Pub Date : 2016-11-01DOI: 10.1358/dot.2016.52.11.2526754
R. Speeckaert, N. van Geel, J. Lambert, L. Claeys, J. Delanghe, M. Speeckaert
Interleukin-17A is an important cytokine in the pathogenesis of psoriatic arthritis. Secukinumab is a recombinant, high-affinity, fully human immunoglobulin G1kappa monoclonal antibody with a selective binding and neutralization of interleukin-17A. By providing an alternative mechanism of action to current treatments, secukinumab has shown efficacy in the key clinical domains of psoriatic arthritis. In the present paper, we discuss the role of interleukin-17A as a clinically relevant target in the treatment of psoriatic arthritis, based on preclinical findings, dose-ranging and regimen-finding, randomized, placebo-controlled clinical trials.
{"title":"Secukinumab: IL-17A inhibition to treat psoriatic arthritis.","authors":"R. Speeckaert, N. van Geel, J. Lambert, L. Claeys, J. Delanghe, M. Speeckaert","doi":"10.1358/dot.2016.52.11.2526754","DOIUrl":"https://doi.org/10.1358/dot.2016.52.11.2526754","url":null,"abstract":"Interleukin-17A is an important cytokine in the pathogenesis of psoriatic arthritis. Secukinumab is a recombinant, high-affinity, fully human immunoglobulin G1kappa monoclonal antibody with a selective binding and neutralization of interleukin-17A. By providing an alternative mechanism of action to current treatments, secukinumab has shown efficacy in the key clinical domains of psoriatic arthritis. In the present paper, we discuss the role of interleukin-17A as a clinically relevant target in the treatment of psoriatic arthritis, based on preclinical findings, dose-ranging and regimen-finding, randomized, placebo-controlled clinical trials.","PeriodicalId":85144,"journal":{"name":"Medicamentos de actualidad. Drugs of today","volume":"52 11 1","pages":"607-616"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66455302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-01DOI: 10.1358/dot.2016.52.11.2546852
R. Sampath, J. Zeuli, S. Rizza, Z. Temesgen
Tenofovir alafenamide fumarate is a recently developed prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor with potent inhibitory activity against HIV. The utility of a previously developed tenofovir prodrug, tenofovir disoproxil fumarate, had been hampered by renal and bone mineral adverse events. Tenofovir alafenamide fumarate overcomes the shortcomings of tenofovir disoproxil fumarate by delivering high intracellular concentrations of the parent drug, tenofovir, while substantially reducing systemic exposure. Tenofovir alafenamide fumarate is currently available as a component of three fixed-dose products: i) coformulation with emtricitabine; ii) coformulation with elvitegravir, cobicistat and emtricitabine; and iii) coformulation with rilpivirine and emtricitabine.
{"title":"Tenofovir alafenamide fumarate for the treatment of HIV infection.","authors":"R. Sampath, J. Zeuli, S. Rizza, Z. Temesgen","doi":"10.1358/dot.2016.52.11.2546852","DOIUrl":"https://doi.org/10.1358/dot.2016.52.11.2546852","url":null,"abstract":"Tenofovir alafenamide fumarate is a recently developed prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor with potent inhibitory activity against HIV. The utility of a previously developed tenofovir prodrug, tenofovir disoproxil fumarate, had been hampered by renal and bone mineral adverse events. Tenofovir alafenamide fumarate overcomes the shortcomings of tenofovir disoproxil fumarate by delivering high intracellular concentrations of the parent drug, tenofovir, while substantially reducing systemic exposure. Tenofovir alafenamide fumarate is currently available as a component of three fixed-dose products: i) coformulation with emtricitabine; ii) coformulation with elvitegravir, cobicistat and emtricitabine; and iii) coformulation with rilpivirine and emtricitabine.","PeriodicalId":85144,"journal":{"name":"Medicamentos de actualidad. Drugs of today","volume":"52 11 1","pages":"617-625"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66455665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-11-01DOI: 10.1358/dot.2016.52.11.2542234
J. Eagles, A. Jimeno
Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.
