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Success and challenges for clinical trials that address these interrelated conditions.
There is no doubt among health care professionals that the United States is experiencing an obesity epidemic. This epidemic cascades to the related diseases from increased weight, including Type 2 diabetes, hypertension, and lipid disorders, which include atherosclerosis and other cardiovascular problems. The epidemic is not confined to the United States, and is becoming a health issue in other developed countries.
Cardiometabolic Drug Trials
Obesity drugs have a long and storied history. In 1997, fenfluramine in the class of anorectics was withdrawn from the U.S. market after reports of heart valve disease and pulmonary hypertension. Fenfluramine was half of fen-phen or Pondimin and also in Redux, marketed by American Home Products, which became Wyeth. In 2008, rimonabant in the class of cannabinoid-1 receptor antagonists, was withdrawn in Europe after being available for two years. A review of postmarketing data showed a doubling of risk for psychiatric disorders in patients taking Acomplia, marketed by sanofi-aventis. And most recently, in late August, the FDA announced it was conducting a review of anti-obesity drug orlistat in the class of lipase inhibitors, marketed as Xenical and Alli by GlaxoSmithKline, for 32 reports of liver-related adverse events, 30 of which were reported outside of the United States and included six cases of liver failure. Xenical was approved as a prescription drug by the FDA in 1999 and Alli was approved for OTC in 2007.
However, the development of obesity drugs is not eclipsed by the adverse events of these representatives in various drug classes. Decision Resources issued a report in mid-September predicting a six-fold increase of the obesity drug market from $512 million in 2008 to $3.2 billion in 2018. The market represents the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan. The authors of the report cite the drivers of the obesity drug market growth as novel therapies. The Decision Resources report found the pipeline had a dearth of cannabinoid receptor-1 antagonists, paving the way for the novel therapies and combination therapies.
One obesity drug that recently went through two Phase III trials with positive results is Qnexa from Mountain View, CA-based Vivus. Qnexa, a combination of phentermine and topiramate, met all primary endpoints of demonstrating statistically significant weight loss in all three doses of the drug, which was evaluated in 3750 subjects at 93 sites for 56 weeks. The FDA requires that there be a 5% loss of body weight between the investigational drug and placebo. For Qnexa, the statistics showed this greater than or equal to 5% weight loss rate among 59% of those completing the trial for the low dose and 84% for the full dose in the first trial, and 75% for the mid-dose and 85% for the full dose in the second trial.
Qnexa also showed a reduction in hypertension, diabetes, and dyslipidemia (lipid disorders). The side effect profile was also positive. Vivus completed a thorough QT prolongation (TQT) study to evaluate subjects. Monthly assessments for prospective psychometric evaluations showed no signals for suicidality risk, and moderate to severe depression or depressed mood adverse events were seen in less than 2% of the subjects.
Another investigational drug that is in preclinical development for Type II diabetes addresses the cardiovascular safety problems found in previous diabetes drugs. Alize Pharma, based in France, is investigating AZP-01 in a new therapeutic class of compounds called growth hormone secretagogues. Alize cofounder and president Thierry Abribat, PhD, told Applied Clinical Trials the company's goal is to move the compound out of the preclinical stage and to then partner with a larger company for regulatory and, hopefully, marketing.
"We feel the compound is quite suited for the current need of the metabolic market because it targets reduced glucose," said Abribat. "The new rules and regulations in the field of Type II diabetes, with Avandia, and the risks with these products...it's not enough to lower HbA1c levels to have efficacy in diabetes, you have to have effects on cardiovascular also." The naturally secreted peptide found in AZP-01 has been shown to exhibit effects on endocrine pancreatic function, glucose metabolism, appetite stimulation, and the cardiovascular system, among others.
The related co-morbidities of obesity, diabetes, and lipids create challenges for the clinical trial professional. Specifically in areas that include:
Overall, there has been an increase in protocols in drug design as noted in a 2007 report from the Tufts Center for the Study of Drug Development. From 1999-2005, the number of unique procedures increased 6.5%, the frequency of procedures was up 8.7%, and the execution burden on the site was up 10.5%. Also, as we reported in our June issue, "Raising the Bar on Subject Recruitment," FDA—just in the past three to five years—is requiring more data from the sponsors.
More complex protocols require more resources. Protocols for the cardiometabolic drugs are also increasingly stringent, based particularly on the side effect histories presented above. More complex protocols require more resources. As noted in the Qnexa trials, both TQT evaluations and psychiatric assessments were necessary. In December 2008, the FDA published a guidance for industry to evaluate cardiovascular risk in new type II antidiabetic therapies. The guidance does not specifically mention the TQT tests, however, many CROs and service vendors provide TQT services including CareFusion, ERT and Quintiles. Protocol requirements then trickle down into inclusion/exclusion criteria, which impact the next area of subject recruitment.
Inclusion/exclusion criteria on the drug protocol is increasingly difficult in recruiting subjects for clinical trials. In diabetes trials, the two most difficult barriers to recruitment are finding treatment naive patients or patients that have the right HbA1c levels.
Sandra Chase, vice president of operations for HCG, told Applied Clinical Trials in a podcast last year, that while genetics plays a role in Type II diabetes development, "Many times especially in Type II there is a lifestyle issue...and that can have co-morbidities which can be exclusionary." In addition, in the United States, most potential subjects have been treated with some kind of diabetes medication, making the treatment naïve more difficult to find. Said Chase, "Finding treatment naïve, means in many cases looking at the uninsured or underinsured or underserved populations that may be difficult to access."
In the end, new retention and recruitment strategies will be necessary in order to find and keep the right subjects for the right cardiometabolic trials.
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