Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety

Frank, Konstantin; Padova, Franco Di; Deodhar, Atul; Hawkes, Jason E.; Huppertz, Christine; Kuiper, Torsten; McInnes, Iain B.; Ritchlin, Christopher T.; Rosmarin, David; Schett, Georg; Carballido, José M.; Häusermann, Peter; Calonder, Claudio; Vogel, B.; Rondeau, Jean‐Michel; Bruin, Gerard

doi:10.1016/j.pharmthera.2021.107925

Cited by 25 publications

(25 citation statements)

References 109 publications

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“…Examples of other drugs in this class include ustekinumab (Stelara ® , Janssen Pharmaceuticals of Johnson and Johnson), bimekizumab [Bimzelx ® , UCB (Union Chimique Belge)], secukinumab (Cosentyx ® , Novartis) and ixekizumab (Taltz, Lilly). This class of drugs has shown effectiveness in treating a range of autoimmune diseases such as plaque psoriasis, psoriatic arthritis, axial spondylarthritis and ankylosing spondylitis (Glatt et al, 2017;Gordon et al, 2021;Loricera et al, 2021;Aparicio et al, 2022;Kolbinger et al, 2022;Oliver et al, 2022) representing an important new treatment tool. Like GP2017 however, these biotherapeutics must be delivered by injection.…”

Section: Discussionmentioning

confidence: 99%

“…However, in the last decade or so, more targeted biotherapeutics, notably monoclonal antibodies directed at specific cytokine targets, have been developed and shown to be highly effective therapies for a range of autoimmune diseases (Lefebvre and McAuliffe, 2016;Jung and Kim, 2022). Some of the clinically available monoclonal antibodies are directed at tumor necrosis factor-alpha (TNFα) (Abramovits and Gupta, 2004;von Richter et al, 2019;Coghlan et al, 2021) and (Raychaudhuri, 2013;Kolbinger et al, 2022;Wohlrab et al, 2022;Xu et al, 2022;Yun et al, 2022) which underlie inflammatory responses in many autoimmune diseases. However, as with all biotherapeutics, the pain associated with frequently injecting these antibodies impacts patient compliance and disease management and several pharmaceutical companies have attempted to address this issue by developing infrequent dosing regimens with less painful and more convenient pen injectors for delivering these antibodies (Kivitz and Segurado, 2007;Karlsdottir et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Yamaguchi

Dam²,

Dhalla³

et al. 2022

Front. Drug. Deliv.

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Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Yamaguchi

Dam²,

Dhalla³

et al. 2022

Front. Drug. Deliv.

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“…In a subset of patients, this standard dosing scheme might lead to potential overdosing or underdosing, subsequently resulting in insufficient response (primary nonresponse) or loss of response (secondary nonresponse). [12][13][14][15] Huang et al reported loss of efficacy of up to 18.9% after 24-32 weeks of secukinumab therapy. 16 In general, these various individual responses can be explained by differences in drug clearance, presence or absence of anti-drug antibodies or mechanistic failure.…”

Section: Introductionmentioning

confidence: 99%

“…However, this dosing regimen is based on a ‘one dose fits all’ principle and does not account for pharmacokinetics (PK) and pharmacodynamics (PD) variability among patients. In a subset of patients, this standard dosing scheme might lead to potential overdosing or underdosing, subsequently resulting in insufficient response (primary nonresponse) or loss of response (secondary nonresponse) 12–15 . Huang et al .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic drug monitoring in dermatology: the way towards dose optimization of secukinumab in chronic plaque psoriasis

