• Pulmonary Clinical Trials
• Lower Respiratory Infections

Lung function in lymphangioleiomyomatosis (LAM) stabilized and symptoms and quality-of-life (QoL) improved significantly during treatment with sirolimus, according to results of the Multicenter International LAM Efficacy of Sirolimus (MILES) Trial, reported Francis X. McCormack, MD, University of Cincinnati, Cincinnati, Ohio, USA, on behalf of the NIH Rare Lung Diseases Consortium.

FEV₁ increased by 1 ml in the sirolimus group compared with a 12-ml decrease with placebo (p<0.0001) over the course of the 1-year treatment period. Forced vital capacity (FVC) also improved with sirolimus, but exercise tolerance and measures of gas exchange did not change. There was a 50% reduction in serum levels of vascular endothelial growth factor-D (VEGF-D), which stimulates pathological growth in LAM. Functional and symptomatic improvement lasted only so long as patients remained on sirolimus.

LAM is a rare cystic lung disease that affects women. The condition arises from mutations in the tuberous sclerosis complex (TSC) genes that regulate mammalian target of rapamycin (mTOR) [Carsillo and Henske. Proc Natl Acad Sci 2000]. Additionally, lung lesions that are associated with LAM exhibit abnormal mTOR activation, providing a rationale to investigate treatment with sirolimus, which inhibits mTOR [Goncharova et al. J Biol Chem 2002].

In a small open-label trial, tumors that were associated with TSC or LAM shrunk by 50% during treatment with sirolimus, and lung function improved by as much as 13% [Bissler et al. N Engl J Med 2008].

The accumulation of clinical and preclinical evidence led to the multicenter trial, reported by Dr. McCormack. Investigators at 13 sites in the United States, Canada, and Japan randomized 89 patients with moderate lung impairment to sirolimus or placebo for 12 months, followed by an additional 12 months of follow-up. The primary endpoint was the change in FEV₁ from baseline to 12 months.

Baseline characteristics did not differ significantly between treatment groups. The patients had an FEV₁ of 49% of predicted, FVC of 80%, total lung capacity of 105%, functional residual capacity of 113%, residual volume of 141%, and carbon monoxide diffusion capacity of 43%, consistent with moderately severe obstructive lung impairment, air trapping, and reduced diffusing capacity.

Patients who were randomized to active therapy received sirolimus 2 mg. Sirolimus levels were measured at every visit after baseline, and the dose was adjusted to maintain a serum level of 5 to 15 ng/ml.

The observation period of the trial was truncated after a planned interim analysis in February 2010 showed that the stopping rule for efficacy had been met.

Among patients in the sirolimus arm, FEV₁ had stabilized or improved in 46% of patients compared with 12% in the placebo group (p<0.001). Moreover, the change in FEV₁ averaged −134 ml in the placebo group versus an increase of 19 ml with sirolimus, resulting in a between-group difference of 153 ml (p<0.001).

“The clinical relevance of an FEV₁ difference of 153 ml is important to consider,” said Dr. McCormack. “It represents more than a 10% increase from baseline mean FEV₁ of 1.37 liters for these patients. It exceeds the estimated minimal clinically important difference in FEV₁ for COPD of 100 to 140 ml, which can be perceived by patients and is typical for bronchodilator response. Another reason that a 153-ml difference might be important is that in any patient with advanced disease, any stabilization that may delay transplantation and associated risk is of value.”

The change in FVC averaged a decrease of 129 ml in the placebo group versus an increase of 97 ml in the sirolimus group. Sirolimus was associated with significant improvement in functional performance and QoL versus placebo (p=0.03). FEV₁ began to decrease soon after patients stopped treatment, although the mean value in the sirolimus group exceeded that of the placebo group through the end of the 12-month follow-up period.

Sirolimus was associated with a higher incidence of adverse events. The most common adverse events were stomatitis, diarrhea, nausea, hypercholesterolemia, acneiform rash, and lower-extremity edema.

“Therapy with sirolimus may be useful in selected LAM patients,” concluded Dr. McCormack. “Longer-term studies are needed to determine if benefit can be sustained with continued therapy.”

• © 2011 MD Conference Express