VBP-15 Novel target Therapy

VBP15: A novel glucocorticoid analogue as
therapeutic option for DMD
Kanneboyina Nagaraju, DVM, PhD.
Professor of Integrative Systems Biology and Pediatrics
Associate Director, Research Center for Genetic Medicine
Children's National Medical Center
111 Michigan Avenue, N.W.
Washington, DC 20010
Disclosures
Member, Board of Directors, ReveraGen Biopharma, Rockville, MD, USA. President, Agada Biosciences, Halifax, Nova ScoCa, Canada. Inflammatory genes up-regulated early in DMD muscle
Control DMD Chen et al., 2005 Hormones of the Adrenal Cortex:
Structure and Biological Effects
The Nobel Prize in Physiology or Medicine 1950 Edward Calvin Kendall
Tadeus Reichstein
Philip Showalter Hench
Side Effects of Glucocorticoids
•  Immunosuppression
•  Hyperglycemia due to increased gluconeogenesis, insulin resistance,
•  Impaired glucose tolerance ("steroid diabetes")
•  Increased skin fragility, easy bruising
•  Reduced bone density (osteoporosis, higher fracture risk, slower fracture repair)
•  Weight gain due to increased visceral and truncal fat deposition (central obesity)
•  Appetite stimulation
•  Adrenal insufficiency (if used for long time and stopped suddenly without a taper)
•  Muscle breakdown (proteolysis), weakness; reduced muscle mass and repair
•  Expansion of malar fat pads and dilation of small blood vessels in skin
•  Growth failure, pubertal delay
•  Increased plasma amino acids, increased urea formation
•  Negative nitrogen balance
•  Excitatory effect on central nervous system
Rationale for Developing of Novel GC Analogues
- Chemistry
•  Dissect 3 sub proper9es of GCs to op9mize for DMD 1. Reduce side effect sub proper9es (muscle wasCng, growth stunCng): transacCvaCon •  GRE-­‐mediated gene transcripCon, transacCvaCon 2. Retain or enhance an9-­‐inflammatory sub proper9es •  NF-­‐κB inhibiCon, transrepression 3. Improve membrane stabiliza9on sub proper9es •  Protect fragile myofiber membranes 6 VBP15 Rationale for Development
•  GlucocorCcoids (steroids) work for DMD •  But glucocorCcoids cause muscle wasCng and weakness in most everyone else as an important side effect (glucocorCcoid myopathy) •  Steroid effect in DMD likely a ‘sum’ of: –  Benefit in strength (anC-­‐inflammatory effect) –  Side effect of weakness •  Makes sense if side effect of weakness could be removed, then this would work be[er for DMD –  Benefit in strength –  Without side effect of weakness –  Sum is be[er Sub Property 1: Dissociation – In vitro
120000
Ø  GRE-­‐mediated hormonal toxicity 100000
UnTx
Prednisolone
VBP15
RFU
80000
Ø  Reporter HEK293 Ø VBP15 << Pred 60000
40000
20000
-10
-9
-8
-7
Concentration [Log M]
-6
-5
Reeves et al. 2013 Ø  Pituitary cells – Sgk1 gene Ø VBP15 << pred/dex 8
Heier et al. 2013 8 Sub Property 1: Dissociation – In vitro
Ø  Adrenal suppression Ø  VBP15 << Pred/Dex 9
9 Heier et al. 2013 Sub Property 2: Efficacy – In vitro
Glucocor9coid receptor nuclear transloca9on; NF-­‐κB inhibi9on
VBP15 = pred 10
Reeves et al. 2013 10 Sub Property 2: Efficacy – In vitro
Inhibi9on of inflammatory transcript in splenocytes VBP15 = pred
11
11 Heier et al. 2013 Sub Property 3: Efficacy – In vitro
Membrane stabiliza9on Ø  Leukocyte degranula9on Ø  VBP15 = pred Ø  Physical injury to myocyte membranes Ø  VBP15 >> pred Damsker et al. 2013 12
12 Heier et al. 2013 Development – Chemistry and in vitro
•  Dissect 3 sub properCes of glucocorCcoids to opCmize for DMD –  Reduced transac9va9on (should reduce side effects) (muscle wasCng, growth stunCng): transacCvaCon •  GRE-­‐mediated gene transcripCon, transacCvaCon –  Retained an9-­‐inflammatory subproper9es •  NF-­‐κB inhibiCon, transrepression –  Improved membrane stabiliza9on subproper9es •  Protect fragile myofiber membranes •  Does it work in the mdx mouse model? 13 In vivo study in mdx mice: Study design
Efficacy of VBP-15 in young
C57Bl/10ScSn-Dmdmdx mice
•  Treatment started at 15 days of age
•  Daily oral administration
•  6 wk treatment period
Measures of Safety – In vivo
Ø  Stun9ng of body length in mdx mice Ø  VBP15 >> Pred Vehicle
15
Pred
VBP15 Pred
Heier et al. 2013 15 Measures of Safety – In vivo
