Li Qin (1), Núria Buil-Bruna (2), Maria Luisa Sardu (1), Alienor Berges (2), Paul Matthias Diderichsen (1), Monica Simeoni (2)
(1) Certara USA, Inc., Princeton NJ, (2) Clinical Pharmacology Modelling and Simulation, GSK UK
Objectives:
Biologics and small-molecule drugs have proven efficacy across many disease states and have revolutionized the treatment of immune-mediated inflammatory diseases (IMIDs) with ostensibly unrelated conditions but sharing multiple common inflammatory pathways, including inflammatory bowel disease (IBD), and other IMIDs [1,2]. Multiple therapies and biosimilars have been approved across IMID indications by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) [3]. In general, relatively wider dose ranges and higher doses are studied in IBD compared to other IMID indications. A framework was developed to compare dose regimens studied for the treatment of IBD compared to other IMID indications based on public domain data. The objective was to explore clinically studied and regulatory approved dose across various drugs and drug classes in IBD vs non-IBD IMID indications, with the aim to support and guide drug development.
We also attempted to explore whether PK/PD modelling (i.e. suppression of circulating target levels in the system and/or the site of action) could provide a rationale for differential dosing in IBD compared to other IMID indications.
Methods:
Certara’s clinical trial outcome databases were used as data sources in the analysis (supported by GlaxoSmithKline) [4]. The databases included summary level clinical data across 7 IMIDs: Crohn’s disease (CD), ulcerative colitis (UC), atopic dermatitis (AD), ankylosing spondylitis (AS), multiple sclerosis (MS), psoriatic arthritis (PsA), and rheumatoid arthritis (RA) [4]. Among 61 drugs studied in IBD (either CD or UC or both), those that were studied in at least 2 IMID indications were selected for inclusion in the analysis (30 drugs). Reported dose levels and dosing frequencies were normalized to standardized dosing regimens for each drug and data was further differentiated by treatment phase (e.g. induction vs maintenance phase in IBD), in order to best compare dose regimens across IMIDs. The development trajectory, as well as normalized absolute dose and dose ratio of these 30 drugs were explored and compared between IBD and non-IBD IMID indications (AD, AS, MS, PsA and RA).
The PK/PD analysis was focused on anti-TNF therapies because this class contains the highest number of compounds approved in IBD. A PK/PD model was built to describe the typical suppression of TNF alpha during the induction phase after clinically studied dosing regimens in IBD. The structural PD model was common for all drugs, with compound-specific parameters [5:7]. The PK model structures and parameters were based on published PK models for each compound [8:11]. Clinical remission (defined by a Mayo score ≤2 points, with no individual subscore >1) reported in Certara’s clinical trial outcome database was used as a measure of efficacy. The relationship between average target engagement and efficacy for each drug and dosing regimen tested in IBD was explored.
Results:
Twenty drugs out of selected 30 drugs were approved in at least one IMID, and 17 drugs were approved in at least 2 IMIDs. Most anti-TNF drugs were approved in more than 4 IMIDs. Regulatory approval in several IMIDs was quite common and occurred more frequently in the past 10 years. Generally, slightly higher doses were studied and approved in IBD compared to non-IBD indications, especially for biological agents. Ratios between normalized dose in IBD to non-IBD indications in the induction phase were generally above 1 suggesting a higher dose in IBD compared to non-IBD indications.
All approved dosing regimens in IBD for anti-TNF therapies were associated with a predicted average inhibition of systemic free TNF-alpha levels during the induction phase of at least 90%. No significant relationship between average systemic target engagement and clinical remission was observed within the predicted studied target engagement range (70 to 98%).
Conclusions:
Exploration of public domain and summary level data can provide an initial understanding of dosing regimens in clinical studies across multiple therapeutic indications which share similar disease pathogenesis. This analysis can be generalized as an empirical framework to support dose bridging across indications.
References:
[1] Al-Bawardy B, Shivashankar R, Proctor DD. Novel and Emerging Therapies for Inflammatory Bowel Disease. Front Pharmacol 2021; 12: 651415.
[2] McInnes IB, Gravallese EM. Immune-mediated inflammatory disease therapeutics: past, present and future. Nat Rev Immunol 2021; 21(10): 680-686.
[3] Kim H, Alten R, Avedano L, Dignass A, Gomollon F, Greveson K et al. The Future of Biosimilars: Maximizing Benefits Across Immune-Mediated Inflammatory Diseases. Drugs 2020; 80(2): 99-113.
[4] Certara. Clinical Outcomes Database Explorer (CODEX) portal. In, https://codex.certara.com 2022.
[5] Kaymakcalan Z et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clinical Immunology 2009; 131.2: 308-316.
[6] Shealy DJ et al. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α. In: MAbs. Taylor & Francis, 2010; p. 428-439.
[7] JIT M et al. TNF-α neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome. Rheumatology, 2005; 44.3: 323-331.
[8] Fasanmade AA et al. Population pharmacokinetic analysis of infliximab in patients with ulcerative colitis. European journal of clinical pharmacology, 2009; 65.12: 1211-1228.
[9] Ternant D et al. Pharmacokinetics of adalimumab in Crohn’s disease. European journal of clinical pharmacology, 2015; 71.9: 1155-1157.
[10] Adedokun OJ, Xu Z, Liao S, Strauss R, Reinisch W, Feagan BG, Sandborn WJ. Population pharmacokinetics and exposure–response modeling of Golimumab in adults with moderately to severely active ulcerative colitis. Clinical Therapeutics. 2020;42(1):157-74.
[11] Wade JR, Parker G, Kosutic G, Feagen BG, Sandborn WJ, Laveille C, Oliver R. Population pharmacokinetic analysis of certolizumab pegol in patients with Crohn’s disease. The Journal of Clinical Pharmacology. 2015 Aug;55(8):866-74.
Reference: PAGE 30 (2022) Abstr 10140 [www.page-meeting.org/?abstract=10140]
Poster: Methodology - New Modelling Approaches