News from 2017 World Muscle Society: Part 1


Annie Kennedy and Kathi Kinnett from the PPMD team are attending the 22nd International Annual Congress of the World Muscle Society and will be reporting back over the next couple of days. More updates to follow!


Day 1: Wednesday


Wednesday was the first day of the WMS meeting, and featured a vast array of posters. Highlighted below are a few that the PPMD team thought were the most novel, interesting, and relevant, especially in the area of Duchenne care.


Upper Limb & Lower Limb
MRI is a huge topic this year, and includes posters around cardiac, upper limb and lower limb MRI, in both Becker and Duchenne. The Imaging DMD group evaluated upper limbs. Looking at 85 boys and 24 controls who were all around 12 years old, the group found that there was an increase in fat in the deltoid and biceps muscles, as compared with the triceps and forearms. The fat fraction of the arms increased with loss of ambulation and a higher “performance of upper limb” score. In addition, group (“Magnetic Resonance Biomarkers in the Proximal and Distal Upper Extremity in a Large Cohort of boys with Duchenne Muscular Dystrophy”) found that the fat fraction in the lower limbs of Becker patients correlated with clinical testing in Becker patients.



The Nationwide Children’s group evaluated the cMRI’s of Duchenne and Becker patients and found that there was significant late gadolinium enhancement (showing fibrosis in the cardiac muscle) by the time Duchenne patients reached late adolescents (“Adolescents with Duchenne and Becker Muscular Dystrophy: a Cardiac Magnetic Resonance Comparative Study”). One third of Becker patients had cardiac fibrosis by their late 30’s, with several showing fibrosis by late adolescence as well.  More than half of the both the Becker and Duchenne patients showed fibrosis while maintaining normal function.  The (“Qualitative Cardiac NMR Imaging in a Large Cohort of Patients with Becker Muscular Dystrophy”) group studied 88 Becker patients, ages 38.7 +/- 13.6 years, showed a low ejection fraction and correlation between low ejection fractions and the presence of fibrosis.   Conclusion: cardiac care for people living with Becker should be the same as those living with Duchenne.


Adult Care & Quality of Life

A few posters focused on adult care and quality of life.  Dr. Ros Quinlivan’s group in the UK evaluated the incidence of premature mortality (“Analysis of Mortality in a Cohort of Adult Duchenne Musculary Dystrophy”).  Her study included a cohort of patients over 5 years with 79% who had not used steroids, or used them briefly.  The factors that led to premature mortality in her population included continuation of regular (at least annual care) and maintenance of pulmonary surveillance/management.  Those patients with learning disabilities seemed to fare worse, possibly due to non-compliance with ventilator assistance. Natalie Goeman’s group from Belgium (“Has Outcome Changed for Adults with Duchenne Muscular Dystrophy?”) also recognized dialog between the pediatric and adult providers was important to continuation of care.


Research from Cincinnati Childrens Hospital Medical Center

Brenda Wong and the Cincinnati group presented a series of 3 papers.

  • Testosterone Therapy in Patients with Duchenne Muscular Dystrophy and Glucocorticoid Induced Delayed Puberty: Patients with pubertal delay, using testosterone initiated puberty in 45% of the patients. This initiation of puberty resulted in stabilized body composition, decrease of body fat and an increase in lean body mass. In addition, there was an increase seen in both spine and whole body bone mineral content.
  • Body Composition of Patients with Duchenne Muscular Dystrophy: This study demonstrated that, in patients living with Duchenne, there is no gain in lean body mass index (LBMI) after age 12yo. Even if patients are still weight bearing, their LBMI was less than normal. 
  • Relationship between Ambulatory Functioning and Body Composition in Patients with Duchenne Muscular Dystrophy: Ambulatory patients are stronger than non-ambulatory patients and have a higher lean body mass index.


Psychological Health

There were also a few posters focused on psychological health and cognition in Duchenne. One study (“Predominant Posterior Cerebral Cortical Atrophy in Patients with DMD Mutations”) looked at the cortex of the brain and found that there is an altered cortex in patients with Duchenne.  It’s unclear if this altered cortex might correlate with behavior and cognitive function.


