Phase 2 Placebo-controlled Study to Assess the
Safety, Efficacy, & PK of ESK-001 in SLE
Scientific Title of Study
A PHASE 2, MULTICENTER, MULTINATIONAL,
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED
STUDY TO ASSESS THE SAFETY, EFFICACY, AND
PHARMACOKINETICS OF MULTIPLE DOSE LEVELS OF
ESK-001 IN ADULT PATIENTS WITH SYSTEMIC LUPUS
ERYTHEMATOSUS
Syneos Health India Private Limited ,4th Floor, Block-2, DLF Downtown, Commercial Site, Block V, DLF City Phase III,Sector-25-A, Gurgaon-122002, Haryana, India
Countries of Recruitment
Argentina Bulgaria Chile Colombia Croatia Denmark Georgia Germany Hungary India Mexico Peru Philippines Poland Republic of Korea Romania Spain Taiwan United Kingdom United States of America
Medanta-The Medicity - Medanta Institute of Education & Research (MIER)
Department of Rheumatology Medanta The Medicity Sector 38 Gurugram Haryana 122001 Gurgaon HARYANA
9810904592
guptarajiva@hotmail.com
Dr Ranjan Gupta
All India Institute of Medical Sciences, New Delhi
Ansari Nagar, New Delhi. PIN Code - 110029, India New Delhi DELHI
9899390715
dr.guptaranjan@gmail.com
Dr Vishnu Sharma
Avron Hospitals Pvt. Ltd.
4, Shantiniketan Park, Nr. Sardar Patel Statue, Naranpura, Ahmedabad – 380013, Gujarat, India. Ahmadabad GUJARAT
9512445550
drvishnusharma@yahoo.co.in
Dr Chandrashekara Srikantiah
ChanRe Rheumatology Immunology Center Research CRICR
Clinical Research Department, CRICR , No.414/65, 20th Main, West of Chord Road, 1st Block, Rajajinagar, Bengaluru-560 010 Bangalore KARNATAKA
9845071151
chandrashekara_s@yahoo.com
Dr Dhaiwat Shukla
Gujarat University - Smt. N.H.L. Municipal Medical College - Sheth Vadilal Sarabhai General Hospital
Medicine department ,Gujarat University - Smt. N.H.L. Municipal Medical College - Sheth Vadilal Sarabhai General Hospital, Ellis Bridge Cross Road Ahmedabad, Gujarat, India , 380006 Ahmadabad GUJARAT
8980024107
dr.dhaiwatshukla89@gmail.com
Dr Smruti Ramteke
Jasleen hospital
Arthritis & Rheumatism clinic, 1 st floor, opposite to big bazar, phanchasheel square, Dhantoli Nagpur, 440012 Nagpur MAHARASHTRA
9823514680
sramteke@rediffmail.com
Dr Nilesh Patil
Lifepoint Multispecialty Hospital
Department of Rhematology, No. 145, Sr, 1, Mumbai Pune Bypass Rd, near Sayaji Hotel, Wakad, Pune, Maharashtra 411057 Pune MAHARASHTRA
9975259101
patilnj81@gmail.com
Dr Girish kakade
Medipoint Hospitals Pvt. Ltd.
Research Department ,Medipoint Hospitals Pvt. Ltd.