{"title":"Cobimetinib: inhibiting MEK1/2 in BRAF V600-mutant melanoma.","authors":"J. Eagles, A. Jimeno","doi":"10.1358/dot.2016.52.11.2542234","DOIUrl":"https://doi.org/10.1358/dot.2016.52.11.2542234","url":null,"abstract":"Historically, metastatic melanoma has had extremely poor survival outcomes. The outlook, however, is rapidly changing as new molecularly targeted therapies have vastly improved patient outcomes. One such therapy is the potent mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor cobimetinib. Recently, cobimetinib was approved for the treatment of metastatic or unresectable melanoma with serine/threonine-protein kinase B-raf (BRAF) V600E or V600K mutations when used in combination with the BRAF inhibitor vemurafenib. Currently, multiple clinical trials are investigating this drug combination for the treatment of various cancer types (e.g., breast, melanoma, colorectal). In the phase III coBRIM trial, this combination therapy showed improved melanoma response rates and patient progression-free survival when compared to vemurafenib alone. Additionally, toxicities were generally found to be manageable with dose modification or interruption. However, tumor response to BRAF/MEK inhibition, though rapid, is often short-lived as tumors develop resistance to this combination therapy. Therefore, new trials are beginning to investigate the addition of a third targeted agent or immunotherapy in order to increase the durability of treatment response. These trials are already showing promising preliminary results.","PeriodicalId":85144,"journal":{"name":"Medicamentos de actualidad. Drugs of today","volume":"52 11 1","pages":"593-605"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66455474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-10-01DOI: 10.1358/DOT.2016.52.10.2543308
C. Xia, M. Ribeiro, S. Scott, S. Lonial
Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed. Given the encouraging efficacy and acceptable safety profile, daratumumab has emerged as a novel treatment option for MM both as a monotherapy and in combination with conventional and novel anti-MM agents. This review will focus on preclinical pharmacology, pharmacokinetics, safety and clinical development of daratumumab in MM.
{"title":"Daratumumab: monoclonal antibody therapy to treat multiple myeloma.","authors":"C. Xia, M. Ribeiro, S. Scott, S. Lonial","doi":"10.1358/DOT.2016.52.10.2543308","DOIUrl":"https://doi.org/10.1358/DOT.2016.52.10.2543308","url":null,"abstract":"Daratumumab (Darzalex[TM]) is a human monoclonal antibody (MAb) that targets CD38; a surface protein highly expressed across multiple myeloma (MM) cells. Preclinical studies have shown daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC) antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), apoptosis upon secondary crosslinking and immunomodulatory effects via a decrease in immune suppressive cells. Daratumumab has a favorable toxicity profile and encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) and stem cell transplant have already failed. Given the encouraging efficacy and acceptable safety profile, daratumumab has emerged as a novel treatment option for MM both as a monotherapy and in combination with conventional and novel anti-MM agents. This review will focus on preclinical pharmacology, pharmacokinetics, safety and clinical development of daratumumab in MM.","PeriodicalId":85144,"journal":{"name":"Medicamentos de actualidad. Drugs of today","volume":"52 10 1","pages":"551-560"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66455618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-10-01DOI: 10.1358/DOT.2016.52.10.2525742
J. Gras
Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease characterized by inflammation and joint destruction, is associated with pain, progressive disability, systemic comorbidities and early death. Conventional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs (bDMARDs) have been able to achieve remission or a very low disease activity status for RA. Nevertheless, since many patients do not reach a sufficient response with DMARDs or present with unacceptable side effects, new therapies are needed. Baricitinib (LY-3009104, INCB-028050), a new potent and selective tyrosine-protein kinase JAK1/JAK2 inhibitor, has shown clinical efficacy in patients with RA refractory to aggressive standard-of-care treatment (with both conventional DMARDs and bDMARDs) when administered orally at 4 mg q.d. in pivotal phase III clinical trials. In these studies, radiographic joint damage assessments showed significant improvements with baricitinib, and the drug was well tolerated with no unexpected safety findings. A phase III study aimed at assessing long-term (4 years) safety and efficacy of baricitinib is ongoing. Registration processes are ongoing in Europe, the U.S. and Japan.
{"title":"Baricitinib: JAK inhibition for rheumatoid arthritis.","authors":"J. Gras","doi":"10.1358/DOT.2016.52.10.2525742","DOIUrl":"https://doi.org/10.1358/DOT.2016.52.10.2525742","url":null,"abstract":"Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease characterized by inflammation and joint destruction, is associated with pain, progressive disability, systemic comorbidities and early death. Conventional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs (bDMARDs) have been able to achieve remission or a very low disease activity status for RA. Nevertheless, since many patients do not reach a sufficient response with DMARDs or present with unacceptable side effects, new therapies are needed. Baricitinib (LY-3009104, INCB-028050), a new potent and selective tyrosine-protein kinase JAK1/JAK2 inhibitor, has shown clinical efficacy in patients with RA refractory to aggressive standard-of-care treatment (with both conventional DMARDs and bDMARDs) when administered orally at 4 mg q.d. in pivotal phase III clinical trials. In these studies, radiographic joint damage assessments showed significant improvements with baricitinib, and the drug was well tolerated with no unexpected safety findings. A phase III study aimed at assessing long-term (4 years) safety and efficacy of baricitinib is ongoing. Registration processes are ongoing in Europe, the U.S. and Japan.","PeriodicalId":85144,"journal":{"name":"Medicamentos de actualidad. Drugs of today","volume":"52 10 1","pages":"543-550"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66455599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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