Soenen

Wang

Grine

et al. 2022

Clin Experimental Derm

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Summary Background Despite the favourable efficacy profile of secukinumab, clinicians encounter varying clinical responses among patients potentially associated with under‐ and overdosing. As biologics are expensive, their rational use is crucial and evident. Therapeutic drug monitoring could guide clinicians in making decisions about treatment modifications. Aim In this multicentre, prospective study, we aimed to develop and validate a secukinumab immunoassay and searched for the therapeutic window in patients with psoriasis. Methods We determined secukinumab concentrations at trough in sera from 78 patients with psoriasis at multiple timepoints (Weeks 12, 24, 36, 48 and 52; after Week 52, measurements could be taken at an additional three timepoints) during maintenance phase, using an in‐house secukinumab immunoassay consisting of a combination of MA‐SEC66A2 as capture antibody and MA‐SEC67A9, conjugated to horseradish peroxidase, as detecting antibody. At each hospital visit, disease severity was assessed using the Psoriasis Area and Severity Index (PASI). Results After quantification, 121 serum samples were included for dose–response analysis. Based on a linear mixed‐effects model, secukinumab trough concentrations were found to decrease with increasing body mass index (BMI). Based on receiver operating characteristic (ROC) analysis, we concluded that the minimal effective secukinumab threshold was 39.1 mg/L in steady state, and that this was associated with a 92.7% probability of having an optimal clinical response (PASI ≤ 2 or reduction in PASI of ≥ 90%). Conclusions Monitoring and targeting a secukinumab trough concentration of 39.1 mg/L may be a viable treatment option in suboptimal responders. In patients with higher BMI, weight‐based dosing may be needed in order to prevent underdosing.

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“…IL-17A can be selectively inhibited by secukinumab, a fully human monoclonal IgG1/κ antibody (mAb), which has been approved to treat moderate-to-severe plaque psoriasis, psoriatic arthritis, as well as ankylosing and axial spondyloarthritis [ 10 , 11 ]. Recent reports have shown that as early as one week after initiation of secukinumab treatment, major changes occurred in psoriasis-related transcripts, along with improved clinical scores and histologic psoriasis features at week 12 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Global circRNA expression changes predate clinical and histological improvements of psoriasis patients upon secukinumab treatment

et al. 2022

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Psoriasis is a common chronic inflammatory skin disease accompanied by heterogenous clinical and histological features, including a characteristic keratinocyte hyperproliferation and dermal immunogenic profile. In addition, psoriasis is associated with widespread transcriptomic alterations including changes in microRNA (miRNA) and circular RNA (circRNA) abundance, which constitute non-coding RNA (ncRNA) classes with specific regulatory capacities in diverse physiological and pathological processes. However, the knowledge about the expression dynamics of ncRNA during psoriasis treatment is sparse. To elucidate the dynamics of miRNA and circRNA abundance during secukinumab (anti-IL-17A) treatment, we studied their expression patterns in skin biopsies from 14 patients with severe plaque-type psoriasis before and during an 84-day secukinumab therapy at day 0, 4, 14, 42, and 84 using NanoString nCounter technology. We found a comprehensive downregulation of the majority of investigated circRNAs and specific alterations in the miRNA profile, including an upregulation of miR-203a-3p, miR-93-5p, and miR-378i in lesional compared to non-lesional skin before treatment. During treatment, the circRNAs progressively returned to the expression levels observed in non-lesional skin and already four days after treatment initiation most circRNAs were significantly upregulated. In comparison, for miRNAs, the normalization to baseline during treatment was delayed and limited to a subset of miRNAs. Moreover, we observed a strong correlation between multiple circRNAs, including ciRS-7 and circPTPRA, and the psoriasis area and severity index (PASI). Similar pronounced correlations could, however, not be found for miRNAs. Finally, we did not observe any significant changes in circRNA expression in peripheral blood mononuclear cells during treatment. In conclusion, we uncovered a rapid shift in global circRNA abundance upon anti-IL-17A treatment, which predated clinical and histological improvements, and a strong correlation with PASI, indicating a biomarker potential of individual circRNAs.

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Secukinumab for the treatment of psoriasis, psoriatic arthritis, and axial spondyloarthritis: Physical and pharmacological properties underlie the observed clinical efficacy and safety

Cited by 25 publications

References 109 publications

Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines

Therapeutic drug monitoring in dermatology: the way towards dose optimization of secukinumab in chronic plaque psoriasis

Global circRNA expression changes predate clinical and histological improvements of psoriasis patients upon secukinumab treatment

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