Efficacy and Safety of Olokizumab in Patients With Polymyalgia Rheumatica (PROMISE)

An International, Multicenter, Randomized, Double-blind, Placebo-controlled Phase 3 Study of the Efficacy and Safety of Olokizumab in Patients With Polymyalgia Rheumatica

The primary objective of the study is to evaluate the efficacy of olokizumab (OKZ) 64 mg administered subcutaneously every 2 weeks compared with placebo in participants with polymyalgia rheumatica (PMR). The secondary objectives are to evaluate the steroid-sparing effect, inflammatory markers, safety, tolerability, immunogenicity, and pharmacokinetics of OKZ in participants with PMR compared with placebo. The exploratory objectives are to evaluate OKZ efficacy in selected participant subgroups, biomarkers of bone metabolism, pharmacodynamic parameters, glucocorticoid-related effects, and quality of life in participants with PMR compared with placebo

This is a Phase 3, double-blind, placebo-controlled, parallel-group study. A total of 120 participants with active polymyalgia rheumatica are planned to be randomized in a 1:1 ratio to one of the following treatment arms:

• OKZ arm: subcutaneous injections of OKZ 64 mg every 2 weeks
• Placebo arm: subcutaneous placebo injections every 2 weeks

Participants may continue stable methotrexate or leflunomide therapy during the screening and treatment periods

The treatment period lasts 16 weeks, during which participants visit the study center every 2 weeks for safety assessments and evaluation of treatment response. Starting from Week 6 (Visit 4), in participants with PMR-AS <10, a gradual weekly glucocorticoid taper is initiated, decreasing by 2.5 mg/week until a dose of 5 mg/day is reached, followed by reductions of 1.25 mg/week until complete discontinuation of glucocorticoids. If complete discontinuation is not feasible at a dose of 5 mg/day or lower, tapering may be paused based on the investigator's clinical judgment

Participants who do not enter an open-label extension study after completion of the 16-week double-blind treatment period enter a 22-week safety follow-up (SFU) period. During follow-up, participants attend clinic visits at 2, 10, and 22 weeks after the end-of-treatment (EOT) visit for SFU assessments. The total duration of the study for participants is approximately 42 weeks

Inclusion Criteria:

• Presence of written informed consent (IC) signed by the participant

• Confirmed diagnosis of polymyalgia rheumatica (PMR) according to the 2012 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria

• At the time of randomization, participants must meet one of the following conditions:

  1. stable glucocorticoid (GC) therapy at a dose of ≤20 mg/day prednisone equivalent for at least 2 weeks; or
  2. no glucocorticoid (GC) therapy for at least 2 weeks

• PMR flare within 3 days prior to randomization meeting the following criteria:

  1. Polymyalgia Rheumatica Activity Score (PMR-AS) ≥10;
  2. C-reactive protein (CRP) level ≥5 mg/L in the absence of alternative causes of elevation

Exclusion Criteria:

• Presence of cranial symptoms of giant cell arteritis (GCA) within 12 weeks prior to screening

• Presence of concomitant fibromyalgia or neuropathic pain syndrome

• Presence of other systemic rheumatic diseases, including rheumatoid arthritis, Sjögren's syndrome, vasculitis (except GCA), dermatomyositis/polymyositis, and others

• Presence of concomitant conditions associated with chronic pain syndrome that could potentially interfere with efficacy assessments in the study

• Bilateral limitation of upper limb elevation above 90° (elevation of upper limbs [EUL] score 1) not related to active polymyalgia rheumatica (PMR)

• Requirement for systemic glucocorticoid (GC) therapy for conditions other than PMR

• Prior treatment with interleukin-6 (IL-6) inhibitors (including OKZ) or IL-6 receptor inhibitors, except when used for treatment of coronavirus disease 2019 (COVID-19). For participants treated with these agents for COVID-19, the last administration must have occurred at least 6 months prior to screening

• Intravenous, intra-articular, periarticular, or intramuscular glucocorticoid administration within 4 weeks prior to screening

• Use of the following medications prior to screening:

  1. Janus kinase (JAK) inhibitors (including tofacitinib, baricitinib, or upadacitinib) within 4 weeks;
  2. Tumor necrosis factor-alpha (TNF-α) inhibitors: etanercept within 2 weeks; adalimumab, golimumab, certolizumab, or infliximab within 8 weeks;
  3. Rituximab within 12 months prior to screening;
  4. Abatacept within 8 weeks prior to screening;
  5. Interleukin-1 (IL-1) inhibitors: canakinumab within 12 weeks; anakinra within 72 hours; goflikicept within 8 weeks;
  6. Interleukin-17 (IL-17), interleukin-23 (IL-23), or interleukin-12/23 (IL-12/23) inhibitors: secukinumab, bimekizumab, ustekinumab, tildrakizumab, risankizumab, mirikizumab, or netakimab within 16 weeks; ixekizumab, brodalumab, or guselkumab within 12 weeks;
  7. Other genetically engineered biologic therapies within at least 5 half-lives prior to screening;
  8. Alkylating agents, including cyclophosphamide, within 24 weeks;
  9. Cyclosporine, azathioprine, or mycophenolate mofetil within 4 weeks

