Inclusion Criteria:

• Participants, or a legally authorized representative (where local regulations and institutional practices permit), must have signed and dated an Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal participant care.
• The investigator must obtain consent consistent with the applicable legal, regulatory, and institutional policy requirements and specifically, taking into account the participant’s state of disease progression and its impact on the participant’s cognitive and motor abilities.
• In the event that the study participant is unable to sign and date the informed consent form, a legally authorized representative, permitted to act on behalf of the participant in the context of this study, may provide consent on behalf of the participant.
• Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
• Participant’s caregiver must have signed and dated an IRB-/IEC-approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal participant care.
• Participant’s caregiver must be willing and able to comply with scheduled visits and other requirements of the study. Only one caregiver can be designated for the participant at a given time. At a minimum, the caregiver should personally attend the following study visits: Screening; Baseline; Weeks 12, 24, 36, 48, and 52; and Early Discontinuation. Although caregiver assessments cannot be conducted by telephone, the caregiver should be available for telephone consultation regarding information on AEs and SAEs when not otherwise attending a scheduled visit.

Type of Participant and Target Disease Characteristics

• Probable or possible PSP defined.  
  • Based on the following:
    • A progressive history of postural instability during the first 3 years that symptoms are present; or
    • A progressive history of falls during the first 3 years that symptoms are present.
  • Based on the following:
    • Vertical supranuclear gaze palsy defined as clear limitation of the range of voluntary gaze in the vertical more than in the horizontal plane, more than expected with age, which is overcome by activation with the vestibulo-ocular reflex (at later stages, the vestibulo-ocular reflex may be lost, or the maneuver prevented by nuchal rigidity); or
    • Slow velocity of vertical saccades (i.e., decreased velocity [and gain] of vertical greater than horizontal saccadic eye movements). Gaze should be assessed by command to a stationary target rather than by pursuit, with the target > 20° from the position of primary gaze. Typically, saccadic movement is slow enough for the examiner to see its progress, rather than just its initial and final positions. Deficits are more prominent in the vertical than the horizontal plane. A delay in initiation of saccades is not considered slowing.
  • Age at symptom onset of 40 to 85 years by history, and current age between 41 and 86 years, inclusive, at the time of screening.
  • An akinetic-rigid syndrome.
  • Presence of PSP symptoms for less than or equal to 5 years (determined by the best judgement of the Investigator) at screening.
• Body weight range of ≥ 43 kg/95 lbs. to ≤ 120 kg/265 lbs.
• Able to ambulate independently or with assistance defined as the ability to take at least 10 steps with a walker (guarding is allowed provided there is no contact) or the ability to take at least 10 steps without a walker or cane with the assistance of another person who can only have contact with one upper extremity.
• Able to tolerate MRI.
• Able to perform all protocol-specified assessments and comply with the study visit schedule.
• Able to comply with neuropsychological evaluation at screening and throughout the 52-week double-blind period of the study (determined by the best judgement of the Investigator).
• Have reliable caregiver to accompany participant to study visits. Caregiver must be able to read, understand, and speak local language fluently to ensure comprehension of informed consent and informant-based assessments of participant. Caregiver must also have frequent contact with participant (at least 3 hours per week at one time or different times) and be willing to monitor the participant’s health and concomitant medications throughout the study. Caregiver must be willing to sign and date an IRB-/IEC- approved written informed consent form in accordance with regulatory and institutional guidelines as appropriate.
• Score ≥ 20 on the Mini Mental State Examination (MMSE) at screening.
• Participant must reside outside a skilled nursing facility or dementia care facility at the time of screening and admission to such a facility must not be planned. Residence in an assisted living facility is allowed.
• If participant is receiving coenzyme Q10, levodopa/carbidopa, levodopa/benserazide, fava bean extract, a dopamine agonist, catechol-O-methyltransferase inhibitor, amantadine, or other Parkinson’s disease medications, the dose must have been stable for at least 60 days prior to baseline and expected to remain stable for the double-blind period of the study.
• Stable on other chronic medications for at least 30 days prior to baseline.

Age and Reproductive Status

• Males and females, ages 41 to 86 years, inclusive.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotrophin) within 24 hours prior to the start of study treatment.
• Women must not be breastfeeding
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study treatment(s) BIIB092 plus 5 half-lives of study treatment BIIB092 plus 30 days (duration of ovulatory cycle) for a total of 155 days post-treatment completion.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for the duration of treatment with study treatment(s) BIIB092 plus 5 half-lives of the study treatment plus 90 days (duration of sperm turnover) for a total of 215 days post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time.
• Azoospermic males are exempt from contraceptive requirements. WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements and still must undergo pregnancy testing as described in this section.

Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise on the use of highly effective methods of contraception.

