Recombinant Biglycan for the Treatment! of Duchenne Muscular Dystrophy!!! PPMD Annual Conference, Jun 2013! By Joel B. Braunstein, MD!

Transcription

1 Recombinant Biglycan for the Treatment! of Duchenne Muscular Dystrophy!!! PPMD Annual Conference, Jun 2013! By Joel B. Braunstein, MD!

2 Tivorsan Overview Commercial operations began in 2010 around biglycan (rhbgn) technology developed within the Fallon Lab at Brown University" Rational product design based on 25+ years of scientific progress by Dr. Fallon, Fallon laboratory, and research collaborators" $10M+ public-private investment support" Clinical biglycan candidate identified (TVN-102) with back-up candidates, as necessary" Unique mechanism of action" Primary focus on Duchenne Muscular Dystrophy" Goal: Safe and effective therapy for all individuals with DMD, regardless of mutation"

3 Rationale for Utrophin-Directed DMD Therapy

4 Dystrophin: Key to Muscle Cell Structure Nature, 1985;! J.Cell. Biol., 1987! Neuron, 1991; 1994! J. Cell. Biol., 2000! J. Cell Phys. 2006! FASEB J., 2006

5 DBMD: Dystrophin Mutations

6 Utrophin can Rescue the DAPC Basal Lamina LN/AG/PN Collagen VI Biglycan (Non-glycanated) G-Dom α Sarcospan γ α β δ Sarcoglycans Dystroglycans β Extracellular Intracellular Muscle Cell Membrane Syntrophins * Utrophin, an autosomal homolog of dystrophin can compensate for loss of dystrophin in animal models Utrophin F-actin Nature, 1985;! J.Cell. Biol., 1987! Neuron, 1991; 1994! J. Cell. Biol., 2000! J. Cell Phys. 2006! FASEB J., 2006 PNAS, 2011

7 About Biglycan!

8 TVN-102 (rh-biglycan) as a DMD Therapy: Structure and Binding Partners

9 TVN-102 as a DMD Therapy: Rationale & Summary of Published Work Biglycan regulates the expression of utrophin and other DAPC components in animal models and in cell culture (Amenta et al., 2011)" Biglycan regulates signaling molecules known to be important for utrophin expression - e.g. nnos and syntrophin (Mercado et al., 2006)" Biglycan is highly expressed in developing human and rodent muscle (Lechner et al., 2006)" Biglycan binds α, γ sarcoglycan, and Collagen VI - potential scaffold for DAPC? (Raffi et al., 2006; Wiberg et al., 2002)" Recombinant human biglycan (rhbgn) can be delivered systemically and is active for at least three weeks (Amenta et al., 2011)" Systemically-delivered rhbgn upregulates utrophin, and improves muscle health and function (Amenta et. al 2011)"

10 Systemically-delivered TVN-102 is Stable for 2 Weeks in Muscle

11 Intravenously (IV) Administered TVN-102 Distributes to Skeletal & Heart Muscle

12 Biglycan Recruits Utrophin to the Muscle Cell Membrane in mdx Mice Utrophin immunostaining fourteen (14) days after rhbgn administration is significantly increased in rhbgn treated animals over control animals (p<0.0001) (a, b), without any significant impact on utrophin transcript levels (c). " Sarcoglycan levels in muscle cell membrane fractions (e) were also increased in rhbgn treated animals" " " " (Amenta et al., PNAS 2011)!

13 Systemic rh-biglycan Reduces Muscle Pathology in mdx Mice Vehicle rhbgn (Amenta et al., PNAS 2011)! Single i.p. injec2on at P16: Diaphragm analyzed 21 days post- injec2on

14 TVN-102 Reduces Muscle Death and Damage in mdx Mice T2- rhbgn

15 TVN-102 Improves Muscle Function in mdx Mice Mdx mice (n=4-6/arm) dosed with 10 mg/kg x 3 months" Dosing performed at Jackson Research Services" ECC measures at U. Penn Wellstone Physiological Assessment Core!

16 Preliminary Safety & Tolerability Well-tolerated in mdx mice" Mdx mice dosed every 3 weeks for 3 mos with 1-3 mg/kg rhbgn" No significant differences in weights of whole animals, liver, kidney, lung or spleen, or all but one muscle" Heart showed 8% decrease in size" Soleus 17% larger in treated animals" No indication of kidney or liver dysfunction" No significant changes in serum levels of Cr, BUN, AST, Bilirubin at doses 1-10 mg/kg administered for 2 wks"

17 Remaining Preclinical and Early Clinical Development Plans!

18 Remaining Preclinical Activities Completion of TVN-102 scale-up production " Optimize route, timing, dose for delivery" Perform range-finding pharmacology" Pre-IND meeting with FDA" Perform definitive pharmacology in two species" File IND application for Phase I Trials"

19 CMC Critical Path Activities for IND IND filing 2014E ü Upstream Process Op2miza2on (Get the cellular manufacturing factory to behave in op2mal fashion) ü Downstream Process Op2miza2on (Purify the ac2ve molecule) ü 10 L Bioreactor Demonstra2on Run ü Master Cell Bank Manufacturing/Tes2ng/Stability (ongoing) q 100 L Non- cgmp Engineering Run (Material for animal / lab studies) q 250 L cgmp run (Material for IND tests and Phase I studies) q Fill/Finish (Prepare drug substance for shipping and inventory )

20 Phase Ia: Healthy Male Volunteers in 2014 Study Phase! Study Design" Study Population" Sample Size" Starting Doses" Ia! Ascending, single-dose" Healthy, male volunteers" 6 TVN-102 and 2 receiving placebo; 5-6 cohorts" 0.1 mg/kg, administered intravenously" Efficacy Endpoints" Single-dose, safety and tolerability" Study Duration" 28 day follow-up (6 month total duration)" Confidential & Proprietary 2013 Tivorsan Pharmaceuticals, Inc.

21 Phase Ib/IIa: Proof-of-Concept Study Study Phase! Study Design" Study Population" Ib/IIa! Ascending, multiple-dose " Placebo-controlled, Double-blind Dose-Ranging Study" Ambulatory boys with DMD (DNA / biopsy-confirmed)" Sample Size" 48-60" Treatment Arms" Efficacy Endpoints" Study Duration" 5 active control arms, 1 placebo" Functional measures and biomarkers of drug activity" Repeat-dose safety and tolerability" 6 months (for functional measures) with open-label extension for at least 12 months" Confidential & Proprietary 2013 Tivorsan Pharmaceuticals, Inc.

22 Conclusions Focused effort towards developing biglycan as a novel Rx for DMD" Unique MOA with potential to treat all mutation types of DMD - Rational product design based on 25+ years of scientific progress by Fallon laboratory and collaborators" Clinical biglycan candidate identified with back-up candidates, as necessary! Clear roadmap in place to advance biglycan to clinic"

23 Acknowledgements Beth McKechnie" Alison Amenta" Michelle Dechene" Altigan Yamaz" Carolyn Schmiedel" Sarah Mentzer" Elizabeth Barton! Wellstone Physiol. Core" U. Penn." " Leon Hall! Jackson Lab West" 2013 Tivorsan Pharmaceuticals, Inc.

24 Utrophin Expression at the Muscle Cell Membrane Vehicle rhbgn Thank you!!! For more information, please contact:! " Joel B. Braunstein" "