Open Pilot Trial of BHV-4157

Inclusion Criteria:

1. Informed Consent a. Subjects (or legally acceptable representative as required by theIRB/IEC) must provide a written signed informed consent form/forms (IRB/EC specific)prior to the initiation of any protocol required procedures.
2. Age and Sex a. Male and female outpatient subjects between the ages of 18 - 75,inclusive
3. Target Populations a. Subjects with (1) a known or suspected diagnosis of a specific hereditary ataxia:SCA3/dizziness-predominant or SCA1, SCA2, SCA3, SCA6, already taking Riluzole for morethan 8 weeks; (2) non-genetic pure cerebellar ataxia; (3) MSA-C: i. SCA subjectsshould have confirmed genotypic diagnosis from a CLIA-certified lab or a family memberthat has had such testing. ii. Alternatively, subjects must be willing to undergo genetic testing from aCLIA-certified lab if testing has not been previously done on the study subject and acopy of results is not available for verification. b. Ability to ambulate 8 meters without assistance (canes and other devices allowed);c. Determined by the investigator to be medically stable at Baseline as assessed bymedical history, physical examination, laboratory test results available in medicalrecord, and electrocardiogram testing available in medical record. Subjects must bephysically able and expected to complete the trial as designed; d. Minimum of 6 yearsof education; e. Subjects must have adequate hearing, vision, and language skills toperform interviews as specified in the protocol; f. Subjects must be able tounderstand and agree to comply with the prescribed dosage regimens and procedures;report for regularly scheduled office visits; and reliably communicate with studypersonnel about adverse events and concomitant medications; g. Women of childbearingpotential (WOCBP) and men must be using an acceptable method of contraception to avoidpregnancy throughout the study and for up to 30 day after the last dose ofinvestigational product in such a manner that risk of pregnancy is minimized. Therequisite drug interaction studies to determine the interaction of BHV-4157 with oralcontraceptives have not been performed to date. It is therefore not possible todetermine the efficacy of oral contraceptives as an effective method of contraceptionfor WOCBP who participation this study. Oral estrogen and progestin hormonalcontraceptives as a sole method of contraception are therefore prohibited. It isrequired that all WOCBP use two methods of contraception for the duration of the study (i.e. beginning at first treatment to 30 days after the last dose of study drug).Thetwo methods should include one barrier method (ex. condom with spermicidal gel,intrauterine devices, cervical cap etc.) and one other method. The other method couldinclude oral contraceptives or another barrier method. h. Women of childbearing potential must have a negative serum pregnancy test atscreening and a negative urine pregnancy test within 72 hours of dosing. i. SCA subjects (SCA3/dizziness predominant; SCA1, 2, 3, 6 on Riluzole for more than 8weeks) will not be limited to Inclusion Criteria of Screening SARA score ≥8 or Scoreof ≥ 2 on gait subsection of the SARA. j. Non-genetic pure cerebellar and MSA-C subjects will be limited to InclusionCriteria of Screening SARA score ≥8 or Score of ≥ 2 on gait subsection of the SARA.

Exclusion Criteria:

