Pharmacokinetics of DMF and the Effects of DMF on Exploratory Biomarkers

Inclusion criteria

(MS Population):

To be eligible to participate in this study, candidates must meet the following eligibility criteria at screening, or at the timepoint specified in the individual eligibility criterion listed:

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local patient privacy regulations. Subjects must provide separate informed consent to participate in this CSF study.
• Aged 25 to 65 years-old, inclusive, at the time of informed consent.
• Male of female subject with a confirmed diagnosis of SPMS.
• EDSS score between 3 and 7, inclusive, at screening.
• Weight should be between 130 and 200 lb.

Exclusion criteria

(MS Population)

• Candidates will be excluded from study entry if any of the following exclusion criteria exist at screening, or at the timepoint specified in the individual criterion listed:

• Unable or unwilling to provide informed consent. (Subjects must provide separate informed consent for this study.)
• A MS relapse, as determined by the Investigator, which occurred within 90 days prior to screening, or the subject has not stabilized from a previous relapse prior to screening.
• Any contraindication to having a brain magnetic resonance imaging (MRI) (e.g., pacemaker, MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed) or contraindication for administration of gadolinium-contrast agent.
• Clinically significant brain MRI finding other than those related to MS, as judged by the Investigator, at screening.
• Any contraindications to having a LP (e.g., aspirin greater than 325 mg/day, warfarin, clopidrogel, decreased platelet count, prolonged PT or PTT more than 1 ½ over normal) as determined by history and Investigator decision.
• Evidence of history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, diabetes mellitus) with the exception of MS.
• Any sign of chronic active infection, requiring antibiotic treatment (refer to Exclusion 23) (e.g., urinary tract infection, bronchitis, hepatitis, and tuberculosis) except for those requiring topical medication for treatment (e.g., athletes foot), or screening laboratory evidence consistent with a significant chronic active acute infection requiring systemic treatment.
• Pregnant; or breastfeeding females; or males of fathering potential or females of childbearing potential who are unwilling or unable to use an effective method of contraception as outlined in this protocol (Section 12.5) for the duration of the study and for at least 28 days after the last dose of DMF use in this protocol. For females of childbearing potential, a positive pregnancy test at any time within the protocol.
• Known positive human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody tests indicative of present or prior infection.
• Any abnormal hematology values or clinical chemistry values judged by the Investigator or Sponsor as clinically significant, including white blood cell count (WBC) 3500/mm3, or absolute lymphocyte count lower limit of normal.
• Positive Quantiferon-Tuberculosis Gold In-Tube test (QFT-GIT) at screening or known history of active tuberculosis not adequately treated.
• Any malignancy within 5 years, except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis.
• Any clinical, CSF, or MRI evidence for progressive multifocal leukoencephalopathy, from historical MRI.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• Subjects participating in or expecting to participate in other interventional clinical trials, except those participating in Study US-BGT-US-10766 at the same site.
• History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to screening.

Exclusion criteria

Related to Medication

• Previous exposure to DMF for disease management at any time in the past.
• History of severe allergic or anaphylactic reactions or known drug hypersensitivity to fumaric acid or fumaric acid esters.
• Treatment with methylprednisolone or other systemic corticosteroid for MS relapse or otherwise within 30 days prior to Day 1 of study treatment.
• Treatment with MS disease modifying therapies as follows:

Beta interferons (interferon beta-1a [Avonex® or Rebif®] or interferon beta-1b [Betaseron®], or glatiramer acetate [Copaxone®] within 6 weeks prior to Baseline.

Fingolimod (Gilenya®), teriflunomide (Aubagio®) within 6 months prior to Baseline, except teriflunomide washout with accelerated elimination and verification of zero serum levels of teriflunomide prior Baseline.

Natalizumab (Tysabri®) within 6 months prior to Screening OR 1 month prior to screening if subject has a positive Nabs (neutralizing antibodies) to Tysabri® Treatment within the past 5 years or current treatment with any of the following agents: cyclosporine, cladribine, agents that are immunosuppressive (e.g., entanercept), murine protein, T-cell vaccination), or stem cell transplantation prior to Screening.

Treatment within the past 2 years with rituximab, IVIG, or mycophenolate

• Receipt of any non-live vaccine within the previous 14 days or live vaccine within 30 days prior to first dose of study treatment.
• Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study treatment, whichever is longer.
• Use of antibiotics for any reason within 3 months of Screening. Inclusion Criteria (for Normal Control Volunteers Only)

To be eligible to participate in this study, normal control candidates must meet the following eligibility criteria at screening:

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local patient privacy regulations. Subjects must provide separate informed consent to participate in this CSF study.
• Male or female, aged 25 to 65 years-old, inclusive, at the time of informed consent.
• Weight should be between 130 and 200 lb. Exclusion Criteria (for Normal Control Volunteers Only)

Normal control candidates will be excluded from study entry if any of the following exclusion criteria exist at screening, or at the timepoint specified in the individual criterion listed:

• Unable or unwilling to provide informed consent. (Subjects must provide separate informed consent for this study.)
• Any contraindications to having a LP (e.g., aspirin greater than 325 mg/day, warfarin, clopidrogel, decreased platelet count, prolonged PT or PTT more than 1 ½ over normal) as determined by history and Investigator decision.
• Evidence of history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, diabetes mellitus) with the exception of MS.
• Any sign of chronic active infection, requiring antibiotic treatment (refer to Exclusion 23) (e.g., urinary tract infection, bronchitis, hepatitis, and tuberculosis) except for those requiring topical medication for treatment (e.g., athletes foot), or screening laboratory evidence consistent with a significant chronic active acute infection requiring systemic treatment.
• Pregnant; or breastfeeding females; or males of fathering potential or females of childbearing potential who are unwilling or unable to use an effective method of contraception as outlined in this protocol (Section 12.5) for the duration of the study and for at least 28 days after the last dose of DMF use in this protocol. For females of childbearing potential, a positive pregnancy test at any time within the protocol.
• Known positive human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody tests indicative of present or prior infection.
• Any abnormal hematology values or clinical chemistry values judged by the Investigator or Sponsor as clinically significant, including white blood cell count (WBC) 3500/mm3, or absolute lymphocyte count lower limit of normal.
• Positive Quantiferon-Tuberculosis Gold In-Tube test (QFT-GIT) at screening or known history of active tuberculosis not adequately treated.
• Any malignancy within 5 years, except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis.
• Any clinical, CSF, or MRI evidence for progressive multifocal leukoencephalopathy, from historical MRI.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• Subjects participating in or expecting to participate in other interventional clinical trials, except those participating in Study US-BGT-US-10766 at the same site.
• History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to screening.