In this first in human study the aim is to assess the safety, pharmacokinetics and
pharmacodynamics of 2B3-201 in a randomized, first in human, double-blind, placebo- and
active comparator- controlled 3-way crossover study in 18 healthy male subjects (part 1).
Furthermore, the findings obtained from part 1 will be extended and confirmed in a
subsequent parallel open label study in 18 healthy male and 12 MS patients and an open label
study with methylprednisolone as comparator in 12 female volunteers (part 2).
Inclusion Criteria:
Healthy subjects
- Healthy male or female subjects, 18 to 45 years of age, inclusive. Healthy status is
defined by absence of evidence of any active or chronic disease following a detailed
medical and surgical history, a complete physical examination including vital signs,
12-lead ECG, hematology, blood chemistry, and urinalysis.
- Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight
of 50 kg.
- Able to participate and willing to give written informed consent and to comply with
the study restrictions.
Relapsing MS patients
- Age: 18 to 65 years, both men and women.
- Patients with relapsing multiple sclerosis (RMS), defined as below, with an acute
exacerbation, who in the opinion of the treating physician should undergo a 3 - 5 day
course of high dose methylprednisolone;
- Patients with Relapsing Remitting Multiple Sclerosis (RRMS).
- Patients with Secondary Progressive Multiple Sclerosis (SPMS) and
- Patients with clinically isolated syndromes (CIS) who show dissemination of
lesions in time (DIT) and space (DIS) on MRI scans according to the 2010
McDonald criteria.
- Able to participate and willing to comply with the study restrictions. Understands
and signs the written informed consent prior to any of the testing under this
protocol, including screening tests and evaluations that are not considered part of
the subject's routine care.
Exclusion Criteria:
Healthy volunteers:
- Any subject who is pregnant or breastfeeding. A urine pregnancy test should be
performed in female subjects of childbearing potential (defined as < 2 years after
last menstruation and not surgically sterile) prior to the start of the study
treatment.
- For female subjects of childbearing potential (defined as < 2 years after last
menstruation and not surgically sterile) and male subjects who are not surgically
sterile or with female partners of childbearing potential: absence of effective,
non-hormonal means of contraception (intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal gel) will be a
contraindication.
- Not willing to use double-barrier contraception, for the duration of the study and
for 3 months after the last dose.
- Positive test for drugs of abuse at screening or pre-dose.
- History of alcohol consumption exceeding 2 standard drinks per day on average (1
standard drink = 10 grams of alcohol) within 3 months of screening. Alcohol
consumption will be prohibited during study confinement and at least 48 hours before
screening, before dosing, and before each scheduled visit.
- History or symptoms of any significant disease including (but not limited to),
neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal,
hepatic, or renal disorder.
- Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human
immunodeficiency virus antibody (HIV Ab) at screening.
- Systolic blood pressure (SBP) greater than 140 mm Hg or less than 90 mm Hg, and
diastolic blood pressure (DBP) greater than 90 mm Hg or less than 50 mm Hg.
- Use of any medications (prescription or over-the-counter [OTC]), vitamin, mineral,
herbal, and dietary supplements within 21 days of study drug administration.
Exceptions are paracetamol (up to 4 g/day).
- Use of CYP3A4-inhibiting drugs, including quinine containing drinks (bitter lemon and
tonic water) is prohibited within 21 days of study drug administration
- Subject has used grapefruit, grapefruit juice, grapefruit-containing products,
Seville oranges, or pomelo-containing products, within 14 days prior to day - 1.
- Clinically significant abnormalities, as judged by the investigator, in laboratory
test results (including hepatic and renal panels, complete blood count, chemistry
panel and urinalysis). In the case of uncertain or questionable results, tests
performed during screening may be repeated before randomization to confirm
eligibility or judged to be clinically irrelevant for healthy subjects.
- Participation in an investigational drug or device study within 3 months prior to
screening.
- Donation of blood over 500 mL within three months prior to screening.
- Concomitant disease or condition that could interfere with, or for which the
treatment of might interfere with, the conduct of the study, or that would, in the
opinion of the Investigator, pose an unacceptable risk to the subject in this study.
- Smoker of more than 10 cigarettes per day prior to screening or who use tobacco
products equivalent to more than 10 cigarettes per day.
- Clinically significant abnormal ECG, as judged by the Investigator.
- Current infection or inflammation study within 1 month prior to screening
- Recent vaccinations study within 3 months prior to screening.
- Positive Mantoux test of 5 mm or more.
- Any confirmed significant allergic reactions (urticaria or anaphylaxis) against any
drug, or multiple drug allergies (non-active hay fever is acceptable).
- Unwillingness or inability to comply with the study protocol for any other reason.
RMS patients:
- Previous acute exacerbations, and/or corticosteroid treatment or ACTH < 1 month
before present exacerbation,
- Hypersensitivity to methylprednisolone.
- Prior use of immunosuppressive treatments / disease-modifying drugs (DMDs) other than
interferon-beta, glatiramer acetate, fingolimod, dimethylfumarate or teriflunomide
within 12 months of the index episode. Shorter periods may be allowed at the
discretion of the PI and after approval from the sponsor. Subjects may continue their
current therapy with interferons, glatiramer acetate, fingolimod, or teriflunomide
throughout the course of the study.
- Non-steroidal anti-inflammatory agents, including salicylic acid, should be avoided
during the administration of the steroid therapy. If absolutely necessary they are
permitted for subjects to treat interferon side effects, when the patient is not
responding to acetaminophen/paracetamol.
- Current or recent (within 30 days of first study treatment) treatment with any other
investigational drug or participation in any other investigational study
- Evidence of psychiatric illness
- History of any significant cardiac, gastrointestinal, hepatic, pulmonary, renal or
active immunosuppressive disease.
- Immune deficiency or any other medical conditions that would preclude corticosteroid
therapy.
- Any patient who is pregnant or breastfeeding. A urine pregnancy test should be
performed in female subjects of childbearing potential (defined as < 2 years after
last menstruation and not surgically sterile) prior to the start of the study
treatment.
- For female subjects of childbearing potential (defined as < 2 years after last
menstruation and not surgically sterile) and male subjects who are not surgically
sterile or with female partners of childbearing potential: absence of effective,
non-hormonal means of contraception (intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal gel) will be a
contraindication.
- Physical examination results or laboratory findings that may interfere with the
planned treatment, affect patient compliance or place the patient at a high risk of
treatment-related complications.
- Known hypersensitivity to any of the cyclodextrin or any excipients in 2B3-201 (e. g.
PEG, Cholesterol, HSPC or GSH).
Gaillard PJ, Appeldoorn CC, Rip J, Dorland R, van der Pol SM, Kooij G, de Vries HE, Reijerkerk A. Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation. J Control Release. 2012 Dec 28;164(3):364-9. doi: 10.1016/j.jconrel.2012.06.022. Epub 2012 Jun 23.
