Durhane Wong-Rieger, PhD President,

Canadian Organizat ion for Rare Disorders

N o v e m b e r 2 0 1 5

Canada Managed Access Case Studies: What Works, What Doesn’t

What  is  aHUS  

�  Atypical  Hemoly3c  Uremic  Syndrome  (aHUS)  is  a  life-­‐threatening  and  progressive  ultra-­‐rare,  gene3c  disease  that  causes  the  forma3on  of  blood  clots  throughout  the  body,  which  can  lead  to  stroke,  heart  aBack  and  kidney  failure.  The  disease  can  affect  both  adults  and  children.

What  is  Soliris  (eculizumab)  

�  Eculizumab  is  a  monoclonal  an3body  and  has  a  Health  Canada  indica3on  for  the  treatment  of  pa3ents  with  aHUS  to  reduce  complement-­‐mediated  thrombo3c  microangiopathy  (TMA).  Eculizumab  is  approved  for  adults  and  adolescents  and  approved  with  monitoring  for  children  less  than  13  years  of  age.

Pa3ent  submission:  Current  therapy

�  Plasma therapy “virtually ineffective” in acute phase to stop systemic clotting or control systemic thrombosis

�  PT  only  in  major  hospitals;  pa3ents  must  travel,  increasing  3me  and  financial  burdens  on  families;  children  miss  30-­‐40%  of  school  year,  parent  has  20-­‐40%  absenteeism  from  work  

�  PT  and  dialysis  merely  buy  3me  before  end  stage  renal  disease;  pa3ents  not  eligible  for  kidney  transplant.  Hemodialysis  requires  at  least  4  hours,  3  days  per  week.

Pa3ent  submission:  Soliris  experience

�  Soliris  controls  systema3c  cloWng  throughout  the  body,  increasing  the  odds  of  survival  and  allowing  a  pa3ent’s  kidneys  to  be  saved  even  in  the  acute  phase.  Soliris  clearly  controls  complement  ac3vity  beBer  than  plasma  therapy,  which  becomes  ineffec3ve  over  3me.

CDEC:  Eculizumab  Not  Be  Listed  for  aHUS

�  No  established  clinical  benefit  from  2  uncontrolled  prospec3ve  studies;  no  clear  diagnos3c  criteria,  no  comparator  group,  short  follow-­‐up,  and  lack  clinical  outcomes  data.    

�  Small  sample;  subpopula3ons  likely  to  benefit  not  iden3fied  

�  No  evidence  of  impact  on  renal  complica3ons  and  mortality  

PBAC  (Australia):  Eculizumab  for  aHUS    

� March  2014:  Only  through  special  arrangements  ¡  Pa3ents  who  achieve  remission  would  be  discon3nue  a^er  six  months    

¡  Managed  Entry  Scheme:  price  to  be  jus3fied  by  evidence  ÷ Newly  diagnosed  and  nondialysis  pa/ents  achieve  complete  remission.  ÷ Rebates  to  PBAC    

¢  Par$al  rebate  for  dialysis  pa$ents  not  achieving  normal  renal  func$on  ¢  Full  rebate  for  pa$ents  who  fail  to  achieve  25%  improvement  in  renal  func$on,  die  in  6  months  or  have  ESRD

PBAC  (Australia):  Eculizumab  for  aHUS    

�  June  2014:  PBAC  proposed  review  at  12  months  (not  company’s  24  months)  based  on  available  evidence  and  significant  cost  differen$al;  welcome  (rapidly)  emerging  data  for  reconsidera$on  

�  July  2014:    ¡  PBAC  proposed:  Con$nua$on  criteria  aQer  12  months  treatment  if  pa$ent  

demonstrates  both  response  AND  evidence  of  severe  cardiac,  neurological,  or  pulmonary  impairment  OR  serious  chronic  kidney  disease  

¡  Sponsor  proposal:    pa$ents  at  higher  risk  of  either  early  mortality  or  significant  morbidity,  given  (accepted)  CT  data  that  long-­‐term  eculizumab  inhibits  TMA  and  improves  renal  func$on;  no  evidence  that  short-­‐term  eculizumab  achieves  [same]  long-­‐term  benefits  of  con$nuous  therap  

�  August  2014:  Government  to  proceed  with  lis$ng  without  MES  or  rebated  

NICE  (UK)  Observa3ons  re:  Soliris  for  aHUS  

�  In  all  of  the  studies,  treatment  led  to  a  substan3al  reduc3on  in  thrombo3c  microangiopathy  ac3vity,  and  improvement  in  kidney  func3on  and  quality  of  life  in  most  pa3ents.    

