The goal of this exploratory study is to evaluate the effect of neflamapimod in participants with nonfluent variant primary progressive aphasia (nfvPPA). We aim to evaluate the safety, pharmacokinetics and clinical effects of neflamapimod of participants with nfvPPA.

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.