A Study of the Efficacy and Safety of Secukinumab 300 mg in Patients With Thyroid Eye Disease (TED)

A Two-year Multi-center Phase 3 Study to Investigate the Efficacy and Safety of Secukinumab in Adult Patients With Active, Moderate to Severe Thyroid Eye Disease (ORBIT), With a Randomized, Parallel-group, Double-blind, Placebo-controlled, 16-week Treatment Period, and a Follow-up/Retreatment Period

Thyroid eye disease (TED) is a rare autoimmune, inflammatory disorder of the orbit and represents the most common extra-thyroidal manifestation of Graves' disease (GD). Several lines of evidence suggest an important role of interleukin-17A (IL-17A) in the pathogenesis of TED; increased levels of IL-17A have been detected in the serum and tears of patients with TED and IL-17A levels correlate with clinical activity of the disease. T-helper 17 cells (Th17 cells) (as well as other cellular sources of IL-17A, e.g., Tc17 cells) have been shown to infiltrate the orbital tissue of affected patients, producing IL-17A. IL-17A stimulates fibroblast activation, leading to retrobulbar tissue expansion and orbital fibrosis, which causes significant functional impairment. Secukinumab is a recombinant high-affinity fully human monoclonal anti-IL-17A antibody currently approved for the treatment of 3 inflammatory/ autoimmune diseases: moderate to severe plaque psoriasis (PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) (ankylosing spondylitis (AS) and non-radiographic axSpA). The purpose of this study was to demonstrate the efficacy and safety of secukinumab 300 mg subcutaneous (s.c.) in adults with active, moderate to severe TED.

This study consisted of the following 3 periods:

1. Screening period (Week -6 to Baseline):

   Participants' eligibility was assessed during the Screening period, which occurred for a maximum of 6 weeks.

2. Treatment period (Baseline to Week 16):

   Eligible participants were randomized in a 1:1 ratio to one of the following double-blinded treatment arms:

   • Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12
   • Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12

   Participants were stratified according to current smoking status (up to 20% smokers per arm) since smoking has a well-known impact on treatment efficacy in TED.

3. Follow-up/open-label retreatment period (Week 16 up to Week 108):

   • Proptosis responders (see definition below) at Week 16 were followed for relapse up to Week 68. If these participants relapsed, they were offered a course of open-label secukinumab at the time of relapse (see "proptosis relapsers" definition below).

   • Proptosis non-responders (see definition below) at Week 16 were offered the option of open-label secukinumab treatment (with maintenance of blind to initial randomized treatment) for a duration of 16 weeks, i.e., up to Week 32 with last dose at Week 28, as follows:

     • Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 28. Thereafter (i.e., from Week 32), participants were followed up for a further 24 weeks to assess the relapse rate.
     • For participants who were proptosis non-responders and who did not receive open-label secukinumab treatment, a follow-up visit 8 weeks after the Week 16 visit needed to be scheduled per protocol. At this follow-up visit, the assessments associated with the Week 24 visit (for responders) were to be performed.

   • Proptosis relapsers (see definition below) during the follow-up period (from Week 16 onward to Week 68) were offered the option of retreatment with open-label secukinumab for a duration of 16 weeks (with maintenance of blind to initial randomized treatment) at the time of relapse as follows:

     • Open-label secukinumab 300 mg s.c. at time of relapse, then at 1, 2, 3, 4, 8 and 12 weeks since time of relapse. Thereafter, participants were followed up for a further 24 weeks (i.e., 40 weeks after start of retreatment) to assess rate of relapse and safety.
     • For participants not receiving open-label secukinumab treatment a follow-up visit 8 weeks after the Week 16 visit were to be scheduled per protocol, if not yet completed. At this follow-up visit, the assessments associated with the Week 24 visit (for responders) were to be performed.

Definitions of proptosis responder, non-responder and relapser:

• Proptosis responders: Participants achieving response in reduction of proptosis at Week 16 defined as follows: reduction of >= 2 mm from Baseline in the study eye without deterioration (>= 2 mm increase) of proptosis in the fellow eye.
• Proptosis non-responders: Participants not achieving response in reduction of proptosis at Week 16 with "response" defined as follows: reduction of >= 2 mm from Baseline in the study eye without deterioration (>= 2 mm increase) of proptosis in the fellow eye.
• Proptosis relapsers: Participants who were "proptosis responders" as defined above, and then relapsed based on proptosis at any time during the 52-week follow-up period with relapse defined as follows: increase in proptosis of >= 2 mm compared to Week 16 in the study eye or deterioration of proptosis (>= 2 mm increase) in the fellow eye at any time during 52-week follow-up period.

