A Study to Evaluate the Safety, Tolerability and Pharmacodynamics of NIO752 in Primary Tauopathies

Common across all cohorts:

1. Signed informed consent must be obtained prior to participation in the study.
2. Participants between the ages of ≥41 and ≤81 years.
3. Able to walk at least 10 steps with minimal assistance (stabilization of one arm or use of cane/walker).
4. Documented symptom (clinical manifestation) onset in the past ≤5 years prior to screening, defined as the first emergence of disease related motor, cognitive, or behavioral symptoms that led to measurable impairment in instrumental or basic activities of daily living (iADLs/ADLs), based on clinical history or reliable informant report.
5. Reliable study partner(s) such as spouse, sibling, close friend or partner, family member or caregiver who are able and willing to provide accurate information (including clinical symptoms and medical history) about the participant and to participate in study visits and informant-based assessments for the duration of the study. A reliable study partner is expected to spend sufficient time (near-daily contact) with the study participant
6. If participant is receiving symptomatic medication, the dose must have been stable for at least 8 weeks prior to randomization.

Cohort specific criteria:

Inclusion criteria (PSP non-RS): Diagnosis of mild-moderate, probable PSP non-RS as per MDS-PSP 2017 criteria with symptoms onset ≤5 years prior to Screening.

Inclusion criteria (CBS non-AD): Diagnosis of possible or probable CBD as per the 2013 consensus criteria, with CBS phenotype and symptom onset ≤5 years prior to screening. Individuals meeting criteria for probable CBD with non-CBS phenotypes (e.g., behavioral variant) are excluded to maintain consistency with the CBS non-AD target population.

Inclusion criteria (MAPT-FTLD): Carriers of a known pathogenic MAPT mutation based on existing evidence of prior genetic testing.

Exclusion Criteria:

1. Diagnosis of other significant neurological or psychiatric disorders including (but not limited to) Parkinson's' Disease (which has not subsequently been revised to a diagnosis of PSP); Alzheimer's disease (AD), dementia with Lewy bodies; prion disease; any psychotic disorders; severe Major Depressive Disorder (MDD); history of epilepsy or seizure disorder (excluding febrile seizures in childhood); brain tumor or other space occupying lesion (e.g., brain tumor, subdural hematoma, abscess, or any intracranial mass causing compression or structural distortion) ; history of clinically significant stroke (e.g., stroke with neurological deficit); history of head injury with loss of consciousness for at least 15 minutes within the past 20 years.
2. Diagnosis of amyotrophic lateral sclerosis and/or motor neuron disease.
3. Diagnosis of cerebellar ataxia, choreoathetosis, and early symptomatic autonomic dysfunction.
4. History of or screening brain Magnetic Resonance Imaging (MRI) scan indicative of significant abnormality, including, but not limited to, prior intracerebral hemorrhage or infarct >1 cm diameter, >3 lacunar infarcts, cerebral contusion, aneurysm, vascular malformation >1 cm diameter, subdural hematoma, hydrocephalus, and space-occupying lesion (e.g., abscess or brain tumor).
5. Contraindications to undergo MRI procedure, including metal (ferromagnetic) implants and/or a cardiac pacemaker that is not compatible with MRI.

6. Medical conditions that would as per Investigator's judgement prevent the participant from undergoing lumbar puncture (LP), including but not limited to:

   • History of/ known allergy to local anesthetic
   • History of back surgery (except for microdiscectomy or laminectomy at level one)
   • Spinal deformities that would interfere with i.t. administration or CSF flow

   • Current dermatological infection at the LP site and/or significant skin alterations at the planned LP site:

     • Presence of increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could increase a participant's likelihood of procedural bleeding. These could include but are not limited to anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms) and underlying disorders of coagulation, platelet function or platelet count (e.g., abnormal coagulation parameters, hemophilia, Von Willebrand's disease, liver disease).
     • Participants on anticoagulants (e.g., warfarin) or antiplatelets therapies [except for low dose aspirin (100 mg/day or lower) and low-dose ibuprofen (600 mg/day or lower) which are allowable], are not eligible to participate, unless temporal suspension of the anticoagulant or antiplatelet therapies for the purpose of the LP is considered safe for the patient, feasible, and guided by a hematologist.
7. History of deep brain stimulator surgery other than sham surgery for participation in a deep brain stimulation clinical trial.

Other protocol defined inclusion/exclusion criteria may apply