active dermatomyositis

To obtain initial data on the dose response relationship for the efficacy and safety of BAF312 (0.5, 2, 10 mg once daily) compared to placebo in active DM patients over a treatment period of 6 months and to determine the minimum dose required for a maximal clinical effect. In a previous study in polymyosytis/dermatomyosytis BAF312 showed promising trends for improvement after 12 weeks of treatment, particularly on the manual muscle testing (MMT-8) and the skin scoring systems. Considering the heterogeneity of PM/DM patient populations which differ in disease etiology, mechanism and clinical manifestation, a more homogenous population of DM only patients will be investigated in this study.

BAF312

Siponimab

tablet

0, 0.5, 2, 10

Primary: To assess the efficacy of different doses of BAF312 after 6 months
of treatment in active DM patients as assessed by manual muscle testing
using the MMT-8 scoring system.
Secondary: To assess the effects of different doses of BAF312 on safety,
pharmacokinetics and peripheral blood lymphocyte counts in active DM
patients
Secondary: To assess the efficacy of different doses of BAF312 after 3
months of treatment in active DM patients as assessed by manual muscle
testing using the MMT-8 scoring system.

• Written informed consent must be obtained before any assessment is
performed.
• Male and female patients between 18 - 70 (inclusive) years of age
who have been defined as "definite" or “probable” based on the
criteria of Bohan and Peter (Bohan and Peter 1975) for
dermatomyositis at least 12 months before screening
• Patients must have active disease as defined by dermatomyositis
skin rash AND Muscle weakness as defined by
• an MMT-8 score of ≤ 130 out of 150
and
• a CDASI score of at least 5
• Patients must have responded inadequately to previous standard of
care or have demonstrated significant toxicity or intolerance to such
therapies. Standard of care is defined as corticosteroids alone or in
combination with DMARDs.
• Patients may be on a stable dose of corticosteroid (up/equal to 20 mg
once daily prednisone equivalent) provided that the dose has been
stable for at least 2 weeks prior to Baseline. Patients should not have
received a daily therapy of more than 80 mg prednisone equivalent
within 8 weeks prior to study entry.
• Patients currently treated with oral or subcutaneous MTX must have
been a stable dose of no more/equal to than 25 mg per week for at
least 3 months prior to baseline.
• Patients currently treated with Azathioprine must have been a stable
maintenance dose of no more/equal to 3 mg/kg/day for at least 3
months prior to baseline.
• Negative cancer screening conducted in the 6 months prior to
screening visit
• Able to communicate well with the investigator, to understand and
comply with the requirements of the study.

