Frontiers in Cardiovascular Drug Discovery

Volume: 4

PCSK9 Inhibition with Evolocumab Reaching Physiologic LDL-C Levels for Reducing Atherosclerotic Burden and Cardiovascular Disease-The Full Landscape

Author(s): Enrique C. Morales-Villegas and Kausik K. Ray

Pp: 148-185 (38)

DOI: 10.2174/9781681083995118040007

* (Excluding Mailing and Handling)

Abstract

Physiologically, in the presence of an intracellular deficit of cholesterol, the LDLR synthesis, expression and function increase, thus uptaking and providing cholesterol to the cell. This process is counter-regulated by PCSK9 expression, the protease inducing LDLR proteolysis, thereby limiting its function maintaining a constant cholesterol intracellular concentration. Accordingly, the balance between PCSK9 and LDLR regulates the intracellular concentration of cholesterol and in consequence has impact on circulating LDL-cholesterol.

This chapter reviews the brief and amazing recent history with PCSK9 inhibition from basic science to current clinical recommendations for MAbs-PCSK9. In 2003 and 2005, respectively, the pcsk9 gene mutations, determinants of the “gain of function” of PCSK9 and severe hypercholesterolemia, and the pcsk9 gene mutations with “loss of function” of PCSK9, determinants of hypocholesterolemia were described; subsequently, in 2006, the association between the pcsk9 gene mutations and the “loss of function” of PCSK9 with hypocholesterolemia and reduction of up to 88% for the risk of a coronary event in the “mutant” population versus the control population was published.

Since evolocumab clinical research program has completed and published their phases I, II and III results including its cardiovascular outcomes trial, this chapter is focused in reviewing the results of evolocumab clinical research program. In 2009, the effect of a “full human” monoclonal antibody vs PCSK9 in mice and non-human primates was first reported; MAb-PCSK9, AMG-145 (evolocumab) produced in cynomolgus monkeys a doubling in the number of LDLR and an average 75% reduction in circulating LDL-cholesterol. In 2012, the first phase I study with evolocumab versus placebo were reported; this program informed very significant reductions in LDLcholesterol in healthy subjects and patients with familial and non-familial hyper-cholesterolemia treated without/with statins; tolerability and safety of evolocumab were similar to placebo. With this evidence, the phase II and III investigations with evolocumab initiated; four years later, the OSLER trial allowed us to envisage the following scenario: MAb-PCSK9 evolocumab have a favorable effect on LDLcholesterol, other apo-B100 lipoproteins and overall mortality and myocardial infarction; all the aforementioned with a very favorable safety and tolerability profile. In the same direction, in 2016 was published the GLAGOV trial, wich demonstrates for the first time that the addition of a non-statin therapy -evolocumab- to the optimal treatment with statins is associated with atheroregression; and finally, in 2017, the FOURIER and the EBBINGHAUS trials were presented, wich confirmed that the addition of evolocumab to the optimal treatment with statins is associated with an additional and significant 20% relative risk reduction -26 months of follow-up- for cardiovascular mortality, myocardial infarction and/or ischemic stroke, all without neurocognitive risk.

Beyond the currently approved indications by regulatory agencies, considering the high cost of PCSK9 inhibitors and financial restraints within healthcare budgets, for now and before definitive and necessary cost-effectiveness analysis and price optimization are in place, evolocumab is recommended in specific clinical scenarios reviewed in this chapter.


Keywords: PCSK9, Mabs-PCSK9, Alirocumab, Bococizumab, Evolocumab, Familial hypercholesterolemia, Non-familial hypercholesterolemia.

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      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314520269 and j.to_ip >=314520269 )) and ((j.from_date <= 1740497926 and j.to_date >= 1740497926 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12028) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314520269 and j.to_ip >=314520269 )) and ((j.from_date <= 1740497926 and j.to_date >= 1740497926 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12028) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314520269 and j.to_ip >=314520269 )) and ((j.from_date <= 1740497926 and j.to_date >= 1740497926 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 12028)
      760μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 2437 and `b`.`banner_from_date` <= 1740497926 and `b`.`banner_to_date` >= 1740497926 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.43msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 2437
      • 3: 1740497926
      • 4: 1740497926
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='3300293f0b70957c8b309b1ac2e50a50'
      240μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    7Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        Cfiyd1lsJrK7qyQZ4gk6S4cVPAbRYEBhQ5DmAlvu
        uc_cart_id
        3300293f0b70957c8b309b1ac2e50a50
        _previous
        array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12028" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/12028
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:16 [ "x-https" => array:1 [ 0 => "1" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] "priority" => array:1 [ 0 => "u=0, i" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate, br, zstd" ] "sec-fetch-dest" => array:1 [ 0 => "document" ] "sec-fetch-user" => array:1 [ 0 => "?1" ] "sec-fetch-mode" => array:1 [ 0 => "navigate" ] "sec-fetch-site" => array:1 [ 0 => "none" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "sec-ch-ua-platform" => array:1 [ 0 => ""Windows"" ] "sec-ch-ua-mobile" => array:1 [ 0 => "?0" ] "sec-ch-ua" => array:1 [ 0 => ""HeadlessChrome";v="129", "Not=A?Brand";v="8", "Chromium";v="129"" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] ]
        request_cookies
        []
        