�  Clinical  experts  remarked:  benefits  seen  beBer  than  originally  an3cipated.  Many  pa3ents  were  able  to  stop  dialysis,  and  non-­‐renal  benefits,  e.g.,  GI  symptoms.    

�  CommiBee  concluded  eculizumab  a  very  effec3ve  treatment  op3on  for  pa3ents  with  aHUS.  

NICE  Recommenda3ons  re:  Soliris  for  aHUS  

�  Eculizumab  recommended  for  funding  if  all  following  condi3ons  ¡  Coordina3on  of  use  through  an  expert  centre  monitoring  systems    ¡  Na3onal  protocol  for  star3ng  and  stopping  eculizumab  when  used  for  clinical  reasons  

¡  Research  programme  with  robust  methods  to  evaluate  when  stopping  treatment  or  dose  adjustment  might  occur.  

CDEC  2nd  Recommenda3on  Soliris  for  aHUS

�  Ra3onale  ¡  RCT  could  be  very  challenging,  due  to  the  rarity  of  aHUS.  ¡  Clinician  and  pa3ent  comment:  Plasma  exchange  provides  modest  symptom  relief  but  limited  long-­‐term  efficacy  

�  Proposed:  pa3ents  who  meet  all  three  diagnos3c  criteria  ¡  Confirmed  diagnosis  of  aHUS  at  ini3al  presenta3on,  defined  by  presence  of  TMA  

¡  Evidence  of  ongoing  ac3ve  TMA,  defined  by  laboratory  test  abnormali3es  despite  plasmapheresis  (minimum  of  4  plasma  exchanges  required  over  4  successive  days).  

¡  Evidence  of  at  least  one  of  the  following  documented  clinical  features  of  ac3ve  organ  damage  or  impairment:  ÷ Kidney  impairment  ÷ Onset  of  neurological  impairment  related  to  TMA  

�  Pa3ent  Group  summary  ¡  Patient groups noted that PT does not address the underlying

cause of aHUS and can be associated with serious risks, in addition to increased fatigue, confused thinking, and nausea post-treatment. PT is available only in major hospitals; therefore, many patients must travel for treatment, which increases the time and financial burdens on families. Parents of patients undergoing PT estimated that their children miss 30% to 40% of their school year, with the parents’ absenteeism from work at 20% to 40%

¡  The two- and three-year analyses of patients in C08-002 and C08-003 demonstrated that longer-term eculizumab therapy maintained inhibition of complement activity, TMA, and improvements in hematologic parameters and renal function. Furthermore, eculizumab continued to prevent progression to end-stage renal disease in the majority of patients with aHUS

What  is  TSC  

�  Tuberous  sclerosis  complex  (TSC)  is  a  gene3c  disease  wherein  non-­‐malignant  tumors  develop  on  vital  organs,  including  the  brain,  heart,  kidneys,  lungs  and  skin  

�  TSC  primarily  affects  central  nervous  system;  may  manifest  as  developmental  delays,  intellectual  disabili3es,  behavioral  problems,  seizures  and  au3sm  

�  Other  features  include  kidney  diseases  and  skin  abnormali3es

Health  Canada/EMA  Regulatory  Approval  

�  Everolimus  treat  benign  (non-­‐cancerous)  tumours  caused  by  TSC  ¡  Shrank  brain  tumours  (SEGA)  by  half  in  approximately  30%  of  pa3ents  and  by  about  a  third  in  around  70%  of  pa3ents  

¡  Shrank  kidney  tumours  in  angiomyolipoma,  (AML)  pa3ents  by  half  in  42%  of  pa3ents  

�  Everolimus  helps  block  mTOR,  which  controls  cell  division  and  the  growth  of  blood  vessels

CDEC:  Do  Not  List  Soliris  for  aHUS

�  In  DB,  RCT,  reduced  size  of  angiomyolipomas  (AML)  in  42%  of  treated  pa$ents.  However,  not  defini$vely  established  that  reduc$on  in  AML  size  is  correlated  with  a  reduc$on  in  bleeding  complica$ons,  avoidance  of  surgery,  or  long-­‐term  preserva$on  of  renal  func$on.  

