Monday’s morning sessions at MDA’s 2018 Clinical Conference focused on what’s new in ALS (amyotrophic lateral sclerosis), Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM) and myasthenia gravis (MG).
Among the highlights:
James D. Berry, M.D., M.P.H., from Massachusetts General Hospital, noted that, “The really profound answer to what’s new in ALS is, everything is new in ALS.” Specifics include:
- Advances in ALS genetics have led to the discovery of new genes and an improved understanding of the disease.
- Innovations in care delivery include refinements to the multidisciplinary care model, which brings all the necessary experts and specialists to MDA Care Centers.
- New frontiers in care include telemedicine and house calls. Importantly, rather than try to reproduce the clinic experience online or at home, we must look to make improvements in these new methods of care. Questions to consider include, for example, managing reimbursement for house calls, and the ways research will fit in to telemedicine and house calls.
- Many new clinical trials are taking place, testing a wide range of strategies to treat ALS.
Promising therapeutic strategies under development include antisense oligonucleotides to degrade SOD1 RNA and knock down SOD1 protein expression in the brain and cerebrospinal fluid; AAV-delivered SOD1 gene therapy to knockdown SOD1 protein; the mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) cell therapy; immunomodulation; and combination therapy.
In addition to the current status of ALS clinical trials, with 345 clinicaltrials.gov entries for ALS in the United States, a robust pipeline of new ALS biomarkers may contain diagnostic, prognostic and pharmacologic information that could help diagnose ALS, predict disease course and help determine whether a drug is having an effect.
Kathryn Wagner, M.D., Ph.D., from the Kennedy Krieger Institute, noted that, “We are potentially looking at some game-changing strategies for Duchenne.”
Recent updates to DMD care considerations originally published in 2010 follow an increase in life span for individuals with DMD and focus on quality of life. The updated considerations recommend early treatment with corticosteroids and the involvement of the endocrinologist as part of the multidisciplinary team to treat growth, delayed puberty, adrenal insufficiency and bone health.
In addition to the evolving perspective on medical management outlined in care considerations, there has also been substantial progress in the development of new therapies. Therapeutic strategies currently approved or under development include:
- Immune modulators such as Emflaza, vamorolone and edasalonexent
- Anti-myostatin drugs such as domagrozumab and BMS-986089
- Antisense oligonucleotides to induce exon skipping such as Exondys 51; golodirsen to target exon 53; and SRP-5051, a PPMO targeting exon 51
- Gene therapy approaches utilizing micro-dystrophin currently undergoing testing in clinical trials
Rabi Tawil, M.D., from the University of Rochester Medical Center, presented a summary of evidence-based FSHD care guidelines that address evaluation, diagnosis and management of FSHD, to include:
- Genetic testing: Genetic diagnosis is important, as other diseases such as limb-girdle muscular dystrophy, Pompe disease and mitochondrial myopathy can present with similar symptoms.
- Diagnosis: A distinctive pattern of weakness is seen at onset, with the face and shoulders being affected first, followed by progression — often asymmetric — to the trunk and lower extremities.
- Predictions of disease severity: There is high variability in disease course; degree of trunk muscle weakness has a positive correlation with level of disability experienced by the patient. A larger D4Z4 deletion can lead to a more aggressive disease with earlier onset, and a mutation in SMCHD1 can be a modulator of FSHD1 severity.
- Pulmonary complications: Anywhere from 1 to 13 percent of individuals with FSHD experience respiratory problems. Baseline measurements should be obtained, and regular monitoring should occur. Pulmonary function also should be tested prior to surgery.
- Retinal vascular disease: Individuals with eye issues should be referred to an ophthalmologist.
- Hearing loss: Children with FSHD should be screened in order to diagnose hearing issues.
- Pain in the neck, back and shoulders: Pain in FSHD should be treated with a pain management regimen.
- Pharmacologic interventions: Albuterol, corticosteroids and diltiazem are not recommended treatments, as there is no evidence to support efficacy.
- Targeted treatments: Treatments for FSHD are in the pipeline.
Charles Thornton, M.D., from the University of Rochester Medical Center, noted, “We are making rapid headway” in DM research and care. Specifically:
- A snapshot of DM1 genetic testing proficiency in the United States shows that 74 labs perform testing; there are about 1 to 2 percent false positives and fewer than 1 percent false negatives.
- With regard to correlation of repeat size and disease severity, there is low predictive power in DM1, and in DM2 there is little correlation and no predictive power.
- Pulmonary complications and cardiac arrhythmia are common causes of death in DM. A full heart evaluation should be performed at diagnosis, followed by annual EKGs. Cardiac symptoms should trigger referral to a cardiologist.
- Myotonia is not always the source of day-to-day disability. Other sources include cataracts, impaired respiratory function, muscle pain and intellectual disability.
- Possibly the most effective current intervention for myotonia is exercise.
- New therapeutic approaches include gene editing (“repeat snipping”), including drugs that block transcription of repeats and drugs that block protein binding to repeats. This method has achieved proof-of-concept in animal models, but it is not in clinical trials at this time.
- Treatments that have reached the clinical trials stage include AMO Pharma’s GSK3B inhibitor tideglusib for DM1 (originally developed for Alzheimer’s disease). In addition, results from a phase 2 clinical trial for Ionis DMPKRx, an antisense oligonucleotide therapy designed to reduce toxic RNA, showed that not enough drug was engaging with the target. Ionis Pharmaceuticals and Biogen currently are working to improve the ASO design.
Overall, Thornton noted that a broad therapeutic pipeline is developing; encouraging results have been achieved in lab testing; the era of clinical trials for targeted therapies is just beginning; prospects for getting effective treatments seem good; and there are opportunities for patients and their families to take part in current research.
“This is a great time to be involved in neuromuscular disease,” said James F. Howard Jr., M.D., FAAN, from the University of North Carolina at Chapel Hill.
Howard noted that although MG is a “snowflake disease,” affecting all ages, both genders and all ethnicities, subsets do exist. Clinical diagnosis can be confirmed by electrophysiology, pharmacology and serology.
Over the lifetime course of the disease, we are now able to reduce incidence of early death and improve quality of life; however, there has been no change in the ability to induce remission in patients.
The first treatment breakthrough occurred last year when trial results indicated that thymectomy was associated with reduced muscles weakness and a lower need for steroids. Although it was thought that thymectomy effects would take years to become evident, trial results have suggested otherwise.
In addition, Soliris, a monoclonal antibody drug targeting a component of the complement pathway, was approved to treat a subset of MG patients.
Emerging therapies include alpha-fetoprotein; an antigen-specific therapeutic vaccine that could help avoid side effects of nonspecific immunosuppressive drugs; and tolerization.
In addition, Howard noted, we may need to consider a paradigm shift to an oncologic approach of early intervention with multiple therapies, including inhibition of the complement pathway before disease progresses.
MDA is grateful to the following companies for their support of the 2018 Clinical Conference:
- Strength for Life supporters — Biogen, PTC Therapeutics
- Muscle Champion supporters — AveXis, Santhera Pharmaceuticals, Inc., Sarepta Therapeutics