Duchenne Muscular Dystrophy Update: Laminin-111 Bradley L. Hodges, PhD Founder and CSO

Conflict of interest statement: Bradley Hodges is a shareholder of Prothelia and possesses a financial interest in laminin-111. The patent inventors are Dean Burkin and Jachinta Rooney. The University of Nevada, Reno, has licensed this technology to Prothelia Inc. and has a small equity share in Prothelia.

Acknowledgements

 Dean Burkin & Jachinta Rooney / UNR  Team at Biomedical Research Models  Rich Cloud and Lance Kawesch  SMAB  Drs. Barton and Sweeney / UPENN  Drs. Goyenvalle and Davies / Oxford  NIH/NIAMS  PPMD, SAM, Hope for Gus  Parents and Patients

Mission: Develop and Commercialize Therapies for Muscular Dystrophy Our Therapeutic Approach

• 

Biologics, morpholinos and small molecules

•  • 

Improve function from within

• 

Single drug for multiple disorders

Treat all patients regardless of their mutation

Kyra

Davies and Nowak, 2006 Nature Reviews

4

Sam

Davies and Nowak, 2006 Nature Reviews

5

Laminins and Laminin Receptors in Normal Muscle

Muscle Exterior

Muscle Membrane Muscle Interior

Laminins and Laminin Receptors in Dystrophic Muscle

Muscle Exterior

Muscle Membrane Muscle Interior

Prothelia Therapeutic Strategy and Pipeline LAM-111 LAM-211 LAM-111 LAM-111 LAM-211

aD bD Utrophin

a7

a7

a7 b1 PRT-300

aD

b1 PRT-20

b1

bD Utrophin PRT-400

2-3 Fold Increase in Alpha7 Integrin is Therapeutic in Utrophin/Dystrophin dKO Animals •  Improved lifespan and weight

•  Improved skeletal and

cardiac muscle integrity

•  Increased regenerative capacity

•  Reduced spine curvature (kyphosis)

Systemically Administered Laminin-111 Reaches Skeletal and Cardiac Muscle WT

Heart

Diaphragm

Gastroc

mdx

mdx + LAM-111

Laminin-111 Protects mdx Muscle from ex vivo Eccentric Contractions LAM-­‐111,  10.0  mg/kg   IV   IP  

EDL  

Diaphragm  

ECC  

1   2   3   0   Weeks  of  Treatment  

mdx saline

mdx LAM-111 IP

C57 WT

mdx LAM-111 IV

Tukey's  Mul+ple  Comparison  Test  

p  value  

mdx  Diaphragm:    Saline  v.  LAM-­‐111  IP  

p  <  0.05  

mdx  EDL:    Saline  v.  LAM-­‐111  IV  

p  <  0.05  

mdx  EDL:    LAM-­‐111  IP  v.  LAM-­‐111  IV  

p  <  0.05  

Dr. Beth Barton, UPenn

ECC  

Laminin-111 Protects mdx Muscle from Damaging Downhill Treadmill Exercise

0  

1  

2  

4  

6  

8  

X  

10  

Weeks  of  Treatment  

1: 2: 3: 4:

Pre Exercise Baseline Control Exercised; Saline Control Exercised; Laminin-111 @ 1.0 mg/kg Exercised; Laminin-111 @ 3.0 mg/kg

* p < 0.05

Alpha 7A Integrin

Alpha 7B Integrin

**  

**  

**  

WT  

Mdx   Mdx   +   +   PBS   LAM-­‐111  

Utrophin **  

*  

6   5   4   3   2   1   0  

Utrophin  /  Cox-­‐1  

*  

6   5   4   3   2   1   0  

Alpha  7B  /  Cox-­‐1  

Alpha  7A  /  Cox-­‐1  

Laminin-111 Increases Alpha7 Integrin and Utrophin in mdx Muscle

**  

WT  

Mdx   Mdx   +   +   PBS   LAM-­‐111  

*: p < 0.05, **: p < 0.001

*  

3   2.5   2   1.5   1   0.5   0  

**  

WT  

Mdx   Mdx   +   +   PBS   LAM-­‐111  

Laminin-111; Mechanism of Action in Dystrophin-Deficient Muscle DMD / mdx Muscle

DMD / mdx + LAM-111

Laminin-111 Positively Regulates Many Facets of Normal and Dystrophic Muscle Muscle Regeneration

•  Mediates adhesion, migration, survival and proliferation of satellite cells

Dystrophic Skeletal Muscle

•  Protection against damaging exercise •  Protection against eccentric contractions •  Prevention of

apoptosis

•  Restored dystrophin associated proteins •  Human laminin-111 is active on DMD muscle cells Dystrophic Cardiac Muscle

•  Normalized ejection fraction

Laminin-111: Progress to Date   Established efficacy in the mdx mouse model of   Validated in four independent laboratories

DMD

  Established efficacy in the dyW mouse model of

MDC1A

  Further evaluations   Dystroglycanopathy   Regenerative medicine   Applied for orphan drug status   Manufacturing human laminin-111   Preclinical development for DMD   Clinical studies in 3 years

PRT-300, PRT-20 and PRT-400: Update   PRT-300: small molecule   Synthesized a library of variants   Under evaluation in vitro and in vivo   Best performing variant to be further optimized

  PRT-20: small molecule   FDA approved for non-MD conditions   Requires reformulation and canine testing   PRT-400: morpholino   SBIR Funding decision next week   Evaluation in vivo Funding levels and data will determine when or if each drug enters into clinical studies