Lilly’s woes highlight the challenges of drug development

lily-drugThe recent announcement that Eli Lilly was halting all clinical testing of its Alzheimer’s drug Semagacestat, was a body blow not only to Lilly, but also to the many other companies who are developing their own Alzheimer’s medications. Lilly had been developing semagacestat for more than a decade, based upon experimental work that demonstrated the compound’s ability to inhibit γ-secretase, an enzyme whose activity is believed to be responsible for the formation of the amyloid plaques found in the brains of Alzheimer’s patients.

Based upon the extensive tissue damage apparently caused by the formation of these amyloid plaques in the brain and the fact that their detection in the brain and spinal fluid of asymptomatic patients has been shown to be prognostic of the eventual onset of the disease, this “amyloid hypothesis” has been the cornerstone of Alzheimer’s research for some time. The potential therefore, that this hypothesis is wrong, incomplete or at least fundamentally misunderstood, has sent shock-waves through a pharmaceutical industry that has at least 100 other Alzheimer’s drugs currently in development, the majority of which are also predicated upon the amyloid hypothesis.

Unfortunately for Lilly, the problems for semagacestat go well beyond the drug simply not working. In its clinical trials it actually proved to be worse than the placebo, with the patients receiving the drug showing a more rapid decline in cognitive function than the patients in the placebo group. As if this was not already bad enough, there was also an increased risk of skin cancer in the patients who received semagacestat. A rash (no pun intended) of negative publicity followed the announcement of these results, amongst which were headlines proclaiming Eli Lilly’s new drug “Worse than nothing”. Any schadenfreude on the part of competing companies however, was probably cut short by the realization that most of them were potentially in the same boat with their own Alzheimer’s programs.

A number of potential mechanistic grey areas surround the development of the current crop of Alzheimer’s drugs. Firstly, the amyloid hypothesis itself is predicated upon the theory that the processing of amyloid precursor protein (APP) in the brain by γ-secretase, yields the (approximately) 40 residue β-amyloid protein whose polymerization drives the formation of the amyloid plaques – and that this process is the causative factor in the development of Alzheimer’s disease. Aside from the many unanswered questions that surround this process and its role in the disease, the biological function of APP is only poorly understood. This is also further complicated by the fact that amongst other things, APP has been shown to be involved in the repair of neurons. Another potential problem for the drug developers is that in addition to APP, γ-secretase also processes other proteins such as notch, an important cell surface receptor that is involved in a plethora of developmental signaling cascades. The complex nature of the γ-secretase activity that is targeted by drugs like semagacestat, has driven some pharmaceutical companies (including Lilly) to explore the development of more “surgical” inhibitors that can block the production of amyloid protein by γ-secretase while leaving its ability to process other proteins intact. This new generation of inhibitors however, still depends upon the primacy of the amyloid hypothesis as the central process in the development of Alzheimer’s disease.

It is clear that the molecular players that have already been identified as having a central role in Alzheimer’s disease, are interconnected by a complex web of cause and effect that will need to be unraveled if we are ever to have a clear understanding of the etiology and development of this dreadful disease. For the time-being however, a significant portion of our knowledge of the underlying biology of Alzheimer’s is still correlative and phenomenological. The oft-repeated maxim that correlation is not causation seems particularly apropos with regard to the unfortunate story of semagacestat, and as with all such misfortune, hopefully some valuable lessons can be taken away from the experience.

The damage to reputation and the loss of hundreds of millions of dollars and more than a decade in the development of semagacestat, are sobering reminders that in our attempts to intervene in these complex biological systems and to modulate their activities to our own ends, we take huge risks venturing into this challenging territory without a good map of the underlying networks of cause and effect to navigate by.

© The Digital Biologist