Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial
Aims Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. Methods and results We studied the effects...
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| Veröffentlicht in: | European journal of heart failure 2020-09, Vol.22 (9), p.1649-1658 |
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| creator | Voors, Adriaan A. Tamby, Jean‐François Cleland, John G. Koren, Michael Forgosh, Leslie B. Gupta, Dinesh Lund, Lars H. Camacho, Albert Karra, Ravi Swart, Henk P. Pellicori, Pierpaolo Wagner, Frank Hershberger, Ray E. Prasad, Narayana Anderson, Robert Anto, Anu Bell, Kaylyn Edelberg, Jay M. Fang, Liang Henze, Marcus Kelly, Cynthia Kurio, Gregory Li, Wanying Wells, Kate Yang, Chun Teichman, Sam L. Rio, Carlos L. Solomon, Scott D. |
| description | Aims
Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.
Methods and results
We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P |
| doi_str_mv | 10.1002/ejhf.1933 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_swepu</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_470377</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2415283063</sourcerecordid><originalsourceid>FETCH-LOGICAL-c6133-67e402089d78da4484142918691bd71f691ea21d321621f0334387581e5000b63</originalsourceid><addsrcrecordid>eNp1ksFu1DAQhiMEoqVw4AWQjyA1rR07ic0BCVXbFlSJC5ytWWfMenHixU522RfiOevtbgs99OSx5_v_f2RNUbxl9IxRWp3jcmHPmOL8WXHMZKtKKoV4nmsuZamkqI6KVyktKWVtxl8WR7yqa6mkOi7-zqxFMyYSLOlgcAb60a1PCZAhrNETA7FzYEi_DckNBEzuwhjiKcm3BUIciQXnp4hk48YFidhNBjuCy-zqwkBshLviI8E_K4yux2EEn7NGIDB0xHi3S_VZmSafB7Ex9Dl-tYCEpAIyRgf-dfHCgk_45nCeFD8uZ98vrsubb1dfLj7flKZhnJdNi4JWVKqulR0IIQUTlWKyUWzetczmE6FiHa9YUzFLORdctrVkWFNK5w0_Kcq9b9rgaprrVR4Y4lYHcPrw9CtXqEVLedtmXj3Jr2Lo_onuhUwIlsNVnbWf9toM9NiZ_DER_GOLR53BLfTPsNZtI1Vbs2zw_mAQw-8J06h7lwx6DwOGKelKsLqSnDY8ox_2qIkhpYj2IYZRvdshvdshvduhzL77f64H8n5pMnC-BzbO4_ZpJz37en15Z3kLpPDUnw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2415283063</pqid></control><display><type>article</type><title>Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>SWEPUB Freely available online</source><source>Access via Wiley Online Library</source><source>Wiley Online Library (Open Access Collection)</source><creator>Voors, Adriaan A. ; Tamby, Jean‐François ; Cleland, John G. ; Koren, Michael ; Forgosh, Leslie B. ; Gupta, Dinesh ; Lund, Lars H. ; Camacho, Albert ; Karra, Ravi ; Swart, Henk P. ; Pellicori, Pierpaolo ; Wagner, Frank ; Hershberger, Ray E. ; Prasad, Narayana ; Anderson, Robert ; Anto, Anu ; Bell, Kaylyn ; Edelberg, Jay M. ; Fang, Liang ; Henze, Marcus ; Kelly, Cynthia ; Kurio, Gregory ; Li, Wanying ; Wells, Kate ; Yang, Chun ; Teichman, Sam L. ; Rio, Carlos L. ; Solomon, Scott D.</creator><creatorcontrib>Voors, Adriaan A. ; Tamby, Jean‐François ; Cleland, John G. ; Koren, Michael ; Forgosh, Leslie B. ; Gupta, Dinesh ; Lund, Lars H. ; Camacho, Albert ; Karra, Ravi ; Swart, Henk P. ; Pellicori, Pierpaolo ; Wagner, Frank ; Hershberger, Ray E. ; Prasad, Narayana ; Anderson, Robert ; Anto, Anu ; Bell, Kaylyn ; Edelberg, Jay M. ; Fang, Liang ; Henze, Marcus ; Kelly, Cynthia ; Kurio, Gregory ; Li, Wanying ; Wells, Kate ; Yang, Chun ; Teichman, Sam L. ; Rio, Carlos L. ; Solomon, Scott D.</creatorcontrib><description><![CDATA[Aims
Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.
