Fear and Loathing in Las Vegas*: The Persistence of Gonzo Neuroscience

Like a chronic gambler who keeps thinking that the next time will turn out different, the pharma industry has developed a nasty habit of sidling back to the Alzheimer’s roulette table, putting all their chips on 7, and watching forlornly as the statistical croupier cleans them out, again and again. Hedging one’s bets, putting a few chips on different numbers, has yet to be universally adopted as a less-masochistic ‘investment’ option. A process that we like to think of as akin to 3D-chess ends up being played as a game of craps, and the dice have yet to roll in pharma’s favor.

Lilly is the most recent company to take the plunge into irrational exuberance, deciding to again take solanezumab into Phase III on the basis of post hoc parsing of grouped results from the previous Phase III trials, hoping that selecting only mild patients–albeit with observable amyloid plaque–is the key to one-pivotal-trial success. A $300-400 million trial will surely consume a prominent share of the resources available to CNS within Lilly, a company now cost-cutting because of Cymbalta’s looming patent expiration. We are not reassured by the somewhat arbitrary–in our view–judgment that the optimal trial population is intact enough to only show mild cognitive impairment, but is advanced enough to show plaque on imaging. The reality is that the plaque requirement, which assures some semblance of patient population homogeneity, runs counter to the thesis that one must intervene early in order to achieve a meaningful effect.

Perhaps such gambles are all we have at present; for all the neuropunditry around validated targets in Alzheimer’s, nothing has truly been proven, and ideology is only slightly less dominant than it was ten years ago. Rather than criticizing companies like Lilly for taking the risk, perhaps they should be supported and cushioned against overcommitment–risk can be titrated by being shared amongst several contenders. No company should take all the risk in the hope of hitting the jackpot. Pfizer and JNJ did have this right when they collaborated with Elan on bapineuzumab: While bruised, none of these companies ended up ruined by bapineuzumab’s failure. For those who continue to consider amyloid the best access point for intervention–we do not claim it isn’t, we simply believe that this has yet to be proven–a few companies could consort around BACE inhibition or gamma secretase modulation; alternatively, tau oligomerization or metal-binding, to name a few. Risk and reward sharing would make this kind of gamble manageable, and it would also let some of the other targets that have long languished in amyloid’s shadow have a few chips placed on them. To this point, they have not had the resources necessary for their evaluation, because Pharma had prematurely decided that they knew what the ‘sure thing’ was. TauRx has only survived because of a cadrĂ© of Singaporean investors, and it is damning that Prana has had to rely for so long upon a network of Australian investors and government grants to crawl its way towards POC–or not. Does this mean that they are right? No one knows, but no one reading this publication can say for sure that they are wrong, either. A good dose of humility is overdue, but this does not mean exiting the field; the societal stakes are too high, and we cannot afford to wait for mechanistic certainty. Humility means acknowledging that we don’t even know what color is going to come up on the wheel, let alone which number, and our bets should be diversified accordingly.

*Thompson, H. 1972

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