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VBP15 in Duchenne muscular dystrophy
Michela Guglieri
JWMDRC Newcastle upon Tyne
Co-applicant for H2020 grant for VBP15 development program
Rationale for anti-inflammatory therapy in DMD
Action Duchenne Conference 2015
Why is anti-inflammatory therapy
important for DMD
Normal muscle
DMD
Action Duchenne Conference 2015
Reeves, et al. Bioorganic & Medicinal Chemistry 2013.Baudy, et al. International Immunopharmacology 2009.
GR
DNA-Dependent Regulation
Glucocorticoid Responsive Element
GRGR
Metabolic Side Effects
Beneficial
Effects
p65
p50IkB
Anti-inflammatory Effects
Protein Interference Mechanisms
GR C-Jun
Fos
NFĸB Response Element
GR
p65
Membrane Stabilization
Cytoplasam
Nucleus
Plasma membrane
1
2
3
Corticosteroids: mechanism of action
Action Duchenne Conference 2015
Side effects Weight gain Growth restriction Bone fragility Adrenal suppression
Adrenal failure Delayed puberty
Immune suppression ………………………. ……………………….
Corticosteroids in Duchenne Muscular
Dystrophy
Action Duchenne Conference 2015
VBP15Glucocorticoids 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
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
VPB15 Scaffold Discovery
OH
O
OOH
HO
Prednisolone
VBP-15
OH
O
OH
O
CH3
Action Duchenne Conference 2015
VPB15: mdx mouse
Action Duchenne Conference 2015
VPB15: Clinical programPhase 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
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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 programPhase 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, non-ambulant subjects)
Action Duchenne Conference 2015
VBP15: Timelines
Aug 2015 2016 2017 2018
Phase 2a, Phase 2a ExtensionPhase 1
Phase 2b, Phase 2b Extension
FDA/EMANDA
2016 2017 2018 2019 2020
Phase 2a4-7 yr old DMD
Phase 2b4-7 yr old DMD
Phase 2b1-3 yr old DMD
Phase 2b0-1 yr old DMD
Phase 2b7-18 yr old DMD
Phase 2b3-17 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
