Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial
Background Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype. Objective To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD). Methods PRESENCE was a phase 2, 12‐week study in participants wi...
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| Veröffentlicht in: | Movement disorders 2022-03, Vol.37 (3), p.513-524 |
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| creator | Biglan, Kevin Munsie, Leanne Svensson, Kjell A. Ardayfio, Paul Pugh, Melissa Sims, John Brys, Miroslaw |
| description | Background
Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.
Objective
To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).
Methods
PRESENCE was a phase 2, 12‐week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13 (ADAS‐cog13), Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC). Numerous safety measures were collected.
Results
Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose‐dependent improvements of MDS‐UPDRS total score (sum of Parts I−III, 10 mg P |
| doi_str_mv | 10.1002/mds.28879 |
| format | Article |
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Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.
Objective
To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).
Methods
PRESENCE was a phase 2, 12‐week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13 (ADAS‐cog13), Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC). Numerous safety measures were collected.
Results
Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose‐dependent improvements of MDS‐UPDRS total score (sum of Parts I−III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS‐CGIC scores compared to placebo (minimal or better improvement: 30 mg P < 0.01, 75 mg P < 0.01; moderate or better improvement: 30 mg P < 0.05, 75 mg P < 0.001). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose.
Conclusions
Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non‐motor symptoms associated with traditional dopaminergic therapy. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society]]></description><identifier>ISSN: 0885-3185</identifier><identifier>EISSN: 1531-8257</identifier><identifier>DOI: 10.1002/mds.28879</identifier><identifier>PMID: 34859493</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Adverse events ; Allosteric properties ; Alzheimer Disease ; Alzheimer's disease ; Blood pressure ; Cognition ; Cognition & reasoning ; Cognitive ability ; Dementia ; Dementia disorders ; dopamine D1 receptor ; Dopamine D1 receptors ; Double-Blind Method ; Humans ; Lewy bodies ; Lewy body dementia ; Lewy Body Disease - drug therapy ; motor impairment ; Movement disorders ; Neurodegenerative diseases ; Neuroprotective Agents - therapeutic use ; Parkinson's disease ; Placebos ; Regular Issue ; Safety ; selective positive allosteric modulator (PAM)</subject><ispartof>Movement disorders, 2022-03, Vol.37 (3), p.513-524</ispartof><rights>2021 The Authors. published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society</rights><rights>2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4439-7c754642e10df961f63dccbb7017ce2f5bb9b32132fc546cf647be2fda6cb5233</citedby><cites>FETCH-LOGICAL-c4439-7c754642e10df961f63dccbb7017ce2f5bb9b32132fc546cf647be2fda6cb5233</cites><orcidid>0000-0001-5114-3755</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fmds.28879$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fmds.28879$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34859493$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Biglan, Kevin</creatorcontrib><creatorcontrib>Munsie, Leanne</creatorcontrib><creatorcontrib>Svensson, Kjell A.</creatorcontrib><creatorcontrib>Ardayfio, Paul</creatorcontrib><creatorcontrib>Pugh, Melissa</creatorcontrib><creatorcontrib>Sims, John</creatorcontrib><creatorcontrib>Brys, Miroslaw</creatorcontrib><title>Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial</title><title>Movement disorders</title><addtitle>Mov Disord</addtitle><description><![CDATA[Background
Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.
Objective
To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).
Methods
PRESENCE was a phase 2, 12‐week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13 (ADAS‐cog13), Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC). Numerous safety measures were collected.
Results
Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose‐dependent improvements of MDS‐UPDRS total score (sum of Parts I−III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS‐CGIC scores compared to placebo (minimal or better improvement: 30 mg P < 0.01, 75 mg P < 0.01; moderate or better improvement: 30 mg P < 0.05, 75 mg P < 0.001). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose.
