A Study to Assess the Safety and Efficacy of Different Doses of ELV001 to Treat Active Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate and Tumor Necrosis Factor Inhibition (START SYNERGY)

The study has 4 study arms: placebo, 25mg, 75mg and 125mg. The study includes a 4 weeks screening period, a double blind placebo controlled period (weeks 0 to 12), a treatment extension (weeks 12 to 24) and a 4 week safety follow-up.

Inclusion criteria

• Provided written informed consent to participate to the study and are able and willing to adhere to the study protocol.
• Male or female, 18 to 75 years of age, at the time of signing the informed consent.
• Body mass index (BMI) between 18.5 and 32.0 kg/m2 and minimum weight of 50 kg at the Screening Visit.
• Have a diagnosis of adult onset RA and fulfill the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria (Aletaha et al. 2010) for at least 6 months prior to Screening.
• Have active RA defined by a DAS28-CRP ≥ 3.2 and the presence of ≥ 3 swollen joints (based on 66 joint count) and ≥ 3 tender joints (based on 68 joint count) at Screening and Baseline. The distal interphalangeal joint should be evaluated but not included in the total count to determine eligibility.
• Have C-reactive protein (CRP) ≥ upper limit of normal (ULN) at Screening.
• Have adequate hematologic function at Screening AND at Baseline.
• Have adequate liver and renal function at Screening.
• Are currently treated with MTX (methotrexate) with folic acid supplementation according to local standard-of-care. The maximum dose of MTX is 25 mg/week for oral use and 20 mg/week for parenteral use. The minimum dose is 15 mg/week, except in case of intolerance or side effects when doses of 7.5 mg/week or above are acceptable. MTX should have been used for at least 6 months, of which at least 3 months at a stable dose.
• Are currently treated with a TNFi for at least 6 months, of which at least 3 months at a stable dose. Participants should have demonstrated a partial response to the TNFi, as evidenced by the Investigator or treating physician based on DAS28-CRP, SDAI, CDAI or any other measure of disease activity as per local treatment guidelines.
• The following therapies for RA are permitted during the study, if the dose is stable for ≥ 4 weeks prior to Screening: hydroxychloroquine up to 400 mg/day, oral prednisone ≤ 7.5 mg daily or equivalent corticosteroid dose. Prior treatment with other csDMARDs, bDMARDs, or tsDMARD is permitted as long as these treatments have been stopped at least 2 months prior to Screening, with exception of cell depleting therapies (eg, rituximab), which should have been stopped at least 12 months prior to Screening.
• Female participants of childbearing potential must:

• Have a negative serum pregnancy test at Screening and a negative urine pregnancy test within 24 hours prior to first dosing.
• Use highly effective contraception from signing the informed consent until at least 90 days after the last dosing.
• Not donate ova from signing the informed consent until at least 90 days after the last dosing.
• Male participants must use condoms and partners of childbearing potential must use highly effective contraception until at least 90 days after the last dosing. Male participants must not donate sperm until at least 90 days after the last dosing

Exclusion criteria

• Class IV RA according to ACR revised response criteria.
• Have been treated with more than 1 previous bDMARDs or tsDMARDs, excluding the current TNFi.
• Has a secondary non-response to the TNFi due to anti-drug antibodies, as assessed by the Investigator.
• Have a dose change of MTX or TNFi within the last 3 months before Baseline, or a dose change of hydroxychloroquine or oral prednisolone within the last 4 weeks before Baseline.
• Have oral prednisone > 7.5 mg/day equivalent or parenteral corticosteroids within the last 4 weeks before Baseline.
• Have intra-articular corticosteroids within the last 4 weeks before Baseline.
• Had any other csDMARD, bDMARD, or immunosuppressive drug in the last 2 months.
• Had any cell depletion therapy (eg, rituximab) in the last 12 months.
• Have QT interval corrected for heart rate (QTc) using Fridericia's correction (QTcF) > 450 ms for males or QTcF > 470 ms for females either at Screening or Baseline, based on safety 12-lead electrocardiogram (ECG). Have a Screening or Baseline ECG with second- or third-degree atrioventricular block, bundle branch block, arrhythmia (but not sinus arrhythmia or supraventricular premature beats), or illegible QT interval.
• Have evidence of interstitial lung disease (ILD) based on either medical history, clinical signs and symptoms, imaging and/or lung function test, independently of the etiology of the ILD.
• Have a condition which could interfere with drug absorption including but not limited to short bowel syndrome.
• Have presence of 1 or more significant concurrent medical conditions, which could interfere with the treatment and/or the study per Investigator judgment, including but not limited to the following: poorly controlled diabetes or hypertension; chronic kidney disease stage IIIb, IV, or V; symptomatic heart failure (New York Heart Association class II, III, or IV); myocardial infarction or unstable angina pectoris within the past 12 months prior to randomization; severe chronic pulmonary disease (eg, requiring oxygen therapy); and major chronic inflammatory disease or connective tissue disease other than RA.
• Have a history of chronic alcohol abuse, IV drug abuse or illicit drug abuse within 1 year before Screening.
• Have a diagnosis or history of malignant disease, with the exceptions of basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Have had any surgical procedure (except for minor surgery requiring local or no anesthesia and without any complications or sequelae) within 12 weeks prior to Screening, or any planned surgical procedure scheduled to occur during the study.
• Have received a Bacillus Calmette-Guerin (BCG) vaccination or BCG treatment within 12 months of Screening; or received any other live vaccine(s) (ie, live attenuated) within 3 months of Screening, or intend to receive a live vaccine during the study.
• Have had any of the following types of infection within 3 months of Screening or develops any of these infections before the randomization visit:

• Serious (requiring hospitalization, and/or parenteral antibiotic treatment),
• Opportunistic, as defined in (Winthrop et al. 2015) (note, Herpes zoster infection is considered active and ongoing until all vesicles are dry and crusted over),
• Chronic (duration of symptoms, signs, and/or treatment of 6 weeks or longer),
• Recurring (including, but not limited to herpes simplex, herpes zoster, recurring cellulitis, chronic osteomyelitis). Participants with recurrent nonserious infections such as cellulitis and uncomplicated orolabial and/or genital herpes may be enrolled at the discretion of the Investigator when deemed not to place participants at an increased risk of complications.
• Have any of the following:

• Human immunodeficiency virus (HIV) infection,
• Current infection with hepatitis B virus (HBV) (ie, positive for hepatitis B surface antigen and/or polymerase chain reaction [PCR] positive for HBV DNA),
• Current infection with hepatitis C virus (HCV) (ie, positive for HCV RNA),
• Active tuberculosis (TB).
• Have or have had latent TB infection (LTBI) that has not been treated with a complete course of appropriate therapy as defined by the World Health Organization (WHO) and/or the United States Centers for Disease Control and Prevention (CDC). Participants with LTBI who have been adequately treated are eligible for the study.
• Current or recent acute active infection (ie, participants must have had no symptoms and/or signs of confirmed or suspected infection and must have completed any appropriate anti-infective treatment within 30 days of Baseline); or fever of 100.5°F (38°C) or above at Screening or Baseline.
• Any other concurrent severe and/or uncontrolled medical, surgical or psychiatric and/or social condition which, in the view of the Investigator, could compromise the participant's safety or ability to participate in the study and make them unsuitable for participation.
• Use of other investigational medicinal products within 12 weeks or at least 5 half-lives (whichever is longer) before study drug administration.
• Women who are pregnant or breast-feeding or planning to become pregnant during the study.