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- Duchenne Muscular Dystrophy in Israel Prof. Yoram Nevo Head, Neuropediatric Unit Hadassah, Hebrew University Medical Center

Current DMD clinical trials in Israel Weissband Elana, Adani Renana -Clinical evaluators Yaffe Debbie, Phontalayev vera, Yosef Lilach – Coordinators Yoram Nevo -PI Dr. Dor, Dr Kaye, Dr. Daana, Dr. Klebanov – sub PI

An effort to globalize therapeutics 27 sites in 10 countries

Patient recruitment sites in the CINRG

All centers are major neuromuscular referral centers with at least 100 DMD patients or more Census: ~3000 Duchenne dystrophy patients

CINRG Website (public/private) www.cinrgresearch

Human clinical trials at Hadassah Medical Center CINRG Natural history • UCD0305 Longitudinal Study of Relationship between Impairment, Activity Limitation, Participation and Quality of Life in Persons with confirmed Duchenne Muscular Dystrophy • 6 years, 20 centers, 300 children, clinical data, SNPs • Currently – recruiting for extension trial

CINRG Natural history UCD0305 • Currently recruiting again • 100 DMD boys ages 4-6 years • 370 healthy control children age 6-16 years evaluated 1/year (including blood sample) • We will recruit 4 children in next 2 months (Debbie or Vera 02-5844751)

Skipping Exon 51 Phase III placebo-controlled (DMD114044 or DEMAND III) study of Drisapersen • 186 DMD patients, 47 sites, 20 countries • No statistically significant or clinically meaningful treatment difference (10.3 meters; p=0.42) in 6MWD between placebo and the treatment group, at dose of 6mg/kg/week after 48 weeks. • No statistically significant or clinically meaningful treatment differences on the majority of secondary endpoints. • A pre-planned subgroup ≤ 7 years showed a non-statistically significant but potentially clinically meaningful treatment difference of 21 meter and a statistically significant (p<0.001) decline in CK, at week 48 for the drisapersen group compared with placebo.

Skipping Exon 51 • Drisapersen – proteinuria and skin scars in injection site • Pts deteriorated following trial discontinuation

• Sarepta (previously AVI)- Eteplirsen (morpholino oligonucleotides) met the primary efficacy endpoints: increase in novel dystrophin (47% of normal) and significant clinical benefit in 6MWT (-42.3 to +16.5 m) in children less than 9.5 years. • Plans for 45, 50, 53

PTC’s RNA-focused small molecule technology platform DNA







5’ cap


poly(A) tail


PTC’s Platform Technologies Nonsense Readthrough

Alternative Splicing

Nucleotide Repeat

Protein Modification

Transcript Regulators


Ataluren phase 2b study design: the first large placebo-controlled, randomized, multicentre study in DMD Double-blind placebo-controlled study ataluren 80 mg/kg/daily* (orally)

Eligibility Criteria: • nmDMD • Nonsense mutation • Males ≥ 5 years • Baseline 6MWD ≥ 75 m • Stable corticosteroid use (if receiving)

n = 60

ataluren 40 mg/kg/daily* (orally)

R/S n = 57

Placebo n = 57

Randomization & stratification:  Age  Corticosteroid use  Baseline 6MWD

Open-label extension study

48 Weeks

Total patients enrolled: 174 37 centres worldwide, 11 countries

Primary outcome measure 6MWD •Secondary outcome measures  TFTs  Other measures of physical function

*Split into three doses per day 80 mg/kg/day = 20, 20 ,40 mg/kg/day 40 mg/kg/day = 10, 10, 20 mg/kg/day

6MWD, 6-minute walk distance; TFTs, timed function tests Barth J et al. ePoster 1807, European Paediatric Neurology Society Congress, September 2013

ACT DMD: Ongoing Phase 3 nmDMD clinical trial designed to target patients in decline ambulation phase Eligibility criteria: ≥7 years and ≤16 years Steroid use 6MWD ≥150m and ≤80% of predicted for age and height

Double-blind placebo-controlled study 40 mg/kg/daily (orally) ataluren [N=110]


Open-label extension study

1:1 randomization Placebo [N=110]

48 weeks Primary outcome measure: 6MWD (change from baseline)

In the EU Atalurenâ&#x20AC;&#x2122;s brand name Translarna â&#x20AC;˘ Today PTC Therapeutics announced (23.5.14) that the CHMP adopted a positive opinion for the conditional marketing authorization of ataluren 40mg/kg/day (10, 10, 20 mg/kg) for the treatment of ambulatory nonsense mutation Duchenne muscular dystrophy patients, who are aged 5 years or above. In the EU, ataluren will now be known by the brand name of Translarna. This positive CHMP opinion will form the basis for a European Commission conditional marketing authorization of ataluren for nmDMD patients to be rendered within the next three months.