�   CDEC  considered  subpopula$ons  of  pa$ents  for  whom  everolimus  could  be  recommended  (e.g.,  those  who  are  experiencing  AML  growth  and  who  are  not  candidates  for  surgery);  however,  there  was  no  evidence  for  making  such  recommenda$ons

CDEC:  Do  Not  List  Soliris  for  aHUS

�  Lack  of  evidence  defini$vely  linking  a  reduc$on  in  tumour  size  to  clinically  relevant  outcomes  such  as  bleeding,  renal  func$on,  and  quality  of  life  precluded  an  analysis  of  cost-­‐effec$veness.    

�  Cost  effec$veness:  ranges  from  $40,254  to  $59,901  over  one  year  compared  with  standard  care.  but  substan$al  uncertainty  ¡ Watchful  wai$ng  (ac$ve  monitoring)  might  be  an  appropriate  comparator.  In  the  absence  of  analysis,  cost-­‐effec$ve  is  unknown.  

Ontario  Lis3ng  Soliris  for  aHUS  

�  For  treatment  of  AML  with  all  the  following  condi$ons:  ¡  Presence  of  coalescent  or  mul$focal  AMLs  in  either  one  or  both  kidneys;  

AND  ¡  AML  progression  despite  previous  emboliza$on  and/or  surgery;  AND  ¡  Further  emboliza$on  and/or  surgery  not  recommended  due  to  a  

documented  clinical  reason  �  Case-­‐by-­‐Case  considera$on  will  be  considered  in  pa$ents  who  have  never  

been  treated  with  invasive  procedures  such  as  emboliza$on  and/or  surgery.  �  Exclusion  criteria:  pa$ents  with  SEGA  �  Renewals:    No  AML  progression  or  reduc$on  in  AML  volue  

¡   (i.e.  no  significant  new  lesions  and  increase  in  kidney  volume,  as  well  as  no  significant  AML  related  bleeding);  AND  

¡  There  is  a  reduc$on  in  volume  of  AMLs  iden$fied  prior  to  treatment  with  the  everolimus.

What  is  PKU  (Phenylketonuria)  

�  Phenylketonuria  (PKU)  is  a  gene$c  disorder:  deficiency  or  absence  of  phenylalanine  hydroxylase  (PAH),  required  for  the  conversion  of  the  phenylalanine  (PHE)  to  tyrosine.

�  High  PHE  levels  in  the  blood  and  brain  lead  to  complica$ons  including  abnormal  brain  development,  impaired  cogni$ve  ability,  mental  illness,  tremors,  and  seizures;  also  psychiatric  symptoms,  

�  Treatment  is  a  PHE  restricted  diet,  which  severely  limits  natural  protein;  may  require  nutri$onal  replacement  products  

�  Adherence  to  the  PHE  restric$ve  diet  is  difficult.    Discon$nua$on  may  result  in  asthma,  headaches,  eczema,  neurological  symptoms,  hyperac$vity  and/or  lethargy,  phobias,  and  depression

What  is  Kuvan  

�  Sapropterin  is  a  synthe$c  form  of  tetrahydrobiopterin  (BH4),  the  cofactor  for  Phe  hydroxylase.  It  is  approved  by  Health  Canada  in  conjunc$on  with  a  Phe-­‐restricted  diet  to  reduce  blood  Phe  levels  in  pa$ents  with  hyperphenylalaninemia  due  to  BH4-­‐responsive  PKU.  

�  Pa$ents  with  mild  PAH  deficiency  most  likely  to  respond  (25%  to  50%  overall)  

�  Two  DB-­‐RCTs:  ¡  Change  in  blood  Phe  level  AND  Phe  supplement  tolerance  while  maintaining  [desired]  blood  Phe  levels  

¡  Other  outcomes:  quality  of  life,  nutri$onal  status,  adverse  events,  and  serious  adverse  events  

�  Neither  trial  included  validated  measures  of  neuropsychological  performance,  quality  of  life,  growth,  or  diet  liberaliza$on

Pa3ent  input:  Kuvan  for  PKU  

�  Phe-­‐restricted  diets  were  described  as  complicated,  unpalatable,  and  financially  burdensome  in  the  case  of  pa3ents  who  do  not  have  coverage  for  low-­‐protein  foods.  

