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Abstract Number: L09

A Phase 2a Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA)

Dinesh Khanna1, Christopher Denton2, Daniel Furst3, Maureen Mayes4, Marco Matucci-Cerinic5, Vanessa Smith6, Dick de Vries7, Liesbeth Deberdt8, Pieter‑Jan Stiers8, Niyati Prasad8 and Sohail Ahmed9, 1University of Michigan, Ann Arbor, MI, 2Royal Free Hospital, University College London, London, United Kingdom, 3David Geffen School of Medicine at UCLA, Los Angeles, CA, 4University of Texas Health Science Center at Houston, Houston, TX, 5Università degli Studi di Firenze, Firenze, Italy, 6Ghent University Hospital, Ghent, Belgium, 7Galapagos BV, Leiden, Netherlands, 8Galapagos NV, Mechelen, Belgium, 9Ahmed Science Medicine, Basel, Switzerland

Meeting: ACR Convergence 2020

Date of first publication: October 23, 2020

Keywords: clinical trial, Late-Breaking 2020, Randomized Trial, Scleroderma, skin, Systemic sclerosis

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Session Information

Date: Monday, November 9, 2020

Session Title: Late-Breaking Abstracts (L06–L11)

Session Type: Late-Breaking Abstract Session

Session Time: 11:30AM-1:00PM

Background/Purpose: There is a high unmet need for systemic sclerosis (SSc) treatments. Ziritaxestat (ziri; GLPG1690) is an autotaxin inhibitor with a novel mechanism of action. NOVESA (NCT03798366) is a phase 2a randomized, double-blind, placebo (PBO)‑controlled trial evaluating the efficacy, safety, and tolerability of ziri for diffuse cutaneous (dc) SSc.

Methods: Patients with dcSSc were randomized (2:1) to receive oral ziri 600 mg once daily or matching PBO for 24 weeks. Protocol-defined immunosuppressive background therapies were allowed to continue unchanged if doses were stable for ≥3 months prior to ziri treatment. Eligible patients were adults with a confirmed diagnosis of dcSSc (by ACR/EULAR/Van den Hoogen/LeRoy 2013 criteria) and a modified Rodnan skin score (mRSS) >10 at screening. The primary endpoint was change from baseline mRSS at 24 weeks. Secondary endpoints were incidence of treatment-emergent adverse events (TEAEs), serious AEs and tolerability of ziri. Additional endpoints included changes in forced vital capacity (FVC), Health Assessment Questionnaire Disability Index (HAQ-DI) and Combined Response Index for Systemic Sclerosis (ACR CRISS) score. Analyses used a mixed-effects model for repeated measures. Least square (LS) mean (95% confidence interval [CI]) was calculated for the primary endpoint, descriptive statistics for other endpoints. Covariates included baseline mRSS and country.

Results: Thirty-three patients with active dcSSc were randomized: 21 to ziri; 12 to PBO. The majority of patients were female (69.7%); mean (standard deviation [SD]) age was 49.3 (15.1) yrs (Table 1). In the ziri and PBO groups, respectively, mean (SD) disease duration was 1.5 (1.0) and 2.6 (2.0) yrs; mean (SD) mRSS was 27.0 (8.8) and 22.5 (6.2). 95.2% and 83.3% of patients in the ziri and PBO groups were on background immunosuppressive therapy. A statistically significant difference was observed between groups for mRSS at Wk 24: LS mean difference (95% CI) was –2.8 (–5.6, –0.1) for ziri vs PBO (p=0.0411; Figure 1). Median CRISS score was 0.97 for ziri and 0.83 for PBO at Wk 24 (0.69 in the PBO group excluding a single outlier patient with implausible Wk 24 FVC change [+1381 mL]). ACR CRISS showed likelihood of improvement (score ≥0.60 on a 0.0–1.0 scale) in 64.7% and 62.5% of patients at Wk 24 in ziri and PBO groups, respectively (57.1% of PBO patients at Wk 24 with exclusion of the FVC outlier). No changes in FVC (mL) or HAQ-DI were observed. Ziri was well tolerated; most AEs were mild or moderate; no TEAEs led to study drug discontinuation. Serious TEAEs occurred in 2 patients in the ziri group (pharyngitis and sepsis; device-related infection and sepsis) and 1 patient in the PBO group (foreign body ingestion); these were considered unrelated or unlikely related to study drug. No deaths occurred. Preliminary data show target inhibition reflected by an average reduction in circulating lysophosphatidic acid of ~80%.