Exclusion Criteria:

• Presence of other significant neurological or psychiatric disorders including (but not limited to) Alzheimer’s disease (AD), dementia with Lewy bodies; prion disease, Parkinson's disease (which has not subsequently been revised to a diagnosis of PSP); any psychotic disorder; severe bipolar or unipolar depression; seizure; brain tumor or other space-occupying lesion; 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.
• Diagnosis of amyotrophic lateral sclerosis or other motor neuron disease.
• Diagnosis of cerebellar ataxia, choreoathetosis, and early symptomatic autonomic dysfunction.
• History of early, prominent rapid eye movement sleep behavior disorder.
• History of or screening brain MRI scan indicative of significant abnormality, including, but not limited to, prior hemorrhage or infarct >1 cm3, 3 lacunar infarcts, cerebral contusion, aneurysm, vascular malformation >1 cm3, subdural hematoma, hydrocephalus, and space-occupying lesion (e.g., abscess or brain tumor).
• Known history of serum or plasma progranulin level less than one standard deviation below the normal participant mean for the laboratory performing the assay.
• Known presence of known disease-associated mutation in C9ORF72, GRN, CHMPB2, TBK1, TARBP, or VCP genes or any other frontotemporal lobar degeneration causative genes not associated with underlying tau pathology (individuals with MAPT mutations may participate if they meet all other eligibility criteria).
• Any major surgery within 4 weeks of screening.
• History of deep brain stimulator surgery other than sham surgery for deep brain stimulation clinical trial.
• Inability to be venipunctured and/or tolerate venous access.
• Contraindication to the MRI examination for any reason.
• For those participating in the CSF substudy, contraindication to undergoing an LP including, but not limited to, inability to tolerate an appropriately flexed position for the time necessary to perform an LP, infection at the desired LP site, taking antiplatelet/anticoagulant medications that cannot be temporarily discontinued prior to performing the LP, degenerative arthritis of the lumbar spine, suspected non-communicating hydrocephalus or intracranial mass, and history of spinal mass or trauma.
• History of cancer within 5 years of screening with the exception of fully excised non-melanoma skin cancers or non-metastatic prostate cancer that has been stable for at least 6 months.
• History of clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal, or neurological disease.
• Autoimmune disease (quiescent rheumatoid arthritis or controlled diabetes are acceptable).
• Blood transfusion within 4 weeks of screening.
• Any vaccination within 30 days prior to screening. Vaccination may be allowed during the study according to guidance issued to study sites by the Sponsor; if necessary, please contact the Medical Monitor for that guidance.
• Known history of human immunodeficiency virus infection.
• Recent (within 6 months of study treatment administration) drug or alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Diagnostic Criteria for Drug and Alcohol Abuse.
• Any history of clinically significant suicidal ideation and/or behavior within 1 year of screening as determined by the Investigator.
• History of a clinically significant medical condition that would interfere with the participant’s ability to comply with study instructions, would place the participant at increased risk, or might confound the interpretation of the study results.
• Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
• Current hepatitis C or hepatitis B infection
  • Current hepatitis C virus (HCV) infection (defined as positive HCV antibody and detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (US Centers for Disease Control and Prevention).
  • Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [anti-HBc]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study (US Centers for Disease Control and Prevention).

Prior/Concomitant Therapy

• Within 4 weeks of screening (first visit) or anticipated during the 52-week double-blind period of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors, antipsychotic agents, or mood stabilizers (e.g., valproate, lithium); or benzodiazepines, with the following exceptions:
  • Low dose lorazepam or other short-acting medications may be used for sedation prior to MRI scans for those participants requiring sedation. At the discretion of the Investigator, 0.5 to 1 mg may be given orally prior to scan with a single repeat dose given if the first dose is ineffective. Neuropsychological testing may not be performed on the same day of lorazepam administration. Participants and caregiver must be informed of risks of lorazepam use prior to administration.
  • Participants who take short-acting benzodiazepines or other hypnotics (e.g., temazepam, zolpidem) for sleep may continue to do so if they have been on a stable dose for 30 days prior to screening.
  • Clonazepam may be used for treatment of restless legs syndrome, dystonia, or painful rigidity associated with PSP if the dose has been stable for 60 days prior to screening.
  • Quetiapine or clozapine may be permitted if at a stable dose for at least 60 days prior to screening.
• Receipt of systemic corticosteroids within 30 days prior to baseline.
• Receipt of an investigational immunomodulator or mAb within 180 days (or 5 half-lives, whichever is longer) prior to screening.
• Treatment with any other investigational drugs (e.g., salsalate) including placebo or devices within 90 days prior to screening.

Physical and Laboratory Test Findings

• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations beyond what is consistent with the target population.
• Clinically significant abnormality on 12-lead ECG prior to study treatment administration, confirmed by repeat.
• Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) greater than 2 times the upper limit of normal (ULN), confirmed by repeat. Elevated total bilirubin suspected to be due to Gilbert syndrome should be discussed with the Medical Monitor.
• Serum creatinine > 168 mol/L (1.9 mg/dL), confirmed by repeat.
• Hematocrit < 30%, absolute neutrophil cell count of ≤ 1500/µL (with the exception of a documented history of a chronic benign neutropenia), or platelet cell count of < 120,000/µL, or International normalized ratio (INR) > 1.4 or other coagulopathy, confirmed by repeat.
  • Note: Participants with INR > 1.4 due to antiplatelet/anticoagulant medications are eligible.
• A clinically significant abnormal thyroid-stimulating hormone test.
• For those participating in the CSF substudy, an abnormally increased number of white blood cells in the CSF obtained at the Screening Visit. Participants with > 7 cells/mm3 white blood cells must be discussed with the Medical Monitor to determine if they may be eligible.
• Hemoglobin A1C (HbA1C) > 8%, confirmed by repeat.

Allergies and Adverse Drug Reaction

• History of allergy, hypersensitivity, or serious adverse reaction to mAbs or related compounds.
• Allergy to any of the components of the study treatment, such as Polysorbate 80.
• History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).

Other Exclusion Criteria

• Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a participant. Strict conditions apply and Biogen approval is required.)
• Participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
• Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.