Novartis Pharmaceuticals‘ investigational compound BVS857 significantly improved muscle volume in patients with X-linked type spinal muscular atrophy (SMA) over a short period of time, Phase 2 clinical results show. However, the compound failed to improve muscle strength and function.
These findings were reported in the study, “Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial,” published in The Lancet Neurology.
X-linked type SMA, also known as spinal and bulbar muscular atrophy (SBMD), or Kennedy’s disease, is caused by a faulty androgen receptor (AR) gene and is characterized by degeneration of muscle and lower motor neurons of the brain stem and spinal cord.
Previous studies have shown that patients with this disease have low amounts (less than 170 ng/mL) of insulin-like growth factor-1 (IGF-1) in the blood. Also, cellular and mouse studies have suggested that by increasing the amount of this signaling molecule it may be possible to ease the features of AR gene mutations.
IGF-1 is a growth factor with different roles in many aspects of childhood growth. It also plays an important role in adult metabolism.
Novartis developed the artificial compound BVS857 specifically to mimic the natural activity of the IGF-1 hormone, while holding enhanced efficiency. This molecule is capable of IGF-1 receptor activation, but has a longer half-life — the time it takes for the body to eliminate half of the substance — than IGF-1.
The safety and effectiveness of BVS857 was evaluated in a Phase 2 trial (NCT02024932) in adult patients with genetically confirmed Kennedy’s disease recruited at six clinical sites in Denmark, Germany, Italy, and the United States. Patients were at least 18 years old, were ambulatory, had muscle weakness and IGF-1 blood serum levels below 170 ng/mL.
The study was divided into two parts. The first part included eight patients who received increasing doses of the investigational compound or a placebo. In the second part, 27 patients received weekly intravenous injections of 0.06 mg/kg BVS857 or placebo for up to 12 weeks.
During the study 89% and 94% of the patients in the placebo and BVS857 groups, respectively, experienced at least one adverse side effect, with the proportion of moderate adverse side effects being higher in the BVS857-treated group.
The most common treatment-related side effects were inflammation of the nose and pharynx, and headache. In general the treatment was found to be safe without inducing any serious problems.
Repeated treatment with BVS857 induced a significant increase in IGF-1 levels up to a mean value of 788 ng/mL.
Evaluation by magnetic resonance imaging (MRI) scans revealed that BVS857 could induce a significant, but mild, improvement of thigh muscle volume (TMV) — a marker of muscle wasting — compared to initial values. Also, TMV in BVS857-treated patients remained stable during the trial, while it decreased in the placebo group.
However, new assessment of TMV approximately 21 and 48 days after completion of the treatment showed no significant differences between the two groups.
“Overall, no significant differences were found in any of the motor functional measures between the BVS857 and placebo groups,” researchers wrote.
During the trial, about 72% of the patients on the BVS857 treatment group developed antibodies against both the investigational compound and natural IGF-1, which in 46% of the cases had a neutralizing effect. This enhanced immunoreactivity was fully resolved upon treatment discontinuation.
Collectively, these results demonstrated that IGF-1 pathway activation over a short period of time can significantly improve muscle volume in patients with Kennedy’s disease. Still, it failed to improve muscle strength and function.
“The evidence of preliminary efficacy over the short timeframe of 12 weeks in this study is encouraging and not previously described,” researchers wrote. “Activation of the IGF-1 pathway by other means, perhaps in combination with an anti-androgen drug, might be worth pursuing in future clinical trials.”
“We believe this result has implications for other clinical proof-of-concept studies in patients with muscle atrophy or wasting,” researchers concluded.