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-‐pe
p<de
con
c (ng/ml)
C-‐pe
p<de
con
c (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-‐pe
p<de
con
c (ng/ml)
0 4 8 12
Time (days)
Semi-‐logarithmic scale
100
1
10
C-‐pe
p<de
con
c (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]
pERK
1/2 [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