Day 2: Thursday


From research on new biomarkers to CRISPR CAS-9 to approaches to gene therapy to clinical trial read outs from many of the companies in the Duchenne space to novel approaches to providing care and psychological support to families within the community. The posters spanned the landscape and reflected both the challenges and opportunities before us. Today’s industry seminar was sponsored by Santhera Pharmaceuticals and centered on Respiratory Function Decline in Duchenne. Once again… The buzz here at WMS is Duchenne.


Some highlights from posters presented today:


Akashi Therapeutics

Presented by Dr. Diana Escolar (Akashi Therapeutics)

  • What is it?
    • AT-300 is a peptide, a calcium modulator that improves muscle force production and decreases muscle degeneration in D2-mdx model of Duchenne Muscular Dystrophy
    • AT-300 protects against decrease muscle force loss in vivo caused by eccentric contraction injury and reduces muscle loss
  • What was reported at WMS?
    • AT-300 treatment at 10 mg/kg for 6 weeks significantly reduced the loss of muscle mass and spared muscle strength in the D2-mdx model of DMD
    • Both doses (1mg/kg and 10 mg/kg) of AT-300 prevented eccentric contraction-induced loss of force production, which is a well established pre-clinical endpoint assay
    • There is a positive effect of AT-300 treatment on muscle fiber size, larger in treated animals
  • What next?
    • Akashi is moving forward with the investigation of the long-term effects of AT-300 in dystrophic muscle as these data support continued development for the potential treatment of Duchenne.


Bamboo Therapeutics
Dr. C. Le Guiner (University of Nantes)

  • What was reported at WMS?
    • Dose Finding Study in the DMD Rat Model to Determine the Efficacious Dose of the rAAV9 Vector Encoding a Human Mini Dystrophin after IV Administration
    • No mortality/morbidity attributed to the test item, no detectible toxicity (even in the high dose groups 1E14 and 3E14 vg/kg)
    • The dys3978 protein was seen by the host immune system
    • The humoral response detected against the transgene product and the AAv capsid had no impact on the therapeutic efficacy of the test item during the 3 or 6 month follow up
    • Overall, the vector copy numbers and the number of muscle fibers expressing the dys3978 polypeptide, the improvement of the skeletal architecture of the muscles of the heart, the correction of muscle strength and fatigability, and the improvement of diastolic function were all directly correlated with the amount of vector administered.
      • Regardless of the time point post-injection, 1E13 vg/kg was sub therapeutic
      • At 6 months post-injection, 3E13 vg/kg dose resulted in increased fatigability compared to the 3 month time point, suggesting that this dose was not sufficient to control the progression of the disease
      • Sustained global therapeutic effect (at 3 and 6 months post-injection) suggests that a dose equal or higher than 1E14 vg/kg can halt the progression of the disease in this DMD mdx rat model. A dose of 1E14 vg/kg may be therefore considered as the Minimal Effect Dose (M.E.D.)



Presented by Dr. Paula Clemens (University of Pittsburgh) (404)

  • What is it?
    • Vamoralone is an anti-inflammatory through inhibition of NF-kB pathway signaliging (steroidal drug) that lacks the subproperties that are thought to be associated with many of the negative side effects of traditional glucocorticoids
  • What was reported at WMS?
    • Phase IIa study is enrolling: open label, multiple ascending dose study to assess safety tolerability, PK, and pharmacodynamics
      • Boys 4-<7, steroid naïve, N=12
      • Oral dosing
      • No safety concerns from Ph I
  • What was observed in Ph I?
    • Pharmacodynamic biomarkers collected in Ph I from  healthy males showed loss of GC side effects:
      • Markers of bone turnover
      • Insulin resistance
      • Immune suppression
      • 100-fold improvement of adrenal suppression


Santhera Therapeutics - Featured Symposium

"Respiratory Function Decline”

Craig McDonald, MD (UCDavis), Hank Mayer,MD (CHOP), Gunnar Buyse, MD PhD (Univ of Leuven, Belgium)


The stated symposium objective was to provide an educational symposium on respiratory decline & clinically relevant thresholds in Duchenne in an effort to impact global Duchenne respiratory clinical care practices.


