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Weekly C-peptide therapy for diabetic neuropathy
- 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