Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
Abstract Introduction Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine stu...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Adis, Springer Healthcare
2024-02-01
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| Series: | Dermatology and Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s13555-024-01097-0 |
| _version_ | 1797275829905915904 |
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| author | Valerie J. Ludbrook David C. Budd Katie Thorn Debra Tompson Bartholomew J. Votta Lucy Walker Amy Lee Xin Chen Amanda Peppercorn Wei Jing Loo |
| author_facet | Valerie J. Ludbrook David C. Budd Katie Thorn Debra Tompson Bartholomew J. Votta Lucy Walker Amy Lee Xin Chen Amanda Peppercorn Wei Jing Loo |
| author_sort | Valerie J. Ludbrook |
| collection | DOAJ |
| description | Abstract Introduction Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. Methods This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. Results GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of − 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Conclusion Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements. |
| first_indexed | 2024-03-07T15:18:42Z |
| format | Article |
| id | doaj.art-1b2c7392c4ac4a949714b6dc004b1758 |
| institution | Directory Open Access Journal |
| issn | 2193-8210 2190-9172 |
| language | English |
| last_indexed | 2024-03-07T15:18:42Z |
| publishDate | 2024-02-01 |
| publisher | Adis, Springer Healthcare |
| record_format | Article |
| series | Dermatology and Therapy |
| spelling | doaj.art-1b2c7392c4ac4a949714b6dc004b17582024-03-05T17:44:46ZengAdis, Springer HealthcareDermatology and Therapy2193-82102190-91722024-02-0114248950410.1007/s13555-024-01097-0Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled StudyValerie J. Ludbrook0David C. Budd1Katie Thorn2Debra Tompson3Bartholomew J. Votta4Lucy Walker5Amy Lee6Xin Chen7Amanda Peppercorn8Wei Jing Loo9Clinical Pharmacology and Experimental Medicine, GSKMedicines Research Centre, GSKBiostatistics, GSKClinical Pharmacology Modelling and Simulation, GSKClinical Pharmacology and Experimental Medicine, GSKClinical Pharmacology and Experimental Medicine, GSKRx Global Clinical Delivery, GSKRx Global Clinical Delivery, GSKClinical Development, GSKDermEffectsAbstract Introduction Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. Methods This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. Results GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of − 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. Conclusion Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.https://doi.org/10.1007/s13555-024-01097-0PsoriasisRIP1KPharmacokineticsPharmacodynamicsPASI |
| spellingShingle | Valerie J. Ludbrook David C. Budd Katie Thorn Debra Tompson Bartholomew J. Votta Lucy Walker Amy Lee Xin Chen Amanda Peppercorn Wei Jing Loo Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Dermatology and Therapy Psoriasis RIP1K Pharmacokinetics Pharmacodynamics PASI |
| title | Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study |
| title_full | Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study |
| title_fullStr | Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study |
| title_full_unstemmed | Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study |
| title_short | Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study |
| title_sort | inhibition of receptor interacting protein kinase 1 in chronic plaque psoriasis a multicenter randomized double blind placebo controlled study |
| topic | Psoriasis RIP1K Pharmacokinetics Pharmacodynamics PASI |
| url | https://doi.org/10.1007/s13555-024-01097-0 |
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