Conference Coverage
HILTON HEAD, SC—Biologics, stem cells, and gene therapy may hold promise as treatments for neuromuscular disorders. Ongoing clinical trials are poised to inform treatment strategies and may identify new therapies for amyotrophic lateral sclerosis (ALS), myasthenia gravis, muscular dystrophy, and neuropathy, according to a lecture delivered at the 39th Annual Contemporary Clinical Neurology Symposium.
Recent developments in neuromuscular disorders include the FDA’s approval of a new drug for Duchenne muscular dystrophy and the publication of a randomized trial that found that thymectomy improves clinical outcomes in patients with myasthenia gravis.
Amanda C. Peltier, MD
ALS
In ALS, many drugs have been studied with little success, said Amanda C. Peltier, MD, Associate Professor of Neurology at Vanderbilt University in Nashville. Riluzole, an approved drug for ALS that may result in a three-month increase in life expectancy or time to mechanical ventilation, targets excitotoxicity. Other drugs targeting excitotoxicity (eg, ceftriaxone and talampanel) have not been found to be effective, however. Agents that target oxidative stress, inflammatory response, protein degradation pathways, mitochondrial dysfunction, and apoptotic pathways have not provided benefit, Dr. Peltier said.
Most trials in ALS use time to mechanical ventilation, time to death, or rate of decline on the ALS Functional Rating Scale as end points. These end points are “very gross measures of how people do,” and researchers are seeking better ways to measure progression in ALS, she said.
Two phase II stem cell studies in ALS are ongoing—the BrainStorm trial in Hassadah, Israel, and the Neuralstem Trial at Emory University and the University of Michigan. Safety data for the Neuralstem Trial that were presented at the 68th Annual Meeting of the American Academy of Neurology (AAN) showed that patients experienced no significant worsening after injections of stem cells in the cervical and lumbar cord. Dose escalation therapy currently is being tested.
Several phase III studies in ALS are under way, including a study of tirasemtiv, an activator of the skeletal muscle troponin complex. “The goal of this [therapy] is to increase muscle force in ALS patients. It is not actually acting at the motor neuron itself,” Dr. Peltier said. In addition, investigators are re-studying creatine, an organic acid involved in ATP formation, at doses of 5 g to 10 g per day. Researchers also are studying masitinib, a biologic targeting inflammation.
Muscular Dystrophies
“There is more gene therapy going on in muscular dystrophy than has ever happened in my lifetime,” Dr. Peltier said. Neuromuscular diseases are caused by genetic mutations in structural proteins that connect the muscle cell membrane to the actin–myosin complex. Dystrophin, one of the largest proteins in the body, is mutated in Duchenne muscular dystrophy and Becker muscular dystrophy.
Some patients with Duchenne muscular dystrophy have a frameshift mutation that results in nonfunctional dystrophin. One treatment strategy entails using an antisense oligonucleotide fragment that binds to messenger RNA to create a more functional protein. “The biggest problem is that those mutations are not the vast majority of mutations in Duchenne,” said Dr. Peltier. “A large proportion of our Duchenne patients are not going to be able to benefit from this technology.”
The FDA on September 19 approved eteplirsen (Exondys 51) injection to treat patients with Duchenne muscular dystrophy who have a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. About 13% of people with Duchenne muscular dystrophy have this mutation. The FDA approved eteplirsen under an accelerated pathway that provides patients with access to the drug while the drug developer conducts trials to verify clinical benefit. The FDA said that the approval was based on an increase of dystrophin in skeletal muscle that was observed in some treated patients. Clinical benefit of eteplirsen has not been established.
“The approval of eteplirsen is a positive first step in gene therapy,” Dr. Peltier said. “The FDA is requiring further clinical trials to establish whether clinical improvement will occur, and hopefully these [trials] will be positive.” Gene therapy may have applications for treating other dystrophies and genetic disorders, and the FDA is considering gene therapy for spinal muscular atrophy that is based on increasing messenger RNA transcripts. “Hopefully this is a signal that the FDA is open to gene therapy for these devastating neuromuscular disorders,” she said.
Idebenone, an analog of coenzyme Q10, may reduce loss of respiratory function in patients with Duchenne muscular dystrophy, according to a post hoc analysis of the phase III Duchenne Muscular Dystrophy Long-term Idebenone Study (DELOS). Patients who received idebenone had a lower risk of bronchopulmonary adverse events and a reduced need for systemic antibiotics, compared with patients who received placebo.
Ataluren, a drug intended to make red blood cells less sensitive to premature stop codons, resulted in faster walk times in the Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy (ACT DMD) study. “So far, it seems to be promising,” Dr. Peltier said.
Many patients with Becker or Duchenne muscular dystrophy develop cardiomyopathy. Drugs that typically are used for heart failure and ischemic cardiomyopathy have not been studied in this patient population, however. An ongoing study comparing ACE inhibitors and beta blockers aims to determine the best strategy for treating cardiomyopathy in this population, she said.
In addition, investigators are studying whether follistatin, delivered by an adeno-associated virus, inhibits the degradation of muscle cells in muscular dystrophy and sporadic inclusion body myositis. A recombinant version of histidyl-tRNA synthetase, aTyr1940, is being studied in facioscapulohumeral muscular dystrophy and limb girdle dystrophies.
Among patients with myotonic dystrophy, a small study found that methylphenidate significantly reduces daytime sleepiness, Dr. Peltier said.