Conclusions
Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non‐motor symptoms associated with traditional dopaminergic therapy. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society]]></description><subject>Adverse events</subject><subject>Allosteric properties</subject><subject>Alzheimer Disease</subject><subject>Alzheimer's disease</subject><subject>Blood pressure</subject><subject>Cognition</subject><subject>Cognition & reasoning</subject><subject>Cognitive ability</subject><subject>Dementia</subject><subject>Dementia disorders</subject><subject>dopamine D1 receptor</subject><subject>Dopamine D1 receptors</subject><subject>Double-Blind Method</subject><subject>Humans</subject><subject>Lewy bodies</subject><subject>Lewy body dementia</subject><subject>Lewy Body Disease - drug therapy</subject><subject>motor impairment</subject><subject>Movement disorders</subject><subject>Neurodegenerative diseases</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Parkinson's disease</subject><subject>Placebos</subject><subject>Regular Issue</subject><subject>Safety</subject><subject>selective positive allosteric modulator (PAM)</subject><issn>0885-3185</issn><issn>1531-8257</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1OFTEYhhsjkSO68AZMEzeaMNCf6cyUhQkeEE0OkQium077VUo6U2zPgQwrLsFr9EosHiRq4qrJ1-d78rYvQi8o2aGEsN3B5h3Wda18hGZUcFp1TLSP0Yx0nag47cQmeprzBSGUCto8QZu87oSsJZ8hf6odLCesR4sPnfNGmwlHh4_hylsdYMR-xAu4nvC7aCd8AAOMS6_38D4-OdcZMNvGn8tyHPwN2G18ErSBPv64_T6P4zLFEMDis-R1eIY2nA4Znt-fW-jL-8Oz-Ydq8eno43x_UZm65rJqTSvqpmZAiXWyoa7h1pi-bwltDTAn-l72nFHOnCmgcU3d9mVudWN6wTjfQm_X3stVP4A1JW_SQV0mP-g0qai9-vtm9Ofqa7xSkpcPqpsieH0vSPHbCvJSDT4bCEGPEFdZsYY0kjEpRUFf_YNexFUay_MKVVPedpLcUW_WlEkx5wTuIQwl6q5AVQpUvwos7Ms_0z-QvxsrwO4auPYBpv-b1PHB6Vr5E-uPpb4</recordid><startdate>202203</startdate><enddate>202203</enddate><creator>Biglan, Kevin</creator><creator>Munsie, Leanne</creator><creator>Svensson, Kjell A.</creator><creator>Ardayfio, Paul</creator><creator>Pugh, Melissa</creator><creator>Sims, John</creator><creator>Brys, Miroslaw</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>24P</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>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5114-3755</orcidid></search><sort><creationdate>202203</creationdate><title>Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial</title><author>Biglan, Kevin ; Munsie, Leanne ; Svensson, Kjell A. ; Ardayfio, Paul ; Pugh, Melissa ; Sims, John ; Brys, Miroslaw</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4439-7c754642e10df961f63dccbb7017ce2f5bb9b32132fc546cf647be2fda6cb5233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adverse events</topic><topic>Allosteric properties</topic><topic>Alzheimer Disease</topic><topic>Alzheimer's disease</topic><topic>Blood pressure</topic><topic>Cognition</topic><topic>Cognition & reasoning</topic><topic>Cognitive ability</topic><topic>Dementia</topic><topic>Dementia disorders</topic><topic>dopamine D1 receptor</topic><topic>Dopamine D1 receptors</topic><topic>Double-Blind Method</topic><topic>Humans</topic><topic>Lewy bodies</topic><topic>Lewy body dementia</topic><topic>Lewy Body Disease - drug therapy</topic><topic>motor impairment</topic><topic>Movement disorders</topic><topic>Neurodegenerative diseases</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Parkinson's disease</topic><topic>Placebos</topic><topic>Regular Issue</topic><topic>Safety</topic><topic>selective positive allosteric modulator (PAM)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Biglan, Kevin</creatorcontrib><creatorcontrib>Munsie, Leanne</creatorcontrib><creatorcontrib>Svensson, Kjell A.</creatorcontrib><creatorcontrib>Ardayfio, Paul</creatorcontrib><creatorcontrib>Pugh, Melissa</creatorcontrib><creatorcontrib>Sims, John</creatorcontrib><creatorcontrib>Brys, Miroslaw</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Movement disorders</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Biglan, Kevin</au><au>Munsie, Leanne</au><au>Svensson, Kjell A.</au><au>Ardayfio, Paul</au><au>Pugh, Melissa</au><au>Sims, John</au><au>Brys, Miroslaw</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial</atitle><jtitle>Movement disorders</jtitle><addtitle>Mov Disord</addtitle><date>2022-03</date><risdate>2022</risdate><volume>37</volume><issue>3</issue><spage>513</spage><epage>524</epage><pages>513-524</pages><issn>0885-3185</issn><eissn>1531-8257</eissn><abstract><![CDATA[Background
Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype.
Objective
To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD).
Methods
PRESENCE was a phase 2, 12‐week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13 (ADAS‐cog13), Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), and Alzheimer's Disease Cooperative Study‐Clinical Global Impression of Change (ADCS‐CGIC). Numerous safety measures were collected.
Results
Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose‐dependent improvements of MDS‐UPDRS total score (sum of Parts I−III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS‐CGIC scores compared to placebo (minimal or better improvement: 30 mg P < 0.01, 75 mg P < 0.01; moderate or better improvement: 30 mg P < 0.05, 75 mg P < 0.001). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose.
Conclusions
Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non‐motor symptoms associated with traditional dopaminergic therapy. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society]]></abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>34859493</pmid><doi>10.1002/mds.28879</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-5114-3755</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Movement disorders, 2022-03, Vol.37 (3), p.513-524 |
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| subjects | Adverse events Allosteric properties Alzheimer Disease Alzheimer's disease Blood pressure Cognition Cognition & reasoning Cognitive ability Dementia Dementia disorders dopamine D1 receptor Dopamine D1 receptors Double-Blind Method Humans Lewy bodies Lewy body dementia Lewy Body Disease - drug therapy motor impairment Movement disorders Neurodegenerative diseases Neuroprotective Agents - therapeutic use Parkinson's disease Placebos Regular Issue Safety selective positive allosteric modulator (PAM) |
| title | Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo‐Controlled Trial |
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