Prof. Annemieke Aartsma-Rus is taking on a challenge by reading and commenting on a paper a day. She shares her insights, findings and thoughts via her @oligogirl Twitter account. See below the overview of March 2022.
Prof. Aartsma-Rus reads and comments on the paper titled: An Open Label Exploratory Clinical Trial Evaluating Safety and Tolerability of Once-Weekly Prednisone in Becker and Limb-Girdle Muscular Dystrophy
Today’s pick is from Journal of Neuromuscular Diseases by Zelikovich et al on steroids in BMD and LGMD patients. Doi: 10.3233/JND-210741
Corticosteroids are used in Duchenne to slow down disease progression. However, this comes with side effects. For less severely progressive limb-girdle muscular dystrophy (LGMD) & Becker muscular dystrophy (BMD) the benefit does not outweigh side effects.
Of course less severe is a relative term – compared to Duchenne these diseases may be less severe, they are still progressive and debilitating diseases. Attempts to treat LGMD patients with steroids in the past have resulted in mixed effects, some showing benefit, some worsening.
A way to reduce side effects is weekend pulse dosing. This is done in Duchenne with high doses. In LGMD mouse models, weekly pulse dosing at lower levels showed beneficial effects. Here authors performed an open label weekly pulse dosing with prednisone in 20 LGMD/BMD patients.
Patients (7 LGMD female, 12 LGMD male, 1 BMD male) received weekly 45-85 mg prednisone (weight based). LGMD patients has mutations in calpain 3, dysferline (3), gamma sarcoglycan, titin, FKRP (3) and ANO5 (3). Both ambulant and non ambulant patients were included.
Patients received weekly doses for 24 weeks – only 3 patients missed 1 dose (very good compliance). 4 patients missed the on-site study end due to the pandemic. Patients were called monthly by the study site.
Serum creatine kinase (CK, marker for muscle damage) was decreased for most patients after 24 weeks compared to baseline. Normally, this can mean: 1.improved muscle quality (less leakage from damaged muscle) or 2. reduced muscle quality (less muscle to leak CK). Here, it was 1.
We know this because authors also performed DEXA scans which showed that on average patients gained 0.5 kg muscle mass and lost 0.2 kg fat. This was not significant, but an increase in muscle mass was seen in 10/15 patients who underwent DEXA. Thus, muscle quality is not reduced
Authors also did functional studies showing increased grip strengths and for ambulant patients longer walk distances in 6 minutes and reduced times to walk/run 10 meters. Treatment was well tolerated. Over half of the patient had osteopenia – however, this was already at baseline.
Authors discuss this as something that needs to be monitored more carefully in LGMD and BMD patients. No signs of the metabolic syndrome were seen in treated patients. Authors discuss limitations of the study: small, single center study with open label set up (no control group)
More work is needed to assess if this regimen is beneficial for LGMD & BMD patients. Authors also indicate dosing & regimen may have to be optimized in future studies. However, results look cautiously optimistic and 19/20 patients wanted to continue treatment beyond the trial.
I think this work is interesting because authors focused on what could work rather than what could not (daily dosing, too many side effects). Also they included multiple LGMD patients with mutations in different genes in one trial and still appear to show a consistent result.
This type of ‘basket trials’ will hopefully be seen more in the future. When a drug works on a general pathological pathway (muscle deterioration) that is common in a group of diseases (LGMDs and BMDs) that are individually extremely rare, basket trials allow larger numbers.
Pictures by Annemieke, used with permission.
Prof. Dr. Annemieke Aartsma-Rus is a professor of Translational Genetics at the Department of Human Genetics of the Leiden University Medical Center. Since 2013 she has a visiting professorship at the Institute of Genetic Medicine of Newcastle University (UK).
Her work currently focuses on developing antisense-mediated exon skipping as a therapy for Duchenne muscular dystrophy. In addition, in collaborative efforts she aims to bridge the gap between different stakeholders (patients, academics, regulators and industry) involved in drug development for rare diseases.
In 2013 she was elected a member of the junior section of the Dutch Royal Academy of Sciences (KNAW), which consists of what are considered the top 50 scientists in the Netherlands under 45. From 2015 to 2022, she was selected as the most influential scientist in Duchenne muscular dystrophy by Expertscape.