Clinical Study of Neflamapimod in Patients With Dementia With Lewy Bodies

Open to people ages 55 years and up

1. Men and women aged ≥55 years.
2. Subject or subject's legally authorized representative is willing and able to provide written informed consent.
3. Probable DLB by consensus criteria (McKeith et al, 2017), including a positive DaTscan™, who are currently receiving cholinesterase inhibitor therapy. If the DaTscan is negative, but the subject has historical polysomnography (PSG)-verified REM sleep behavioral disorder (RBD), this will also qualify as probable DLB.
4. CDR Global Score 0.5 or 1.0 during Screening
5. If the patient is currently receiving cholinesterase inhibitor therapy, the patient must have received such therapy for greater than 3 months and on a stable dose for at least 6 weeks at the time of randomization. Except for reducing the dose for tolerability reasons, the dose of cholinesterase inhibitor may not be modified during the study. If the patient is not currently receiving cholinesterase inhibitor therapy, but received such therapy previously, that therapy must have been discontinued at least 3 months prior to randomization. Memantine therapy is allowed, if it had been started at least 3 months prior to randomization and the patient is also receiving cholinesterase inhibitor therapy (memantine monotherapy, i.e., without concomitant cholinesterase inhibitor therapy, is excluded).
6. Normal or corrected eyesight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
7. No history of learning difficulties that may interfere with their ability to complete the cognitive tests.
8. Received vaccination for SARS-CoV-19 unless medical contraindications prevent being vaccinated.
9. Must have reliable informant or caregiver.

1. Diagnosis of any other ongoing central nervous system (CNS) condition other than DLB, including, but not limited to, post-stroke dementia, vascular dementia, Alzheimer's disease (AD), or Parkinson's disease (PD).
2. Plasma ptau181 > 2.4 pg/mL (i.e., above cut-off for pathology associated with Alzheimer's disease) at Screening.
3. 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 C-SSRS, or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
4. 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.
5. Diagnosis of alcohol or drug abuse within the previous 2 years.
6. Poorly controlled clinically significant medical illness, such as hypertension (blood pressure >180 mmHg systolic or 100 mmHg diastolic); 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.
7. 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.
8. Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.

9. Participated in a study of an investigational drug less than six weeks or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.

   10. History of previous neurosurgery to the brain within the past five years. 11. If male with female partner(s) of child-bearing potential, unwilling or unable to

   adhere to contraception requirements specified in the protocol.

   12. If female who has not has not reached menopause >1 year previously or has not had a

   hysterectomy or bilateral oophorectomy/salpingo-oophorectomy, has a positive pregnancy test result during Screening and/or is unwilling or unable to adhere to the contraception requirements specified in the protocol.

   13. Weight less than 60kg. All participants who complete the initial 16-week period of the study will be able to continue in the study and receive neflamapimod for an additional 32 weeks (8 months) regardless of whether they received neflamapimod of placebo during the the first 16 weeks.