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VBP15 in Duchenne muscular
dystrophy
Rationale for anti-inflammatory therapy in DMD
Action Duchenne Conference 2015
Michela Guglieri
JWMDRC Newcastle upon Tyne
[email protected]
Co-applicant for H2020 grant for VBP15 development program
Why is anti-inflammatory
therapy important for DMD
Normal muscle
DMD
Action Duchenne Conference 2015
Corticosteroids: mechanism of action
Cytoplasam
Membrane
Stabilization
p65
GR
p50
Plasma membrane
C-Jun
IkB
Fos
Anti-inflammatory
Effects
GR
Nucleus
NFĸB Response
Element
2
Beneficial
Effects
p65
GR
Protein Interference
Mechanisms
Glucocorticoid Responsive
Element
GR
Reeves, et al. Bioorganic & Medicinal Chemistry 2013.
Baudy, et al. International Immunopharmacology 2009.
GR
DNA-Dependent Regulation
1
Metabolic
Side
Effects
Action Duchenne Conference 2015
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
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
VPB15 Scaffold Discovery
Efficacy: Retention of NF-kB inhibition
 Can increase dose
Efficacy: Gain of membrane stabilization
Prednisolone
 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
VBP-15
Action Duchenne Conference 2015
VPB15: mdx mouse
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
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
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 2016-1Q 2017)
 Newcastle Team (Kate Bushby and Michela Guglieri)
 EU, Israel, (Australia)
VBP15 – Verolone:
Oral syrup suspencion
Once daily administration
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
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
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
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, nonambulant subjects)
Action Duchenne Conference 2015
VBP15: Timelines
Phase 2a
4-7 yr old DMD
Phase 2b
1-3 yr old DMD
Phase 2b
0-1Extension
yr old DMD
Phase 2b, Phase 2b
Phase 2b
4-7 yr old DMD
2016 Phase 1
Aug 2015
2017 Phase 2a, Phase
2018 2a Extension
2019
2016
2020
2017
Phase
2b
7-18 yr old DMD
2018
FDA/EMA
NDA
Phase 2b
3-17 yr old Pediatric Ulcerative Colitis
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
VBP15:Made possible by…… the
community
[email protected]