of childbearing potential (see Section 5.10), with a positive pregnancy test result during Screening and are unwilling or unable to adhere to contraception requirements specified in the protocol.
* Weight less than 50 kg at Screening.

The following additional exclusion criteria applies for participants undergoing (18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography) 18F-FDG PET-CT (18F-FDG PET-CT scans are optional):

* Blood glucose levels \>200 mg/dL.
* Contraindications to having a PET scan.

Where this trial is running

Chicago, Illinois and 6 other locations

• Northwestern Memorial Hospital — Chicago, Illinois, United States (ACTIVE_NOT_RECRUITING)
• Mayo Clinic — Rochester, Minnesota, United States (ACTIVE_NOT_RECRUITING)
• Columbia University — New York, New York, United States (ACTIVE_NOT_RECRUITING)
• The Ohio State University — Columbus, Ohio, United States (ACTIVE_NOT_RECRUITING)
• Hospital of the University of Pennsylvania — Philadelphia, Pennsylvania, United States (ACTIVE_NOT_RECRUITING)
• Windsor Research Unit, Fulbourn Hospital — Cambridge, United Kingdom (RECRUITING)
• Clinical Ageing Research Unit, Campus for Ageing and Vitality, Biomedical Research Building — Newcastle upon Tyne, United Kingdom (RECRUITING)

Study contacts

• Study coordinator: Amanda Gardner

Conditions: Nonfluent Variant Primary Progressive Aphasia, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurocognitive Disorders, Mental Disorders, Neurodegenerative Diseases, Aphasia