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1	
  CONFIDENTIAL	
  
Development	
  of	
  a	
  once-­‐weekly	
  C-­‐pep<de	
  product	
  
Disclosure	
  
•  James	
  Callaway	
  is	
  an	
  employee	
  and	
  
shareholder	
  of	
  Cebix	
  Incorporated	
  
An agent for the treatment of mild to
moderate peripheral neuropathy in type 1
diabetes
The therapy of choice in the treatment of
this significant unmet medical need,
based on improvement of sensory
function
Initial Target Indication
3	
  
Product Profile
Restores	
  Sensory	
  Nerve	
  Conduc<on	
  
Ekberg	
  et	
  al,	
  	
  
Diabetes	
  2003	
  
50
52
54
56
Baseline 6	
  wks 12	
  wks
SCV	
  (m/s)	
  
C-­‐pep<de	
  n=26
Placebo	
  n=23
Healthy	
  Controls	
  
p<0.05	
  
Required	
  4	
  subcutaneous	
  
doses	
  per	
  day	
  
5	
  
Drug	
  Product	
  Development	
  
 Unmet	
  medical	
  need	
  
 Biology	
  	
  -­‐	
  	
  Func<on	
  and	
  Pathophysiology	
  
 Safety	
  
 Efficacy	
  
 Dose	
  	
  -­‐	
  	
  Replacement	
  
 Drug	
  manufacturing	
  
 Regulatory	
  Path	
  
 End	
  Points	
  
 Drug	
  delivery	
  
Formula<on	
  Criteria	
  
6	
  
Product	
  load	
  >1%	
  of	
  volume	
  
1	
   2	
   3	
   4	
   5	
   6	
   7	
  
Syringeability	
  ≤	
  27	
  gauge	
  
	
   	
  	
  	
  	
  	
  	
  <	
  20	
  seconds	
  	
  
<20%	
  drug	
  loss	
  in	
  burst	
  
PK	
  profile	
  consistent	
  with	
  	
  
once	
  weekly	
  dosing	
  
Selected	
  Formula<on	
  Technologies	
  
7	
  
PROMAXX	
  
Atrigel	
  
Pumps	
  
Trans-­‐	
  
dermal	
  
patch	
  
Alkermes	
  
Octoplus	
  
Eryto-­‐	
  
pharm	
  
Halozyme	
  
Altus	
  
Alkamer	
  
Nektar	
  
Enzon	
  
Syringability	
  ≤	
  27	
  gauge	
  	
  
Stable	
  for	
  	
  >	
  1.5	
  years	
  at	
  4°C	
  
PK	
  profile	
  consistent	
  with	
  once	
  weekly	
  dosing	
  
No	
  more	
  than	
  20	
  percent	
  drug	
  loss	
  in	
  burst	
  
Product	
  load	
  of	
  at	
  least	
  1	
  percent	
  of	
  volume	
  
Winning	
  Formula<ons	
  
Slow	
  Release	
  PK	
  Profile	
  (Dog)	
  
Lot	
  1	
  
Lot	
  2	
  
Aqu	
  
C-­‐pep<de	
  conc	
  (ng/ml)	
  
C-­‐pep<de	
  conc	
  (ng/ml)	
  
Depot	
  Characteris<cs	
  
•  Approximates	
  7	
  day	
  coverage	
  	
  	
  
•  2-­‐Log	
  span	
  spread	
  from	
  Cmax	
  to	
  Cmin	
  
•  Volume	
  of	
  injec<on	
  less	
  than	
  1	
  mL	
  
•  Viscosity	
  keeps	
  injec<on	
  above	
  20	
  second	
  
target	
  
Extended	
  half-­‐life	
  
Extended	
  Half-­‐life	
  PK	
  profile	
  (monkey)	
  
12	
  
Linear	
  scale	
  
60	
  
100	
  
40	
  
20	
  
0	
  
C-­‐pep<de	
  conc	
  (ng/ml)	
  
0	
   4	
   8	
   12	
  
Time	
  (days)	
  
Semi-­‐logarithmic	
  scale	
  
100	
  
1	
  
10	
  
C-­‐pep<de	
  conc	
  (ng/ml)	
  
0	
   4	
   8	
   12	
   16	
  16	
  
Time	
  (days)	
  
T1/2	
  =	
  3	
  days	
  
Extended	
  Half-­‐life	
  or	
  Depot	
  
Half-­‐life	
  
•  Chemically	
  altered	
  
•  Ideal	
  PK	
  profile	
  
•  Ideal	
  Presenta<on	
  
–  like	
  water	
  
–  31	
  G	
  
•  Excellent	
  Tolerability	
  
•  Manufacturing	
  
–  Simple	
  
Depot	
  
•  Natural	
  C-­‐pep<de	
  
•  PK	
  Profile	
  not	
  op<mal	
  
–  Exceeding	
  Cmax	
  by	
  a	
  Log	
  
•  Presenta<on	
  
–  Ajrac<ve	
  
–  Injectability	
  acceptable	
  
•  Acceptable	
  tolerability	
  
•  Manufacturing	
  
–  Unknown	
  risk	
  
Long-­‐Ac(ng-­‐
CP	
  
CP	
  
0	
  
5	
  
10	
  
15	
  
20	
  
25	
  
0	
   0.5	
   1	
   3	
   10	
   100	
  
CP/Long-­‐Ac(ng	
  -­‐CP	
  [nmol/L]	
  
pERK1/2	
  [AU]	
  
