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 Therapeutic  intervention  for  

age  related  macular  degeneration  

     

Nicholas  G.  P.  Harper        

MDEMO    29/03/2010  –  02/06/2010  

 Word  count:  1995  

     

Candidate  No.  21019    

Tutor:  Mr  Kesavan  Ramanujam          

“This  project  is  all  my  own  work  unless  otherwise  stated.  All  text,  figures,  tables,  data  or  results  which  are  not  my  own  work  are  indicated  and  the  sources  acknowledged.”  

 

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Therapeutic  intervention  for  age  related  macular  degeneration  

   

Introduction    Age  related  macular  degeneration  was  first  described  in  1874  as  a  “symmetrical  central  choroido-­‐retinal  disease  occurring  in  senile  persons”13.  Today,  it  is  widely  recognised  as  one  of  the  leading  causes  of  blindness  in  the  developed  world19.  AMD  mainly  affects  the  elderly,  with  a  prevalence  of  15%  for  those  80  years  or  older8.  This  figure  is  projected  to  increase  by  50%  over  the  next  10  years,  in  line  with  the  aging  population21.    The macula is the area of the retina that contains the highest density of photoreceptors. It is this area that is responsible for high-resolution vision, enabling us to see fine detail crucial for reading and recognising face    

Clinical  features    Progressive  loss  of  central  vision  

• Decrease  in  visual  acuity  • Blurring  • Central  scotomas  • Decreased  contrast  sensitivity  • Decreased  colour  discrimination    

Sparing  of  peripheral  vision  -­‐  The  area  of  the  retina  surrounding  the  macula  is  responsible  for  peripheral  vision  important  for  navigation.  As  this  is  largely  spared  in  AMD,  patients  are  usually  able  to  maintain  independent  lifestyles.  

               

Fig 1. A representation of the vision experienced by patients with AMD. (From 31)

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Pathogenesis    Age  related  changes  to  the  macula  can  be  viewed  as  a  progression.  Until  there  is  visual  impairment,  they  are  classified  as  an  age  related  maculopathy.  Past  this  point,  they  are  referred  to  as  age  related  macular  degeneration.  It  is  important  to  note  that  this  is  a  distinction  based  purely  on  function  rather  than  pathogenesis.      

 Drusen  The  principal  feature  of  AMD  is  the  deposition  of  drusen  between  the  retinal  pigment  epithelium  and  Bruch’s  membrane.  The  word  Druse  is  derived  from  the  German,  meaning  Geode  (a  crystal  lined  rock).  They  are  visible  on  opthalmoscopy  when  ≥25um  and  appear  as  yellow/white  dots  within  the  macula.    

     Geographic  atrophy  (GA)    

• Atrophy  of  the  retinal  pigment  epithelium  

• Causes  visual  loss  in  affected  areas    

         Choroidal  neovascularisation  (CNV)    

• New  vessel  growth  within  the  choroid.  This  can  lead  to  many  complications  including:  subretinal  fluid,  hemorrhage,  retinal  

detachment  and  fibrotic  scars.    

• Present  in  10%  of  patients  with  AMD  

• Referred  to  as  “wet”  AMD    

 

Fig 4. A.) Fundus photograph. B.) fluorescein  angiogram  showing  vascular  leakage.  (From  30)

Fig 2. From 34

Fig 3. From 33

A

B

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Treatment      

Aetiology  The  main  risk  factor  for  AMD  is  age35.  Studies  have  however  consistently  found  associations  between  AMD  and  smoking.  Zanke  et  al  (2010)  reports  that  current  smokers  are  3.14  times  more  likely  to  develop  geographic  atrophy  or  choroidal  neovascularisation  compared  to  non-­‐smokers35.      On  the  grounds  of  this  research,  all  patients  with  AMD  should  be  advised  to  stop  smoking.  Research  has  also  pointed  to  obesity,  hypertension,  high  fat  intake  and  low  dietary  antioxidant  intake  as  further  modifiable  risk  factors  for  AMD14.    

Treating  -­‐  CNV  Although  only  present  in  about  10%  of  people  with  AMD,  choroidal  neovascularisation  accounts  for  80%  of  all  severe  visual  loss  caused  by  AMD7.  Due  to  this  huge  impact  on  vision  and  the  fact  that  pathological  angiogenesis  occurs  in  many  disease  processes,  this  is  the  area  of  AMD  research  that  has  seen  the  most  progress.  The  following  are  some  of  the  methods  developed  for  halting  this  process.    

