Marginally ineffective

In the past, we've not been shy about pointing out how companies have killed their own valuations through their own stumbles in the clinical process. This week, however, the unhappy picture above says not much about Athena Neurosciences Inc. Rather, it says a whole lot about the failure of drug regulators to make decisions.

The FDA's move last week to turn down ATHN's NDA for Zanaflex (tizanidine) - a drug that is approved in 50 countries and has been used by about 15 million patients - highlights so many flaws in the regulatory system that it's hard to know where to start. In this week's Commentary, we'll focus on two - the agency's inability to make decisions at the margin, and the imposition of regulators in clinical choices that should be made by physicians and their patients.

The facts of the case are as follows:

ATHN submitted three studies of the drug, which is designed to treat spasticity of spinal cord origin associated with multiple sclerosis (MS) and spinal cord injury (SCI). There are no quibbles about the SCI trial, which showed clear efficacy on its two primary end points - muscle tone assessed by the Ashworth scale and a pendulum test where the patient's leg is allowed to fall and its swing is measured, as well as on a secondary end point of spasms and clonus as recorded in patient diaries.

The U.S. multiple sclerosis trial missed its primary end point, muscle tone on the Ashworth scale, apparently because measurements were taken too late, after the effect of the drug had worn off. (In fact, the SCI study was designed based on that knowledge.) The MS study hit its secondary end point measuring spasms and clonus.

The third study, a U.K. trial in MS patients conducted by Sandoz, from whom ATHN licensed the drug, met its primary end point on the Ashworth measure.

Another study, new endpoint

In issuing its non-approvable letter, the agency cited both efficacy and safety concerns. The efficacy question hinges on the requirement for two statistically significant clinical studies for approval, while safety questions are focused on long-term high dose use of the drug.