LA-­‐CP	
  
CP	
  
n=6-­‐8	
  
Chibalin	
  lab	
  at	
  Karolinska:	
  HEK-­‐293	
  cells	
  
ERK1/2	
  phosphoryla(on	
  
CP	
  versus	
  Long-­‐Ac(ng	
  CP	
  	
  
Regulatory	
  &	
  Clinical	
  	
  
Path	
  Forward	
  
Pre-­‐IND	
  Mee<ng	
  with	
  FDA	
  
July	
  2010	
  
•  Regulatory	
  
–  FDA	
  Confirmed	
  qualifica<on	
  of	
  Subpart	
  H	
  
•  Allows	
  use	
  of	
  surrogate	
  end	
  point	
  for	
  Pivotal	
  Phase	
  2b	
  
•  Clinical	
  
–  Nerve	
  conduc<on	
  velocity	
  accepted	
  as	
  the	
  sole	
  
primary	
  endpoint	
  for	
  approval	
  
•  Nonclinical	
  
–  IND-­‐enabling	
  tox	
  plan	
  endorsed	
  by	
  FDA	
  
16	
  
FDA
Road	
  to	
  the	
  Clinic	
  
17	
  
pre-­‐IND	
  mee<ng	
  
Acute	
  monkey	
  tox	
  
In	
  life	
   Analysis	
  
Human	
  PK	
  study	
  
IND	
  
submission	
  
Acute	
  rodent	
  tox	
  
In	
  life	
   Analysis	
  
Formula<ons	
  screen	
  
Qualify	
  analy<cal	
  methods	
  (DS)	
  
Methods	
  create/approve	
  (DP)	
  
Fill	
  prep	
   Batch	
  
records	
  
Fill	
  
6-­‐month	
  rodent	
  tox	
  
6-­‐month	
  monkey	
  tox	
  
DS	
  Process	
  Development	
  
Tox	
  supplies	
  
Develop	
  	
  &	
  	
  
Dec	
   Jan	
   Feb	
   Mar	
  
2010	
   2011	
  
Apr	
  May	
   Jun	
   Jul	
   Aug	
   Oct	
   Nov	
  Sep	
  
DS	
  	
  Manufacturing	
  
2011	
  
Cebix	
  Development	
  Program	
  
2012	
  
18	
  
2014	
  2013	
   2015	
  2010	
  
Formula<on	
  
Pre-­‐clinical	
  
6-­‐mo	
  interim	
  data:	
  
surrogate	
  marker	
  
NDA	
  submission	
  
12-­‐mo	
  data:	
  
clinical	
  end-­‐point	
  
Phase	
  2b	
  NEUROPATHY	
  
Confirm	
  surrogate	
  
marker	
  
Phase	
  3	
  NEUROPATHY	
  
Human	
  PK	
  
Summary	
  
•  Clear	
  biological	
  ra<onale	
  for	
  C-­‐pep<de	
  
replacement	
  
•  Company	
  set	
  Target	
  Product	
  Profile	
  for	
  pa<ent	
  
to	
  have	
  a	
  once	
  weekly	
  “insulin-­‐like	
  experience”	
  
