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.

Cardiovascular Risk-Benefit Profile of Sibutramine

“…[22] Although >5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy endpoint for anti-obesity agents, an associated reduction in CVD risk factors is considered as an important secondary endpoint that may help for grant approval by the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA). [23,24] Safety aspects are also critical in this indication essentially because antiobesity agents are known to be associated with adverse events and several of them have been withdrawn from the market because of serious safety problems. [25][26][27][28] Sibutramine is one of the few established and well-proven agents for obesity and may be considered effective in the management of patients requiring pharmacotherapy as part of the multi-modal approach to weight-loss.…”

Coumarin and Biscoumarin Inhibit <i>in Vitro</i> Obesity Model

“…Only five new drugs have been registered over the last fifteen years, namely, dexfenfluramine (Redux®), sibutramine (Meridia®, Reductil®), orlistat (Xenical®) and rimonabant (Acomplia®), for the treatment of obesity. The antiobesity drug candidates in different phases of clinical trials include the centrally-acting monoaminergic food intake regulators (tesofensine, ATHX-105 and PRX-0703), hypothalamic neuropeptides (obinepitide), gut hormones (TKS 1225), and various combination products (empatic®, contrave® and pramlintide/ metreleptin) [6]- [8]. Besides the pharmacological treatment, the emphasis is now on behavior therapy, as adjunct therapy, that aims to modify the dietary habits and sedentary life style.…”

Long-term health benefits of appetite suppressants remain unproven

“…Both drugs and a combination of fenfl uramine and phentermine (known as "fen-phen") were widely used as weight-loss drugs until 1997 when they were withdrawn from the market in the US, Europe and other countries after reports of valvular heart damage, apparently caused by a selective stimulation of 5-HT 2B receptors on human cardiac valves, and concerns on their possible association with pulmonary hypertension. 2,3,5,9 Rimonabant, an endocannabinoid receptor (subtype CB1) blocker, received marketing approval from the European Medicines Agency (EMA) in June 2006 for treatment of obese or overweight (BMI >27 kg/ m 2 ) patients with associated risk factors such as type 2 diabetes or dyslipidemia. In Brazil, where it was popularly known as "stomach fat pill," rimonabant was approved with similar indications in April 2007.…”

“…3 Benfl uorex, a fenfl uramine-derivative, was recently withdrawn (November 2009) from the market in France and other European, Asian and South American countries where it had been used since 1976 for treating patients with high blood levels of triglycerides and overweight plus type-2 diabetes. A cohort study including a million patients with diabetes revealed that Benfl uorex was signifi cantly associated with hospitalization for valvular heart disease during the 2-year follow-up after drug exposure.…”