• Initiation, discontinuation, or dose modification of methotrexate or leflunomide within 12 weeks prior to screening

• Modification of other PMR therapy within 4 weeks or 5 half-lives prior to screening, whichever is longer

• Administration of a live vaccine within 6 weeks prior to baseline assessment or planned live vaccination during the study

• Participation in another clinical study within 30 days prior to baseline assessment or within 5 half-lives of the investigational product used in that study, whichever is longer

• Previous participation in this study (participant randomized and received at least one dose of investigational product)

• Hematologic disorders, including platelet, leukocyte, or erythrocyte disorders (e.g., sickle cell anemia, myelodysplastic syndrome, hematologic malignancies, multiple myeloma, hemolytic anemia, or thalassemia) or coagulopathies

• Current malignancy or history of malignancy within the past 5 years, except adequately treated cervical carcinoma in situ, basal cell carcinoma, or squamous cell skin carcinoma treated at least 1 year prior to screening (with no more than 3 excised skin cancers within 5 years prior to screening)

• Screening laboratory abnormalities including:

  1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥1.5 × upper limit of normal (ULN);
  2. Platelet count <100 × 10^9/L (<100,000/mm^3);
  3. White blood cell count <3.5 × 10^9/L;
  4. Absolute neutrophil count <2,000 × 10^6/L (<2,000/mm^3)

• Positive human immunodeficiency virus (HIV) test at screening or history of HIV infection

• Screening evidence of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection:

  1. Participants previously treated for HCV infection with undetectable viral load for at least 6 months may be eligible with specialist approval;
  2. Participants positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBc) are excluded;
  3. Participants with isolated positive hepatitis B surface antibody (anti-HBs) and prior vaccination history may be eligible

• History of active tuberculosis (TB); suspected or confirmed active TB; radiographic evidence of active pulmonary TB at screening; or TB risk factors including recent incarceration, homelessness, occupational exposure, or close contact with individuals with active TB within 1 year prior to randomization

• History of latent tuberculosis infection (LTBI) without adequate treatment regardless of QuantiFERON-TB/T-SPOT.TB results, or positive QuantiFERON-TB/T-SPOT.TB test at screening. Participants may be re-screened if active TB is excluded by a qualified specialist, at least 30 days of prophylactic therapy for LTBI have been completed, and the participant agrees to complete the recommended course of therapy

• Participants with the following cardiovascular diseases:

  1. Decompensated congestive heart failure or New York Heart Association (NYHA) Class III or IV heart failure;
  2. Resistant or uncontrolled hypertension requiring adjustment of antihypertensive therapy;
  3. Severe or uncontrolled cardiovascular disease, including acute coronary syndrome, stroke, or transient ischemic attack within 3 months prior to screening

• Any severe and/or uncontrolled concomitant disease (including uncontrolled severe hyperlipidemia, uncontrolled diabetes mellitus, respiratory, hepatic, renal, gastrointestinal, endocrine, dermatologic, neurologic, psychiatric, hematologic, immunologic, or immunodeficiency disorders) that, in the investigator's opinion, may interfere with study participation or interpretation of study results

• Acute infection at screening, exacerbation of chronic infection, infection requiring oral antimicrobial therapy within 4 weeks prior to screening, injectable antimicrobial therapy within 6 weeks prior to randomization, or severe/recurrent infections requiring hospitalization within 6 months prior to randomization

• History within 6 months prior to screening of disseminated herpes zoster infection, herpes zoster-associated encephalitis or meningitis, or other severe herpes zoster infections not resolving without treatment

• Any other clinically significant chronic infection (including invasive fungal infections or osteomyelitis) that, in the investigator's opinion, may increase the risk of infectious complications during the study

• Planned surgical intervention during the study, surgery within 4 weeks prior to screening (except minimally invasive diagnostic procedures), or incomplete recovery from surgery in the investigator's opinion

• History or presence of diverticulitis, ulcerative colitis, Crohn's disease, gastrointestinal perforation, or other gastrointestinal conditions associated with increased risk of perforation

• Alcohol or substance abuse in the investigator's opinion

• Pregnancy, breastfeeding, or planned pregnancy during the study or within 6 months after the last dose of investigational treatment

• Women of childbearing potential unwilling to use highly effective contraception during the study and for 6 months after the last dose of investigational product, or men with partners of childbearing potential unwilling to use highly effective contraception during the study and for at least 3 months after the last dose of investigational product

• Known hypersensitivity to OKZ, any component of the investigational product, or placebo

• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies

• Unwillingness or inability to comply with study procedures required by the protocol

• Any medical, psychiatric, or laboratory abnormality that, in the investigator's opinion, may increase the risk associated with study participation or interfere with interpretation of study results, making the participant unsuitable for the study