1. VBP15 in Duchenne muscular dystrophy
Rationale for anti-inflammatory therapy in DMD
Action Duchenne Conference 2015
Michela Guglieri
JWMDRC Newcastle upon Tyne
Co-applicant for H2020 grant for VBP15 development program

2. Why is anti-inflammatory therapy important for DMD
Normal muscle
Action Duchenne Conference 2015
DMD
Action Duchenne Conference 2015

3. Corticosteroids: mechanism of action
Cytoplasam
Membrane Stabilization
Beneficial Effects
p65
p50
IkB
Anti-inflammatory Effects
Protein Interference Mechanisms GR
C-Jun
Fos
NFĸB Response
Element 3
Plasma membrane GR 2
Nucleus
DNA-Dependent Regulation
Glucocorticoid Responsive Element GR
Metabolic Side Effects
The Anti-inflammatory activities via inhibition of NF-κB pathways seems to be of particular importance to DMD treatment
Other immunosuppressive compounds reduce inflammation in DMD but fail to increase patient strength 1
Reeves, et al. Bioorganic & Medicinal Chemistry 2013.
Baudy, et al. International Immunopharmacology 2009.
Action Duchenne Conference 2015

4. Corticosteroids in Duchenne Muscular Dystrophy
Side effects
Weight gain
Growth restriction
Bone fragility
Adrenal suppression
Adrenal failure
Delayed puberty
Immune suppression
……………………….
Action Duchenne Conference 2015

5. Action Duchenne Conference 2015
VBP15
Glucocorticoids have many different activities
Efficacy (good layers)
Anti-inflammatory
NFkB inhibition
Side effects (bad layer)
Mineral-corticoid agonist
Peel away layers
Keep or enhance the ‘good layers’
Reduce or remove the ‘bad layers’
Action Duchenne Conference 2015

6. VPB15 Scaffold Discovery
Efficacy: Retention of NF-kB inhibition
Can increase dose
Efficacy: Gain of membrane stabilization
Changes pred damage to VBP15 protection
Safety: Loss of transactivation
Loss of some GRE-mediated activities relative to pred
Safety: MR antagonist (instead of agonist)
Loss of growth stunting, Cushingoid
Prednisolone
VBP-15
Action Duchenne Conference 2015

7. Action Duchenne Conference 2015
VPB15: mdx mouse
Action Duchenne Conference 2015

8. Action Duchenne Conference 2015
VPB15: Clinical program
Phase 1 study: Healthy adult volunteers. August 2015-November 2015
Single Ascending Dose (SAD)
0.1, 0.3, 1.0, 3.0, 8.0, 8.0 fed, 20.0 mg/kg
Multiple Ascending Dose (MAD)
1.0, 3.0, 9.0, 20.0 mg/kg/day 2 weeks
Action Duchenne Conference 2015

9. Phase 1 data through SAD Cohort 4 (3.0 mg/kg)
Excellent dose proportionality
Short half-life (2 hrs) – similar to pred
Consistent findings between subjects
No adverse events reported through 8.0 mg/kg
Action Duchenne Conference 2015

10. VPB15: DMD Clinical program
Phase 2a and 2a extension studies (1Q 2016)
CINRG international trials group (Paula Clemens) US
Phase 2b and 2b extension (4Q Q 2017)
Newcastle Team (Kate Bushby and Michela Guglieri)
EU, Israel, (Australia)
VBP15 – Verolone:
Oral syrup suspencion
Once daily administration
Action Duchenne Conference 2015

11. Action Duchenne Conference 2015
Phase 2a and 2a extension
10 US CINRG sites
Dose escalation study (4 doses)
Subjects: 3-12 subjects per cohort
Duration of treatment: 2 weeks
Primary outcome: PK and safety
Inclusion criteria: 4-7 year old, steroid naïve
Start date: 1Q 2016 (February 2016)
Action Duchenne Conference 2015

12. Action Duchenne Conference 2015
Phase 2b and 2b extension
30 sites (EU, Israel, Australia)
Double-blind, prednisolone-placebo-control study, two doses of Verolone
Primary outcomes: Efficacy (versus placebo)
Safety (versus daily prednisolone)
Subjects: 100 subjects (25 per cohort)
Duration of treatment: 6 months
Inclusion criteria: 4-7 year old, steroid naïve, able to stand from the floor
Start date: 4Q 2016 – 1Q 2017
Action Duchenne Conference 2015

13. Pharmacodynamic biomarkers
Objective measures (blood not subject to placebo effect)
Possibly an acute read out (changes in blood seen before clinical changes)
SAFETY
Steroid related side effects
Insulin resistance
Adrenal suppression
Bone remodeling
EFFICACY
Exploratory
Pro-inflammatory proteins
Should help build ‘compelling case’ for regulators: accelerated approval
Action Duchenne Conference 2015

14. Pharmacodynamic biomarkers
Should support and extend clinical outcomes
Should help build ‘compelling case’ for regulators: accelerated approval
Could allow clinical trials in populations where there are no strong clinical outcomes (young boys and older, non- ambulant subjects)
Action Duchenne Conference 2015

15. Action Duchenne Conference 2015
VBP15: Timelines
Phase 2a
4-7 yr old DMD
Phase 2b
1-3 yr old DMD
0-1 yr old DMD
7-18 yr old DMD
3-17 yr old Pediatric Ulcerative Colitis
Phase 2b, Phase 2b Extension
Phase 2a, Phase 2a Extension
Phase 1
Aug
FDA/EMA
NDA
Action Duchenne Conference 2015

16. Action Duchenne Conference 2015
VBP15: Innovation
Venture philanthropy - Sustainable drug
Reduce costs
To build a compelling case that ‘drug works’
Accelerated approvals
Action Duchenne Conference 2015

17. VBP15:Made possible by…… the community
National Institutes of Health; NCATS, TRND; SBIRs
US Department of Defense (CDMRP DMDRP)
National Institute on Disability and Rehabilitation Research (NIDRR)
NIH NICHD RPDP U54
Foundation to Eradicate Duchenne (FED) (USA)
MDA (USA)
Joining Jack (UK)
Duchenne Research Foundation (UK)
Duchenne Children’s Trust (UK)
PPMD (USA)
Clark Charitable Foundation (USA)
ActionDuchenne (UK)
DuchenneAlliance (Michael’s Cause- USA, Pietro’s Fight - USA, Alex’s Wish - UK, Ryan’s Quest - USA, Save Our Sons - AUS)

18. National Institutes of Health; NCATS, TRND; SBIRs
US Department of Defense (CDMRP DMDRP)
National Institute on Disability and Rehabilitation Research (NIDRR)
NIH NICHD RPDP U54
Foundation to Eradicate Duchenne (FED) (USA)
MDA (USA)
Joining Jack (UK)
Duchenne Research Foundation (UK)
Duchenne Children’s Trust (UK)
PPMD (USA)
Clark Charitable Foundation (USA)
ActionDuchenne (UK)
DuchenneAlliance (Michael’s Cause- USA, Pietro’s Fight - USA, Alex’s Wish - UK, Ryan’s Quest - USA, Save Our Sons - AUS)