Vitreoretinal  surgery    Surgical  methods  for  removing  CNV  have  been  described  since  the  1980s11.  To  investigate  their  effectiveness,  the  Submacular  Surgery  Trials  (SST)  carried  out  3  RCTs  between  1997  and  2003.  Unfortunately,  results  showed  that  after  24  months,  there  was  no  difference  in  visual  acuity  between  surgical  treatment  and  observation11.    For  subfoveal  neovascular  AMD,  a  method  has  since  been  developed  where  instead  of  removing  the  vessels  themselves,  the  fovea  is  moved  to  an  area  free  from  CNV.  This  macular  translocation  has  shown  positive  results  in  a  small  study  in  which  50%  of  treated  patients  experienced  a  1  line  improvement  in  visual  acuity  at  12  months  26.  Due  to  the  invasive  nature  and  only  mild  improvements  gained  from  this  procedure,  it  is  not  considered  routine  treatment.                      

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Laser  Photocoagulation    This  was  the  first  laser-­‐based  treatment  used  for  neovascular  AMD.  The  aim  was  to  use  a  laser  to  coagulate  the  newly  formed  choroidal  vessels.    The  Macular  Photocoagulation  Study  Group  carried  out  a  number  of  clinical  trials  between  1979  and  199417.  They  showed  that  compared  to  patients  treated  with  laser  photocoagulation,  untreated  patients  had  a  1.2-­‐1.5  relative  risk  of  significant  visual  deterioration.  (Results  summarised  in  fig  6).  There  are  however  serious  limitations  to  this  treatment:        

1. The  laser  creates  a  burn  that  destroys  vision  in  that  area  of  the  retina.  As  such,  this  treatment  is  only  appropriate  when  the  neovascularisation  is  outside  the  central  area  of  the  macula.  Only  10-­‐15%  of  patients  with  CNV  were  suitable  for  this  treatment17.  

2. Inadvertent  coagulation  of  the  fovea  (rare)  

3. Subretinal  Haemorrhage  

4. At  2  years,  >50%  of  the  patients  had  a  recurrence  of  neovascularisation17.    

   

                                     

Fig 6. Relative risk of visual loss in photocoagulation treated vs observed patients for A.) All patients with extrafoveal lesion, B.) New subfoveal lesions C.) Recurrent subfoveal lesions. (From 28)

Fig 5. Retinal scars produced by photocoagulation. (From 32)

A C

B

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Laser  Photodynamic  therapy  Laser  photocoagulation  causes  irreversible,  non-­‐specific  thermal  damage.  In  the  aim  of  minimising  this  retinal  damage,  the  method  of  laser  photodynamic  therapy  (PDT)  was  developed  in  the  late  1990s:    A  light  sensitive  dye,  which  concentrates  in  newly  formed  vessels,  is  injected  into  the  patient.  when  excited  by  laser  light  of  a  specific  wavelength,  the  dye  undergoes  a  reaction,  causing  selective  chemical  destruction  of  those  vessels.      The  groundbreaking  “treatment  of  age  related  macular  degeneration  with  photodynamic  therapy”  (TAP)  study  used  a  verteporfin  (Visudyne)  as  their  light  sensitive  dye24.  Results  showed  that  photodynamic  treatment  lead  to  a  significant  improvement  in  visual  acuity,  contrast  sensitivity  and  retinal  appearance  under  fluorescein  angiography  compared  to  placebo  treated  patients  at  1  and  2  years  follow  up24.  Side  effects  included  transient  visual  disturbances  (18%),  an  adverse  reaction  at  the  injection  site  (13%)  and  transient  photosensitivity  (3%)24.  This  TAP  study  lead  to  the  FDA’s  approval  of  verteporfin  photodynamic  therapy  in  2000.      The  main  drawback  of  photodynamic  therapy  is  that  for  macular  lesions  in  which  CNV  accounted  for  <50%  of  the  total,  PDT  showed  no  significant  benefit  in  any  of  the  measured  outcome  variables24.                                                    

Fig  7.  A  typical  patient  from  the  TAP  study  -­‐  Fundus  photographs  and  late-­‐phase  fluorescein  angiograms  taken  at  baseline  (A,B),  3  months  (C&D)  and  12  months  (E,F),  during  the  12  month  course  of  verteporfin  PDT  therapy.  Therapy  was  applied  every  3  months.  Images  clearly  show  an  improvement  in  fundus  appearance,  with  no  deterioration  in  vascular  leakage.  (From  24)  

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Anti  VEGF    Vascular  Endothelial  Growth  Factor  A  (VEGF-­‐A)  is  a  key  regulatory  cytokine  in  the  process  of  angiogenesis.  As  well  as  being  researched  extensively  in  the  fields  of  oncology  and  cardiology,  it  has  been  shown  to  have  a  central  role  in  neovascular  ocular  diseases20.    

