ARTICLE IN BRIEF
In a small study, 11 patients with sporadic inclusion body myositis experienced a statistically significant increase in thigh muscle volume after eight weeks — after being given a monoclonal antibody — compared with the three patients who received placebo. Lean body mass also increased after eight weeks to a statistically significant degree over patients in the placebo group.
NEW ORLEANS — In a small proof-of-concept trial, treatment with a monoclonal antibody led to gains in thigh muscle volume in sporadic inclusion body myositis (sIBM). The findings could lay the groundwork for a larger trial on the drug, investigators reported here at the annual meeting of the American Neurological Association in October.
Bimagrumab, a fully human monoclonal antibody from Novartis, blocks muscle-inhibiting transforming growth factor-beta (TGF-beta) superfamily members from binding to type 2 activin receptors (ActRII).
The study's 11 patients with sIBM experienced a statistically significant increase in thigh muscle volume after eight weeks compared with the three patients who received placebo. Lean body mass also increased after eight weeks to a statistically significant degree over patients in the placebo group.
Novartis is now conducting a randomized trial that is projected to include 240 patients in 13 countries. In August, the drug was given breakthrough status by the US Food and Drug Administrations for expedited development and review.
This latest attempt at least deserves a broader trial, said study author Steven A. Greenberg, MD, associate professor of neurology at Harvard Medical School.
“It wasn't a pivotal study to decide if this drug works in IBM,” he said. “It was a small proof-of-concept study to see if the predicted mechanism of increasing muscle mass would work in a person with the disease, and it did.”
The researchers found, through assays of the phosphorylation of the Mothers Against DPP Homolog 2/3 (SMAD2/3) protein, that TGF-beta superfamily signaling was elevated in the muscle tissue of patients with the disease. Phosphorylation of SMAD2/3 was significantly elevated in the muscle samples of sIBM patients compared with patients with dermatomyositis, polymyositis, and other muscle diseases (p=.004).
The investigators turned to bimagrumab to try to block the receptors that might be leading to that signaling. Patients in the bimagrumab group were 67 years old on average, and were 68 on average in the placebo group. But there were striking differences in weight and body-mass index. The weight averaged 79 kg in the bimagrumab group and 95 kg in the placebo group; BMI was 26.6 in the bimagrumab group and 31.4 in the placebo patients.
Before treatment, the right thigh muscle volume (TMV) in the bimagrumab group averaged 2,445 cubic centimeters. That rose to an average of 2,602 cubic centimeters by the time patients received MRIs after 8 weeks. That was a significant increase (p=.02) over the placebo group, in which the right TMV dropped from 2,484 cubic centimeters to 2,245 cubic centimeters.
There was also a statistically significant difference between the groups after 8 weeks in left TMV (p=.009) and in the secondary outcome measure of lean body mass (LBM) (p=.01).
Dr. Greenberg emphasized the connection between the biological mechanism of the drug and the results that were seen. “It's a drug that biologically increases muscle mass, and the primary outcome measure is simply a measure of muscle mass. There's a very close link there, and I think that contributed to a successful study,” he said.
There were trends favoring the bimagrumab group in 6-minute mean walking distance and quantitative muscle tests, an assessment of muscle strength — but these weren't statistically significant.
Six of 11 patients in the bimagrumab group had muscle cramps, and 3 of 11 developed acne despite their age. Twelve of the 14 patients, comprising the placebo group patients as well, agreed to be followed for another 16 weeks — and the thigh muscle volume and lean body mass started to decline again after the imaging at eight weeks.
Researchers found a correlation between increases in right TMV and LBM at eight weeks and maximum walking distance achieved over 24 weeks, saying that suggests that increased muscle mass leads to better function.
Neuromuscular disease experts had mixed responses to the findings. Glenn Lopate, MD, associate professor of neurology at Washington University, said he is “not very impressed with the results.” He pointed to the differences in weight and BMI for the two patient groups.
He added that there were no changes in strength or function, except for the correlation between walking distance and the TMV and LBM changes. And the TMV improvements fell off over time, he noted.
The link with the TGF-beta pathway is plausible, he said, as that has been found with other chronic myopathies, but there is “not enough data to know how this link translates to progressive muscle weakness in IBM.”
“The main pitfall, as with many other drugs tried in IBM, is that nothing seems to work,” Dr. Lopate said. “Too many phase 3 trials have had negative results after promising phase 2 trials for me to get too excited.”
But other neurologists were more optimistic about the findings. Jerry Mendell, MD, professor of pediatrics and neurology at Nationwide Children's Hospital, said it is encouraging to see new efforts in IBM treatments, including those from Dr. Greenberg's lab.
“Sporadic inclusion body myositis, the most enigmatic disease we have on our plate, is making strides,” he said. “Things were stagnant for so long in sIBM, so it is a breath of fresh air to see research moving in a direction that gives patients and doctors hope for helping this disease.”
Yadollah Harati, MD, professor of neurology and chief of the Neuromuscular Section at the Baylor College of Medicine, said he, too, is “delighted to see that there is some movement in IBM.”
But, he noted, “the drug [bimagrumab] goes to all muscles in the body, probably to the muscles that are not clinically affected as well. So, the question of side effects will come into play: What will this drug do to the muscles that are not clinically affected? What is the effect of unwanted hypertrophy?”
Because the study was of a short duration, the long-term effects are unknown, he said. “Any meaningful study in sIBM should be at least two years, for us to get a good understanding of whether the drug works or not,” Dr. Harati said.
“What the drug did even on the involved muscle, in the quadriceps muscle, basically enhanced or made the remaining muscles, that were not affected, larger,” he continued. “It really didn't do anything for the diseased muscle fibers. Are these enlarged muscle fibers also going to get sick later on? We don't know.”