�  The  outcome  of  greatest  importance  to  pa3ents  is  the  ability  to  eat  a  more  ordinary  diet  while  avoiding  the  adverse  consequences  of  increased  blood  Phe  levels.  

�  Liberaliza3on  of  diet  is  expected  to  decrease  the  financial  burden  on  pa3ents  and  improve  their  quality  of  life.

CDEC:  Do  Not  List  Kuvan  for  PKU  

�  The  Canadian  Expert  Drug  Advisory  Commijee  (CEDAC)  recommends  that  sapropterin  not  be  listed.  

�  Although  the  Commijee  found  sufficient  evidence  that  sapropterin  lowers  blood  phenylalanine  (Phe)  levels  in  certain  pa$ents  with  phenylketonuria  (PKU),  the  submission  did  not  provide  sufficient  details  of  how  to  iden$fy  the  pa$ents  who  would  benefit  in  a  cost-­‐effec$ve  manner.  The  proposed  Kuvan  Starter  Program  is  suitable  only  to  screen  pa$ents  to  iden$fy  “responders,”  but  such  a  response  in  the  clinical  trials  did  not  differen$ate  low  response  from  clinically  important  response.  Star$ng  and  stopping  rules,  beyond  the  screening  stage,  that  are  linked  to  substan$ve  benefit  are  needed

California  Health  Services:  Kuvan  for  PKU  

�  Sapropterin  may  be  considered  as  an  adjunc$ve  therapy  for  any  PAH  deficient  client.  

�  A  trial,  not  to  exceed  two  months,  to  determine  responsiveness,  may  be  authorized  

�  At  least  one  of  the  following  criteria  must  be  met  to  determine  responsiveness  and  jus$fy  con$nued  therapy  with  the  medica$on:  ¡  A  clinically  significant  reduc$on  in  blood  PHE.    A  30%  reduc$on  is  

frequently  regarded  as  responsive  ¡  An  increase  in  PHE  tolerance,  that  is,  increase  in  tolerance  is  determined  by  

maintenance  of  low  blood  PHE  levels  or  improvement  in  neuropsychiatric  symptoms  with  increased  dietary  PHE.  

¡  A  documented  improvement  in  neuropsychiatric  symptoms,  improved  seizure  control  or  enhanced  mental  func$oning  leading  to  improved  func$oning  at  school,  work  or  social  obliga$ons

Canada:  Consensus  Guidelines  Kuvan  for  PKU  

�  SubmiBed  to  Ontario  (March  2014)  ¡  Have  hyperphenylalaninemia  requiring  treatment,  based  on  Phe  level;  AND  

¡  Respond  to  Kuvan,  defined  as  a  decrease  of  blood  phenylalanine  levels  of  at  least  30%  from  baseline  during  a  4  week  Kuvan  challenge;  AND  

¡  Demonstrate  therapeu3c  blood  phenylalanine  levels  while  on  Kuvan,  defined  as  blood  phenylalanine  levels  consistently  in  the  control  range  

�  Phenylalanine  control  will  be  audited  at  6  months  a^er  comple3ng  the  Kuvan  responsiveness  trial  and  therea^er  every  12  months.

Ontario  Access  Guidelines:  Kuvan  for  PKU  

�  Ini$al  6  months  paid  by  Manufacturer,  with  criteria  including  baseline  Phe  >  360  μmol/L  despite  low-­‐protein  diet  

�  Reimbursement  criteria  including  ¡  Compliance  with  low  protein  diet,  AND  ¡  Normal  sustained  blood  Phe  levels  OR  Sustained  blood  Phe  reduc$on  of  at  least  30%    or  50%  (depending  on  Phe  baseline)  

¡  Demonstrated  increase  of  dietary  protein  tolerance  based  on  targets  set;  AND    

¡  Clinically  meaningful  age-­‐appropriate  improvement  in:  neuro-­‐behavioural  or  neuro-­‐cogni$ve  func$on  or  impairment;  OR  Demonstrated  improvement  in  QoL  using  peer  reviewed  validated  scales

Thank You!

November 2015 Rare Disease Drug Access

Durhane Wong-Rieger, PhD President

Canadian Organization for Rare Disorders

www.raredisorders.ca 416-969-7435

durhane@sympatico.ca