In the EU Ataluren brand name – Translarna • We are working with Medison to enhance regulatory issues in Israel • For DMD with point mutation resulting in stop codon (10-15%) • > 5 years • Ambulatory • Non candidates for the clinical trial • We’ll look into regulatory option of treatment of non-ambulatory (29 g) • Cost not determined yet

CATENAÂŽ - Phase 3 Study of Idebenone in Duchenne Muscular Dystrophy (DELOS) SANTHERA â&#x20AC;˘ Once-daily oral Catena idebenone met the primary endpoint vs. placebo in the Phase III DELOS trial to treat Duchenne muscular dystrophy (DMD). Catena improved or delayed the loss of respiratory function as measured by peak expiratory flow from baseline to week 52 vs. placebo (p=0.04). The double-blind, international trial enrolled 65 DMD patients ages 1018 years who were not using concomitant corticosteroids.

Losartan, a therapeutic candidate for MDC1A Prof. Yoram Nevo Unit of Neuropediatrics Hadassah Medical Center

Regeneration vs. Fibrosis Therapeutical •Controlled and balanced production of connective tissues •Transient gene activation •Tissue development •Wound Wound--healing processes •Regeneration

Pathological •Excessive production of connective tissues •Persistent gene activation •Destruction of normal tissue architecture and function •Replacement of normal tissue by fibrotic •Scarring

MDC1A - AR Clinical characteristics • • • • • • • •

Early onset Joint contractures Most pts do not acquire independent walking Peripheral neuropathy cognition WNL in most patients Brain MRI - white matter signal abnormalities Progressive restrictive lung disease Death in severe cases at age 15 to 30 years

dy2j MDC1A Mouse model The dy2j mouse model is similar to the human MDC1 MDC 1A in clinical and histological features Clinical: progressive unremitting muscle weakness and reduced life span Histological: ineffective regeneration and progressive severe fibrosis

Losartan • 2-butyl-4-chloro-1 – {p- (o-1H-tetrazol-5ylphenyl) benzyl} imidazole-5-methanol monopotassium salt • Losartan, an angiotensin II type I receptor antagonist is a commercially available and extensively used medication for hypertension • Angiotensin II mediates fibrotic response via the TGFβ1 pathway

Losartan effect on body weight

Losartan treatment improved fore & hind limb muscle strength

Losartan treatment improved muscle pathology and significantly reduced fibrosis in the dy2J/dy2J mice

Losartan treatment inhibited TGFβ signaling pathway

Losartan decreases Fibronectin and Vimentin fibrosis markers

Losartan reduces MAPK signaling pathway

Finding Losartan effects on signaling pathways involved in the pathophysiology of MDC1A after 12 weeks treatment with Losartan â&#x20AC;&#x201C;


Losartan treatment inhibited TGF-β signaling pathway and MAPK cascade in the dy2J/dy2J mouse model for MDC1A.

Conclusions • We have previously shown that Losartan treatment significantly improves hind and fore limb muscle strength and ameliorates muscle fibrosis in the treated dy2J mice

• TGF-β1 , MAPK inhibition and SMAD7 up-regulation are involved in fibrosis reduction in this model • Our recent findings suggest that NFκB serves as an important regulatory pathway which following Losartan treatment, promotes survival in the dy2J/dy2J mouse model of MDC1A.

NM lab Prof. Yoram Nevo Dr. Nurit Yannay Moran Elbaz Sivan Gelm Boutrous Issa Dr. Malcolm Rabie

Many thanks to: Clinical trials Drs. Dor, Kaye, Daana, Klebanov Dr, Abu -Eita Debbie Yaffe, Vera Phontalayev Lilach Yoseph Elana Weissband, Renana Adani Liora Shiloni

Prof. Phillip Lazarovizi Prof. Shimon Benita Prof Chezy Barenholtz Prof. Stella Mitterani-Rosenbaum Prof. Vivian Barak Dr. Yaakov Felig This work was supported by grants from CINRG, Stitching Porticus, AFM, the chief scientist of the Israeli Ministry of Health and Israel Science Foundation, Teva (NNE) and Israel Minuistry of Science Technology and space. Parents organizations Meshi, ADI and Little steps

Thank You

Anti inflammatory/anti fibrotic agents in muscular dystrophy and clinical trials in DMD  

כנס נוירומוסקולרי, עמותת צעדים קטנים, מאי 2014 פרופ' יורם נבו, מנהל היחידה לנוירולוגית ילדים, בי"ח הדסה