•  Established	
  long-­‐ac<ng	
  C-­‐pep<de	
  which	
  met	
  
the	
  profile	
  
– Biological	
  ac<vity	
  confirmed	
  in	
  3	
  separate	
  models	
  
– Patents	
  have	
  been	
  filed	
  
•  Full	
  development	
  program	
  ini<ated	
  

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Easd Stockholm 2010

  • 1. 1  CONFIDENTIAL   Development  of  a  once-­‐weekly  C-­‐pep<de  product  
  • 2. Disclosure   •  James  Callaway  is  an  employee  and   shareholder  of  Cebix  Incorporated  
  • 3. An agent for the treatment of mild to moderate peripheral neuropathy in type 1 diabetes The therapy of choice in the treatment of this significant unmet medical need, based on improvement of sensory function Initial Target Indication 3   Product Profile
  • 4. Restores  Sensory  Nerve  Conduc<on   Ekberg  et  al,     Diabetes  2003   50 52 54 56 Baseline 6  wks 12  wks SCV  (m/s)   C-­‐pep<de  n=26 Placebo  n=23 Healthy  Controls   p<0.05   Required  4  subcutaneous   doses  per  day  
  • 5. 5   Drug  Product  Development    Unmet  medical  need    Biology    -­‐    Func<on  and  Pathophysiology    Safety    Efficacy    Dose    -­‐    Replacement    Drug  manufacturing    Regulatory  Path    End  Points    Drug  delivery  
  • 6. Formula<on  Criteria   6   Product  load  >1%  of  volume   1   2   3   4   5   6   7   Syringeability  ≤  27  gauge                <  20  seconds     <20%  drug  loss  in  burst   PK  profile  consistent  with     once  weekly  dosing  
  • 7. Selected  Formula<on  Technologies   7   PROMAXX   Atrigel   Pumps   Trans-­‐   dermal   patch   Alkermes   Octoplus   Eryto-­‐   pharm   Halozyme   Altus   Alkamer   Nektar   Enzon   Syringability  ≤  27  gauge     Stable  for    >  1.5  years  at  4°C   PK  profile  consistent  with  once  weekly  dosing   No  more  than  20  percent  drug  loss  in  burst   Product  load  of  at  least  1  percent  of  volume  
  • 9. Slow  Release  PK  Profile  (Dog)   Lot  1   Lot  2   Aqu   C-­‐pep<de  conc  (ng/ml)   C-­‐pep<de  conc  (ng/ml)  
  • 10. Depot  Characteris<cs   •  Approximates  7  day  coverage       •  2-­‐Log  span  spread  from  Cmax  to  Cmin   •  Volume  of  injec<on  less  than  1  mL   •  Viscosity  keeps  injec<on  above  20  second   target  
  • 12. Extended  Half-­‐life  PK  profile  (monkey)   12   Linear  scale   60   100   40   20   0   C-­‐pep<de  conc  (ng/ml)   0   4   8   12   Time  (days)   Semi-­‐logarithmic  scale   100   1   10   C-­‐pep<de  conc  (ng/ml)   0   4   8   12   16  16   Time  (days)   T1/2  =  3  days  
  • 13. Extended  Half-­‐life  or  Depot   Half-­‐life   •  Chemically  altered   •  Ideal  PK  profile   •  Ideal  Presenta<on   –  like  water   –  31  G   •  Excellent  Tolerability   •  Manufacturing   –  Simple   Depot   •  Natural  C-­‐pep<de   •  PK  Profile  not  op<mal   –  Exceeding  Cmax  by  a  Log   •  Presenta<on   –  Ajrac<ve   –  Injectability  acceptable   •  Acceptable  tolerability   •  Manufacturing   –  Unknown  risk  
  • 14. Long-­‐Ac(ng-­‐ CP   CP   0   5   10   15   20   25   0   0.5   1   3   10   100   CP/Long-­‐Ac(ng  -­‐CP  [nmol/L]   pERK1/2  [AU]   LA-­‐CP   CP   n=6-­‐8   Chibalin  lab  at  Karolinska:  HEK-­‐293  cells   ERK1/2  phosphoryla(on   CP  versus  Long-­‐Ac(ng  CP    
  • 15. Regulatory  &  Clinical     Path  Forward  
  • 16. Pre-­‐IND  Mee<ng  with  FDA   July  2010   •  Regulatory   –  FDA  Confirmed  qualifica<on  of  Subpart  H   •  Allows  use  of  surrogate  end  point  for  Pivotal  Phase  2b   •  Clinical   –  Nerve  conduc<on  velocity  accepted  as  the  sole   primary  endpoint  for  approval   •  Nonclinical   –  IND-­‐enabling  tox  plan  endorsed  by  FDA   16   FDA
  • 17. Road  to  the  Clinic   17   pre-­‐IND  mee<ng   Acute  monkey  tox   In  life   Analysis   Human  PK  study   IND   submission   Acute  rodent  tox   In  life   Analysis   Formula<ons  screen   Qualify  analy<cal  methods  (DS)   Methods  create/approve  (DP)   Fill  prep   Batch   records   Fill   6-­‐month  rodent  tox   6-­‐month  monkey  tox   DS  Process  Development   Tox  supplies   Develop    &     Dec   Jan   Feb   Mar   2010   2011   Apr  May   Jun   Jul   Aug   Oct   Nov  Sep   DS    Manufacturing  
  • 18. 2011   Cebix  Development  Program   2012   18   2014  2013   2015  2010   Formula<on   Pre-­‐clinical   6-­‐mo  interim  data:   surrogate  marker   NDA  submission   12-­‐mo  data:   clinical  end-­‐point   Phase  2b  NEUROPATHY   Confirm  surrogate   marker   Phase  3  NEUROPATHY   Human  PK  
  • 19. Summary   •  Clear  biological  ra<onale  for  C-­‐pep<de   replacement   •  Company  set  Target  Product  Profile  for  pa<ent   to  have  a  once  weekly  “insulin-­‐like  experience”   •  Established  long-­‐ac<ng  C-­‐pep<de  which  met   the  profile   – Biological  ac<vity  confirmed  in  3  separate  models   – Patents  have  been  filed   •  Full  development  program  ini<ated