On July 7th, 2011, Sanofi announced the termination of its Phase III study, called PALLAS, which was investigating dronedarone's (Multaq) potential benefits in patients with permanent AF. The trial was called to a halt due to an increased incidence of cardiac events in dronedarone-treated patients. For a drug expected to help support Sanofi's revenue in light of blockbuster patent expirations such as enoxaparin (Lovenox), whose sales are already reeling from last year's FDA approval of a generic, this news is just the latest in a series of setbacks. In the wake of the PALLAS trial's termination, what now are dronedarone's prospects in the AF market and will this result have an impact on its current use?
The announcement of the PALLAS study, which coincided with the Heart Rhythm Society conference in May 2010, was expected to bring a much-welcomed increase in sales for dronedarone, by providing the drug with access to a new patient population. In 2010 we estimated that permanent AF patients accounted for approximately 35% of the total AF patient population in the major pharmaceutical markets. PALLAS was designed to explore for dronedarone's benefits in patients with permanent AF which, for antiarrhythmic drugs whose sole intention has traditionally been to restore sinus rhythm, was uncharted territory.
On the outset, dronedarone's prospects for favourable outcomes in PALLAS seemed positive. The trial, which planned to enrol over 10,000 patients, was to compare dronedarone, on top of addition to standard medications, to placebo for its effects on major cardiovascular events, cardiovascular hospitalization, or death. An earlier study demonstrated that dronedarone can provide notable rate-controlling effects in AF patients (this is a common treatment strategy in patients with permanent AF); the ERATO trial showed that the drug lowered patients heart rates by almost 9 beats per minute after 4 months of therapy. We forecasted that favourable outcomes from PALLAS could have generated additional sales of up to $180 million by 2016 and catalysed its sales across the non-permanent AF population. This scenario would have driven dronedarone's sales to blockbuster status by 2016; however, in light of PALLAS's termination, dronedarone's prospects have been significantly dampened.
The discontinuation of the PALLAS trial was driven by cardiac safety concerns. According to Sanofi's press release, dronedarone treatment resulted in a significant increase in cardiovascular events. While further information on the nature of these major adverse events is unknown, one of PALLAS's primary outcome measures was the time to first occurrence of a composite of stroke, systemic arterial embolism, myocardial infarction, or death; whether a particular component of this end point drove its overall higher incidence in the dronedarone arm is unclear.
This is not the first major setback for dronedarone, nor is the first time that its safety has been called into question. The Phase III ANDROMEDA trial, which studied the drug in patients with severe heart failure, was prematurely terminated in January 2003, due to an increased incidence of mortality in patients assigned dronedarone; the main cause of death was found to be a worsening of heart failure. More recently, in January 2011, the potential for drug-induced liver injury with dronedarone was brought to light after 2 patients developed liver failure; we note that this event was associated with a reduction in new U.S. prescriptions of dronedarone (as a percentage of all antiarrhythmic prescriptions) by 8% between January and February, 2011.
Some important differences exist between the patients studied in PALLAS and those in dronedarone's earlier, successful trial, ATHENA. In the United States, for example, dronedarone is approved for use in non-permanent AF patients with risk factors including advanced age, hypertension, and diabetes. In PALLAS, patients had permanent AF in addition to comorbidities such as coronary artery disease and prior stroke. Nonetheless we expect that the effects of PALLAS's termination will be difficult to contain; the European Medicines Agency is currently reviewing these new safety data and similar actions by the FDA may soon follow. This could place the drug's positioning in the AF treatment algorithm, and its fortunes, in jeopardy. In contrast to other analysts forecasted annual sales projections for dronedarone (which, in some cases, were in the order of $4 billion), we have always remained conservative in our estimates for dronedarone's predicted sales, owing primarily to the use of an unconventional efficacy end point in ATHENA and its failure to resonate with prescribers. With this latest setback, dronedarone's potential for achieving blockbuster status is now in serious doubt.