Every year over 1,500,000 new diagnoses of cancer are made in the U.S. In most cases, this condition can have a significant impact on the individuals’ survival and quality of life. Cachexia, a complex metabolic syndrome associated with underlying illness, is common in patients with cancer. Many cancer patients have diminished appetite, food intake and insulin sensitivity which contribute to a decrease in functional performance, takes a heavy toll on patients’ quality of life and is associated with poor survival.
In cancer patients, caachexia is generally characterized by diminished appetite and food intake in cancer patients, and defined as an involuntary weight loss of at least 5% of the pre-illness body weight over the previous 6 months.
Despite the significant burden that cachexia and other cancer-related symptoms such as anorexia and poor functional status represent to cancer patients, these symptoms often remain undiagnosed and untreated. There are currently no approved treatments for cancer-related cachexia and off-label treatments used for this condition such as appetite stimulants (e.g., megestrol acetate) are largely ineffective and are associated with potentially serious side effects (i.e., adrenal insufficiency, hypogonadism, deep venous thrombosis, etc).
Earlier today, the U.S. Food and Drug Administration (FDA) granted Jose M. Garcia, MD, PhD, Assistant Professor, Division of Diabetes Endocrinology and Metabolism, Departments of Medicine and Molecular and Cell Biology, Baylor College of Medicine and Michael I. DeBakey Veterans Administration Medical Center, in Houston Texas, an Investigational New Drug (IND) approval for the initiation of a Phase IIA trial to assess the safety and efficacy of repeated doses of the ghrelin agonist, AEZS-130 (macimorelin/Solorel; AEterna Zentaris Inc), in patients with cancer cachexia.
The Phase IIA trial is designed to include in 18 to 26 patients with cancer-cachexia and will be conducted under a cooperative research and development agreement (CRADA) with the Michael I. DeBakey Veterans Administration Medical Center which will be funding the study. The drug candidate AEZS-130 will be provided by Aeterna Zentaris, a late-stage oncology drug development company.
The study will involve 3 sequential groups receiving differing doses of AEZS-130. Each dose group will have 6 patients who will receive AEZS-130 and 2 patients who will receive placebo. After analysis of safety and efficacy at each dose level vs. placebo, a decision will be taken either to decrease or increase the dose. If there are major safety issues, the study will be stopped. For this study, adequate efficacy will be defined as a ?0.8 kg of body weight gain or a ?50 ng/mL increase in plasma IGF-1 levels. The primary objective of the study is to evaluate the safety and efficacy of repeated oral administration of AEZS-130 at different doses daily for 1 week in view of developing a treatment for cachexia. Among the parameters recorded to assess efficacy during the study are a change of body weight, change of IGF-1 plasma levels, and change of quality of life score (Anderson Symptom Assessment Scale, FACIT-F). Other secondary objectives will include food intake, change of appetite, muscle strength and energy expenditure.
Jose M. Garcia, MD, PhD, the principal investigator noted that, “Weight loss and decreased appetite (cachexia and anorexia) are devastating complications of cancer. However, treatments for this condition are lacking. Ghrelin agonists have the potential of benefiting these patients by virtue of their anabolic and appetite-stimulating properties. The current proposal will explore the safety and efficacy of the novel ghrelin agonist, AEZS-130, in this setting. If effective, this could allow subjects to receive more effective doses of chemotherapy and to have a better functional status. The results generated by the proposed experiments will set the bases for future trials in this and other wasting conditions that also are very prevalent including chronic obstructive pulmonary disease (COPD), renal failure or chronic heart failure (CHF)-induced cachexia.”
Growth hormone secretion
AEZS-130, a ghrelin agonist, is a novel orally active small molecule that stimulates the secretion of growth hormone. It can be used in both endocrinology and in oncology indications. In endocrinology, the Company has completed a Phase III trial for use as a simple oral diagnostic test for adult growth hormone deficiency (AGHD). The drug candidate works by stimulating a patient’s growth hormone secretion, which normally only occurs during sleep, after which a healthcare provider will measure how well the body responds to that stimulation based on the patient’s growth hormone levels over a period of time. Low growth hormone levels, despite giving an effective stimulating agent, confirm a diagnosis of AGHD. The drug has been granted orphan-drug designation by the FDA for use as a diagnostic test for growth hormone deficiency. Because ghrelin agonists have been shown to stimulate food intake and increase body weight in rats and mice, AEZS-130 could lead to better quality of life for patients with cancer induced cachexia. Ghrelin agonists have been in clinical trials for over a decade and have demonstrated good safety and efficacy profiles.