Clinical Study of Neflamapimod in Patients With Primary Progressive Aphasia

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:

• Agrammatism in language production
• 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:

• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• 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.