Vincent Hurez (1), Michael Weis (1), Rebecca Baillie (1), Mike Reed (1), Markus Rehberg (2), Katharina Beuke (2), Axel Dietrich (2), Britta Göbel (2), Nadine Biesemann (2), Christian Asbrand (2), Arun Subramaniam (2), Werner Seiz (2), Matthias Herrmann (2), Thomas Klabunde (2), Frank Nestle (2)
(1) Rosa and Co. LLC, USA, (2) Sanofi, Germany/USA
Introduction
Psoriasis is a chronic, debilitating autoimmune skin disease affecting ~2% of the population with itching, thickened, red scaly skin, and more rarely psoriatic arthritis. Despite several therapeutic options including topical agents and systemic therapies, there is widespread undertreatment due to lack or loss of response, safety concerns, and tolerability. Novel drugs (small molecules, new biologics) with fewer side-effects or more convenient dosing may help overcome these obstacles.
Objectives
Quantitative Systems Pharmacology (QSP) can provide insight into disease pathophysiology, help optimize the efficacy of novel therapies, and reduce the risk at various stages of drug development. The main objectives were to:
- Assess the potential of novel oral drugs and anti-cytokine antibodies in psoriasis.
- Compare efficacy to standard of care therapies, i.e., methotrexate, adalimumab, guselkumab, and secukinumab.
- Identify mechanistic drivers and impact of patient variability on treatment response.
Methods
We developed a mechanistic QSP model using algebraic and ordinary differential equations to represent the physiology of a single chronic psoriatic plaque (including keratinocytes, immune cells, cytokines, chemokines, and their regulation), drug pharmacokinetics, and clinical outcomes (PASI score). The model was designed and qualified in accordance with Rosa’s Model Qualification Method [1]. Over 450 individual parameters were assessed from more than 2000 literature references to quantify cell numbers, lifecycle parameters, mediator production rates and their effects on cellular functions (e.g., EC50 and Emax), and the impact of therapies. The Psoriasis Platform was qualified using published clinical and histology data for four standard of care therapies (Table 1).
Table 1. Standard therapies dosing and outcomes used to qualify the Psoriasis Platform
|
Outcomes |
Therapy |
Dosing schedule |
References |
|
· PASI score & subscores · Reduction in cellular infiltration |
Adalimumab (anti-TNFα) |
80 mg SC once, then, after 1 week, 40 mg SC Q2W |
[2-7] |
|
Guselkumab (anti-IL-23) |
100 mg SC at week 0, week 4, and Q8W thereafter |
[3, 8-12] |
|
|
Secukinumab (anti-IL-17) |
300 mg SC at weeks 0, 1, 2, 3, and 4 followed by 300 mg SC Q4W |
[13-17] |
|
|
Methotrexate |
15 mg oral weekly dose |
[2, 18-22] |
Research simulations provided insights into the potential efficacy of a novel orally delivered drug targetting the IL-17 pathway as well as novel anti-TNFα and IL-23 antibodies. Sensitivity analysis was used to determine pathways and drug characteristics critical for decreasing skin inflammation and improvement in the PASI clinical score. Alternate disease phenotypes were created to define best- and worst-case scenarios and to evaluate the impact of variability in key target-related pathways.
Results
Research using the Psoriasis QSP Platform predicted that targeting IL-17 pathways with a novel oral compound would be more efficacious than methotrexate in most disease phenotypes. Simulations in a moderate psoriasis virtual patient predicted that 20 mg QD of oral anti-IL-17 drug would reduce the PASI score by 49 to 64% after 4 weeks depending on its pharmacokinetic properties, compared to only 33% reduction with methotrexate. The novel anti-TNFα and anti-IL-23 antibodies were predicted to be very efficacious, achieving a PASI 90 clinical response in all virtual disease phenotypes tested, better than adalimumab, guselkumab, or secukinumab responses. Clinical efficacy was sensitive to skin immune cell infiltration (Th17 versus Th1/macrophages), and to drug distribution and bioavailability. Simulations confirmed that a short-term (4-weeks) Phase I clinical trial design is sufficient to demonstrate efficacy and competitive differentiation for the new therapies.
