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A Phase 2 Study of E6011 in Subjects With Rheumatoid Arthritis Inadequately Responding to Biologics

A Phase 2 Study of E6011 in Subjects With Rheumatoid Arthritis Inadequately Responding to Biologics

66

Overall, in the Core Treatmemnt Phase (Weeks 0-12), mean (SD) age was 51.5 (11.05) years. The majority of subjects were female (50/64 subjects, 78.1%). Overall, the mean (SD) RA duration was 9.2 (6.26) years. A total of 65.6% of subjects received 1 prior biologic with inadequate response and 34.4% of subjects received 2 prior biologics. The majority of prior biologics was anti-TNF (67.2%, 43/64 subjects). The mean (SD) dose of MTX was 9.4 (2.86) mg/week.

In the Treatmemnt Phase, a total of 66 subjects were randomized into the study. After randomization, 2 of 66 subjects discontinued the study before starting study drug treatment. A total of 64 subjects (33 in the placebo group and 31 in the E6011 group) received at least 1 dose of study drug (E6011 400 mg or placebo). Of the 64 subjects, 55 subjects (29 in the placebo group, 26 in the 400 mg group) completed the planned treatment regimen and 9 discontinued study treatment prematurely during the Core Treatment Phase (Weeks 0-12). All of the treated subjects (64 subjects) were included in the FAS and Safety Analysis Set. Fifty-five subjects were re-randomized at Week 12 and treated with E6011 200 mg or 400 mg (15 subjects for placebo/200 mg, 14 subjects for placebo/400 mg, 14 subjects for 400/200 mg, 12 subjects for 400/400 mg). Of the 55 subjects re-randomized, 48 completed the planned treatment regimen and 7 discontinued study treatment prematurely between Week 12 and Week 24. In the Extension Phase, a total of 47 subjects completed the Treatment Phase and were rolled over in the Extension Phase. Of the 47 subjects, 21 subjects completed the Extension Phase and 26 subjects discontinued study treatment prematurely during the Extension Phase. All of the subjects who were rolled over in the Extension Phase (47 subjects) were included in the FAS and the Safety Analysis Set.

During the Core Treatment Phase, the incidence of TEAEs was 57.6% (19/33 subjects) in the placebo group and 45.2% (14/31 subjects) in the E6011 group. The incidence of treatment-related TEAEs was 27.3% (9/33 subjects) in the placebo group and 25.8% (8/31 subjects) in the E6011 group. TEAEs that occurred in at least 2 subjects in the E6011 group were stomatitis, injection site erythema, nasopharyngitis, and blood creatine phosphokinase increased. Among those TEAEs, stomatitis (0% in the placebo group, 6.5% in the E6011 group), injection site erythema (0% in the placebo group, 6.5% in the E6011 group), blood creatine phosphokinase increased (0% in the placebo group, 6.5% in the E6011 group) occurred more frequently in the E6011 group than the placebo group. During the Entire Treatment Phase, the incidence of TEAEs was 80.0% (12/15 subjects) in the placebo/200 mg group, 92.9% (13/14 subjects) in the placebo/400 mg group, 92.9% (13/14 subjects) in the 400/200 mg group and 75.0% (9/12 subjects) in the 400/400 mg group. The incidence of treatment-related TEAEs was 46.7% (7/15 subjects) in the placebo/200 mg group, 42.9% (6/14 subjects) in the placebo/400 mg group, 42.9% (6/14 subjects) in the 400/200 mg group, and 33.3% (4/12 subjects) in the 400/400 mg group. TEAEs that occurred in at least 2 subjects in the 400/200 mg group or 400/400 mg group were injection site erythema and nasopharyngitis. Two of 14 subjects (14.3%) experienced injection site erythema in the 400/200 mg group while no subjects experienced it in the 400/400 mg group. The incidence of nasopharyngitis was similar between the 400/200 mg group and 400/400 mg group (28.6% in the 400/200 mg group, 33.3% in the 400/400 mg group). In the Extension Phase, TEAEs that occurred in at least 10% of subjects in the overall population were nasopharyngitis (51.1%, 24/47 subjects), and gastroenteritis, rash, back pain, anaemia, and hepatic function abnormal (10.6% each, 5/47 subjects).