Methods and results
We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.
Conclusions
Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.]]></description><identifier>ISSN: 1388-9842</identifier><identifier>ISSN: 1879-0844</identifier><identifier>EISSN: 1879-0844</identifier><identifier>DOI: 10.1002/ejhf.1933</identifier><identifier>PMID: 32558989</identifier><language>eng</language><publisher>Oxford, UK: John Wiley & Sons, Ltd</publisher><subject>Aged ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Animals ; Cardiac myosin activator ; Cardiac Myosins ; Clinical trial ; Danicamtiv ; Dogs ; Echocardiography ; Female ; Heart Failure - drug therapy ; Heart failure with reduced ejection fraction ; Humans ; Male ; Medicin och hälsovetenskap ; Middle Aged ; Myotrope ; Stroke Volume ; TREATMENT OF HFrEF ; Ventricular Function, Left</subject><ispartof>European journal of heart failure, 2020-09, Vol.22 (9), p.1649-1658</ispartof><rights>2020 The Authors. published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.</rights><rights>2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6133-67e402089d78da4484142918691bd71f691ea21d321621f0334387581e5000b63</citedby><cites>FETCH-LOGICAL-c6133-67e402089d78da4484142918691bd71f691ea21d321621f0334387581e5000b63</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%2Fejhf.1933$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fejhf.1933$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,315,553,781,785,886,1418,1434,27926,27927,45576,45577,46411,46835</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32558989$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:144116295$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Voors, Adriaan A.</creatorcontrib><creatorcontrib>Tamby, Jean‐François</creatorcontrib><creatorcontrib>Cleland, John G.</creatorcontrib><creatorcontrib>Koren, Michael</creatorcontrib><creatorcontrib>Forgosh, Leslie B.</creatorcontrib><creatorcontrib>Gupta, Dinesh</creatorcontrib><creatorcontrib>Lund, Lars H.</creatorcontrib><creatorcontrib>Camacho, Albert</creatorcontrib><creatorcontrib>Karra, Ravi</creatorcontrib><creatorcontrib>Swart, Henk P.</creatorcontrib><creatorcontrib>Pellicori, Pierpaolo</creatorcontrib><creatorcontrib>Wagner, Frank</creatorcontrib><creatorcontrib>Hershberger, Ray E.</creatorcontrib><creatorcontrib>Prasad, Narayana</creatorcontrib><creatorcontrib>Anderson, Robert</creatorcontrib><creatorcontrib>Anto, Anu</creatorcontrib><creatorcontrib>Bell, Kaylyn</creatorcontrib><creatorcontrib>Edelberg, Jay M.</creatorcontrib><creatorcontrib>Fang, Liang</creatorcontrib><creatorcontrib>Henze, Marcus</creatorcontrib><creatorcontrib>Kelly, Cynthia</creatorcontrib><creatorcontrib>Kurio, Gregory</creatorcontrib><creatorcontrib>Li, Wanying</creatorcontrib><creatorcontrib>Wells, Kate</creatorcontrib><creatorcontrib>Yang, Chun</creatorcontrib><creatorcontrib>Teichman, Sam L.</creatorcontrib><creatorcontrib>Rio, Carlos L.</creatorcontrib><creatorcontrib>Solomon, Scott D.</creatorcontrib><title>Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial</title><title>European journal of heart failure</title><addtitle>Eur J Heart Fail</addtitle><description><![CDATA[Aims
Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.
Methods and results
We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.
