Therapeutic approaches in development for DMD (cell therapy, gene therapy and genetic therapies)

Overview of therapeutic approaches in development for DMD May 29 2014

Dystrophin

Dystrophin

Annemieke Aartsma-Rus

Therapeutic approaches • Cell therapy • Genetic therapy • Exon skipping • Stop codon read through

Annemieke Aartsma-Rus

4 | TREAT-NMD Outcome Patient Care Joint EuroBioBank Standards Action & Website 2007-2011 Registries measures Trial research TACT SOPs Plan Site of & EU fundedRegistry Network Diagnosis Communication & Care

Three year work plan

www.treat-nmd.eu

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advisory boardVolker (“task force”) Marco Crimi Straub Coordinated Hugh by University Dawkins Funding - Telethon & Parent of NMD leaders Funding - US Sejersen (Dept of Leads - Thomas Medical Center Freiburg Organizations Funding COST Funding -Kathy Fondazione Funding – EC Defense) Funding -(operating AFM North & EC Telethon grant) (operating grant)

Cell therapy

Muscle stem cells • Isolate muscle stem cells from healthy donor • Expand outside the body (culture in lab) • Transplant into patients • Transplanted cells repair muscle • Transplanted cells make dystrophin Annemieke Aartsma-Rus

Muscle stem cells (myoblasts) • Immune response (suppress) • Do not exit circulation after injection • Local injection: stay close to injection site • Tremblay (Canada): multiple local injections • Local dystrophin restoration • Not feasible for larger muscles

Annemieke Aartsma-Rus

Stem cell therapy Stem cells from fat, bone and bloodvessel walls • Can exit bloodstream and migrate into muscle • Very low efficiency Mesangioblasts most promising • Encouraging results in dog model • Safety trial ongoing in Italy (Giulio Cossu) • 3 patients received stem cells • Some side effects • Preparing for injection 2 more patients Annemieke Aartsma-Rus

Niche Muscle damage

Repair

Inflammation

Fibrosis • Dystrophic muscle is damaged (scar tissue/fibrosis) • The few transplanted stem cells that reach muscle • Do not receive proper signals to become muscle • Receive signals from scar tissue: more fibrosis Annemieke Aartsma-Rus

Cell therapy summary • Opportunities • Applicable to all patients • Deliver dystrophin gene and repair muscle • Currently in very early stage clinical development • Challenges • Efficiency very low • Damaged muscle gives wrong signals to cells • Immunity (only with allogenic transplantation) Annemieke Aartsma-Rus

Exon skipping Normal

Annemieke Aartsma-Rus

Duchenne

Dystrophin gene

Annemieke Aartsma-Rus

Duchenne: genetic code disrupted

Annemieke Aartsma-Rus

Duchenne: genetic code disrupted Exon 46

Exon 47

?

Exon 51

Exon 52

Protein translation stops prematurely

Dystrophin not functional Annemieke Aartsma-Rus

Becker: genetic code maintained Exon 46

Exon 47

Exon 52

Exon 53

Protein translation continues

Dystrophin partly functional Less damage Annemieke Aartsma-Rus

Exon skipping: restore genetic code

Annemieke Aartsma-Rus

Applicability

hotspot

Annemieke Aartsma-Rus

Aartsma-Rus Hum Mutat 2009, 30:293-9

Exon skip chemistries • Two chemistries in clinical development • GSK/Prosensa: 2’-O-methyl phosphorothioate (drisapirsen) • AVI-Biopharma/Sarepta: phosphorodiamidate morpholino oligomers (eteplirsen) • Exon 51

Annemieke Aartsma-Rus

Systemic study Sarepta II AVI-4658 (30 and 50 mg/kg) • Intravenous delivery • Earlier trial:20 mg/kg (12 weeks) is not sufficient • Weekly 12 weeks 50 mg/kg: biopsy • Weekly 24 weeks 30 mg/kg: biopsy • Weekly placebo 12 or 24 weeks: biopsy • After 24 weeks treatment: all 30 or 50 mg/kg/week • Patients have been treated for >90 weeks now Annemieke Aartsma-Rus

Dystrophin staining

Annemieke AartsmaRus

Department of Human Genetics

Annemieke Aartsma-Rus

19

Dystrophin results

Annemieke AartsmaRus

Department of Human Genetics

Annemieke Aartsma-Rus

20

Eteplirsen summary • Dystrophin restored for all patients 24 weeks after treatment • 6 minute walk test stabilized in 10/12 treated patients • No real placebo group • Sarepta plans confirmatory study for 2014 • Also preclinical work ongoing for exon 50, 45, 53 and 44 Annemieke Aartsma-Rus

Systemic trial (GSK/Prosensa) • Subcutaneous treatment for 5 weeks • 0.5, 1, 2 & 6 mg/kg • Dystrophin restored in 10/12 patients • 60-100% fibers dystrophin positive • Dystrophin levels up to 15.6% • Dose dependent increase in dystrophin levels