ACR20 response rate at Week 12 was 27.3% (9/33 subjects) in the placebo group and 22.6% (7/31 subjects) in the E6011 group. No statistically significant differences were found between the placebo group and the E6011 group (P=0.621; a logistic regression model).

ACR50 response rate at Week 12 was 3.0% in the placebo group and 9.7% in the E6011 group. ACR70 response rate at Week 12 was 0.0% in the placebo group and 3.2% in the E6011 group. No statistically significant differences were found in ACR50 and ACR70 between the placebo and E6011 groups (P=0.131 and P=0.479, respectively; a logistic regression model). In the Extension Phase, ACR20 response rate at Weeks 52 and 72 was 38.5% and 38.5% in the placebo/200 mg group, 45.5% and 45.5% in the placebo/400 mg group, 53.8% and 53.8% in the 400/200 mg group, and 50.0% and 20.0% in the 400/400 mg group, respectively. ACR50 response rate at Weeks 52 and 72 was 15.4% and 15.4% in the placebo/200 mg group, 27.3% and 27.3% in the placebo/400 mg group, 30.8% and 30.8% in the 400/200 mg group, and 10.0% and 10.0% in the 400/400 mg group, respectively. ACR70 response rate at Weeks 52 and 72 was 0% and 0% in the placebo/200 mg group, 18.2% and 9.1% in the placebo/400 mg group, 15.4% and 15.4% in the 400/200 mg group, and 10.0% and 10.0% in the 400/400 mg group, respectively.

E6011 400 mg did not show clear efficacy in ACR20 response rate at Week 12 compared with placebo in Japanese RA subjects with inadequately responding to biologics. E6011 was well tolerated with no notable safety concerns at doses of 200 to 400 mg when administered subcutaneously every 2 weeks for up to 102 weeks.

Yes

https://www.eisai.com/company/business/research/clinical/index.html

Eisai Co., Ltd.

eisai-chiken_hotline@hhc.eisai.co.jp

Eisai Co., Ltd.

eisai-chiken_hotline@hhc.eisai.co.jp

completed

Nov. 26, 2016

Interventional

This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study in rheumatoid arthritis participants inadequately responding to biologics.

treatment purpose

2

(1)Diagnosed with rheumatoid arthritis (RA) under the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) criteria >=12 weeks before informed consent
(2)Received biologics treatment under approved dosage and administration for >=12 weeks but discontinued it before screening because of inadequate response
(3)History of biologics treatment should be limited to 2 agents among adalimumab, infliximab, golimumab, certolizumab pegol, etanercept, tocilizumab, and abatacept (including biosimilars).
(4)Presented >=6 tender joints (out of 68 joints) and >=6 swollen joints (out of 66 joints) in the Screening and Observation Phases
(5)Can continue stable dose regimen of methotrexate at 6 to 16 milligrams (mg)/week from 4 weeks before starting the study treatment until completion of the Extension Phase (or until study discontinuation)
(6)C-reactive protein (CRP) level >=0.6 mg/deciliter (dL) or erythrocyte sedimentation rate (ESR) >=28 millimeters per hour (mm/hr) in the Screening Phase
(7)Weighs >=30 kilograms (kg) and <=100 kg in the Screening Phase
(8)Has voluntarily consented, in writing, to participate in this study. If a participant is below the age of 20, also consented, in writing by a legally acceptable representative.
(9)Has been thoroughly briefed on the conditions for participation in the study, is able to understand, and is willing and able to comply with all aspects of the protocol

