ORLANDO – Although the mean increase in body weight was "impressive," ghrelin treatment failed to improve functional outcomes for patients with cachexia associated with chronic obstructive pulmonary disease in a phase II trial.
Although this exploratory trial revealed that ghrelin use caused gains in lean muscle mass and function in COPD patients with severe cachexia, improvements in patient function were "rather disappointing," Dr. Joseph M. Gertner said at an international symposium on IGF-1, GH, and Gherlin/GHS.
Improvement in patient function was a study end point stipulated by the Food and Drug Administration for the preclinical trials of ghrelin agent SUN11031 (Asubio Pharmaceuticals).
"If the only thing you think you need to do to correct cachexia is increase body weight, then this trial worked just fine," said Dr. Gertner, vice president of medical affairs at Asubio. The study showed a 2.5-kg mean weight gain in the high-dose group (40 mcg/kg twice daily) and a 1.5-kg gain in the low-dose group (20 mcg/kg twice daily) at 12 weeks, he said.
"The secondary end point, mean change in baseline body weight, was impressive," Dr. Gertner said at the meeting, sponsored by the University of South Florida, Tampa.
The 214 patients with COPD and cachexia in the intent-to-treat analysis included 73 patients randomized to receive the low dose of ghrelin, 69 to the high dose, and 72 to placebo. Patients were aged 50 years or older (average, 65 years).
The primary end point was performance on a 6-minute walk test, which is widely used to assess physical performance in COPD. Dr. Gertner and his associates also used the short physical performance battery (SPPB), a validated measure that is predictive of morbidity and mortality. The SPPB has three components: a balance test ("no influence in our study"), a chair stand (number of times a patient can stand from a sitting position in 5 or 10 seconds), and a gait speed test (time to walk 4 m).
Handgrip strength, maximum inspiratory pressure, and changes in body weight, body composition, and appetite were also assessed.
"No evidence of strength or functional improvement was observed in the [intent-to-treat] population," Dr. Gertner said. For example, the low-dose group fared significantly worse on the 6-minute walk test than did the placebo group, and no significant improvements on the SPPB test were seen, he said.
Cachexia was defined as a body mass index of 21 kg/m2 or less for men and 20 or less for women, or documented involuntary weight loss of more than 5% over 12 months.
More advanced cachexia was defined as a BMI of less than 16 for men or less than 15 for women.
Among those in the subgroup with more advanced cachexia, significant improvements on the 6-minute walk and SPPB tests were seen with high-dose ghrelin, and positive trends on these tests were found with low-dose ghrelin. In addition, "more than 80% of these very severely cachectic patients increased their lean body mass," Dr. Gertner said.
Ghrelin is a logical choice to combat cachexia, Dr. Gertner said, because "the properties of this hormone seem to line up well with pathophysiologic properties of cachexia." For example, ghrelin causes the release of growth hormone, which might counter catabolism. Ghrelin also increases appetite, improves metabolic rate (thereby improving efficiency of food conversion to body mass), and stimulates gastrointestinal motility. "With all these properties of one ligand, it is not surprising many companies have tried to use ghrelin and the ghrelin secretagogues to reverse cachexia."
Dr. Gertner and his coauthors are full-time employees of Asubio Pharmaceuticals.