1. Target Disease Exceptions a. Any medical condition other than one of the hereditary ataxias specified in theinclusion criteria that could predominantly explain or contribute significantly to thesubjects' symptoms of ataxia (for example, alcoholism, vitamin deficiencies, multiplesclerosis, vascular disease, tumors, paraneoplastic disease, head injury, idiopathiclate onset ataxia, multisystem atrophy) or that can confound assessment of ataxiasymptoms (for example, stroke, arthritis); b. MMSE score < 24; c. Subjects withprominent spasticity or dystonia that meet either of the following criteria: i. In theopinion of the investigator will compromise the ability of the SARA instrument toassess underlying ataxia severity; or, ii. Are associated on the INAS instrument atscreening with moderate or severe scores on dystonia (at least 3 of 5 items) orspasticity (at least 2 of 3 items) or rigidity (at least 2 of 3 items) d. SARA totalscore of > 30 points at screening; e. Subjects may not have started physical oroccupational therapy within one month of screening and are not expected to start suchtherapy during the initial 12 week treatment phase. Subjects with ongoing occupationalor physical therapy may be allowed to continue as long as the intensity remainsunchanged from two months prior to screening throughout the randomization period.
2. Medical History Exclusions a. Clinical history of stroke. Note: Subjects with a history of transient ischemicattack (TIA) may be enrolled, if it occurred at least 3 months prior to screening andthe subject is prescribed appropriate treatment [e.g., platelet aggregationinhibitors]; b. Immunocompromised subjects. Note: Subjects taking a systemicimmunosuppressive agent may enter treatment phase if they are on a stable dose, haveno clinically relevant immunosuppression, and have a white blood count (WBC) withinnormal limits; c. Active liver disease or a history of hepatic intolerance tomedications that in the investigator's judgment, is medically significant; d. Historyof medically significant gastrointestinal (GI) illnesses including: i. A currentdiagnosis of active, peptic ulceration or gastrointestinal bleeding within the last 6months and/or chronic inflammatory bowel disease at screening; ii. A history of anygastrointestinal surgery that impacts the absorption of study drug; iii. Chronic orfrequent episodes of loose stools; bowel movements; e. Vitamin B12 or folatedeficiency Note: Subjects with a B12 deficiency can participate in the study if theyare on stable Vitamin B12 replacement for at least 3 months prior to randomization andtheir B12 levels are within normal limits prior to randomization; f. Hematologic orsolid malignancy diagnosis within 5 years prior to screening. (Note: Subjects with ahistory of localized skin cancer, basal cell or squamous cell carcinoma, may beenrolled in the study as long as they are cancer free prior to randomization. Subjectswith other localized cancers (without metastatic spread) who have previously completedtheir course of treatment more than 2 years prior to baseline, are not currentlyreceiving treatment and have been in remission may be enrolled only if, in the opinionof the investigator, there is no expectation for recurrence or further cancertreatment during the study period. Antihormonal therapy (e.g., tamoxifen) is allowedif the subject's cancer is in remission and the subject is on maintenance therapy toreduce their risk of recurrence; g. Any unstable cardiovascular (includes uncontrolledhypertension), pulmonary, gastrointestinal, or hepatic disease 30 days prior toscreening; h. End-stage cardiovascular disease (e.g., Congestive Heart Failure NewYork Heart Association/CHF NYHA Class III or IV or unstable angina); i. Treated for,or have had a lifetime diagnosis of, schizophrenia or bipolar disorder; j. Activemajor depressive episode within the past 6 months. Note: Subjects on a stablemaintenance dose of a non- tricyclic, non-monoamine oxidase inhibitor (MAOI)antidepressant medication (e.g., serotonin reuptake inhibitor, bupropion) withsymptoms in remission may be eligible; k. History of neurosyphilis (as indicated by apositive rapid plasma reagin [RPR] test and a positive confirmatory test); l. Historyof drug or alcohol abuse within 12 months as defined by DSM-IV-TR-TR criteria; m.History or evidence of any medical, neurological or psychological condition that wouldexpose the subject to an undue risk of a significant adverse event or interfere withassessments of safety and efficacy during the course of the trial as determined by theclinical judgment of the investigator; n. History of chronic pulmonary disease orchronic pulmonary symptoms
3. Physical and Laboratory Test Findings a. Uncontrolled hypertension at screening (e.g., repeated diastolic measurements ≥ 96mmHg); b. Subjects with history of hypothyroidism may participate in the study,provided they are euthyroid on stable thyroid replacement therapy for at least 3months prior to Baseline, and therapy is expected to remain stable during the courseof the study; c. Hepatic test abnormalities at screening: i. AspartateAminotransferase (AST), Alanine Aminotransferase (ALT) or GGT > 2 times the upperlimit of normal; or ii. Total bilirubin > 2 times the upper limit of normal (ULN); d.If diabetic, HbA1C > 7.5% within 3 months of screening; e. Pathologic renal findingsat screening as defined by the presence of either of the following criteria within 3months of screening: i. Estimated glomerular filtration rate (eGFR) according to there-expressed abbreviated (four- variable) Modification of Diet in Renal Disease (MDRD)Study equation < 30 ml/min/ 1.73m2; The MDRD estimation is calculated as follows: eGFR (mL/min/1.73m2) = 175 x (standardized Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if Black). [Scr: Standardized serum creatinine] ii. Quantitative urineprotein/creatinine ratio greater than 0.2. This test may be repeated if clinicallyindicated. In the event of a urinary tract infection (UTI), the test may be repeatedafter the UTI has resolved; f. Hematologic abnormalities within 3 months of screening:i. Hemoglobin < 10 g/dL; or ii. WBC < 3.0 x 103/mm3; or iii. Platelet count < 100,000/mm3; g. QTc (Bazett's) and QTc (Fridericia) interval > 480 msec within 3months of screening and confirmed by repeat measurement or uncontrolled arrhythmia orfrequent premature ventricular contraction (PVCs) (> 5/minute) or Mobitz Type IIsecond or third degree atrioventricular (AV) block or evidence of acute or sub-acutemyocardial infarction or ischemia. [Note: Subjects with MRI compatible pacemakers orbundle branch block (BBB) and a paced QTc (Fridericia) < 480 msec and a stable cardiacstatus may be enrolled after obtaining a cardiology consult. It must be determined bythe consulting cardiologist that the subject's cardiac status is stable and does notpose a risk for participation in the trial.]
4. Prohibited Treatments and/or Therapies
5. History of not tolerating treatment with riluzole for any reason
6. Treatment with riluzole in the 30 days prior to screening and/or during thestudy; [with the exception of the switch group of SCA subjects].
7. Prior trial of riluzole treatment of at least 8 weeks duration ; [with theexception of the switch group of SCA subjects].
8. Use of chlorzoxazone is prohibited 30 days prior to screening and during thestudy;
9. Use of aminopyridine is prohibited 30 days prior to screening and during thestudy;
10. Use of tricyclic antidepressants and mono-amine-oxidase (MAO) inhibitors areprohibited 30 days prior to screening and during the study;
11. Use of any approved treatments for Alzheimer's Disease (AD). Subjects should befree of such medications (donepezil, galantamine, rivastigmine and memantine) forat least 3 months prior to Baseline with no plans to start such medicationsduring the study; or, subjects should be on stable doses of these medications forat least 3 months prior to the baseline visit;
12. Use of memantine is prohibited 30 days prior to screening and during the study;
13. A new anxiolytic or sleep medication not taken at a stable dose within 30 daysprior to screening. Note: Low dose anxiolytic pre-medications prior to diagnostictesting (e.g., MRI) as well as sleep medications taken prn (as needed) areallowed;
14. Chronic NSAID use (e.g., naproxen, acetylsalicylic acid, ibuprofen) should betreated with proton pump inhibitors unless otherwise clinically prohibited;
15. Medical marijuana use within 30 days of baseline visit (and subjects will beexpected to refrain from use during the period of the study).