Characterization Of Changes In Gene Expression and Inflammatory Proteins In Systemic Juvenile Idiopathic Arthritis Patients On Canakinumab Therapy

Nanguneri R. Nirmala¹, Nico Wulffraat², Hermine Brunner³, Pierre Quartier⁴, Riva Brik⁵, Liza McCann⁶, Huri Ozdogan⁶, Lidia Rutkowska-Sak⁶, Rayfel Schneider^3,7, Valeria Gerloni⁸, Liora Harel⁹, Maria Terreri³, Kristin Houghton³, Rik Joos⁶, Daniel Kingsbury³, Jorge M. Lopez-Benitez³, Arndt Brachat¹⁰, Stephan Bek¹⁰, Martin Schumacher¹⁰, Marie-Anne Valentin¹¹, Hermann Gram¹⁰, Ken Abrams¹², Alberto Martini⁶, Nicolino Ruperto⁶ and Daniel J. Lovell³, ¹Novartis Institutes for Biomedical Research, Cambridge, MA, ²PRINTO, Genoa, Italy, ³Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati, OH, ⁴Necker-Enfants Malades Hospital, Paris, France, ⁵Pediatrics, Rambam Medical Center, Haifa, Israel, ⁶Paediatric Rheumatology International Trials Organization (PRINTO), Genova, Italy, ⁷Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati, OH, Canada, ⁸Istituto Gaetano Pini, Milan, Italy, ⁹Pediatric Rheumatology unit, Schneider Children's Medical Center, Tel Aviv University, Petach Tikvah, Israel, ¹⁰Novartis Institutes for Biomedical Research, Basel, Switzerland, ¹¹Biomarker Development, Novartis Pharma AG, Basel, Switzerland, ¹²Novartis Pharmaceuticals Corporation, East Hanover, NJ

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Systemic JIA and interleukins (IL)

Session Information

Title: ACR Plenary Session II: Discovery 2013

Session Type: Plenary Sessions

Background/Purpose: Interleukin (IL)-1β plays a key role in the pathogenesis of systemic juvenile idiopathic arthritis (SJIA). Canakinumab (CAN), a selective, fully human, anti-IL-1β monoclonal antibody, has been shown to be efficacious in the treatment of SJIA. Here we present the analysis of changes in peripheral blood gene expression and inflammatory proteins in SJIA patients (pts) on CAN therapy and report the identified baseline biomarkers that predict clinical response to CAN treatment.

Methods: Levels of inflammatory biomarkers (IL-6; total IL-18) and gene expression profiles of active SJIA pts (aged 2 to <20 yrs) before and during CAN treatment enrolled in 2 phase III trials were analyzed.

Results: Gene Expression: Transcriptional changes upon CAN treatment at Day 3 were assessed. When applying cut-offs of ≥2 fold and p≤0.05, no transcript passed this filter for placebo-treated pts (n=9) or for CAN treated pts (n=11) that were ACR30 (adapted pediatric ACR) non-responders at Day 15, while 171 probesets passed the filter for pts (n=52) showing ≥ACR30 response. Pts who showed strong transcriptional changes also showed a strong ACR response (≥ACR50) at Day 15, while pts with eg, TLR1, TLR4, TLR5, TLR6, TLR8), including several members of the IL-1β signaling pathway, such as IL-1β, IL1R1, IL1R2 and IL1RAP. A set of transcripts was identified for which high baseline expression levels predicted a subgroup of strong (≥ACR50) responders at Day 15. However, another subgroup of strong responders was indistinguishable from weak responders (≤ACR30) based on baseline transcript levels.

Protein markers: IL-6 protein levels were strongly reduced by Day 3 (4.7 x and 4.4 x with p=0.002 and 0.0001, n=20 and n=51 for the 2 trials), and at Day 29 (12.5 x and 8.1 x with p=0.01 and 0.00005, n=20 and n=65) while total IL-18 levels remained largely unchanged until Day 29 (n=22 and n=76) and showed a moderate reduction only at Day 57. For IL-6, stronger reduction at Day 3 and Day 29 was observed for pts who showed stronger ACR response at Day 15. Only 3 baseline samples were available from pts who developed macrophage activation syndrome during the studies.

Conclusion: CAN treatment resulted in a rapid, strong reduction of many pro-inflammatory leukocyte transcripts and serum IL-6. Compared with IL-6, IL-18 protein levels were reduced upon treatment much later and less strongly. About two thirds of pts with a strong treatment response (≥ACR50) were characterized by a set of leukocyte transcripts with high baseline levels and strong reduction upon CAN treatment. However, the remaining one third of CAN strong responders did not show these characteristic transcriptional patterns, suggesting some heterogeneity at the molecular level in SJIA pts showing strong response to CAN treatment.

Disclosure:

N. R. Nirmala,

Novartis,

Novartis ,

N. Wulffraat,

Novartis, Pfizer, Roche,

Roche, Abbott,

H. Brunner,

Novartis, Genentech, Medimmune, EMD Serono, AMS, Pfizer, UCB, Jannsen,

Genentech ,

P. Quartier,

Abbvie, Chugai-Roche, Novartis, Pfizer,

Abbott/Abbvie, BMS, Chugai-Roche, Novartis, Pfizer, Servier, SOBI, Speakers Bureau: Chugai-Roche, Novartis, Pfizer,

R. Brik,

Novartis ,

Novartis,

L. McCann,
None;

H. Ozdogan,

Novartis,

L. Rutkowska-Sak,
None;

R. Schneider,

Hoffmann-La Roche, Novartis, Innomar Stragegies,

V. Gerloni,
None;

L. Harel,
None;

M. Terreri,
None;

K. Houghton,
None;

R. Joos,
None;

D. Kingsbury,
None;

J. M. Lopez-Benitez,
None;

A. Brachat,

Novartis,

Novartis ,

S. Bek,

Novartis ,

M. Schumacher,

Novartis ,

M. A. Valentin,

Novartis ,

Novartis,

H. Gram,

Novartis ,

K. Abrams,

Novaris Pharmaceutical corporation,

Novartis Pharmaceutical Corporation,

A. Martini,

Abbott, Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Ely Lilly and Company, “Francesco Angelini”, Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc.,

Astellas, Astrazeneca, Bristol Myers and Squibb, -Glaxo Smith & Kline, Italfarmaco , MedImmune, Novartis ,

N. Ruperto,

To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, “Francesco Angelini”, Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuti,

Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth, Pfizer,

D. J. Lovell,

NIH ,

Astra-Zeneca, Centocor, Jansen, Wyeth, Amgen, Bristol-Meyers Squibb, Abbott, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Genentech,

Genentech, Roche,

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-changes-in-gene-expression-and-inflammatory-proteins-in-systemic-juvenile-idiopathic-arthritis-patients-on-canakinumab-therapy/