Effect of Secukinumab on Radiographic Progression in Ankylosing Spondylitis as Compared to GP2017 (Adalimumab Biosimilar)

This was a Phase IIIb, multi-center, randomized, partially-blinded, active-controlled, parallel-group design in subjects with AS. The study consisted of a screening period (up to 10 weeks before randomization), a treatment period (104 weeks), and two follow-up visits (Weeks 112 and 120).

Subjects in both secukinumab dose groups received study treatment at baseline, Weeks 1, 2, 3 and 4 followed by treatment every 4 weeks through Week 100. Subjects in the GP2017 group received study treatment at baseline and every two weeks through Week 102. Subjects could self-administer all secukinumab / placebo and GP2017 doses at the study site or at home. Study treatment (secukinumab vs. GP2017) was provided in an open-label fashion. Subjects in the secukinumab groups were blinded to the dose (150 mg vs. 300 mg). Subjects who received rescue treatment with prohibited medications were allowed to remain in the study but had to discontinue study treatment. Subjects were treated for 104 weeks with two follow-up visits (Weeks 112 and 120).

A total of 859 subjects were randomized to treatment at 171 sites in 30 countries in Europe, North America, South America, and Asia.

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• Placebo (Biological): Matching placebo to AIN457 150 mg dose administered with AIN457 via pre-filled syringes
• GP2017 (adalimumab biosimilar) (Biological), also known as adalimumab biosimilar: 40 mg in pre-filled syringes was administered subcutaneously
• AIN457 150 mg (Biological), also known as secukinumab: 150 mg in pre-filled syringes was administered subcutaneously

Primary outcomes

• Percentage of Participants With no Radiographic Progression at Week 104 (Multiple Imputation) (Full Analysis Set) [Baseline and at Week 104]: Radiographic progression was based on scores from the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The mSASSS is the sum of scores assessing the vertebral corners of the lumbar and cervical spine as 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), or 3 (bridging syndesmophyte) with a total range from 0-72. No radiographic progression was defined as the change from baseline in mSASSS score <= 0.5.

Secondary outcomes

• Change From Baseline in mSASSS at Week 104 (Multiple Imputation) (Full Analysis Set) [Baseline and at Week 104]: Radiographic changes in the spine were based on the change in score of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) from baseline to Week 104. The mSASSS is the sum of scores assessing the vertebral corners of the lumbar and cervical spine as 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), or 3 (bridging syndesmophyte) with a total range from 0-72.
• Percentage of Participants Without New Syndesmophytes by mSASSS Between Baseline and Week 104 (Multiple Imputation) (Syndesmophyte Subset) [Baseline and at Week 104]: Syndesmophytes are bony growths that develop on corner of the vertebrae of the spine which are indicators of AS. A participant was considered to have a syndesmophyte if at least one reader assessed vertebral corner as >= 2 at on the mSASSS scale at baseline. Only participants with a syndesmophyte at baseline were evaluated at Week 104 for new syndesmophytes. A new syndesmophyte was a syndesmophyte present at Week 104 which was not present at baseline. Absence of new syndesmophyte was defined as having individual vertebral score < 2 on the mSASSS scale for all interpretable locations that had no syndesmophyte at baseline. Missing responses for subjects without new syndesmophyte at Week 104 were imputed by multiple imputation (MCMC).
• Change From Baseline in MRI Berlin Sacroiliac (SI) Joint Edema Score (Observed Data) (MRI Subset) [Baseline and at Week 104]: Magnetic Resonance Images (MRI) of the Sacroiliac Joint (SIJ) were assessed for the presence and severity of SIJ bone marrow edema according to the Berlin Active Inflammatory Lesions Scoring with a minimum score of 0 and a maximum score of 24. Higher scores indicate more inflammation.
• Change From Baseline in Berlin Modification of ASspiMRI-a Edema Score (MRI Subset) [Baseline and at Week 104]: Magnetic Resonance Images (MRI) of the spine were assessed for the presence and severity of bone marrow edema in the spinal vertebrae according to the Berlin modification of the ASspiMRI-a edema score with a score range of 0 to 69. Higher scores indicate more inflammation.
• Percentage of Responders for Assessment of SpondyloArthritis International Society 20 (ASAS20) [Week 104]: Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 4 domains measured on visual analog scales (VAS): 1. Patient's global assessment; 2. Patient's assessment of back pain; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). ASAS 20 response is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the remaining domain. A higher score on the VAS signifies higher severity.
• Percentage of Responders for Assessment of SpondyloArthritis International Society 40 (ASAS 40) [Week 104]: Assessment of SpondyloArthritis International Society criteria (ASAS) consist of 4 domains measured on visual analog scales (VAS): 1. Patient's global assessment; 2. Patient's assessment of back pain; 3. Function represented by Bath Ankylosing Spondylitis Functional Index (BASFI) average of 10 questions; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at least three of the four ASAS main domains and no worsening at all in the remaining domain. A higher score on the VAS signifies higher severity.
• Percentage of Responders for Assessment of SpondyloArthritis International Society With a Partial Remission Response (Full Analysis Set) [Week 104]: The Assessment of SpondyloArthritis International Society (ASAS) partial remission response criteria consisted of the following assessment domains measured on visual analogue scales (VAS): 1. Patient's global assessment; 2. Patient's assessment of back pain; 3. Function represented by BASFI average of 10 questions regarding ability to perform specific tasks; 4. Inflammation represented by mean duration and severity of morning stiffness, on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The ASAS partial remission criteria was defined as a value not above 2 units in each of the four domains on a scale of 10.
• Percentage of Participants With Assessment of SpondyloArthritis International Society for Inactive Disease Response (Observed Data) (Full Analysis Set) [Week 104]: The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess disease activity in AS. Parameters used for the ASDAS include spinal pain (BASDAI question 2), the patient's global assessment of disease activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI question 6) and C-reactive protein (CRP) in mg/L (Sieper 2009, Lukas 2009). Disease activity states are inactive disease, moderate disease activity, high disease activity, and very high disease activity. The 3 values selected to separate these states were < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and > 3.5 between high disease activity and very high disease activity. Selected cutoffs for improvement scores were a change ≥ 1.1 unit for "minimal clinically important improvement" and a change ≥ 2.0 units for "major improvement" (Machado 2011).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or non-pregnant, non-nursing female patients at least 18 years of age
* Diagnosis of moderate to severe Ankylosing Spondylitis with radiologic evidence (centrally read X-ray) fulfilling the Modified New York criteria for AS despite previous or current NSAID/ nonbiologic DMARD therapy
* Active AS assessed by total BASDAI ≥ 4 on a scale of 0-10
* Spinal pain as measured by BASDAI question #2 ≥ 4 (0-10)
* Total back pain as measured by visual analog scale (VAS) ≥ 40 mm (0-100 mm)
* hsCRP ≥ 5 mg/L OR presence of at least 1 syndesmophyte on centrally read spinal X-ray

