An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod

Roger Hesselstrand, Jörg H W Distler, Gabriela Riemekasten, Dirk M Wuttge, Marie Törngren, Helén C Nyhlén, Fredrik Andersson, Helena Eriksson, Birgitta Sparre, Helén Tuvesson, Oliver Distler, Roger Hesselstrand, Jörg H W Distler, Gabriela Riemekasten, Dirk M Wuttge, Marie Törngren, Helén C Nyhlén, Fredrik Andersson, Helena Eriksson, Birgitta Sparre, Helén Tuvesson, Oliver Distler

Abstract

Objectives: To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc).

Methods: In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study.

Results: Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase.

Conclusions: Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs.

Trial registration: ClinicalTrials.gov, NCT01487551 . Registered on 7 September 2011.

Keywords: Clinical trial; Paquinimod; Skin fibrosis; Systemic sclerosis.

Conflict of interest statement

RH received funding from Active Biotech AB related to the study. JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi, and UCB. JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, and UCB. JHWD is a stock owner of 4D Science.

GR and DMW declare that they have no competing interests.

MT, HT, and HE are employees and stock owners of Active Biotech AB.

HCN is a former employee at Active Biotech AB and owns stocks in Active Biotech AB.

FA and BS are former employees at Active Biotech AB.

OD has/had consultancy relationship and/or has received research funding from Abbvie, Actelion, Acceleron Pharma, Amgen, AnaMar, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, Catenion, Competitive Drug Development International Ltd., CSL Behring, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, Glenmark Pharmaceuticals, GSK, Inventiva, Italfarmaco, iQone, iQvia, Lilly, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Target BioScience, and UCB in the area of potential treatments of scleroderma and its complications. He has a patent mir-29 for the treatment of systemic sclerosis issued (US8247389, EP2331143).

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Plasma levels of paquinimod in each individual patient were analyzed at weeks 2, 4 and 8, and at follow-up week 12, by using LC-MS/MS
Fig. 2
Fig. 2
A Type I IFN activity in plasma in each individual patient was analyzed at baseline, weeks 4 and 8, and at follow-up week 12, by using a functional receptor assay. B The gene expression of five type I IFN responsive genes, IFI44, IFI44L, IFI6, IFI27, and RSAD2, in the skin was analyzed by real-time PCR. The forest plot shows mean fold changes (log2) of each gene after 8 weeks of treatment. The dashes indicate mean fold changes (log2) after 8 weeks of treatment with paquinimod, and the horizontal bars show 95% CIs
Fig. 3
Fig. 3
Changes in the levels of CCL2 in the serum during the whole study in each individual patient. The recorded baseline values ranged between 427 and 1309 pg/mL. A reduction was observed in 7 out of 9 patients during treatment; the mean (shown in red) reduction was 18% (p = 0.07)
Fig. 4
Fig. 4
Changes in normalized gene expression of CCR2 in the skin. The mean fold reduction was 0.59 (p = 0.019) (shown in red) after 8 weeks of treatment
Fig. 5
Fig. 5
Changes of the number of myofibroblasts in skin biopsies from each individual patient treated with paquinimod. The myofibroblasts were analyzed by immunohistochemistry and detected by using an antibody recognizing α-smooth muscle actin (αSMA) in skin biopsies taken at baseline and week 8. The mean (shown in red) reduction was 8% (p = 0.023)
Fig. 6
Fig. 6
Modified Rodnan Skin Score (mRSS) at baseline, at weeks 4 and 8, and at follow-up in each individual patient treated with paquinimod

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