Dr. Craig McDonald (UC Davis) opened the symposium and gave an eloquent presentation which discussed:

  • changing natural history and standards of care
  • natural history of pulmonary endpoints in younger ambulatory and older non-ambulatory boys
  • %FVC and %PEF can be reliably measured in teenage patients and show steady declines across all stages of DMD and correlate with clinical mobility milestones
  • glucocorticoid (GC) use confers significant functional benefit but is limited by side effects in a significant proportion of the population
  • In the 2nd decade of life, the annual rate of change in PFTs is comparable irrespective of GC use
  • relationship between pulmonary decline and upper extremity decline
  • many non-ambulatory patients have discontinued GC (unmet need)
  • there is an area of high unmet need for those patients in the 2nd decade for treatment of pulmonary function loss
  • progression of pulmonary impairment to critical thresholds is associated with increase in mortality
  • Progression below 1 liter (L) absolute FVC and risk of death


Dr. Hank Mayer reviewed linking pulmonary function to skeletal muscle function in that the earlier you lose ambulation, the more comprised vital capacity is expected to be. He further discussed the various measures of pulmonary function including: Peak expiratory flow (PEF), forced vital capacity (FVC), and forced expiratory volume (FEV). Dr. Mayer reviewed critical clinical thresholds and recommended interventions for each point of clinical progression. He then concluded his presentation by showing encouraging emerging data from recently approved therapies in Duchenne (Deflazacort) demonstrating an attenuation in the loss of pulmonary function.


Dr. Gunnar Buyse then reviewed the safety and efficacy findings on Ph III DELOS trial. Ph III randomized trial to investigate idebenone for use in Duchenne with 64 steroid naïve patients age 10-18 in respiratory decline phase of disease with PEF % <80%. Primary endpoint, change on PEF over 52 weeks. Within the study, 92.2% were non-ambulatory, 56.3% had used steroids previously, mean age of participants was 14.3 years, 60% had a Brooke Score >5.


More patients on idebenone remained above the 50% FVC% threshold than those on placebo. Fewer patients on idebenone experienced an FVC decline >10%. Idebenone reduced the risk of bronchopulmonary complications and rate of hospilatization for respiratory reasons. More patients on idebenone maintained FVC>1 L over study period compared to placebo.


Dr. Buyse continued by reviewing the SIDEROS trial to assess the efficacy of idebenone compared to placebo in slowing the loss of respiratory function in patients who are receiving glucocorticoicds.


For more on the Sideros study, visit or watch PPMD’s March 2017 webinar with Santhera.



Presented by Francesco Muntoni (Institute of Child Health, London, UK)


  • What is it?
    • PhaseOut DMD (SMT C1100) is a phase 2, proof of concept study to investigate the hypothesis that Duchenne can be treated by up-regulating utrophin expression to replace dystrophin.
    • Ezutromid (SMT c1100) is an oral utrophin modulator that was shown to be safe & well-tolerated in Phase I studies in the mdx mouse
  • What was presented?
    • PhaseOut DMD
      • A Phase 2 proof of concept study assessing safety in boys with Duchenne ages 5-10 (taken orally)
      • Multicenter study in US & UK, includes 28 day baseline & screening phase, 48 week open label treatment phase, and 30 day safety follow up phase
      • Details of the protocol and baseline data were presented



Catabasis had two poster presentations, including one poster that was included in the Breakthrough Presentations.