Conclusion
The Psoriasis QSP Platform was designed to quantitatively assess the clinical efficacy of novel therapeutics for moderate to severe psoriasis and reduce risk throughout the drug development process. Research in the Psoriasis Platform identified:
- Dosing regimens and pharmacokinetics constraints under which novel experimental drug would be superior to standard of care therapies
- IL-17 pathways as critical to disease pathophysiology and response to therapies in all virtual patient phenotypes evaluated
- Key uncertainties related to target expression and drug biodistribution in the skin
- A shorter trial duration sufficient to demonstrate efficacy while significantly reduced cost
References:
[1] Friedrich, C.M., A model qualification method for mechanistic physiological QSP models to support model-informed drug development. CPT Pharmacometrics Syst Pharmacol, 2016. 5(2): p. 43-53.
[2] Saurat, J.H., et al., Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol, 2008. 158(3): p. 558-66.
[3] Micali, G., et al., Clinical, ultrasound, and videodermatoscopy monitoring of psoriatic patients following biological treatment. Skin Res Technol, 2016. 22(3): p. 341-8.
[4] Balato, A., et al., Effects of adalimumab therapy in adult subjects with moderate-to-severe psoriasis on Th17 pathway. J Eur Acad Dermatol Venereol, 2014. 28(8): p. 1016-24.
[5] Rios-Navarro, C., et al., Differential effects of anti-TNF-alpha and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions. Eur J Pharmacol, 2015. 765: p. 355-65.
[6] Marble, D.J., K.B. Gordon, and B.J. Nickoloff, Targeting TNFalpha rapidly reduces density of dendritic cells and macrophages in psoriatic plaques with restoration of epidermal keratinocyte differentiation. J Dermatol Sci, 2007. 48(2): p. 87-101.
[7] Hendriks, A.G., et al., The effect of adalimumab on key drivers in the pathogenesis of psoriasis. Br J Dermatol, 2014. 170(3): p. 571-80.
[8] Hu, C., et al., Information contributed by meta-analysis in exposure-response modeling: application to phase 2 dose selection of guselkumab in patients with moderate-to-severe psoriasis. J Pharmacokinet Pharmacodyn, 2014. 41(3): p. 239-50.
[9] Reddy, M., et al., Positive treatment effects of ustekinumab in psoriasis: analysis of lesional and systemic parameters. J Dermatol, 2010. 37(5): p. 413-25.
[10] Sofen, H., et al., Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol, 2014. 133(4): p. 1032-40.
[11] Pierard-Franchimont, C. and G.E. Pierard, Ustekinumab biotherapy and real-time psoriasis capacitance mapping: a pilot study. J Biomed Biotechnol, 2012. 2012: p. 870194.
[12] Toichi, E., et al., An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol, 2006. 177(7): p. 4917-26.
[13] Langley, R.G., et al., Secukinumab in plaque psoriasis–results of two phase 3 trials. N Engl J Med, 2014. 371(4): p. 326-38.
[14] Krueger, J.G., et al., IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol, 2012. 130(1): p. 145-54 e9.
[15] Reich, K., et al., Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. Exp Dermatol, 2015. 24(7): p. 529-35.
[16] Russell, C.B., et al., Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol, 2014. 192(8): p. 3828-36.
[17] Hueber, W., et al., Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med, 2010. 2(52): p. 52ra72.
[18] Sigmundsdottir, H., et al., Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin. Exp Dermatol, 2004. 13(7): p. 426-34.
[19] Yazici, A.C., et al., The changes in expression of ICAM-3, Ki-67, PCNA, and CD31 in psoriatic lesions before and after methotrexate treatment. Arch Dermatol Res, 2005. 297(6): p. 249-55.
[20] Ozkanli, S., et al., A comparative study of histopathological findings in skin biopsies from patients with psoriasis before and after treatment with acitretin, methotrexate and phototherapy. Cutan Ocul Toxicol, 2015. 34(4): p. 276-81.
[21] Elango, T., et al., Methotrexate normalized keratinocyte activation cycle by overturning abnormal keratins as well as deregulated inflammatory mediators in psoriatic patients. Clin Chim Acta, 2015. 451(Pt B): p. 329-37.
[22] Warren, R.B., et al., An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017. 389(10068): p. 528-537.
Reference: PAGE 28 (2019) Abstr 9155 [www.page-meeting.org/?abstract=9155]
Poster: Drug/Disease Modelling - Other Topics