(1)Any history or complication of inflammatory arthritic disorder other than RA or Sjogren's syndrome
(2)Meets the ACR 1991 Revised Criteria for the Classification of Global Functional Status in RA Class IV in the Screening Phase
(3)Received immunoglobulin preparations or blood products within 24 weeks before starting the study treatment
(4)Received a live vaccine within 12 weeks before starting the study treatment, or is planning to receive
(5)Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, or renal disease) that could affect the participant's safety or interfere with the study assessments in the opinion of the investigator or subinvestigator
(6)Complication of uncontrolled disorders such as acute cardiac infarction, unstable angina, brain infarct, or symptomatic intracerebral hemorrhage
(7)History of severe allergy (shock or anaphylactoid symptoms)
(8)History or current clinical condition of malignant tumor, lymphoma, leukemia, or lymphoproliferative disease, except for skin carcinoma (epithelial carcinoma or basal cell carcinoma) and cervix carcinoma which has completely excised and without metastasis or recurrence for more than 5 years before informed consent
(9)Immunodeficiency or history of human immunodeficiency virus (HIV) infection
(10)Infection requiring hospitalization or intravenous administration of antibiotics or disease requiring administration of antivirus drugs (e.g., herpes zoster) within 4 weeks before starting the study treatment
(11)History of tuberculosis or current complication of active tuberculosis
(12)History of clinically important vasculitis
(13)Tested positive for any of the following in the Screening Phase: HIV, hepatitis B virus surface antigen (HBs antigen), hepatitis B virus surface antibody (HBs antibody), hepatitis B virus core antibody (HBc antibody), hepatitis B virus deoxyribonucleic acid (HBV DNA), hepatitis C virus antibody (HCV antibody), human T-lymphotrophic virus Type I antibody (HTLV-1 antibody), or syphilis
(14)Positive in tuberculosis test (QuantiFERONTB Gold Test or T-SPOT.TB Test) in the Screening Phase
(15)Findings indicating a history of tuberculosis on chest x-ray in the Screening Phase
(16)Neurological findings such as paralysis, visual impairment, or language disorder in the Screening Phase
(17)Demonstrated prolonged QTcF (Fridericia's Correction Formula) interval (>450 milliseconds [ms]) in repeated electrocardiogram examinations
(18)Females of childbearing potential who have a positive pregnancy test in the Screening or Observation Phase or are breastfeeding
(19)Females of childbearing potential who:
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 70 days after study drug discontinuation
Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from being sexually active during the study period or for 70 days after study drug discontinuation
Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 70 days after study drug discontinuation.
(NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]).
(20)Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period or for 70 days after study drug discontinuation). No sperm donation is allowed during the study period or for 70 days after study drug discontinuation.
(21)Scheduled for surgery during the study
(22)Currently enrolled in another clinical study or used any investigational drug or device within 28 days (or 5* the half-life, whichever is longer) before informed consent
(23)Has been treated with E6011 or any biologics for use in RA that has not been approved
(24)Use of a psychotropic agent as recreational purpose other than therapeutic purpose
(25)Any history of a medical condition or a concomitant medical condition that in the opinion of the investigator or subinvestigator would compromise the participant's ability to safely complete the study

Both

Rheumatoid Arthritis Inadequately Responding to Biologics

investigational material(s)
Generic name etc : E6011
INN of investigational material : -
Therapeutic category code : 399 Agents affecting metabolism, n.e.c.
Dosage and Administration for Investigational material : Experimental: E6011 400 mg In the Treatment Phase (24 weeks), subjects will receive E6011 400 mg at Weeks 0, 1, 2, and every 2 weeks subsequently until Week 10 and then E6011 200 mg or 400 mg every 2 weeks between Weeks 12 and 22 in a double-blind manner. The Extension Phase is up to Week 104 from the starting of the study treatment, and subjects will receive an open-label E6011 200 mg every 2 weeks until Week 102. When subjects insufficiently respond to the treatment or when their disease relapses in the Extension Phase, a dose escalation will be allowed only once.

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Experimental: Placebo In the Treatment Phase (24 weeks), subjects will receive placebo at Weeks 0, 1, 2, and every 2 weeks subsequently until Week 10 and then placebo or E6011 200 mg every 2 weeks between Weeks 12 and 22 in a double-blind manner. The Extension Phase is up to Week 104 from the starting of the study treatment, and subjects will receive an open-label E6011 200 mg every 2 weeks until Week 102. When subjects insufficiently respond to the treatment or when their disease relapses in the Extension Phase, a dose escalation will be allowed only once.

safety
efficacy
American College of Rheumatology 20 (ACR20) response rate at Week 12 [ Time Frame: Week 12 ] [ Designated as safety issue: No ]

efficacy
-

Oct. 03, 2016