June 01, 2016
By Michelle Strausbaugh
|Mazen Dimachkie, M.D.|
A ray of hope is on the horizon for patients facing the debilitating effects of the muscle-wasting disease inclusion body myositis (IBM). University of Kansas Medical Center researchers conducting a joint study with the Medical Research Council (MRC) Centre for Neuromuscular Diseases at University College London are poised to take the next step in testing the drug, arimoclomol.
There is currently no treatment for IBM, but research conducted by the KU/UCL partnership, published in the March 23 issue of Science Translational Medicine, revealed that the drug deserves further study on its potential to slow patients' crippling debilitation.
The most common muscle disease in people over 50, IBM is incurable and causes progressive muscle degeneration leading to severe disability, paralysis and dependency.
"IBM is a disease that no one's ever heard of until it affects them or someone in their family," said Richard Barohn, M.D., KU Medical Center Vice Chancellor for Research and chairman of the neurology department, and a co-senior author of the study.
IBM at first hampers and later severely restricts patients' everyday activities. Inflammation results in loss of finger dexterity, which progresses to total loss of hand function. Thigh muscle weakness results in falling, and most patients need a cane or walker within five years of diagnosis, then a wheelchair or scooter after 10 years. More than half of IBM patients will have difficulty swallowing, which may result in poor nutrition.
"In many ways it's like the Alzheimer's of muscles," Barohn said. "It occurs in an older population, and the same type of proteins accumulate in the brains of people with Alzheimer's as accumulate in the muscles of those with IBM."
"This is a dire situation," said Mazen M. Dimachkie, M.D., neurology professor and director of the neuromuscular division at KU Medical Center, and a co-senior author of the study. "We don't have a treatment that works, but we're on the hunt to find one."
What scientists have observed so far is that muscle tissue from IBM patients contains many misfolded proteins, which Dimachkie compared to crumpled pieces of paper. "You can't write on a crumpled piece of paper," he said. But Dimachkie said arimoclomol could be the right tool to refold those proteins or eliminate them. The drug was part of a previous trial KU Medical Center was part of to determine if it was safe to give patients with amyotrophic lateral sclerosis (ALS).
"Research, unfortunately, is a slow, labor-intensive process," said Dimachkie. "It needs time, resources and funding. It requires collaboration between us, UCL and Orphazyme, the company who currently owns this experimental drug."
Prior to initiating its investigation into the drug, KU Medical Center researchers learned that the British team also had approached the drug company about evaluating the same patient population using the same therapy.
"It was quite good that more than one brain thought of it at the same time," said Michael Hanna, professor and director of the MRC Centre for Neuromuscular Diseases and the UCL Institute of Neurology, also a co-senior author of the paper.
The two scientists - Hanna and Barohn - originally met through Muscle Study Group Society annual meetings and are now co-chairmen of that organization.
"The combined force of teams of researchers from two large universities - and their teams of lawyers - gave us a kind of triangulation that wouldn't have happened with a single institution," Hanna said.
Coordination between two institutions in two countries is highly unusual, and it made the investigation more complicated, Hanna said. "However, it was quite beneficial because having the two different sites added validity to the study."
To begin, UCL scientists created cells in a petri dish to mimic the muscle tissue of IBM patients and successfully tested arimoclomol on those cells. Linda Greensmith, professor and head of the Sobell Department of Motor Neuroscience and Movement Disorders at the UCL Institute of Neurology and a co-senior author of the paper, was the lead basic scientist in the process.
When the cell-level experiments proved promising, researchers analyzed the muscle biopsies of genetically modified mice whose muscle cells and symptoms closely resembled those in humans with IBM, and they found that arimoclomol was well-tolerated in the mice, reversed key features of the disease, and improved muscle strength.
The drug's positive effect in the animal model led to a safety trial with 24 IBM patients conducted at UCL and KU Medical Center that found that the drug was safe and well-tolerated in humans. "Then we made the case quite strongly that arimoclomol should be properly tested in a large trial in humans," Hanna said.
"It's really satisfying as a basic scientist when you see that you're on to a good idea," said Greensmith. "All previous trials focused on IBM have failed, and these patients have no help for their illness. The most exciting experiments - in patients - are just about to start."
The team has now secured $1.6 million from the United States Food and Drug Administration-Orphan Products Division to conduct that full-scale randomized, controlled clinical trial to formally assess whether or not the drug can slow the disease's progression. Clinical trials are tentatively scheduled for later this year, with a projected enrollment of 150 patients to be distributed between 10 sites in the United States and one in the United Kingdom.
It's difficult to do research studies in rare diseases, Dimachkie said, and getting patients involved is a challenge. "But I have faith in the drive and commitment our team and people with IBM have to get this started, completed and results announced in the next few years," he said.
Studying the misfolded proteins in IBM patients may have even more far-reaching effects, according to Barohn. "A drug that successfully addresses protein misfolding might potentially be useful in Alzheimer's and Parkinson's," he said. "If we can show it works in any of these diseases-that would be a huge step forward in translational research."