Conclusions
Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.]]></description><subject>Aged</subject><subject>Angiotensin Receptor Antagonists</subject><subject>Angiotensin-Converting Enzyme Inhibitors</subject><subject>Animals</subject><subject>Cardiac myosin activator</subject><subject>Cardiac Myosins</subject><subject>Clinical trial</subject><subject>Danicamtiv</subject><subject>Dogs</subject><subject>Echocardiography</subject><subject>Female</subject><subject>Heart Failure - drug therapy</subject><subject>Heart failure with reduced ejection fraction</subject><subject>Humans</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Middle Aged</subject><subject>Myotrope</subject><subject>Stroke Volume</subject><subject>TREATMENT OF HFrEF</subject><subject>Ventricular Function, Left</subject><issn>1388-9842</issn><issn>1879-0844</issn><issn>1879-0844</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp1ksFu1DAQhiMEoqVw4AWQjyA1rR07ic0BCVXbFlSJC5ytWWfMenHixU522RfiOevtbgs99OSx5_v_f2RNUbxl9IxRWp3jcmHPmOL8WXHMZKtKKoV4nmsuZamkqI6KVyktKWVtxl8WR7yqa6mkOi7-zqxFMyYSLOlgcAb60a1PCZAhrNETA7FzYEi_DckNBEzuwhjiKcm3BUIciQXnp4hk48YFidhNBjuCy-zqwkBshLviI8E_K4yux2EEn7NGIDB0xHi3S_VZmSafB7Ex9Dl-tYCEpAIyRgf-dfHCgk_45nCeFD8uZ98vrsubb1dfLj7flKZhnJdNi4JWVKqulR0IIQUTlWKyUWzetczmE6FiHa9YUzFLORdctrVkWFNK5w0_Kcq9b9rgaprrVR4Y4lYHcPrw9CtXqEVLedtmXj3Jr2Lo_onuhUwIlsNVnbWf9toM9NiZ_DER_GOLR53BLfTPsNZtI1Vbs2zw_mAQw-8J06h7lwx6DwOGKelKsLqSnDY8ox_2qIkhpYj2IYZRvdshvdshvduhzL77f64H8n5pMnC-BzbO4_ZpJz37en15Z3kLpPDUnw</recordid><startdate>202009</startdate><enddate>202009</enddate><creator>Voors, Adriaan A.</creator><creator>Tamby, Jean‐François</creator><creator>Cleland, John G.</creator><creator>Koren, Michael</creator><creator>Forgosh, Leslie B.</creator><creator>Gupta, Dinesh</creator><creator>Lund, Lars H.</creator><creator>Camacho, Albert</creator><creator>Karra, Ravi</creator><creator>Swart, Henk P.</creator><creator>Pellicori, Pierpaolo</creator><creator>Wagner, Frank</creator><creator>Hershberger, Ray E.</creator><creator>Prasad, Narayana</creator><creator>Anderson, Robert</creator><creator>Anto, Anu</creator><creator>Bell, Kaylyn</creator><creator>Edelberg, Jay M.</creator><creator>Fang, Liang</creator><creator>Henze, Marcus</creator><creator>Kelly, Cynthia</creator><creator>Kurio, Gregory</creator><creator>Li, Wanying</creator><creator>Wells, Kate</creator><creator>Yang, Chun</creator><creator>Teichman, Sam L.</creator><creator>Rio, Carlos L.</creator><creator>Solomon, Scott D.</creator><general>John Wiley & Sons, Ltd</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>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>202009</creationdate><title>Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial</title><author>Voors, Adriaan A. ; Tamby, Jean‐François ; Cleland, John G. ; Koren, Michael ; Forgosh, Leslie B. ; Gupta, Dinesh ; Lund, Lars H. ; Camacho, Albert ; Karra, Ravi ; Swart, Henk P. ; Pellicori, Pierpaolo ; Wagner, Frank ; Hershberger, Ray E. ; Prasad, Narayana ; Anderson, Robert ; Anto, Anu ; Bell, Kaylyn ; Edelberg, Jay M. ; Fang, Liang ; Henze, Marcus ; Kelly, Cynthia ; Kurio, Gregory ; Li, Wanying ; Wells, Kate ; Yang, Chun ; Teichman, Sam L. ; Rio, Carlos L. ; Solomon, Scott D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6133-67e402089d78da4484142918691bd71f691ea21d321621f0334387581e5000b63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Angiotensin Receptor Antagonists</topic><topic>Angiotensin-Converting Enzyme Inhibitors</topic><topic>Animals</topic><topic>Cardiac myosin activator</topic><topic>Cardiac Myosins</topic><topic>Clinical trial</topic><topic>Danicamtiv</topic><topic>Dogs</topic><topic>Echocardiography</topic><topic>Female</topic><topic>Heart Failure - drug therapy</topic><topic>Heart failure with reduced ejection fraction</topic><topic>Humans</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Middle Aged</topic><topic>Myotrope</topic><topic>Stroke Volume</topic><topic>TREATMENT OF HFrEF</topic><topic>Ventricular Function, Left</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Voors, Adriaan A.