Rheumatoid arthritis

Primary Objectives: To evaluate the safety and tolerability of single, ascending doses of CFZ533 administered via intravenous infusion or subcutaneous injection in healthy adult subjects and via intravenous infusion in rheumatoid arthritis patients. Secondary Objectives: 1: To assess the pharmacokinetics of single doses of CFZ533 in healthy subjects and rheumatoid arthritis patients. 2: To evaluate the immunogenicity of single doses of CFZ533 via the quantitative analysis for anti-CFZ533 antibodies in healthy subjects and rheumatoid arthritis patients.

CFZ533

Lyophilisate in vial

3 mg/kg

Primary Endpoint:
 Safety Labs
 ECG
 Vital signs
 EBV, CMV surveillance
 Adverse events
 Coagulation studies
 Renal function
 Immunoglobulin titers
 Inflammatory marker

Secondary endpoints:
 PK
 CD40 receptor occupancy (free and total CD40 on B cells)
 PD functional activity (for non-Chinese healthy subjects only)
 Immunophenotyping (for healthy subjects only)
 sCD40
 sCD154 (for healthy subjects only)
 Anti-KLH titers (IgG, IgM) (for non-Chinese healthy subjects only)
 Immunogenicity
 Cytokine assessment

Inclusion criteria of Healthy Volunteers :
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Healthy male and surgically sterilized or post-menopausal female subjects 18 to 55 years of age included, and in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
3. For Cohort 9 only, subjects must be of Chinese descent.
4. At screening, and first baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes and again (when required) after three minutes in the standing position. Sitting vital signs should be within the following ranges:
oral body temperature between 35.0-37.5 0C
systolic blood pressure, 90-150 mm Hg
diastolic blood pressure, 50-90 mm Hg
pulse rate, 40-100 bpm
During screening and baseline only, subjects should be excluded if their standing vital signs (relative to sitting) show either a > 20 mm Hg decrease in systolic or a >10 mm Hg decrease in diastolic blood pressure, accompanied by a > 20 bpm increase in heart-rate (comparing standing to sitting results) and clinical manifestation of postural hypotension. Asymptomatic changes in heart rate and blood pressure is not an absolute exclusion.
5. Subjects must weigh at least 50 kg and no more than 150 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 32 kg/m2. BMI = Body weight (kg) / [Height (m)]2 .
6. Able to communicate well with the Investigator, to understand and comply with the requirements of the study.

Exclusion criteria of Healthy Volunteers :
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, whichever is longer; or longer if required by local regulations.
2. Previous treatment with a B cell-depleting agent.
3. History of hypersensitivity to vaccines, the study drug, or to drugs of similar chemical classes (i.e., IgG1-related biologic agents).
4. History of allergy to shellfish or shellfish derivative.
5. History of Guillain-Barré syndrome.
6. Previous exposure to the immunogen Keyhole Limpet Hemocyanin (KLH).
7. Abnormal total IgG (below 705 mg/dL) or total IgM (below 46 mg/dL) concentrations; elevated IgG and IgM concentrations are not exclusionary unless deemed clinically significant per the primary investigator.
8. History of thromboembolic events or conditions with a high risk of thromboembolic complications, e.g., antiphospholipid syndrome.
9. Known history or current clinically significant arrhythmias.
10. 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.
11. 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.
12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
• 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.
13. Smokers (use of tobacco products in the previous 3 months) due to potential risk for associated hypercoagulability. Urine cotinine levels will be measured during screening and at each baseline for all subjects. Smokers will be defined as any subject who reports tobacco use and/or who has a urine cotinine ≥500 ng/ml.
14. Use of any prescription drugs or herbal supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medications within one (1) week prior to initial dosing. If needed, (i.e., an incidental and limited need) acetaminophen is acceptable, but must be documented in the Concomitant medications / Significant nondrug therapies page of the CRF.
15. Donation or loss of 400 ml or more of blood within eight (8) weeks prior to initial dosing,or longer if required by local regulation.
16. Clinically significant deviation in hematology laboratory results, as determined by theinvestigator, and/or WBC (total white count) below the lower limit of the normal range at screening or baseline.
17. Significant illness which has not resolved within two (2) weeks prior to initial dosing.
18. History of recurrent clinically significant infection or of recurrent bacterial infections with encapsulated organisms.
19. Recent (within the last three years) and/or recurrent history of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
20. History of multiple and recurring allergies or allergy to the investigational compound/compound class being used in this study (monoclonal antibodies or human plasma products).
21. Pancreatic injury or pancreatitis as indicated by abnormal signs or symptoms of pancreatitis or clinically significant elevations in amylase or lipase.
22. Liver disease or liver injury as indicated by abnormal liver function tests. ALT (SGPT), AST (SGOT), γ-GT, alkaline phosphatase and serum bilirubin will be tested. Any single parameter of ALT, AST, γ-GT, alkaline phosphatase or serum bilirubin must not exceed >1.5 x the upper limit of normal (ULN). If necessary, laboratory testing may be repeated on one occasion (as soon as possible) prior to randomization, to rule out any laboratory error.
23. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or BUN and/or urea values, or abnormal urinary constituents (e.g.,albuminuria).
24. History of primary or secondary immunodeficiency diseases, including a positive HIV test result.
25. A positive Hepatitis B surface antigen or Hepatitis C test result.
26. A positive TB test, i.e, ≥15mm induration with PPD TST or QuantiFeron.
27. History or evidence of tuberculosis.
28. Negative Epstein Barr virus (EBV) test.
29. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening or baseline.

No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible patients.