In this blog, I plan to focus on the negative, but I don't want to be negative. In fact some of the most interesting data presented at the 63rd Annual Scientific Sessions of the American College of Cardiology were just that negative. Often overlooked, negative trial findings can be very useful, suggesting more research is need, the methodology might not have been optimal, a theory is defunct or the risks of an agent may outweigh the benefits. The STABILITY, ALECARDIO and SYMPLICITY HTN-3 trials were all negative, but all important.
Quest for plaque STABILITY continues
Atherothrombotic disease is still increasing in prevalence, despite improvements in public health and primary prevention. GlaxoSmithKline's darapladib is a potent and reversible oral inhibitor of lipoprotein-associated phospholipase A2 that is being developed to stabilize atherosclerotic plaques through targeting inflammation. The Phase III STABILITY study, involving more than 15,000 patients with coronary heart disease, tested darapladib's efficacy on a composite of cardiovascular (CV) death, myocardial infarction, and stroke. After a mean follow up of 3.7 years, there was no significant difference in the number of composite events between darapladib and placebo (819 versus 769 events, respectively). However, there was a significant advantage in terms of major coronary events for darapladib over placebo (737 versus 814 events).
Negative trial. However, the results highlight a new avenue of research and a subpopulation that may benefit. DRG's Conor Walsh and Graeme Green discuss this possibility in further detail here.
No go after ALECARDIO
Speak of peroxisome proliferator-activated receptor (PPAR) agonists for patients with type 2 diabetes and people start to get nervous think the PPAR-gamma agonists rosiglitazone (GlaxoSmithKline's Avandia), linked to heart disease and pioglitazone (Takeda's Actos), linked to bladder cancer. Roche's PPAR alpha/gamma agonist aleglitazar was developed to see if a dual approach would be beneficial in patients with type 2 diabetes. This group has an increased risk of CV disease. The theory behind developing aleglitazar was that it would provide improved lipid profiles associated with PPAR-alpha receptor activity and improved insulin sensitivity via PPAR-gamma receptor activity. Unfortunately, in the Phase III ALECARDIO trial, involving more than 7,000 patients with type 2 diabetes and recent acute coronary syndrome, aleglitazar was associated with increased risks of heart failure, renal dysfunction, fractures, gastrointestinal bleeding and hypoglycemia. Moreover, it had no positive effect on CV outcomes. Unsurprisingly, the trial was terminated early.
Negative result. However, important findings regarding the safety and efficacy of the approach were identified, and the drug has been discontinued.
SYMPLICITY HTN-3 results: a simple message
Over the last 20 years, drug development for hypertension has stagnated. Once there seemed to be a plethora of new antihypertensives, now the novelty is limited to new fixed-dose combinations. Moreover, no single agent is particularly efficacious, so patients frequently require multiple medications to manage their hypertension. Consequently, patients with resistant hypertension remain at a greater risk of CV events. However, after links between the sympathetic nervous system and resistant hypertension were identified, denervation of the renal arteries was tested with encouraging results, although the quality of the trials sustained doubts over the procedure. Consequently, the SYMPLICITY HTN-3 investigators conducted the first prospective, multi-center, randomized, blinded, sham controlled study to evaluate both the safety and efficacy of percutaneous renal artery denervation in patients with severe treatment-resistant hypertension. After six months, there was no difference in the BP reductions for the denervation and sham groups (-14 versus -12 mmHg), all of whom were receiving at least three medications. Why? Perhaps the procedure was not carried out well. Perhaps all of the patients in the sham group improved adherence to their medications. Perhaps renal denervation is not effective maybe drugs are the answer, for hypertension, at least.
Negative results but new questions to answer and possibly an old adage supported. SYMPLICITY might just reinforce a simple fact: drugs only work when patients take them. Indeed, renal denervation might have a place for patients who do not adhere with their medications.
Sometimes negatives can still yield positives.
Tim Blackstock, M.B. Ch.B., is a business insights analyst in the Cardiovascular, Metabolic, and Renal Disorders team at Decision Resources Group.
In-depth analysis of the disease areas covered in this blog, with accompanying epidemiology driven sales forecast models, are presented in Decision Resources Group's Atherothrombotic Diseases, Hypertension, Type 2 Diabetes and Acute Coronary Syndrome Pharmacor reports; find out more.