</creatorcontrib><creatorcontrib>Tamby, Jean‐François</creatorcontrib><creatorcontrib>Cleland, John G.</creatorcontrib><creatorcontrib>Koren, Michael</creatorcontrib><creatorcontrib>Forgosh, Leslie B.</creatorcontrib><creatorcontrib>Gupta, Dinesh</creatorcontrib><creatorcontrib>Lund, Lars H.</creatorcontrib><creatorcontrib>Camacho, Albert</creatorcontrib><creatorcontrib>Karra, Ravi</creatorcontrib><creatorcontrib>Swart, Henk P.</creatorcontrib><creatorcontrib>Pellicori, Pierpaolo</creatorcontrib><creatorcontrib>Wagner, Frank</creatorcontrib><creatorcontrib>Hershberger, Ray E.</creatorcontrib><creatorcontrib>Prasad, Narayana</creatorcontrib><creatorcontrib>Anderson, Robert</creatorcontrib><creatorcontrib>Anto, Anu</creatorcontrib><creatorcontrib>Bell, Kaylyn</creatorcontrib><creatorcontrib>Edelberg, Jay M.</creatorcontrib><creatorcontrib>Fang, Liang</creatorcontrib><creatorcontrib>Henze, Marcus</creatorcontrib><creatorcontrib>Kelly, Cynthia</creatorcontrib><creatorcontrib>Kurio, Gregory</creatorcontrib><creatorcontrib>Li, Wanying</creatorcontrib><creatorcontrib>Wells, Kate</creatorcontrib><creatorcontrib>Yang, Chun</creatorcontrib><creatorcontrib>Teichman, Sam L.</creatorcontrib><creatorcontrib>Rio, Carlos L.</creatorcontrib><creatorcontrib>Solomon, Scott D.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>European journal of heart failure</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Voors, Adriaan A.</au><au>Tamby, Jean‐François</au><au>Cleland, John G.</au><au>Koren, Michael</au><au>Forgosh, Leslie B.</au><au>Gupta, Dinesh</au><au>Lund, Lars H.</au><au>Camacho, Albert</au><au>Karra, Ravi</au><au>Swart, Henk P.</au><au>Pellicori, Pierpaolo</au><au>Wagner, Frank</au><au>Hershberger, Ray E.</au><au>Prasad, Narayana</au><au>Anderson, Robert</au><au>Anto, Anu</au><au>Bell, Kaylyn</au><au>Edelberg, Jay M.</au><au>Fang, Liang</au><au>Henze, Marcus</au><au>Kelly, Cynthia</au><au>Kurio, Gregory</au><au>Li, Wanying</au><au>Wells, Kate</au><au>Yang, Chun</au><au>Teichman, Sam L.</au><au>Rio, Carlos L.</au><au>Solomon, Scott D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial</atitle><jtitle>European journal of heart failure</jtitle><addtitle>Eur J Heart Fail</addtitle><date>2020-09</date><risdate>2020</risdate><volume>22</volume><issue>9</issue><spage>1649</spage><epage>1658</epage><pages>1649-1658</pages><issn>1388-9842</issn><issn>1879-0844</issn><eissn>1879-0844</eissn><abstract><![CDATA[Aims
Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.
Methods and results
We studied the effects of danicamtiv on LV and LA function in non‐clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double‐blind, single‐ and multiple‐dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment‐emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.
Conclusions
Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre‐clinical findings of direct activation of LA contractility.]]></abstract><cop>Oxford, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>32558989</pmid><doi>10.1002/ejhf.1933</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of heart failure, 2020-09, Vol.22 (9), p.1649-1658 |
| issn | 1388-9842 1879-0844 1879-0844 |
| language | eng |
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| subjects | Aged Angiotensin Receptor Antagonists Angiotensin-Converting Enzyme Inhibitors Animals Cardiac myosin activator Cardiac Myosins Clinical trial Danicamtiv Dogs Echocardiography Female Heart Failure - drug therapy Heart failure with reduced ejection fraction Humans Male Medicin och hälsovetenskap Middle Aged Myotrope Stroke Volume TREATMENT OF HFrEF Ventricular Function, Left |
| title | Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial |
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