1)  Edasalonexent (CAT-1004)

Presented by Dr. Andrew Nichols  (Catabasis)

  • What was presented?
    • NK-kB pathway is activated from birth in boys with Duchenne and yields muscle degeneration, while inhibiting muscle regeneration.
    • NF-kB driven micro RNA also directly impair dystrophin protein translation, limiting the full potential of exon-skipping therapy
    • Edasalonexent has been shown to inhibit muscle inflammation and fibrosis, ND improve muscle function and endurance in the mdx mouse model and the GRMD dogs.
    • In young mdx mice, edasalonexent was combined with an exon skipping therapy agent. The combination treatment in the mdx mouse:
      • Enhanced the sarcolemmal dystrophin detected in the quadriceps of the mice beyond that detected in exon skipping alone
      • Increased dystrophin levels in the heart, a tissue known to have low efficacy of dystrophin up-regulation by each of these agents when used alone
  • Impact Going forward?
    • Patients screening into the MoveDMD (Ph 2 study of endasalonexent) are able to participate in the clinical trial even if they are also on an exon-skipping therapy.


2) MoveDMD Ph2 Edasalonexent

Presented by Dr. Richard Finkel (Nemours Children’s) 

  • Background:
    • NK-kB pathway is activated from birth in boys with Duchenne and yields muscle degeneration, while inhibiting muscle regeneration.
    • Edasalonexent (CAT-1004) is an oral small molecule that has been shown to have positive effects on skeletal muscle, diaphragm, and the heart in pre-clinical animal models.
  • What was presented? MoveDMD Part B
    • MoveDMD is a 3 part, Ph2 study of Edasalonexent in boys with Duchenne.
    • Part A: 1 week safety/PK study
    • Part B: 12 week, randomized, double blind, placebo controlled trial of 67 and 100 mg/kg/day
    • Part C: 60 week, open label extension study
    • 31 Boys ages 4-7, all mutation types enrolled in Part B (which included 16 patients who’d previously participated in Part A)
    • Results were described in detail and are available here
  • What Next?
    • Part C, the 60 week, open-label extension study is on-going



Presented by Patrick Gonzalez, Solid Biosciences

  • Pre-clinical work has demonstrated that a single dose of SGT-001leads to widespread biodistribution  and long-term micro-dystrophin expression in skeletal and cardiac muscle in dystrophin mouse and dog models
  • SG-001 treatment results in a dose dependent product of micro dystrophin protein
  • Micro-dystrophin protein is membrane localized and increased levels improves muscle histology and B-sarcoglycan expression
  • Microdystrophin protein expression is readily quantified by Western Blot and Mass Spectrometry assays
  • Microdystrophin expression correlates to improved functional outcome; preclinical data support SGT-001 for the treatment of Duchenne
  • Solid is currently on track to move into the clinic this year


Injection site reactions as a consequence of long-term subcutaneous administration of drisapersen in DMD

Presented by E. Niks, Leiden University Medical Center, Netherlands

  • 49 patients were included whose drisapersen treatment durations ranged from 15-42 months
  • All patients had developed injection site reactions (ISRs) at the last follow up
  • Evolution was typically with erythema and pigmentation in the first months, followed by thinning of the skin, induration, and sclerotic changes
  • Subcutaneous lipatrophy, calcifications, and ulceration with slow healing were observed in a significant number of patients
  • Some patients experienced hair loss
  • ISR severity could increase after subcutaneous dosing had stopped or after switch to IV administration
  • MRI of the injection sites revealed severe loss of subcutaneous, but not intramuscular fat and increased STIR signals


PTC (406 & 407)


Phase 2 trial of the safety and pharmacokinetics of ataluren in patients aged 2 to 5 years with nonsense mutation Duchenne muscular dystrophy

Presented by P. Riebling (PTC Therapeutics)

  • Since initiation of treatment prior to substantial muscle loss may maximize benefit, it is critical to understand the safety and PK in patients under age 5 (particularly since ataluren is dosed by weight).
  • A Phase 2, open-label trial to evaluate safety and PK in boys aged 2 to <5 with nmDMD and with body weight equal to or greater than 12 kg.
  • Trial will include 4 week assessment of safety and PK of ataluren, and a 48 week extension period to assess safety and long-term administration
  • Motor function will also be evaluated
  • 14 patients are currently enrolled




Design of a Phase 3 trial to evaluate the long-term efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (Study 041)