Exclusion Criteria:

* Patients with total ankylosis of the spine
* Pregnant or nursing (lactating) women
* Evidence of ongoing infectious or malignant process
* Previous exposure to any biologic immunomodulating agent, including those targeting IL-17, IL-17 receptor or TNFα
* Subjects taking high potency opioid analgesics
* Previous treatment with any cell-depleting therapies including but not limited to anti-CD20, investigational agents

Other protocol-defined inclusion/exclusion criteria may apply

Participant flow

Outcome results

• Percentage of Participants With no Radiographic Progression at Week 104 (Multiple Imputation) (Full Analysis Set) (Primary), Number, Percentage of participants: AIN457 150 mg/Placebo 66.1; AIN457 300 mg 66.9; GP2017 40mg 65.6 (p 0.7164)
• Change From Baseline in mSASSS at Week 104 (Multiple Imputation) (Full Analysis Set) (Secondary), Least squares mean, mSASSS scores: AIN457 150 mg/Placebo 0.54 +/- 0.175; AIN457 300 mg 0.55 +/- 0.180; GP2017 40mg 0.72 +/- 0.177
• Percentage of Participants Without New Syndesmophytes by mSASSS Between Baseline and Week 104 (Multiple Imputation) (Syndesmophyte Subset) (Secondary), Number, Percentage of participants: AIN457 150 mg/Placebo 56.9; AIN457 300 mg 53.8; GP2017 40mg 53.3
• Change From Baseline in MRI Berlin Sacroiliac (SI) Joint Edema Score (Observed Data) (MRI Subset) (Secondary), Least squares mean, scores on a scale: AIN457 150 mg/Placebo -1.527 +/- 0.1057; AIN457 300 mg -1.378 +/- 0.1097; GP2017 40mg -1.710 +/- 0.1087
• Change From Baseline in Berlin Modification of ASspiMRI-a Edema Score (MRI Subset) (Secondary), Least squares mean, Berlin mod. of ASspiMRI-a edema scores: AIN457 150 mg/Placebo -1.224 +/- 0.2306; AIN457 300 mg -1.683 +/- 0.2373; GP2017 40mg -2.101 +/- 0.2378
• Percentage of Responders for Assessment of SpondyloArthritis International Society 20 (ASAS20) (Secondary), Number, Percentage of participants: AIN457 150 mg/Placebo 83.1 (77.8 to 87.4); AIN457 300 mg 82.9 (77.3 to 87.4)
• Percentage of Responders for Assessment of SpondyloArthritis International Society 40 (ASAS 40) (Secondary), Number, Percentage of participants: AIN457 150 mg/Placebo 69.9 (63.7 to 75.4); AIN457 300 mg 73.5 (67.3 to 78.9)
• Percentage of Responders for Assessment of SpondyloArthritis International Society With a Partial Remission Response (Full Analysis Set) (Secondary), Number, Percentage participants: AIN457 150 mg/Placebo 31.5 (25.9 to 37.7); AIN457 300 mg 30.2 (24.5 to 36.6)
• Percentage of Participants With Assessment of SpondyloArthritis International Society for Inactive Disease Response (Observed Data) (Full Analysis Set) (Secondary), Number, Percentage of participants: AIN457 150 mg/Placebo 31.1 (25.5 to 37.4); AIN457 300 mg 31.7 (25.7 to 38.3)

Adverse events

Time frame: Adverse events were reported from first dose of study treatment until end of study treatment plus 84 days up to a maximum of 900 days for AIN 457 and 939 days for GP2017.

Serious adverse events by term

33 more terms not shown.

Other adverse events by term

71 more sites not listed.

• Results publication: Sieper J, Poddubnyy D. Twenty years of clinical trials in axial spondyloarthritis: what can we learn for the future? Curr Opin Rheumatol. 2021 Jul 1;33(4):363-369. doi: 10.1097/BOR.0000000000000804. PMID 33978600
• Results publication: Baraliakos X, Ostergaard M, Gensler LS, Poddubnyy D, Lee EY, Kiltz U, Martin R, Sawata H, Readie A, Porter B; SURPASS Study Group. Comparison of the Effects of Secukinumab and Adalimumab Biosimilar on Radiographic Progression in Patients with Ankylosing Spondylitis: Design of a Randomized, Phase IIIb Study (SURPASS). Clin Drug Investig. 2020 Mar;40(3):269-278. doi: 10.1007/s40261-020-00886-7. PMID 31983056

• Study Protocol (PDF, 2021-02-04)
• Statistical Analysis Plan (PDF, 2022-05-10)