Pegaptanib  The  first  anti-­‐VEGF  agent  shown  to  be  effective  in  AMD  was  pegaptanib  (Macugen),  a  ribonucleic  acid  aptamer  that  prevents  VEGF  from  binding  to  its  receptor.      The  “VEGF  Inhibition  Study  in  Ocular  Neovascularization  Clinical  Trial  Group”  found  pegaptanib  to  be  effective  in  70%  of  patients,  with  the  risk  of  severe  loss  in  visual  acuity  12%  lower  in  pegaptanib  treated  patients  compared  to  controls10.  They  also  observed  a  43%  increase  in  the  number  of  patients  who  had  maintained  or  gained  visual  acuity  after  the  1  year  duration  of  the  study10.  Unlike  photodynamic  therapy,  this  treatment  was  found  to  be  effective  in  neovascular  AMD  independently  of  precise  lesion  composition.  On  the  basis  of  these  results  pegaptanib  became  the  first  FDA  licensed  anti-­‐angiogenic  therapy  for  AMD  in  2004.    

Bevacizumab  VEGF  can  also  be  silenced  effectively  using  monoclonal  antibodies.  Genentech  had  indeed  already  developed  bevacizumab  (Avastin),  an  anti  VEGF  antibody  for  the  treatment  of  colon  cancer.  Although  still  only  indicated  for  colon  cancer,  several  small-­‐uncontrolled  pilot  studies  have  reported  improved  visual  outcome  and  decreased  macular  oedema  when  used  for  AMD2,  22,  25.  On  the  grounds  of  these  results  and  its  low  cost,  bevacizumab  is  being  increasingly  used  off  label  for  the  treatment  of  neovascular  AMD.  Due  to  a  lack  of  large  trials,  it  is  still  however  unclear  as  to  its  safety  and  the  most  effective  method  and  timing  of  administration.      

Ranibizumab  In  trying  to  develop  the  most  effective  monoclonal  antibody  treatment  for  AMD,  Genentech  developed  ranibizumab  (Lucentis).  Essentially  the  antigen-­‐binding  fragment  of  bevacizumab,  engineered  to  have  an  even  higher  affinity  for  VEGF.  The  first  RCT  to  assess  the  effectiveness  of  this  treatment  was  the  “Minimally  Classic/Occult  Trial  of  the  Anti-­‐VEGF  Antibody  ranibizumab  in  the  Treatment  of  Neovascular  Age-­‐  Related  Macular  Degeneration  (MARINA)”.  Results  showed  that  after  24  months,  on  average,  ranibizumab  treated  patients  gained  6.5  letters  of  visual  acuity,  whereas  sham  injected  patients  lost  10.4  letters23.  Endopthalmitis  was  observed  in  1%  of  treated  patients  and  uveitis  in  1.3%.            

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                             The  “Anti  –VEGF  Antibody  for  the  Treatment  of  Predominantly  Classic  Choroidal  Neovascularization  in  Age  –  related  Macular  Degeneration  (ANCHOR)  study  went  on  to  compare  the  effectiveness  of  ranibizumab  against  verteporfin  PDT4.  Results  showed  that  fewer  Ranibizumab  patients  experienced  15  letters  visual  loss  (RR  0.13,  NNT  3.33)  and  more  patients  experienced  visual  gain  (RR  6.79)4.    The  2008  Cochrane  review  comparing  pegaptanib,  ranibizumab  and  verteporfin  PDT  concluded  that  whilst  all  three  significantly  decrease  visual  loss,  ranibizumab  is  most  likely  to  actually  cause  an  improvement  in  visual  acuity27.    

Cost  effectiveness    As  can  be  seen  from  Table  1,  there  is  a  large  discrepancy  in  price  for  these  treatments.  NICE  analysis  of  the  incremental  cost  effectiveness  ratio  (ICER)  per  quality  adjusted  life  year  (QALY)  found  Ranibizumab  to  be  more  cost  effective  than  pergaptanib18.  As  a  result,  NICE  have  decided  not  to  recommend  the  use  of  Pegaptanib  for  neovascular  AMD18.  Note  that  Bevacizumab  could  not  be  included  in  this  analysis  due  to  not  being  licensed  for  AMD  and  therefore  a  lack  of  data.      Therapeutic   Cost  Bevacizumab   £1.21  (a)  Pegaptanib   £514.00  Ranibizumab   £761.20              

 

Table 1. net prices of the anti-angiogenic drugs3. (a) Based on using the same dose (500ug) as for ranibizumab.

