Phase II Interventional Study Evaluating Efficacy and Safety of Secukinumab in Active Severe Takayasu Patients

Prospective, Bayesian, Randomized, Controlled, Open-label, Parallel-group, Phase II Interventional Study Evaluating Efficacy and Safety of Secukinumab in Active Severe Takayasu Patients

Takayasu's arteritis (TAK) is a large vessel vasculitis preferentially affecting the aorta and its main branches, leading to wall vessels thickening, fibrosis, stenosis, and occlusion. Patients with TAK have a high morbidity rate, 50% will relapse and experience a vascular complication within 10 years from diagnosis. TAK inflammation is mediated by T cells and macrophages. Pro-inflammatory Th1 and Th17 cells are dominant infiltrates in the vascular walls, producing IFN-γ and IL-17 to drive the systemic and vascular manifestations of TAK. Currently, TAK patients are principally treated with non-specific steroids, which are associated with potential side effects, especially when used for a long-time course. Steroid treatment preferentially target innate cytokines, such as IL-1β, IL-12, and IL-6 but have little effect on tissue-residing T cells. Novel approach needs to eliminate all T-cell effectors. The use of classical immunosuppressive drugs (IS) (methotrexate, Leflunomide) and biotherapies are prescribed earlier in the management of the disease in order to improve remission, spare corticosteroids and reduce relapses. Data from observational series report remission in 37-76% of cases with anti TNF alpha and 68% with Tocilizumab. However, a placebo-controlled trial failed to show superiority of tocilizumab in TAK.

To date, no immunomodulatory treatment has been approved for the management of TAK and corticosteroids sparing remains a major challenge in this disease. Our team has demonstrated the key role of Th1 and Th17 responses in the pathophysiology of TAK. We found that Th17 and Th1 pathways contribute to the systemic and vascular manifestations of TAK and glucocorticoid treatment suppresses Th1 cytokines but spares Th17 cytokines in patients with TAK. Other teams further confirmed the significant increase in Th17 axis in TAK, and its correlation with disease activity, clinical relapse and arterial fibrosis. Secukinumab is a fully human monoclonal antibody that selectively inhibits IL-17A. Secukinumab received approval for adult treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, active non-radiographic axial spondyloarthritis, and active ankylosing spondylitis in numerous countries, including the EU and the USA Recently, a phase II clinical trial assessing the efficacy and safety of secukinumab vs placebo in combination with glucocorticoid taper regimen in giant cell arteritis showed that patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, and is now being studied in a phase 3 study (NCT04930094).Secukinumab was well tolerated with no new safety concerns. In TAK, recent observational data suggested that secukinumab might be an effective alternative to TNFi in severe TAK patients.

Inhibition of IL-17A could represent a potential new therapeutic option for the treatment of severe TAK disease, hence the need for a prospective study to evaluate secukinumab in the management of active severe TAK.

Inclusion Criteria:

1. Patients ≥15 years

2. Signed informed consent

3. Affiliation with the French national social security system.

4. Adequate and effective contraceptive measures based on CTFG update of recommendations version 1.1 dated 21-Sep-2020

5. For women of childbearing age, a negative serum or urinary pregnancy test.

6. Diagnosis of TAK based on the 2022 American College of Rheumatology/EULAR and/or Ishikawa criteria modified by Sharma (Appendix 1) for patients with age ≥ 18 years and based the PRINTO/EULAR/PReS criteria for patients with age between 15 and 17 years

7. Active TAK defined by a National Institutes of Health [NIH] score >1 in the past 2 months (Appendix 2)

8. Severe TAK, defined as either refractory/relapsing disease or by the presence of severe arterial involvement at baseline.

   1. refractory/relapsing disease is defined as the recurrence or persistence of vasculitis activity confirmed by a specialized physician despite adequate corticosteroid tapering (i.e., inability to taper corticosteroids below 1mg/kg/day within 1 month due to disease activity, or inability to taper corticosteroids below 10mg/day within 6 months, or inability to discontinue corticosteroids after 1 year of treatment, or relapse of disease during/after gradual decrease of corticosteroids therapy) and/or immunosuppressive treatment (e.g., azathioprine, methotrexate, mycophenolate mofetil, leflunomide)
   2. Severe arterial involvement is defined by the presence of stroke, retinopathy, coronary artery stenosis, pulmonary artery stenosis, mesenteric arteries or celiac trunk stenosis, renal artery stenosis or limb ischemia at baseline.

