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SHJ Vol 5, No 1                                M Ibrahim, Putting PCSK9 Inhibitors into practice
                                                          http://dx.doi.org/10.25239/SHJ/Vol5/No1/ReviewArticle
            The  hypothesis  that  inhibiting  PCSK9  activity    (LY)  by  Lilly;  a  neutralizing  antibody  of
            could  reduce  cholesterol  became  an  important     proprotein  convertase  subtilisin/kexin  type  9
            research topic. This led to experimental studies      (PCSK9),  administered  every  4  or  8  weeks  in
            in  animal  models  showing  that  inhibition  of     patients  with  primary  hypercholesterolemia,
            PCSK9 was a potent way to reduce cholesterol          when  added  to  a  background  of  standard-of-
            levels in blood.                                      care  lipid-lowering  therapy,  including  statins
                                                                  (23).
            Pcsk9 inhibitors unveil
            The  year  2015  had  been  a  big  year  for         Other approaches
            cardiology. Attendees  of  that  year‘s American      Beyond  monoclonal  antibody  therapy,  other
            College  of  Cardiology  (ACC)  meeting  were         approaches for targeting PCSK9 are also being
            buzzing  about  the  clinical-trial  sessions         investigated.   These    include   an    RNA
            highlighting  the  breakthrough  in  cardiology  -    interference  (RNAi)  molecule  (ALN-PCSsc,
            the  PCSK9  inhibitors.  Cardiologists  and           Alnylam and The Medicines Company), small
            general practitioners alike are excited about the     molecule  candidates,  which  in  general  are
            two  PCSK9  inhibitors,  alirocumab  and              orally available, as well as vaccine candidates.
            evolocumab, in late-stage clinical development,       To date, there are 8 preclinical drugs and a total
            because  of  their  ability  to  lower  LDL-C  in     of  7  in  clinical  trials  with  the  associated
            patients  for  whom  other  treatments  have  been    mechanism of action of ‗PCSK9 inhibitor‘. Of
            ineffective.                                          these  novel  agents,  ALN-PCSsc  has  attracted
                                                                  attention following encouraging Phase I results.
            Approach: monoclonal antibody therapy                 This  first-in-class  RNAi  therapeutic  inhibits
            Monoclonal antibody therapy targeting PCSK9           PCSK9  gene  expression,  typically  by  causing
            has  led  the  field  in  clinical  development.  The   the  destruction  of  specific  messenger  RNA
            first  of  these  agents,  alirocumab  (Praluent,     (mRNA)  molecules,  thus  inhibiting  PCSK9
            Sanofi/Regeneron)  and  evolocumab  (Repatha,         synthesis.  In  multiple  subcutaneous  dosing  in
            Amgen),  received  regulatory  approval  in           hypercholesterolemia patients on or off statins,
            Europe and the USA in 2015. Both agents are           ALN-PCSsc lowered LDL cholesterol by up to
            licensed  for  the  management  of  adult  patients   83%  (least  squares  mean  change  up  to  54%).
            with     hypercholesterolemia     or     mixed        This  response  was  durable,  suggesting  the
            dyslipidemia;  evolocumab  is  also  licensed  for    possibility  of  injecting  every  6  months.  The
            the treatment of adults and adolescents aged 12       treatment  was  also  well  tolerated  (24).  ALN-
            years  and  over  with  homozygous  familial          PCSsc is now in Phase II development (ORION
            hypercholesterolemia.  These  agents  are  given      program).
            by  subcutaneous  injection  and  have  a  long
            duration  of  action  requiring  infrequent           Do we need guidelines?
            administration (either 2-weekly for alirocumab        The  availability  of  the  proprotein  convertase
            or  monthly  or  2-weekly  for  evolocumab)           subtilisin/kexin  type  9  (PCSK9)  inhibitors,
            compared with current therapies. Bococizumab;         alirocumab  and  evolocumab,  for  use  has
            is  a  drug  that  was  in  development  by  Pfizer   highlighted the need for practical guidance. In
            targeting  PCSK9  to  reduce  LDL  cholesterol.       response, practice guidelines have been issued
            Pfizer withdrew the drug from development in          to aid clinicians in the appropriate use of these
            November 2016, after  completion of 6  ―phase         novel treatments. In balancing the clinical need
            3‖ studies; determining that it was "not likely to    for  these  treatments  with  their  cost,  a
            provide  value  to  patients,  physicians  or         conservative approach has to be considered.
            shareholders" (23).                                   In May 2017; an Expert Panel convened by the
                                                                  National  Lipid  Association  was  charged  with
            Another  investigational  product;  LY3015014         updating  the  recommendations  on  the  use  of
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