Month

Fig 8. Mean changes in visual acuity against time for ranibizumab (0.5mg & 0.3mg) and sham injection. (From 23)

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Future  anti-­‐angiogenic  therapies      

Fusion  proteins  These  proteins  are  formed  by  replacing  the  stop  codon  at  the  end  of  one  gene  with  the  DNA  from  another.  The  resultant  hybrid  gene  is  inserted  into  bacteria  and  the  protein  product  collected.  This  technique  has  been  used  to  combine  the  binding  domains  of  several  VEGF  receptors  with  human  Immunuloglobulin  G  to  produce  a  protein  that  will  tightly  bind  and  effectively  inactivate  VEGF12.  This  therapeutic,  aptly  named  VEGF  Trap  produced  promising  results  in  phase  II  clinical  trials  (Fig  9.)  with  no  reported  adverse  effects6.  Phase  III  Clinical  trials  comparing  VEGF  Trap  to  Ranibizumab  were  initiated  in  2007  and  are  due  to  be  completed  in  December  201129.                                                Anti  VEGF  therapeutics  also  under  research  include,  Angiostatic  cortisenes,  RNA  interference  agents,  Aminosterols  and  further  anti  VEGF  antibodies.      

Treatments  –  Drusen  Drusen  only  cause  visual  loss  If  they  are  larger  than  125um  or  are  present  in  extremely  large  numbers21.  With  this  said,  they  are  present  to  some  degree  in  almost  all  patients  with  AMD  and  may  represent  an  early  part  of  a  more  complex  pathogenic  pathway  leading  to  GA  and  CNV.    

Fig 9. Results from Phase II Clinical trial comparing VEGF Trap against laser photocoagulation for neovascular AMD (ref). Graphs to show A.) Mean change in visual acuity (Gain in ETDRS letters) against time in study. B.) Mean change in central retinal thickness against time in study. (From 6)

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Complement  Drusen  contain  many  complement  and  complement  related  proteins,  research  has  therefore  targeted  this  pathway  to  try  and  determine  a  method  of  halting  their  development.  Many  complement  pathway  genes  have  since  been  linked  to  AMD.  These  include9:  

               

With  this  in  mind,  it  could  be  possible  to  stop  drusen  formation  by  designing  therapeutics  that  will  target  these  pathways.  Fig  10.  summarises  those  currently  in  development                                                              

 

• CFH   • CFB    

• CFHR1    

• C2    

• CFHR2    

• C3    

Fig 10. A). The complement system. B). The actions of some of the many therapeutics currently under development. Compstatin and eculizumab are currently in Phase 2 clinical trials29. (From 9)

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Treatments  –  GA  Due  to  progress  made  in  treating  the  “wet”  aspects  of  AMD,  research  into  therapeutics  for  geographic  atrophy  has  become  somewhat  overshadowed.  Although  there  are  currently  no  licensed  drugs  for  geographic  atrophy,  there  are  numerous  therapeutics  currently  undergoing  clinical  trials29.  

 Drug   Mechanism  

Clinical  trial  phase  

Estimated  completion  

Tandospirone  (AL-­‐8309B)  

Neuroprotective  by  inhibiting  oxidative  stress  within  the  retinal  pigment  epithelium  (RPE)  

III   February  2012  

Alprostadil  Prostaglandin  E1  –  has  a  vasodilatory  effect  that  is  hoped  will  increase  blood  flow  to  atrophic  areas  and  slow/halt  disease  progression.  

III  Terminated  as  study  was  under  powered.  Currently  re-­‐planning  

Fenretinide  

Retinol  metabolism  within  the  eye  creates  lipofuscin  and  A2E,  which  can  cause  damage  to  the  RPE.  Fenretindie  binds  Retinol  Binding  Protein,  decreasing  serum  retinol  concentrations.  This  reduces  retinol  uptake  by  the  RPE  and  therefore  damage.  

II   June  2010  

NT501  

Implant  of  human  cells  genetically  modified  to  release  Ciliary  Neurotrophic  Factor  (CNTF),  a  neuroprotective  agent  shown  to  inhibit  photoreceptor  apoptosis.  

II   unknown  

Brimonidine   Neuroprotective   II   December  2011  

OT551  Antioxidant,  anti-­‐inflammatory  and  anti-­‐angiogenic.  Phase  II  results  are  encouraging  

II   Completed  

     

   

Conclusion      Much  progress  has  been  made  in  developing  therapeutics  for  this  potentially  sight  threatening  disease.  Drugs  targeting  drusen  and  GA  are  in  advanced  clinical  trials  and  with  the  new  anti-­‐VEGF  agents  we  are  now  in  a  position  to  give  real  benefit  to  patients  with  CNV.  The  prevalence  of  age  related  macular  degeneration  will  continue  to  increase  in  line  with  the  aging  population.  In  order  that  everyone  can  access  this  treatment  however,  pharmaceutical  companies  need  to  recognise  the  need  to  lower  their  prices.    

 

Table 2. Summary of therapeutics for GA currently undergoing phase II and III clinical trials29.

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