241/1 New D. P. road, Aundh, Pune-411007, Maharashtra, India Pune MAHARASHTRA
9021984612
drgirishk.medipoint@gmail.com
Dr Bankim Desai
Nirmal Hospital Pvt Ltd
Adult OPD ,Nirmal Hospital Pvt Ltd, Ring Road, Surat-395010, Gujarat, India Surat GUJARAT
9825136077
drbankim.desai@gmail.com
Dr Puja Srivastava
Panchshil Hospital
Clinical research Department,Near CanaraBank,Highway,Ramnagar,Sabarmati,Ahmedabad 380005Â Ahmadabad GUJARAT
8155891234
Dr.pujasrivastava@gmail.com
Dr Manish Rathi
Post Graduate Institute of Medical, Education and Research
Department of Nephrology ,AKU Ward Block C, Nehru Hospital,
Post Graduate Institute of Medical, Education and
Research ,Madhya Marg, Sector 12, Chandigarh, 160012ndia, Chandigarh CHANDIGARH
9216721287
drmanishrathi@gmail.com
Dr Amita Aggarwal
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Department of Clinical Immunology
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Rae Bareli Road, Lucknow,
Uttar Pradesh,India , 226014 Lucknow UTTAR PRADESH
9473584267
AA.AMITA@GMAIL.COM
Dr Avinash jain
Sawai Man Singh (SMS) Medical College - SMS Hospital
Department of Clinical Immunology & Rheumatology ,Sawai Man Singh (SMS) Medical College - SMS Hospital
J. L. N Marg, Jaipur, Rajasthan-302004,India Jaipur RAJASTHAN
8980005584
docavinashjain@gmail.com
Dr Reena Sharma
Shalby Hospitals
Clinical Research Department,Shalby Hospitals , 9th Floor, Clinical Research Department,
Shalby Hospital, Opp Karnavati Club, SG Highway, Ahmedabad , 380015 Ahmadabad GUJARAT
7940203115
reena142@gmail.com
Dr Vineeta Shobha
St. John’s Medical College Hospital
Dept. of Clinical Immunology & Rheumatology, Unit of Hope, 3rd Floor, Sarjapur Road, John Nagar, Bangalore – 560034, Karnataka, India Bangalore KARNATAKA
9845021146
Vineeta_shobha@yahoo.com
Dr Romi Shah
Unity Hospital
OPD, Unity trauma center and ICU , Nr. D.R World, OPP. Raghuvir business Empire Aai Mata Road , Parvat Patiya
Surat Gujarat 3950001
India Surat GUJARAT
Study drug to to be taken by mouth with a glass of water from Day 1 to week 48.
Comparator Agent
Placebo
To be taken by mouth with a glass of water from Day 1 to week 48
Inclusion Criteria
Age From
18.00 Year(s)
Age To
70.00 Year(s)
Gender
Both
Details
1. Able and willing to provide written informed consent (signed and dated) to participate in this
study and comply with all requirements in the study protocol
2. Males or females, age 18 to 70 years, inclusive, at the time of informed consent
3. Body mass index 18 to 40 kg/m2 and total body weight >40 kg (88 lbs).
Adequate peripheral venous access
5. Diagnosed with SLE ≥6 months prior to screening, fulfills the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria at the time of
screening, AND has at least one of the following:
i) Positive antinuclear antibody test at screening by immunofluorescent assay at the
central laboratory with titer ≥1:80;
ii) Elevated anti-dsDNA antibodies as determined by the central laboratory;
iii) Elevated anti-Smith antibody at screening as determined by the central laboratory; or
IV) C3 or C4 below the lower limit of normal as determined by the central laborator
6. During screening and prior to first administration of study drug, Central Review Team’s confirmation of the following:
6.a SLEDAI-2K Criteria: At screening the SLEDAI-2K score of ≥6. “Clinicalâ€
SLEDAI-2K score of ≥4 points. The “Clinical†SLEDAI-2K is the SLEDAI-2K
assessment score without the inclusion of points attributable to any urine or laboratory
results including immunologic measures:
1. Includes points from the following clinical components: arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, and vasculitis
2. Excludes points attributable to fever, an SLE headache, and organic brain syndrome
6b BILAG-2004 Index Level Criteria: At least 1 of the following:
1. BILAG-2004 Index level A disease in at least 1 body/organ system
1.a Excludes scores from Lupus Headache
1.b BILAG-2004 Index level B disease in more than 1 body/organ system
2.a Excludes scores from Lupus Headache
2.b PGA score of >1.0 on a 0 to 3 VAS at screening
7. Clinical SLEDAI-2K score ≥4 points with skin involvement prior to first administration of study drug
8. Currently receives at least 1 of the following:
8.a A stable dose of oral corticosteroid (≤40 mg/day prednisone or equivalent) for a
minimum of 2 weeks prior to signing of the informed consent form (ICF) at the
Screening Visit. The dose of oral corticosteroid the patient is taking should not
increase between screening and Week 0 (Day 1).