Conclusion: In the small NOVESA study, ziri significantly improved mRSS vs PBO at Wk 24 and was well tolerated when administered with standard-of-care immunosuppressive therapy. Results support a possible role for the autotaxin pathway in the pathogenesis of SSc skin disease and warrant further clinical research.

Table 1. Demographics and baseline patient characteristics.
*Includes MTC, MYC, and Pred
FVC, forced vital capacity; HAQ-DI, Health Assessment Questionnaire Disability Index; mRSS, modified Rodnan skin score; MTX, methotrexate; MYC, mycophenolate; Pred, prednisone; SD, standard deviation; yr, year

Figure 1. Change in mRSS from baseline.
Changes in N are due to 1 patient being lost to follow-up and patients having the mRSS assessment outside the allowable window, due to COVID-19 restrictions limiting onsite visits
COVID-19, coronavirus disease 2019; mRSS, modified Rodnan skin score; SE, standard error


Disclosure: D. Khanna, Pfizer, 2, AbbVie, 5, Acceleron, 5, Actelion, 5, Amgen, 5, Boehringer Ingelheim, 5, CSL Behring, 5, Corbus, 5, Galapagos, 5, Genentech/Roche, 5, Gilead, 5, GlaxoSmithKline, 5, Merck, 5, Mitsubishi Tanabe Pharma, 5, Sanofi-Aventis, 5, United Therapeutics, 5, Eicos Sciences, Inc, 9, CiviBioPharma/Eicos Sciences, Inc, 9, Bayer, 2, 5, Bristol-Myers Squibb, 2, Horizon, 2, 5, Immune Tolerance Network, 2, National Institutes of Health, 2; C. Denton, Acceleron, 2, 9, Actelion, 2, 9, Arxx Therapeutics, 2, 9, Bayer, 2, 9, Boehringer Ingelheim, 2, 9, Bristol-Myers Squibb, 2, 9, Corbus, 2, 9, CSL Behring, 2, 9, Galapagos, 2, 9, GlaxoSmithKline, 2, 9, Horizon, 2, 9, Inventiva, 2, 9, Leadiant Biosciences, 2, 9, Roche, 2, 9, Sanofi, 2, 9; D. Furst, Actelion, 2, Amgen, 2, 9, Bristol Myers Squibb, 2, 9, Galapagos, 2, 9, Novartis, 2, 9, Pfizer, 2, 9, Sanofi, 2, Roche/Genentech, 2, Corbus, 2, 9, GlaxoSmithKline, 2; M. Mayes, Galapagos, 2, 9, Actelion Pharma, 9, Astellas, 9, Medtelligence, 9, Mitsubishi-Tanabe, 9, Bayer, 2, Corbus, 2, GlaxoSmithKline, 2, Reata, 2, Sanofi, 2, Boehringer Ingelheim, 2, 9, EICOS, 2, 9; M. Matucci-Cerinic, Acceleron, 5, Actelion, 5, Bayer, 5, Boehringer Ingelheim, 5, Chemomab, 5, CSL Behring, 5, Corbus, 5, Galapagos, 5, Janssen, 5, Inventiva, 5, Lilly, 5, Mitsubishi, 5, MSD, 5, Pfizer, 5, Regeneron, 5, Roche, 5, Samsung, 5, Biogen, 5; V. Smith, Actelion, 2, 5, 8, Bayer, 2, 5, 8, Boehringer Ingelheim, 2, 5, 8; D. de Vries, Galapagos, 3, 9; L. Deberdt, Galapagos, 3, 9; P. Stiers, Galapagos, 3, 9; N. Prasad, Galapagos, 3, 9; S. Ahmed, Galapagos, 3, 9.

To cite this abstract in AMA style:

Khanna D, Denton C, Furst D, Mayes M, Matucci-Cerinic M, Smith V, de Vries D, Deberdt L, Stiers P, Prasad N, Ahmed S. A Phase 2a Randomized, Double-blind, Placebo-controlled Study of Ziritaxestat in Early Diffuse Cutaneous Systemic Sclerosis (NOVESA) [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/a-phase-2a-randomized-double-blind-placebo-controlled-study-of-ziritaxestat-in-early-diffuse-cutaneous-systemic-sclerosis-novesa/. Accessed January 24, 2021.
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