Presented by P. Riebling, PTC Therapeutics


  • Background:
    • Ataluren is conditionally approved by the EMA with an obligation to conduct a longer-term trial.
    • This Ph 3, randomized, double-blind, placebo-controlled trial with an open-label extension period is designed to evaluate the long-term safety and efficacy of ataluren on boys with nmDMD (Study 041)
    • Inclusion criteria:
      • nmDMD
      • age 5 and over
      • corticosteroid use for at least 12 months
      • 6MWD equal to or greater than 150m
      • ability to perform timed function tests within 30 seconds
    • Patients will be randomized to receive ataluren (40 mg/kg/day) or placebo for 72 weeks; all patients will receive open-label ataluren in the 72 week extension period
    • This study will enroll ~250 patients at sites in North America, Latin America, Europe, and Asia Pacific
    • Primary endpoint:
      • Slope change from baseline to week 72 in 6MWD in a subset of patients aged 7-16 years with baseline 6MWD greater than equal to 300m, and time to stand from supine greater than equal to 5 seconds
    • Patient recruitment is planned to begin in mid 2017 and close in mid 2018.


Cardiac and Pulmonary Surveillance and Management

This year there were platform sessions on cardiac and pulmonary surveillance and management, as well as consideration of potential alternative measures that might be used in clinical trials.


While most trials include forced vital capacity to measure pulmonary strength and volume, Brigitte Fauroux, pulmonologist from Paris suggested that perhaps including other measure that patients of all ages might be able to perform might be appropriate. Some of the measures that she suggested include the SNIP (sniff nasal inspiration pressure) and cough (which indirectly measure diaphragm strength and function). These are both very easy to manage for patients of all ages and correlate will with FVC.


Linda Cripe, cardiologist from Nationwide Children’s Hospital, discusses 4.areas of cardiac care.  The first was the efficacy of cardiac MRI as compared to echocardiogram. Ina recent study, of 314 patients of all ages, 17% of patients less than 10yo showed myocardial fibrosis; 59% of patients over age 15yo had fibrosis.  30% of patients had normal function with fibrosis, while 89% showed abnormal function.  The second included a discussion of assist devices (ICD’s, and LVAD’s (left ventricular assist devices). While there have been patients who have used these devices, their use is still very new and it is somewhat unclear if these devices can enhance quality and quantity of life.  Third was a discussion of their recent study of chest pain correlated with abnormal findings on MRI and increased cardiac enzymes, indicating cardiac muscle damage. Some of the results of this study showed that, of 8 Duchenne patients admitted to Nationwide with complaints of chest pain, all patients presented with abnormal EKG’s, increased enzymes, EKG and MRI changes.  7of the 8 patients had normalization of all if those studies over the next week without normalization of MRI findings. This study was performed subsequent to the PPMD Acute Cardiac Episodes in Duchenne meeting, spring 2016, and has been submitted for publication. The last area included the interim results of the ongoing carrier study, sponsored by PPMD.  Of the 34 carriers (average age 44yo) who have been screened with cardiac MRI, 17 have shown fibrosis, 5 have shown decreased heart function and 3 have shown some dilation of the cardiac chambers. More data to follow!


Neurocognitive Issues

One of the interesting posters was reviewed by Dr. Tim Cripe from Nationwide Children’s Hospital. This poster addressed the effects of DMD on the brain. Although we know some people with DMD and BMD have cognitive and behavioral issues, little is known about why. A group from the University of Campinas in Brazil compared brain MRI findings in 8 DMD and 2 BMD patients (average age 13.2 years, half were non-ambulatory) to age-matched children without DMD or BMD. They found that DMD and BMD patients had decreased thickness of the surface of the brain in two areas that could explain neurocognitive issues. While the authors couldn’t determine whether the reduced thickness resulted from a defect in development or a degenerative process, they concluded it would be worth looking at more patients longitudinally with a larger study.


Stay tuned for more!

Part 2 of our WMS update will be coming soon, covering additional updates from Day 2 and the remainder of the meeting!

Views: 924


You need to be a member of PPMD Community to add comments!

Join PPMD Community

Need help using this community site? Visit Ning's Help Page.



© 2021   Created by PPMD.   Powered by

Badges  |  Report an Issue  |  Privacy Policy  |  Terms of Service