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 15:38:46 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjhOQSt0OHg4R0dyN2l3OEUxV25Mc3c9PSIsInZhbHVlIjoiM3dMWWo1VjhJNDJxSUUybVpGNDR6eE5ZeDIweXlYalZHeURrU0xXalVmamdrVWh1NEVrOHJHU2xjNEE0L2xxcmxWT3JoVWRPZGQwVlRjUXN0QnlJbjJZUndDU1ZUQXR2VkhrWjRCN2dPK0hDMnU3SGZoeHJqWDkwTHFsV2p6RTciLCJtYWMiOiJhYzJjODQ0YTQ5NjVlY2YxY2NhM2M0ZDNlYTU1M2ZjZDUwMDM1NjViMzE3NmExMThlMjFjYTQ4ZjUxOTZkNDU2IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 03:38:46 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IjhOQSt0OHg4R0dyN2l3OEUxV25Mc3c9PSIsInZhbHVlIjoiM3dMWWo1VjhJNDJxSUUybVpGNDR6eE5ZeDIweXlYalZHeURrU0xXalVmamdrVWh1NEVrOHJHU2xjNEE0L2xxcmxWT3JoV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkFYYzh3VDRXem1OdC9MNWtuaG5zUUE9PSIsInZhbHVlIjoidUF2Z2ZDN3lGaG9hbmliU2VzcmR1ejdGVjZmcVdhRkRYbzAxclViQVFCS2lvVEtUMVlTMnVwZUI5QW9rS3dScm5leTN5RzZJYUM4SEV5OFNldkVVdXROS3hNZjVEdWJXVzFBVjJBUUFBbVVnWDRWTEQzOWdacG13c0l5VlE3NVMiLCJtYWMiOiIxNWQwZGJlZDE1OTkzNGExYmNlZWE2YWE4YWQ0NDQyOWJhODg4MzRkNTE3OWY3OWY1YmU3YjY0YmI5ZTA2MTVkIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IkFYYzh3VDRXem1OdC9MNWtuaG5zUUE9PSIsInZhbHVlIjoidUF2Z2ZDN3lGaG9hbmliU2VzcmR1ejdGVjZmcVdhRkRYbzAxclViQVFCS2lvVEtUMVlTMnVwZUI" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IjhOQSt0OHg4R0dyN2l3OEUxV25Mc3c9PSIsInZhbHVlIjoiM3dMWWo1VjhJNDJxSUUybVpGNDR6eE5ZeDIweXlYalZHeURrU0xXalVmamdrVWh1NEVrOHJHU2xjNEE0L2xxcmxWT3JoVWRPZGQwVlRjUXN0QnlJbjJZUndDU1ZUQXR2VkhrWjRCN2dPK0hDMnU3SGZoeHJqWDkwTHFsV2p6RTciLCJtYWMiOiJhYzJjODQ0YTQ5NjVlY2YxY2NhM2M0ZDNlYTU1M2ZjZDUwMDM1NjViMzE3NmExMThlMjFjYTQ4ZjUxOTZkNDU2IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 03:38:46 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IjhOQSt0OHg4R0dyN2l3OEUxV25Mc3c9PSIsInZhbHVlIjoiM3dMWWo1VjhJNDJxSUUybVpGNDR6eE5ZeDIweXlYalZHeURrU0xXalVmamdrVWh1NEVrOHJHU2xjNEE0L2xxcmxWT3JoV" 1 => "alphaeurekaselectnet_session=eyJpdiI6IkFYYzh3VDRXem1OdC9MNWtuaG5zUUE9PSIsInZhbHVlIjoidUF2Z2ZDN3lGaG9hbmliU2VzcmR1ejdGVjZmcVdhRkRYbzAxclViQVFCS2lvVEtUMVlTMnVwZUI5QW9rS3dScm5leTN5RzZJYUM4SEV5OFNldkVVdXROS3hNZjVEdWJXVzFBVjJBUUFBbVVnWDRWTEQzOWdacG13c0l5VlE3NVMiLCJtYWMiOiIxNWQwZGJlZDE1OTkzNGExYmNlZWE2YWE4YWQ0NDQyOWJhODg4MzRkNTE3OWY3OWY1YmU3YjY0YmI5ZTA2MTVkIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IkFYYzh3VDRXem1OdC9MNWtuaG5zUUE9PSIsInZhbHVlIjoidUF2Z2ZDN3lGaG9hbmliU2VzcmR1ejdGVjZmcVdhRkRYbzAxclViQVFCS2lvVEtUMVlTMnVwZUI" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "Cfiyd1lsJrK7qyQZ4gk6S4cVPAbRYEBhQ5DmAlvu" "uc_cart_id" => "3300293f0b70957c8b309b1ac2e50a50" "_previous" => array:1 [ "url" => "https://alpha.eurekaselect.com/chapter/12028" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 15:38:46GET/chapter/12028112199