i) If corticosteroid is the only medication used for SLE activity, the daily dose
must have been ≥10 mg and ≤40 mg prednisone equivalent for a minimum of 8
weeks prior to screening, and stable ≥10 mg and ≤40 mg for at least 2 weeks
prior to screening.
8.b And/or antimalarial treatment (e.g., hydroxychloroquine, chloroquine, quinacrine),
8.c And/or no more than 1 of the following conventional DMARDS:
i) Azathioprine ≤200 mg/day
ii) Mycophenolate mofetil ≤2 g/day or mycophenolic acid ≤1.44 g/day
iii) Oral, subcutaneous, or intramuscular (IM) methotrexate ≤20 mg/week.
9. Negative serum ß-human chorionic gonadotropin (ß-hCG) test at screening (women of
childbearing potential [WOCBP] only)
9.a WOCBP must agree to adhere to highly effective methods of contraception for the
entirety of the study and for 30 days after the last dose of study drug
9.b Nonsterilized male patients who are sexually active with WOCBP must agree to use
highly effective methods of contraception for the entirety of the study and for 90 days
after the last dose of study drug
10. At Day 1, prior to randomization
i) “Clinical†SLEDAI-2K score of ≥4 points
ii) OC dose stable for at least 2 weeks
iii) WOCBP must have a negative urine pregnancy test prior to administration of IP
ExclusionCriteria
Details
1. Any acute or chronic illness/condition or evidence of an unstable clinical condition that, in the Investigator’s judgment, will substantially increase the risk to the patient if he or she
participates in the study.
2. Current or history within 1 year of screening of alcohol or drug abuse (excluding cannabis) based on Investigator’s clinical judgment.
3. Pregnant, lactating, or planning to get pregnant during the study period and for 1 month after
study completion or discontinuation
4. Patients with QTcF >450 msec on ECG at screening
5. Unstable cardiovascular disease, defined as a recent clinical deterioration (eg, unstable angina,rapid atrial fibrillation) or a cardiac hospitalization within the last 3 months.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
On-site computer system
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To compare the effect on disease activity
measured by the proportion of patients
achieving British Isles Lupus Assessment
Group (BILAG)-based Composite Lupus
Assessment (BICLA) response at Week 48
between doses of ESK-001 & placebo
up to 48 weeks
Secondary Outcome
Outcome
TimePoints
To assess the safety & tolerability of
multiple dose levels of ESK-001
To compare the effect on disease activity
measured by the proportion of patients
achieving an SLE Responder Index of ≥4
(SRI[4]) response at Week 48
Composite endpoint SRI(4), defined by the
following criteria:
• Reduction from baseline of ≥4 points in
the SLEDAI-2K, and
• No new BILAG A or more than
1 BILAG B domain score, and
• No deterioration from baseline ≥0.3 in
the PGA
To compare corticosteroid use in patients at
Week 48
Proportion of patients who achieve a
corticosteroid dose of ≤5 mg/day prednisone
equivalent by Week 40 & maintain
through Week 48
• AUC analysis of Corticosteroid use by
Week 48
To compare the effect on cutaneous disease
activity measured by the proportion of
patients with a CLASI activity score of ≥8 at
baseline achieving ≥ 50% reduction in the
CLASI activity score at Week 48 between
doses of ESK-001 & placebo
50% reduction in CLASI activity score
compared to baseline defined by the
following criteria:
• Baseline CLASI activity score ≥8
• ≥50% reduction of CLASI activity score
at Week 48 compared to baseline
To compare the effect on disease activity
measured by the proportion of patients
achieving BICLA responses at Week 48
between doses of ESK-001 & placebo in
the interferon gene signature (IGS) high
subgroup
BICLA response described above
To compare the Lupus Low Disease Activity
State (LLDAS) response between doses of
ESK-001 & placebo at Week 48
