Snatched from oblivion: “second lives” of bespoke drugs
Thoru Pederson
Abstract
"Lay down your weary tune…" Although cast in a different context, that opening line of Bob Dylan's 1963 song applies to the theme of this editorial: when to give up, or not. For those of us engaged in either basic, translational, or clinical research in universities and academic medical centers, deciding when it is time to give up a project is among the more vexing decisions we ever make. It is both a scientific and emotional decision and, if executed, includes "what if's?" such as "If I had stayed with this one more year maybe…." But that said, these decisions we've made in our guild don't compare with those of the pharmaceutical industry, where hundreds of millions of dollars have been spent, and the market that might have been is in the billions. Some recent events have gotten me thinking about this. For one, The FASEB Journal published a series of Perspectives on Alzheimer's Disease in 2018 and 20191-10 that collectively conveyed findings and ideas other than the "standard model" of AD pathogenesis (tangled amyloid and/or tau protein). The editor of this series, Joel Buxbaum, concluded it with a superb, comprehensive overview11 but he and I were careful not to claim that the mere existence of alternative ideas constitutes evidence that the amyloid/tau hypotheses are invalid.11, 12 Neither Dr Buxbaum nor I anticipated, when we launched this series, that during their publication we would witness several pharmaceutical companies dropping their lead drugs based on the amyloid/tau hypothesis, such corporate decisions not necessarily signifying that the hypothesis is wrong. Recently, one of the companies, Biogen, has reanalyzed data from the trial of their lead drug for Alzheimer's and claim they have found reason to reconsider their decision to terminate this drug development program. This has to do with the company's decision to isolate data from a subject cohort that received the highest dose of the drug. One is tempted to recall the quip "Lies, damned lies and statistics" (which, despite its fame, no scholars have ever been able to attribute). And then, a few weeks later, a surprising discovery was published that may be an Alzheimer's Disease gamechanger.13 A comprehensive genetic analysis of a large family cohort in Colombia, afflicted over several generations with an early-onset form of dementia, typically evident by the age of 40, uncovered an outlier woman in this family. At 70 years of age, MRI analysis revealed that her brain has extensive fibrillar protein tangles, considered to be the hallmarks of Alzheimer's Disease. And yet her cognitive impairment was minor. Analysis of her DNA revealed that she carries, on both chromosomal copies, a mutation in a gene for a protein that is not related to protein tangles. This protein is one that research back in the 1990s had focused on but that momentum ebbed. The new work suggests that this gene, when not mutated, either permits or even promotes cognitive decline, but when mutated can actually retard it. Admittedly, these are early days but the stunning finding is the possibly protective power of this gene mutation. Pondering this, I remembered how many times in medical history a disease pathogenesis hypothesis has suddenly changed, and also how existing drugs have found new applications, a variation on this theme. The compound that became the birth control pill was already being marketed for a menstrual cycle disorder when an independent team of scientists discovered that it inhibited ovulation. The frontline breast cancer drug Tamoxifen was resurrected from the shelves of a British pharmaceutical company that had abandoned it. Perhaps the most widely known case, not of a drug but a commercially sensational product, is aspartame, which a company employee was instructed to dispose of and, doing so, noted its intense sweet taste as the powder lifted to his nose. It became the first low-calorie nutritional sweetener. The idea that companies should be open to offering "failed drugs" to other endeavors has been thoughtfully discussed14 and is not an entirely quixotic idea. Appropriate licensing deals can be struck in which the new party, willing to invest and take the risk, can properly share rights with the parent company that had "laid down its weary…." And here's another ironic story. Last year the German chemical company IG Farben reported on an insecticide that new research has revealed to be far more effective against mosquitoes than DDT,15 offering hope that, if re-purposed, substance might advance in the eradication, or at least effective control, of a disease that kills more than 40 000 people annually. A final point is the problem of how pharmaceutical companies can hide their failed clinical studies. They do so, of course, in the fear that other parties, commercial or academic, might be able to nonetheless extract useful information and ply it into new advances. This is a parallax universe of the whole issue of why pharmaceutical companies are not legally compelled to conduct continuing clinical research of their drugs, postmarketing, often when the initial study that won then FDA approval was not ideally robust statistically. Having more transparency around these issues would serve the needs of patients in the long run. Most of them want to, at last, lay down their "weary tune" (acute disease or a life of chronic suffering) and have hopes for continued quality of life and potentially curative care. So the discussion I have suggested here must continue.