BIIB092 in Primary Tauopathies: CBS, nfvPPA, sMAPT, and TES

1. Between 35 and 80 years of age (inclusive);

2. Able to walk at least 10 steps with minimal assistance (stabilization of one arm or use of cane/walker);

3. MRI at Screening is consistent with the underlying neurodegenerative disease of the respective diagnostic cohort (i.e., CBS, nfvPPA, sMAPT, or TES), with no large strokes or severe white matter disease;

4. Mini Mental State Exam (MMSE) at Screening is between 20 and 30 (inclusive);

5. Amyloid beta (Aβ) positron emission tomography (PET) scan (florbetapir or equivalent) at Screening is not consistent with underlying Alzheimer's disease (AD).

Previous Aβ PET scan negativity (assessed by a certified neuro radiologist) or previous AD CSF biomarker (Aβ)/tau level) negativity may be used instead of performing an Aβ PET scan at Screening at the PI's discretion;

6. The following medications are allowed, but must be stable for 2 months prior to

Screening:

1. FDA-approved AD medications

2. FDA-approved Parkinson's disease medications;

7. Other medications (except those listed under exclusion criteria) are allowed as long as the dose is stable for 30 days prior to Screening;

8. Has a reliable study partner who agrees to accompany the participant to visits, and spends at least 5 hours per week with the participant;

9. Agrees to 3 lumbar punctures;

10. Signed and dated written informed consent obtained from the participant and the participant's study partner in accordance with local IRB regulations;

11. Women of childbearing potential (WCBP) must agree to abstain from sex or use an adequate method of contraception for the duration of the Screening period, the study drug treatment period, and for 155 days after the last dose of study drug;

12. Males must agree to abstain from sex with WCBP or use an adequate method of contraception for the duration of the study drug treatment period and for 215 days after the last dose of study drug.

For CBS Only

13. Meets 2013 consensus criteria for possible or probable corticobasal degeneration (CBD), CBS subtype (Armstrong et al. 2013).

For nfvPPA Only

14. Meets 2011 consensus criteria for nfvPPA (Gorno-Tempini et al. 2011). Patients meeting 2013 Armstrong criteria for CBS-nfvPPA or 2017 Movement Disorder Society (MDS) criteria for progressive supranuclear palsy and speech/language disorders (PSP-SL) (Höglinger et al. 2017) would be assigned to this cohort since both of these definitions were derived from the 2011 Gorno-Tempini criteria.

For sMAPT Only

15. Has known frontotemporal lobar degeneration- (FTLD-) causative MAPT mutation confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory (Ghetti et al. 2015);

16. CDR-FTLD (Knopman et al. 2008) sum of boxes score ≥ 1.0. Sum of boxes is used instead of the global Clinical Dementia Rating Scale (CDR) because the global CDR does not take into account FTLD specific measures;

17. Has any clinical phenotype of sMAPT.

For TES Only

18. Meets 2016 criteria for probable TES (Reams et al. 2016);

19. At least 5 years or greater between symptom onset and 1st known traumatic brain injury/concussive episode

The exclusion criteria are listed below and are the same for each diagnostic cohort. Participants meeting any of the following exclusion criteria will be excluded from randomization to study drug (active or placebo) treatment.

1. A diagnosis of probable AD (McKhann et al. 2011) or progressive supranuclear palsy- Richardson's syndrome (PSP-RS) (Höglinger et al. 2017). Since variants of progressive supranuclear palsy (PSP) are known to cause nfvPPA and CBS, a diagnosis of PSP-SL or progressive supranuclear palsy-corticobasal syndrome (PSP- CBS) would not be exclusionary;

2. Any other medical condition other than CBS, nfvPPA, sMAPT or TES that could account for cognitive or motor deficits (e.g., active seizure disorder, stroke, vascular dementia, substance abuse or alcoholism);

3. History of a prominent and sustained response to levodopa therapy in the opinion of the PI;

4. History of significant cardiovascular, hematologic, renal, or hepatic disease (or laboratory evidence thereof);

5. History of major psychiatric illness or untreated depression that in the opinion of the PI would pose a safety risk or interfere with the appropriate interpretation of study data;

6. Neutrophil count <1,500/mm3, platelets <100,000/mm3, serum creatinine >1.5 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, alanine aminotransferase (ALT) >3 x ULN, aspartate aminotransferase (AST) >3 x ULN, or International Normalized Ratio (INR) >1.2 at Screening evaluations;

7. Evidence of any clinically significant findings on Screening or baseline evaluations which, in the opinion of the PI would pose a safety risk or interfere with appropriate interpretation of study data;

8. Current or recent history (within four weeks prior to Screening) of a clinically significant bacterial, fungal, or mycobacterial infection;

9. Current clinically significant viral infection;

10. Major surgery within four weeks prior to Screening;

11. Any contraindication for MRI or unable to tolerate MRI scan at Screening;

12. Any contraindication to or unable to tolerate lumbar puncture at Screening, including use of anti-coagulant medications such as warfarin. Daily administration of 81 mg aspirin will be allowed as long as the dose is stable for 30 days prior to Screening;

13. Participants who, in the opinion of the PI, are unable or unlikely to comply with the dosing schedule or study evaluations;

14. Prior treatment with BIIB092;

15. Treatment with another investigational drug within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with investigational drugs other than BIIB092 while on study will not be allowed;

16. Treatment with systemic corticosteroids within 30 days or 5 half-lives of drug before Screening, whichever is longer. Treatment with systemic corticosteroids while on study will not be allowed;

17. Known hypersensitivity to the inactive ingredients in the study drug (BIIB092 or placebo);

18. Known to be pregnant or lactating; or positive pregnancy test at Screening or Baseline (Day 1);

19. Cancer within 5 years of Screening, except for basal cell carcinoma;

20. History of serum or plasma progranulin level less than one standard deviation below the normal participant mean for the laboratory performing the assay;

21. History or evidence at Screening of known disease-associated mutations in GRN, TBK1, C9ORF72, TARBP, CHMPB2, or VCP genes (FTLD causative gene mutations not associated with underlying tau pathology).