• Use of other investigational drugs (other than BAF312) at the time of
enrollment, or within 5 half-lives of enrollment, or within 30 days,
whichever is longer; or longer if required by local regulations
• History of hypersensitivity to any of the study drugs or to drugs of similar
chemical classes
• Dermatomyositis patients having overlap myositis if the muscle
symptoms (for example, weakness or pain) are attributable to other
causes such as arthritis, scleroderma, statin myopathy or steroid
induced myopathy and/or significant organ damage e.g. lupus
nephritis, central nervous system are present. Patients with overlap
myositis having other clinical or laboratory signs of autoimmune
disease such as lupus or secondary Sjögren`s syndrome may be
eligible for the study at the Investigator’s discretion, preexisting
severe cardiac or pulmonary involvement or any major internal organ
damage which deemed by the Investigator to be clinically significant,
late-stage dermatomyositis whose muscle weakness, according to
the Investigator, could be attributable to muscle damage rather than
to myositis disease activity
• Patients with other types of myositis or myopathies
including:Polymyositis, paraneoplastic myositis. Documentation with
regard to the exclusion of malignancies as per standard medical
practice at the time of diagnosis of DM must be available; inclusion
body myositis using the European Neuromuscular Centre (ENMC) or
modified Hilton-Jones criteria or equivalent. Particular attention
should be paid to those patients presenting with weakness in
wrists/finger flexors more than wrist extensors and shoulder
abductors, necrotizing myopathy, any myopathy due to conditions
other than DM such as drug-induced myopathy, metabolic or
neurological diseases
• Patients who have been treated with: immunoglobulins such as
intravenous immunoglobulin (ivIg) therapy within 3 months prior to
randomization, monoclonal antibodies within 6 months prior to
randomization. Cyclophosphamide within 6 months prior to
randomization. For patients treated with rituximab in the past 12
months, peripheral B cell count should be in the normal range to be
eligible for the study; second line immunosuppressive agents
including mycophenolate, cyclosporine A, leflunomide within 2
months prior to randomization, intramuscular methotrexate therapy
within 2 months prior to randomization (while oral or subcutaneous
methotrexate at a stable dose is allowed as a concomitant
medication, total lymphoid irradiation or bone marrow transplantation.
• Patients with concurrent or history of macular edema or any
significant eye disease that increases the risk of macular edema
(e.g. diabetic retinopathy or retinal vein occlusion)
• Any of the following cardiovascular conditions:
• History of or current significant cardiac disease including cardiac
failure (NYHA, functional class II-IV), myocarditis, cardiomyopathy,
stable or unstable angina pectoris or myocardial infarction (within
12 months), or uncontrolled arterial hypertension.
• Cardiac conduction or rhythm disorders including complete left
bundle branch block, sinus arrest or sino-atrial block, symptomatic
bradycardia, sick sinus syndrome, Mobitz Type II second degree AVblock or high grade AV-block (either history or observed at
screening),
• Cardiac arrhythmias requiring treatment , or a history of cardiac
syncope.
• Patients receiving current treatment with Class Ia or III antiarrhythmic
drugs (e.g., quinidine, disopyramide, amiodarone, bretylium, sotalol,
ibulitide, azimilide, dofelitide, ajmaline, procainamide).
• Conditions requiring treatment with medication that may cause AV
block and suppress AV conduction (e.g. carbamazepine, lamotrigine,
non-dihydropyridine calcium-channel blockers e.g. verapamil or
diltiazem, or cardiac glycosides), with the exception of beta-blockers.
If patients are under treatment with beta-blockers, the dose may not
be increased throughout the study. Beta-blockers may not be
introduced as new medication during the study.
• PR interval >220 msec. Long QT syndrome or QTcF
prolongation >450 msec in males or >470 msec in females, on
screening electrocardiogram (ECG)
• Severe autonomic nervous system dysfunction
• Cardiac condition requiring catheter ablation
• Resting heart rate of <50 bpm prior to randomization
• Any of the following pulmonary conditions:
• History of / or active severe respiratory disease, including severe
COPD or pulmonary fibrosis
• tuberculosis, except for history of successfully treated tuberculosis or
history of prophylactic treatment after positive PPD skin reaction
• patients with severe asthma or asthma requiring regular treatment
with oral steroids
• History of malignancy of any organ system (other than localized
basal cell carcinoma of the skin), treated or untreated, within the past
5 years, regardless of whether there is evidence of local recurrence
or metastases.
• Uncontrolled diabetes mellitus or diabetes complicated with organ
involvement such as diabetic nephropathy or retinopathy.
• Active systemic bacterial, viral or fungal infections, or diagnosis of
AIDS, Hepatitis B, Hepatitis C infection.
• Evidence of any other acute or chronic infectious diseases.
• Negative for varicella-zoster virus IgG antibodies at Screening.
• Have received any live or live attenuated vaccines (including for
varicella-zoster virus or measles) within 2 months prior to
randomization.
• Homozygosity for CYP2C9*3 (will be tested at Screening), and/or
refusal to test for CYP2C9*3 haplotype.
• Patients using (or having used within four (4) weeks or 5 half- lives,
whichever is greater before initial dosing) concomitant medications
that are strong or moderate inducers of CYP2C9.
• Evidence of drug or alcohol abuse as indicated by the laboratory
assays conducted during the screening or baseline evaluations
• Patients with any condition (e.g. allergy to hydrogel) or an
implantable device that is incompatible with the mobile cardiac
telemetry monitoring or 24-hr Holter ECG
• Pregnant or nursing (lactating) women, where pregnancy is defined
as the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.
• Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception during dosing and for 28
days after the last dose of BAF312. Highly effective contraception
methods include:
• Total abstinence (when this is in line with the preferred and usual
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or
without hysterectomy) or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow
up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female
subjects on the study the vasectomized male partner should be the
sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c):
a) Use of oral, injected or implanted hormonal methods of
contraception or other forms of hormonal contraception that have
comparable efficacy (failure rate <1%), for example hormone vaginal
ring or transdermal hormone contraception.
b) Placement of an intrauterine device (IUD) or intrauterine system
(IUS)
c) Barrier methods of contraception: Condom or Occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/vaginal suppository
o In case of use of oral contraception, women should have
been stable on the same pill for a minimum of 3 months
before taking study treatment.
o Women are considered post-menopausal and not of child
bearing potential if they have had 12 months of natural
(spontaneous) amenorrhea with an appropriate clinical profile
(e.g. age appropriate, history of vasomotor symptoms) or
have had surgical bilateral oophorectomy (with or without
hysterectomy) or tubal ligation at least six weeks ago. In the
case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up
hormone level assessment is she considered not of child
bearing potential. This group does not need to use
contraception.
• Patients with any of the following hepatic conditions prior to
randomization:
• History of chronic liver or biliary disease
• Total or conjugated bilirubin greater than 1.5 times ULN range,
unless in the context of Gilbert’s syndrome
• Alkaline phosphatase (AP) greater than 1.5 times the ULN range
• AST (SGOT), ALT (SGPT) greater than 3 times the upper limit of the
normal range if the elevation of AST or ALT, according to the
Investigator, is attributable to liver disease. Patients with elevated AST
and/or ALT due to myositis disease activity are eligible
• Gamma-glutamyl-transferase (GGT) greater than 3 times the ULN
range
• Patients with any of the following abnormal laboratory values prior to
randomization:
• serum creatinine > 1.7 mg/dL (150 µmol/L)
• total white blood cell count (WBC) outside the range of 3,500 –
12,000 /µl. Patients with leukocytosis (WBC not higher than 18,000
/µl) may be eligible, if the elevated WBC, according to the
Investigator is attributable to corticosteroid therapy and other causes
such as hematological or infectious diseases can be excluded
• lymphocyte count < 750/mm3 (< 0.75 x 109
/L)
• serum potassium > ULN
• Any other disease of condition which could interfere with the
participation in the study according to the study protocol, or with the
ability with the patients to cooperate and comply with the study
procedures
• Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the
C-SSRS, if this ideation occurred in the past 6 months, or “yes” on
any item of the Suicidal Behavior section, except for the “NonSuicidal Self-Injurious Behavior” (item also included in the Suicidal
Behavior section), if this behavior occurred in the past 2 years.