Ø  Bone length in mdx mice Ø  VBP15 >> Pred Heier et al. 2013 16 Measures of Safety – In vivo
Ø  Bone thickness in mdx mice Ø  VBP15 >> Pred Heier et al. 2013 17 Measures of Efficacy – In vivo
Ø Muscle strength Ø  Primary outcome; mice, humans 18
18 Heier et al. 2013 Measures of Efficacy – In vivo
Ø  Muscle inflamma9on n = 6, * mdx, P < 0.05, *** < 0.005
Optical Imaging: In vivo NIR imaging of muscle inflammation using Cy5.5 labeled cathepsin
19 Probes in live mice. Fluorescence intensity 19
(photon counts) is quantified in fore- and hindlimbs
Heier et al. 2013 Summary: Efficacy
Measures of efficacy -­‐ in vitro Measure Potency difference prednisone vs. VBP15 NFkB myoblasts NFkB myotubes NfkB lung epithelium Inhibition inflammatory transcripts in splenocytes GR translocation Leukocyte membrane stabilization Myocyte membrane protection from physical injury VBP15 = Pred VBP15 = Pred VBP15 = Pred VBP15 = Pred VBP15 = Pred VBP15 = Pred VBP15 >> Pred (>100 fold difference) VBP15 protects, Pred damages Measures of efficacy-­‐ in vivo Measure Potency difference prednisone vs. VBP15 Measure of muscle strength VBP15 >> Pred (>10-­‐fold difference) 20
20 Summary: Pharmacological Safety Profiles
Measures of toxicity -­‐ in vitro Measure Potency difference prednisone vs. VBP15 GRE-­‐mediated transcription ACTH suppression in pituitary cells SGK1 pituitary cell GRE induction VBP15 << Pred (>100 fold difference) VBP15 << Pred (>100 -­‐fold difference) VBP15 << Pred (>100 -­‐fold difference) Measures of toxicity -­‐ in vivo Measure Potency difference prednisone vs. VBP15 Stunting of growth Loss of bone length Loss of bone trabecular thickness Immune suppression – reduced peripheral blood leukocytes Immune suppression – spleen size reduced less than WT Increased muscle fibrosis Increased degenerating myofibers VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) VBP15 << Pred (>10-­‐fold difference) 21
21 Where do we stand?
Ø  Done requisite IND enabling studies for FDA Ø Tox studies (3 SAD; 6 MAD; 3 species each) Ø PK, Cyps, gene tox, Chemistry Manufacturing Control Ø SCll need to do: long term chronic tox, juvenile tox Ø  Phase 1 clinical trials Ø Safety, tolerability, PK Ø Normal volunteers Ø Funded by MDA, UK foundaCons (Joining Jack, DRF, Duchenne Children’s Trust) Ø Enrollment January 2015 Ø  Phase 2a, 2b trials in DMD Ø 6 months amer Phase 1 start 22
22 VBP15: Development Working Timeline
API process chemistry 28-­‐day tox non-­‐GLP GMP Drug Product Stability 6 Month Toxicology Study start GMP API 28-­‐day GLP tox studies File IND Phase 1 Study Start Healthy Adults Phase 2a Study Start DMD Dose Range 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 2012 2013 2014 2015 23 VBP15 development path is different
•  InnovaCons in IP transfer –  Assignment of IP, rather than license –  Freedom to operate •  InnovaCons in drug development –  Concept to approval in 6 yrs (best case scenario) –  Co-­‐development with US government •  Department of Defense CDMRP •  NIH TRND – experCse plus payment in kind –  Venture philanthropy model •  Shared risk with stake holders •  ROI to stakeholders –  No VC or financial shareholders to date – focus on DMD 24 Summary
•  VBP15 may be a ‘be[er steroid’ •  Shared development, risk, and ROI with foundaCons and government •  Steroids among most highly prescribed drugs since 1950’s (~10% of women ages 55-­‐65) •  If VBP15 works for DMD, will likely be developed for other disorders •  Likely to start enrollment of DMD boys within the next year 25 Acknowledgments
•  Developers: John McCall, Eric Hoffman, NIH TRND •  ReveraGen staff: Ed Connor, Erica Reeves, Jesse Damsker •  Clinical development plan: Ed Connor –  Newcastle group (Kate Bushby, Michela Guglieri, Monica Ensini) –  CINRG group (Avital Cnaan, Paula Clemens, Heather Gordish, Craig McDonald, Eric Hoffman, Lauren Morganroth) –  TREAT-­‐NMD group (TACT, post-­‐markeCng) 26 Acknowledgments Financial support: Federal: Department of Defense CDMRP, NIH TRND FoundaCons: USA: FED, MDA, CureDuchenne UK: Joining Jack, DRF, Duchenne Children’s Trust Australia: Save Our Sons 27