In case of worsening of the disease, participants were allowed to receive alternative treatment for TED at the discretion of the investigator and were discontinued from the study treatment.

The primary endpoint analysis was planned to be performed once all participants had reached Week 40, which included the primary efficacy endpoint (Week 16), efficacy of retreatment for initial non-responders and relapse rates during 24 weeks of follow-up.

The final analysis was planned to be performed when the last participant had reached the end of trial.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) expressed different preferences regarding the primary and secondary objectives and endpoints and their ordering. Therefore, this study intended to have 2 different analysis strategies and corresponding primary, secondary objective and endpoint definitions; Plan A was intended for submission in Europe (EU) and other applicable countries and Plan B was intended for submission in the United States (US) and other applicable countries. As the study was early terminated, only Plan A analysis was conducted.

Key Inclusion Criteria:

• Patient had to be able to understand and communicate with the investigator and comply with the requirements of the study and had to give a written, signed and dated informed consent before any study assessment was performed.

• Male or non-pregnant, non-lactating female patients ≥ 18 years of age.

• Clinical diagnosis of active, moderate to severe TED (not sight-threatening) in the study eye at Baseline associated with 2 or more of the following:

  • Lid retraction >= 2 mm
  • Moderate or severe soft tissue involvement
  • Exophthalmos >= 3 mm above normal
  • Inconstant or constant diplopia

• Onset of TED symptoms fewer than 12 months prior to Baseline.

• CAS >= 4 (on a 7-point scale, with a score of >= 3 indicating active TED) in the more severely affected (study) eye at Screening and Baseline. Note: Proptosis is the primary qualifier for selection of the study eye. In case both eyes showed a similar degree of proptosis, other inflammatory signs and symptoms (CAS) were taken into account by the investigator for the selection of the study eye.

• Peripheral euthyroidism or mild hypo-/hyperthyroidism defined as free T3 (fT3) and free T4 (fT4) < 30% above/below normal limits at Screening. Every effort was to be made to correct the mild hypo-/hyperthyroidism promptly and to maintain the euthyroid state until the end of this study.

• Orbital MRI assessment available confirming the diagnosis of TED for patients initially presenting with hypo- or euthyroidism (without treatment for hyperthyroidism) before or at the time of TED diagnosis (to rule out other potential causes of orbital signs and symptoms.

Key Exclusion Criteria:

• Improvement in CAS of >= 2 points and/or improvement in proptosis of >= 2 mm in the study eye between Screening and Baseline.
• Signs of sight-threatening TED defined by optic neuropathy or severe corneal injury.
• Patients, in the opinion of the investigator, requiring immediate or urgent medical treatment with glucocorticoids for TED.
• Patients requiring immediate surgical ophthalmological intervention or planning corrective surgery/irradiation during the course of the study.
• Decreased best corrected visual acuity (BCVA) as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect or color defect within the last 6 months.
• Any other ophthalmic and/or orbital disease or condition that might interfere with the assessment of TED.
• Previous orbital radiotherapy.
• Previous ophthalmological/orbital surgery for TED (e.g., orbital decompression).
• Previous use of biological agents for the treatment of TED.
• Previous use of systemic, non-biologic, immunomodulatory agents for the treatment of TED (e.g., mycophenolate or cyclosporine).
• Previous exposure to secukinumab or other biologic drugs directly targeting IL-17A or the IL 17 receptor (e.g., ixekizumab, brodalumab).
• Previous treatment with rituximab, tocilizumab or teprotumumab.
• Previous use of systemic corticosteroids for the treatment of TED, except for oral corticosteroids with a cumulative dose equivalent to < 1 g oral prednisone/prednisolone if the corticosteroid was discontinued at least 4 weeks prior to Baseline.
• Previous treatment with any cell-depleting therapies including but not limited to anti-cluster of differentiation 20 (CD20) or investigational agents (e.g., CAMPATH, anti CD4, anti-CD5, anti-CD3, anti-CD19).
• Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, whichever is longer.
• Previous or ongoing use of prohibited treatments (see Appendix 16.1.1-Protocol Section 6.2.2). Respective washout periods detailed in this section needed to be adhered to.
• History of hypersensitivity to any of the study drug constituents.

Other protocol defined Inclusion/Exclusion may apply.