Annemieke Aartsma-Rus

Systemic trial (GSK/Prosensa) • All patients then enrolled in an open label extension study • 6 mg/kg drisapirsen per week for 72 weeks • Then 8 weeks break • Then cycles of 8 weekly doses, 4 week break • All patients still in trial • Treated now for almost 4 years

Annemieke Aartsma-Rus

Goemans et al, NEJM 2011, 364: 1513-22

PRO051-02 / DMD114673 Distance walked (m)

Efficacy

intermittent

Annemieke AartsmaRus

Weeks in extension study

24

Open Label Extenion Trial Drisapersen • Side effects observed • Local injection site reactions • Proteinuria (reversible during breaks) • Thrombocytopenia seen for some patients • Seen in all phase 2/3 trials drisapersen • 6 minute walk distance maintained for >3.5 years in 8/10 ambulant patients • Very encouraging results but no placebo group Annemieke Aartsma-Rus

Placebo-controlled trial drisapersen • 54 patients • Early stage of disease • Steroid treated • Treatment for 48 weeks with 6 mg/kg drisapersen subcutaneous or placebo • Weekly injections (18 patients) • Intermittent regimen (17 patients) • Placebo (18 patients) Annemieke Aartsma-Rus

Primary Endpoint: Change from Baseline (95% CI) in 6MWD (m), ITT Population

Visit

Comparison

Week 25 (Primary)

Week 49 (Secondary)

Treatment Difference

P-value

Weekly vs Placebo

35.09

0.014

Intermittent vs Placebo

3.51

0.801

Weekly vs Placebo

35.84

0.051

Intermittent vs Placebo

27.08

0.147

Drisapersen preliminary further analysis

Annemieke Aartsma-Rus

Placebo-controlled trial drisapersen • 51 patients • Early stage of disease (rise from floor <15 seconds) • Steroid treated • Treatment for 24 weeks with 3 or 6 mg/kg drisapersen subcutaneous or placebo • 24 week wash out Increased 6 minute walk distance for patients treated with 6 mg/kg vs placebo and 3 mg/kg Annemieke Aartsma-Rus

Study Design large placebo controlled trial

n = planned number randomized Numbers randomized (ITT and safety population) 6 mg/kg/week = 125 Placebo = 61

Primary Endpoint: 6MWD Adjusted Mean Change from Baseline (95% CI) in 6MWD (m) â&#x20AC;&#x201C; Primary MMRM analysis ITT Population

Treatment difference = 10.3m, p-value = 0.415 at Week 48

- 42.3 m 4.7m

4.8m

1.8m

- 52.7 m Curves offset for visualization

Drisapersen most recent news • GSK stops drisapersen development • Prosensa obtained all rights and data

• Further analysis done • Phase 3 population more advanced disease • For many patients 96 week information available Annemieke Aartsma-Rus

Drisapersen preliminary further analysis

Annemieke Aartsma-Rus

Drisapersen preliminary further analysis

Annemieke Aartsma-Rus

Other trials Prosensa/GSK Drisapersen •Redosing patients anticipated to start Q3 2014 •Discussion with regulators ongoing

Exon 44: •Study completed, extension anticipated Q3/4 2014

Exon 45 and Exon 53: •Dose finding studies ongoing •Anticipate 2nd phase 2015

Preclinical work: •Exon 55 & exon 52 and rare mutations Annemieke Aartsma-Rus

Stop codon readthrough

1

79

Annemieke Aartsma-Rus

PTC124/ataluren PTC

1

79 Cell ignores new stop signal Complete protein is made

Annemieke Aartsma-Rus

Stop codon readthrough summary • Opportunities • Oral delivery • Applicable to multiple diseases • Challenges • Mutation specific approach (15%)

Annemieke Aartsma-Rus

PTC124/Ataluren • Tested in healthy controls: safe • Tested in 28 patients (dose finding) • Safe • Increased dystrophin expression

• Tested in 174 patients in 48 week trial • Placebo, high dose and low dose • Safe!

• No significant different in primary outcome (6MWT) • Dystrophin levels? (analysis pending) Annemieke Aartsma-Rus

PTC124/Ataluren dosing • Dosing not optimal • Research done • Optimized dosing

effect

• Bell shaped curve

concentration

• May be responders and non-responders • Extension studies re-initiated in USA and Europe • New placebo-controlled trial started in USA and Europe in 220 patients • Request for conditional approval in Europe Annemieke Aartsma-Rus

Stop codon readthrough summary

Annemieke Aartsma-Rus

Summary • Some therapeutic approaches are mutation specific: good diagnostics crucial • Much is known about Duchenne – mainly through research funded by patient organisations • No treatment available yet • Improved care has had huge impact on disease progression and quality of life

Annemieke Aartsma-Rus