Response to Inhibition of Receptor‐Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo‐Controlled Study
Receptor‐interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune‐mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double‐blind, placebo‐controlled study was to evaluate safety, toler...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2020-10, Vol.108 (4), p.808-816 |
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| container_title | Clinical pharmacology and therapeutics |
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| creator | Weisel, Kathleen Berger, Scott Papp, Kim Maari, Catherine Krueger, James G. Scott, Nicola Tompson, Debra Wang, Susanne Simeoni, Monica Bertin, John Peter Tak, Paul |
| description | Receptor‐interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune‐mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double‐blind, placebo‐controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque‐type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug‐related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs. |
| doi_str_mv | 10.1002/cpt.1852 |
| format | Article |
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The objective of this phase IIa multicenter, randomized, double‐blind, placebo‐controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque‐type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug‐related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1002/cpt.1852</identifier><identifier>PMID: 32301501</identifier><language>eng</language><publisher>United States: John Wiley and Sons Inc</publisher><subject>Adult ; Canada ; CD3 Complex - metabolism ; Dermis - drug effects ; Dermis - enzymology ; Dermis - immunology ; Dermis - pathology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Oxazepines - adverse effects ; Oxazepines - therapeutic use ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - therapeutic use ; Psoriasis - diagnosis ; Psoriasis - drug therapy ; Psoriasis - enzymology ; Psoriasis - immunology ; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors ; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism ; Remission Induction ; Signal Transduction ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Time Factors ; Treatment Outcome ; Triazoles - adverse effects ; Triazoles - therapeutic use</subject><ispartof>Clinical pharmacology and therapeutics, 2020-10, Vol.108 (4), p.808-816</ispartof><rights>2020 GlaxoSmithKline. published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.</rights><rights>2020 GlaxoSmithKline. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4762-d3835b112f6156909104de80d39822cd0e0e0a9cc85c2f7e6590c2bef1e994783</citedby><cites>FETCH-LOGICAL-c4762-d3835b112f6156909104de80d39822cd0e0e0a9cc85c2f7e6590c2bef1e994783</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcpt.1852$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcpt.1852$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,882,1412,27905,27906,45555,45556</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32301501$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Weisel, Kathleen</creatorcontrib><creatorcontrib>Berger, Scott</creatorcontrib><creatorcontrib>Papp, Kim</creatorcontrib><creatorcontrib>Maari, Catherine</creatorcontrib><creatorcontrib>Krueger, James G.</creatorcontrib><creatorcontrib>Scott, Nicola</creatorcontrib><creatorcontrib>Tompson, Debra</creatorcontrib><creatorcontrib>Wang, Susanne</creatorcontrib><creatorcontrib>Simeoni, Monica</creatorcontrib><creatorcontrib>Bertin, John</creatorcontrib><creatorcontrib>Peter Tak, Paul</creatorcontrib><title>Response to Inhibition of Receptor‐Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo‐Controlled Study</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>Receptor‐interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune‐mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double‐blind, placebo‐controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque‐type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug‐related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.</description><subject>Adult</subject><subject>Canada</subject><subject>CD3 Complex - metabolism</subject><subject>Dermis - drug effects</subject><subject>Dermis - enzymology</subject><subject>Dermis - immunology</subject><subject>Dermis - pathology</subject><subject>Double-Blind Method</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Oxazepines - adverse effects</subject><subject>Oxazepines - therapeutic use</subject><subject>Protein Kinase Inhibitors - adverse effects</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Psoriasis - diagnosis</subject><subject>Psoriasis - drug therapy</subject><subject>Psoriasis - enzymology</subject><subject>Psoriasis - immunology</subject><subject>Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</subject><subject>Remission Induction</subject><subject>Signal Transduction</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>Triazoles - adverse effects</subject><subject>Triazoles - therapeutic use</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc9OGzEQhy1UBIFW4gmQj3BY8J_1Zt1DpSgqJQKpUUrPltc7C6429tZ2qMKJF6jUZ-yT4BCK2kPlw8gz33y29EPoiJIzSgg7N0M6o7VgO2hEBWdFJbh4g0aEEFlIxqt9dBDjt3wtZV3voX3OOKGC0BH6uYA4eBcBJ49n7s42NlnvsO_wAgwMyYffj79mLkHQJll3i-fBJ7AOX1mn8xrFJ4vZ_Iqe4tybZOQe8LzX31e5RB-sjja-xxO80K71S_sA7WZsoPHZO_UuBd_3ufklrdr1W7Tb6T7Cu5d6iL5efLyZXhbXnz_NppPrwpTjihUtr7loKGVdRUUliaSkbKEmLZc1Y6YlkI-WxtTCsG4MlZDEsAY6ClKW45ofog9b77BqltAayN_QvRqCXeqwVl5b9e_E2Tt16-_VWJSEM5YFJ1uBCT7GAN3rLiVqE4nKkahNJBk9_vutV_BPBhkotsAP28P6vyI1nd88C58AkECY9Q</recordid><startdate>202010</startdate><enddate>202010</enddate><creator>Weisel, Kathleen</creator><creator>Berger, Scott</creator><creator>Papp, Kim</creator><creator>Maari, Catherine</creator><creator>Krueger, James G.</creator><creator>Scott, Nicola</creator><creator>Tompson, Debra</creator><creator>Wang, Susanne</creator><creator>Simeoni, Monica</creator><creator>Bertin, John</creator><creator>Peter Tak, Paul</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>202010</creationdate><title>Response to Inhibition of Receptor‐Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo‐Controlled Study</title><author>Weisel, Kathleen ; Berger, Scott ; Papp, Kim ; Maari, Catherine ; Krueger, James G. ; Scott, Nicola ; Tompson, Debra ; Wang, Susanne ; Simeoni, Monica ; Bertin, John ; Peter Tak, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4762-d3835b112f6156909104de80d39822cd0e0e0a9cc85c2f7e6590c2bef1e994783</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>Canada</topic><topic>CD3 Complex - metabolism</topic><topic>Dermis - drug effects</topic><topic>Dermis - enzymology</topic><topic>Dermis - immunology</topic><topic>Dermis - pathology</topic><topic>Double-Blind Method</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Oxazepines - adverse effects</topic><topic>Oxazepines - therapeutic use</topic><topic>Protein Kinase Inhibitors - adverse effects</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Psoriasis - diagnosis</topic><topic>Psoriasis - drug therapy</topic><topic>Psoriasis - enzymology</topic><topic>Psoriasis - immunology</topic><topic>Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</topic><topic>Remission Induction</topic><topic>Signal Transduction</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>Triazoles - adverse effects</topic><topic>Triazoles - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Weisel, Kathleen</creatorcontrib><creatorcontrib>Berger, Scott</creatorcontrib><creatorcontrib>Papp, Kim</creatorcontrib><creatorcontrib>Maari, Catherine</creatorcontrib><creatorcontrib>Krueger, James G.</creatorcontrib><creatorcontrib>Scott, Nicola</creatorcontrib><creatorcontrib>Tompson, Debra</creatorcontrib><creatorcontrib>Wang, Susanne</creatorcontrib><creatorcontrib>Simeoni, Monica</creatorcontrib><creatorcontrib>Bertin, John</creatorcontrib><creatorcontrib>Peter Tak, Paul</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Weisel, Kathleen</au><au>Berger, Scott</au><au>Papp, Kim</au><au>Maari, Catherine</au><au>Krueger, James G.</au><au>Scott, Nicola</au><au>Tompson, Debra</au><au>Wang, Susanne</au><au>Simeoni, Monica</au><au>Bertin, John</au><au>Peter Tak, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Response to Inhibition of Receptor‐Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo‐Controlled Study</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2020-10</date><risdate>2020</risdate><volume>108</volume><issue>4</issue><spage>808</spage><epage>816</epage><pages>808-816</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><abstract>Receptor‐interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune‐mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double‐blind, placebo‐controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque‐type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug‐related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.</abstract><cop>United States</cop><pub>John Wiley and Sons Inc</pub><pmid>32301501</pmid><doi>10.1002/cpt.1852</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical pharmacology and therapeutics, 2020-10, Vol.108 (4), p.808-816 |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adult Canada CD3 Complex - metabolism Dermis - drug effects Dermis - enzymology Dermis - immunology Dermis - pathology Double-Blind Method Female Humans Male Middle Aged Oxazepines - adverse effects Oxazepines - therapeutic use Protein Kinase Inhibitors - adverse effects Protein Kinase Inhibitors - therapeutic use Psoriasis - diagnosis Psoriasis - drug therapy Psoriasis - enzymology Psoriasis - immunology Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Remission Induction Signal Transduction T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism Time Factors Treatment Outcome Triazoles - adverse effects Triazoles - therapeutic use |
| title | Response to Inhibition of Receptor‐Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo‐Controlled Study |
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