Regulatory challenges for new drugs to treat obesity and comorbid metabolic disorders

Abstract

Obesity is a major cause of morbidity and mortality through cardio- and cerebrovascular diseases and cancer. The metabolic consequences of obesity include dyslipidaemia, hypertension, proinflammatory atherogenesis, pre-diabetes and Type 2 diabetes. For a significant proportion of patients, pharmacotherapy to tackle obesity is required as adjunctive support to diet, exercise and lifestyle modification. To this end, the pharmaceutical industry is pursuing many novel drug targets. Although this view is probably not justified, the recent tribulations of rimonabant have created a perception that the regulatory bar for the approval of antiobesity drugs has been raised. Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end-point, it is improvements in cardiovascular risk factors that the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) require to grant approval. Safety aspects are also critical in this indication. Many companies are now switching development of their antiobesity drug candidates into other metabolic disorders. Type 2 diabetes is accepted by the industry and FDA, but not EMEA, as the most appropriate alternative. On the other hand, improvements in plasma lipids produced by antiobesity drugs are moderate compared with established therapies, suggesting dyslipidaemia is not a viable development option. Metabolic Syndrome is not accepted by FDA or EMEA as a discrete disease and the agencies will not licence antiobesity drugs for its treatment. The regulatory environment for antiobesity drugs and the spectrum of indications for which they can be approved could change dramatically if positive data for sibutramine emerge from the SCOUT outcome trial.

Figure 1

Qnexa – weight-loss in a Phase II study. The results are from a randomized, double-blind, placebo-controlled Phase II trial performed by Vivus Pharmaceuticals to evaluate Qnexa® (phentermine + topiramate). The trial was conducted on 200 obese (body mass index >30) subjects (159 women and 41 men). The figure shows the completers data at week 24; 92% of enrolled patients on Qnexa vs. 62% on placebo. Using an intention to treat-last observation carried forward (ITT-LOCF) analysis, the percentages of patients achieving 5, 10 and 15% weight loss on Qnexa® were 83% (P < 0.0001), 50% (P < 0.0001) and 20% (P < 0.0007) vs. on placebo 14, 8 and 0%. Data taken from the Vivus website (http://www.vivus.com) and presentations at scientific symposia. Placebo (—○—); Phentermine (); Topiramate (—▴—); Qnexa (—◊—)

Figure 2

The components of the Metabolic Syndrome