Secukinumab, a Monoclonal Antibody to Interleukin-17A, Significantly Improves Signs and Symptoms of Active Ankylosing Spondylitis: Results of a 52-Week Phase 3 Randomized Placebo-Controlled Trial with Intravenous Loading and Subcutaneous Maintenance Dosing

Dominique L. Baeten¹, Juergen Braun², Xenofon Baraliakos³, Joachim Sieper⁴, Maxime Dougados⁵, Paul Emery⁶, Atul A. Deodhar⁷, Brian Porter⁸, Ruvie Martin⁸, Shephard Mpofu⁹ and Hanno Richards¹⁰, ¹Department of Clinical Immunology and Rheumatology and Department of Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands, ²Rheumazentrum Ruhrgebiet, Herne, Germany, ³Rheumatology, Rheumazentrum Ruhrgebiet, Herne, Germany, ⁴Charité University Medicine Berlin, Berlin, Germany, ⁵Université Paris René Descartes and Hôpital Cochin, Paris, France, ⁶University of Leeds, Leeds, United Kingdom, ⁷Oregon Health and Sciences University, Portland, OR, ⁸Novartis Pharma AG, East Hanover, NJ, ⁹Novartis Pharma AG, Basel, Switzerland, ¹⁰Clinical Immunology / Dermatology, Novartis Pharma AG, Basel, Switzerland

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Ankylosing spondylitis (AS), AS, monoclonal antibodies, randomized trials and treatment

Session Information

Title: ACR Plenary Session I: Discovery 2014

Session Type: Plenary Sessions

Background/Purpose

A phase 2, proof-of-concept study indicated that secukinumab, an anti–IL-17A monoclonal antibody, suppressed signs and symptoms of active ankylosing spondylitis (AS) by Week (Wk) 6. We present Wk 16 and Wk 52 efficacy and safety data from MEASURE 1 (NCT01358175), a phase 3 study assessing secukinumab vs. placebo (PBO) in patients (pts) with AS.

Methods

Pts with active AS fulfilling modified New York Criteria and BASDAI ≥ 4, despite current or previous therapy with NSAIDs, DMARDs and/or anti-TNF agents, were randomized to receive: i.v. secukinumab 10 mg/kg (Wk 0, 2, 4) followed by s.c. secukinumab 75 mg every 4 wks (10 IV → 75 SC), s.c. secukinumab 150 mg every 4 wks (10 IV → 150 SC), or PBO on same i.v. and s.c. schedules. Endpoints included ASAS20 at Wk 16 (primary), ASAS40, hsCRP, ASAS 5/6, BASDAI, SF-36 PCS, ASQoL and ASAS partial remission. Statistical analyses followed a pre-defined hierarchical hypothesis testing strategy to adjust for multiplicity. PBO pts were re-randomized to secukinumab 75 mg or 150 mg s.c. based on ASAS20 response at Wk 16, with non-responders switched at Wk 16 and responders at Wk 24.

Results

Baseline characteristics of the 371 randomized pts were similar between study arms: mean age 40.1-43.1 years, mean disease duration 6.5-8.3 years, mean BASDAI 6.05-6.51, ~27% inadequate response to anti-TNF agents (TNF-IR). The study met its primary efficacy endpoint with a significantly higher ASAS20 response at Wk 16 in the 10 IV → 75 SC (59.7%) and 10 IV → 150 SC (60.8%) groups vs. PBO (28.7%; P < 0.01 for each dose); ASAS20 response rates in TNF-naïve pts were 60.0%, 66.3% and 32.6%, and in the TNF-IR pts were 58.8%, 45.5% and 18.2%, in the 10 IV → 75 SC, 10 IV → 150 SC and PBO groups, respectively (P< 0.01 vs. PBO). Significant improvements with both doses of secukinumab vs. PBO were observed for all pre-specified secondary endpoints at Wk 16 (Table), with responses sustained through Wk 52. Onset of action of secukinumab was rapid, with significant improvements in ASAS20, ASAS40, hsCRP, ASAS5/6 and BASDAI seen at Wk 1. Through to Wk 16, drug exposure levels were similar in the secukinumab groups due to the i.v. loading doses. Secukinumab was generally well tolerated. At Wk 16, 66.9% of pts in the 10 IV → 75 SC group and 69.6% in the 10 IV → 150 SC group experienced an AE, vs. 55.7% on PBO; SAE rates were 1.6%, 2.4% and 4.1%, respectively. Through Wk 52 visit of the last pt (average exposure [range]: 451.7 [8–757] days), AE/SAE rates were 76.5%/10.1% and 85.1%/9.4% for pts receiving secukinumab 75 or 150 mg s.c., respectively, at any point in the study.