9. Patients must be eligible to receive prednisone (or equivalent) 10-50 mg daily at baseline. Oral corticosteroids must be at a stable dose for at least 2 weeks prior to the first administration of study drug at Day 0.

10. Absence of chronic active infections. Patients with a positive TB test may participate in the study if further work up (according to local practice/guidelines) conclusively establishes that the patient has no evidence of active tuberculosis. If the test result is indeterminate, the investigator may repeat the test once or may proceed directly to perform the work-up for TB as per local procedure. If presence of latent tuberculosis is established then treatment according to local country guidelines must be initiated prior to randomization

Exclusion Criteria:

1. Inability to comply with study guidelines or provide informed consent

2. 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 human Chorionic Gonadotropin (hCG) laboratory test.

   Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 6 months after stopping of investigational drug. Highly effective contraception methods include:

   • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (e.g., calendar, ovulation, symptotherma), post- ovulation methods) and withdrawal are not acceptable methods of contraception.
   • Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
   • Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
   • Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.

   In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

   Contraception should be used in accordance with locally approved prescribing information of concomitant medications administered.

   Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women are considered of not child-bearing potential if • they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral 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 If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the informed consent form (ICF).

   Sexually active males, unless they agree to use barrier protection during intercourse with a woman of child-bearing potential, while taking study treatment. As condom use alone has a reported failure rate exceeding 1% per year, it is recommended that female partners of male study participants use a second method of birth control.

   Globally, for all sexually active males, contraception should be used in accordance with the locally approved prescribing information of concomitant medications administeredPregnancy or breastfeeding;

3. History of severe immunosuppression, positive serology for HIV or positive HBsAg

4. Infection requiring treatment with intravenous antibiotics within 2 weeks prior to the inclusion & randomization visit

5. Contraindication or hypersensitivity to Secukinumab, TNF inhibitors or tocilizumab, corticosteroids, TB prophylactic treatment or to any of their excipients. For contra-indications related to the standard of care medications refer to the summary of each Product Characteristics (SmPC) refer to EMA links (7.1.2)

6. Have received live vaccines within 3 months prior to inclusion

7. Indication to initiate infliximab, adalimumab, tocilizumab, secukinumab for another active disease than Takayasu arteritis (retained)

8. Use of the following systemic treatments during the specified periods

   1. Treatment with biologic therapy secukinumab, within 3 months prior to the inclusion & randomization visit
   2. Treatment with any systemic alkylating agents within 3 months prior to the inclusion & randomization visit (e.g., cyclophosphamide, chlorambucil)

9. Presence of any of the following on-ongoing and on-treatment disease processes (vasculitis and auto- immunes disease):

   Microscopic polyangiitis

   • Granulomatosis with polyangiitis Eosinophilic granulomatosis with polyangiitis
   • Polyarteritis nodosa o Cogan's syndrome
   • Behcet's disease
   • Kawasaki's disease
   • Atypical mycobacterial infections
   • Deep fungal infections o Lymphoma, lymphomatoid granulomatosis, or other type of malignancy that mimics vasculitis o Cryoglobulinemic vasculitis
   • Systemic lupus erythematosus
   • Rheumatoid arthritis o Mixed connective tissue disease or any overlap autoimmune syndrome
   • Known constitutive immunodeficiency

10. History of malignancy in the last 5 years (except adequately treated basal or squamous cell carcinoma of the skin)

11. Severe renal impairment (creatinine clearance <30mL/min/1.73m2)

12. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as Aspartate Aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) or serum bilirubin. The investigator should be guided by the following criteria:

    1. SGOT (AST) and SGPT (ALT) may not exceed 3 × the upper limit of normal (ULN). A single parameter elevated up to and including 3 × ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization, to rule-out laboratory error.
    2. Alkaline phosphatase may not exceed 4 × ULN. An elevation up to and including 4 × ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization, to rule-out laboratory error.
    3. Total bilirubin may not exceed 4 × ULN. If the total bilirubin concentration is increased above 4 × ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin

13. Blood count abnormality:

    1. Platelet count < 50 x 10.3/mm3
    2. Neutropenia < 1000/mm3
    3. Haemoglobin < 8 g/dl