LLDAS as measured by achieving the following:
• SLEDAI-2K ≤4, with no activity in
major organ systems & no hemolytic
anemia or gastrointestinal activity,
• No new lupus disease activity compared
with the previous SLEDAI-2K
assessment
• PGA ≤1
• Current prednisone (or equivalent) dose
≤7.5 mg daily
• Well-tolerated standard maintenance doses
of immunosuppressive drugs and approved
biological agents
To compare the annualized flare rate through
Week 48
Annualized flare rate with flare defined as
≥ 1 BILAG A or ≥ 2 BILAG B scores due to
items rated as new or worse
To compare the effect on health-related
quality of life (HRQOL) between doses of
ESK-001 & placebo
Difference between baseline (Day 1) and
Week 48 in the Short Form 36 Health
Survey, version 2 acute (SF-36 v.2) acute
physical and/or mental component summary
scores
To compare disease-specific QoL between
doses of ESK-001 & placebo
Difference between baseline (Day 1) and
Week 48 in the Lupus QoL
To compare Fatigue measured by FACIT-F
between doses of ESK-001 & placebo
Difference between baseline (Day 1) and
Week 48 in FACIT-F
To compare patient global assessment of
disease activity (PtGA) between doses of
ESK-001 & placebo
Difference between baseline (Day 1) and
Week 48 in PtGA
Target Sample Size
Total Sample Size="388" Sample Size from India="40" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems and presents in a variety of clinical features. The cause of SLE development is unknown, and both genetic and environmental factors appear to contribute to disease susceptibility. The systemic effects of SLE lead to many different symptoms, including arthritis and neurological, renal, cutaneous, and gastrointestinal disorders. These effects have a substantial impact on patient quality of life (QoL). Patients with SLE report decreased vitality and general health. SLE can also lead to loss of employment, lower health-related QoL, and a 10-year decrease in lifespan (American College of Rheumatology). Current treatment options such as chronic oral corticosteroids (OCs) and immunosuppressive agents also cause side effects that further contribute to SLE disease burden. There remains a large, unmet medical need to improve treatment options for patients with SLE. Development of targeted therapies for the treatment of SLE will improve long-term patient prognosis and decrease toxic effects associated with current therapies.The pathogenesis of SLE is complex, involving the interplay of genetic and environmental factors, resulting in an autoimmune reaction where the innate and adaptive immune systems direct an inappropriate immune response to nucleic acid-containing cellular particles. The immune system activation, along with a dysregulated repair response orchestrates the tissue damage associated with SLE. Certain cytokines produced by both innate and adaptive immune system cells promote inflammation and contribute to tissue damage. Type I interferons (IFNs), IFNγ, interleukin (IL)-6, IL-12, IL-21, and IL-23 mediate inflammation by altering the function of local tissue cells and activating T cells, B cells, macrophages, and dendritic cells in target organs.
The search for effective small molecules led to the discovery of tyrosine kinase 2 (TYK2) inhibitors. TYK2 is required for signaling through IFN-α, IL-12, and IL-23. Importantly, TYK2 has also been validated as a therapeutic target by studies examining the use of oral TYK2 inhibitors in Phase 3 studies in psoriasis, as well as a Phase 2 study in SLE with deucravacitinib. Based on available clinical data it appears these inhibitors’ specificity for TYK2 avoids the safety liabilities associated with Janus kinase (JAK) inhibitors.
Based on its ability to inhibit key signaling pathways driving immune activation and tissue damage, ESK-001 has the potential to downregulate inflammation and reduce tissue damage in SLE.