Table. Summary of 16-week efficacy results
Week 16 Data	Secukinumab 10 mg/kg i.v. → 75 mg s.c. (N = 124)	Secukinumab 10 mg/kg i.v. → 150 mg s.c. (N = 125)	Placebo (N = 122)
ASAS20 response	59.7%*	60.8%*	28.7%
ASAS40 response	33.1%*	41.6%*	13.1%
hsCRP, post-baseline to baseline ratio (LSM±SE)	0.45 ± 1.092*	0.40 ± 1.090*	0.97 ± 1.095
ASAS5/6	45.2%*	48.8%*	13.1%
BASDAI, mean change from baseline score (LSM±SE)	-2.34 ± 0.175*	-2.32 ± 0.172*	-0.59 ± 0.180
SF-36 PCS, mean change from baseline score (LSM±SE)	5.64 ± 0.595*	5.57 ± 0.586*	0.96 ± 0.612
ASQoL, mean change from baseline score (LSM±SE)	-3.61 ± 0.424*	-3.58 ± 0.420*	-1.04 ± 0.437
ASAS partial remission	16.1%*	15.2%*	3.3%
*P<0.01 vs. placebo Prespecified hierarchical statistical testing strategy used to account for multiplicity. Missing data for categorical variables were imputed as nonresponse ASAS, Assessment of SpondyloArthritis International Society Criteria; ASQoL, Ankylosing Spondylitis Quality of Life; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; hsCRP, high-sensitivity C-reactive protein; LSM, least square mean; SE, standard error; NS, not significant; SF-36 PCS, short form 36 physical component summary

Conclusion

The selective IL-17A inhibitor secukinumab provided rapid and significant improvement of signs and symptoms in pts with active AS, regardless of prior anti-TNF exposure. Improvements were observed from Wk 1 and sustained through 52 wks. Secukinumab was well tolerated through 52 wks with no unexpected safety findings.

Disclosure:

D. L. Baeten,

Research grants from Boehringer Ingelheim, Jannsen, MSD, Novartis, Pfizer,

2, 9,

Consulting fees from AbbVie, Boehringer Ingelheim, BMS, Eli Lilly, Jannsen, MSD, Novartis, Pfizer, Roche, UCB,

J. Braun,

Honoraria for talks: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB,

Honoraria advisory boards: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB,

Honoraria for paid consultancies: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB,

Grants for studies from Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB,

X. Baraliakos,

Research funds from AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai,

Consulting fees from AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai,

Speaker’s fees from AbbVie, Merck, Pfizer, UCB, Novartis, and Chugai,

J. Sieper,

Consulting fees from AbbVie, Pfizer, Merck, UCB and Novartis,

Research grants from AbbVie, Pfizer and Merck,

Speaker’s bureau for AbbVie, Pfizer, Merck and UCB,

M. Dougados,

Research grants from AbbVie, BMS, Eli Lilly, Merck, Pfizer,

Consulting fees from Eli Lily,

P. Emery,

Consulting fees from AbbVie, BMS, Merck, Novartis, Pfizer, Roche, UCB,

A. A. Deodhar,

Research grants from AbbVie, Amgen, Novartis, Pfizer and UCB,

Consulting fees from AbbVie, Celgene, Novartis, Pfizer and UCB,

B. Porter,

Employee of Novartis ,

Novartis stock ,

R. Martin,

Employee of Novartis ,

S. Mpofu,

Employee of Novartis ,

Novartis stock,

H. Richards,

Employee of Novartis ,

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