- 1.Hillary’s speech writers were right—it takes a village, and in this case several villages—some with village elders such as J.B. Howell and other dermatologists who began describing patients with what now is termed BCNS in the 1950s; Robert Gorlin, who (like Columbus) was the “last” to describe the syndrome and therefore has the honor of having his name attached; Eric Wieschaus and Christiane Nüsslein-Volhard, the Nobel laureates who described the hedgehog signaling pathway in 1980; and hunter-gatherers such as the near dozen labs that worked collaboratively and competitively in the 1980s and 1990s to identify the gene whose mutations cause BCNS. Success also requires one or more of the near completely separate villages (such as Genentech or Novartis) that have the resources to fund the highly specialized armies of medicinal chemists, regulatory personnel, clinical trialists, and many others needed to move from concept and opportunity to supplying an effective drug to the shelves of pharmacies around the world.
- 2.It takes a lot of money to feed and maintain even the last of these villages. The National Institutes of Health traditionally has supported the first villages. But these villages need enormous amounts of funds to develop new drugs—the estimates continue to climb from the hundreds of millions to more than a billion—and hence pharmaceutical companies need to invest in drugs that have at least a chance of returning large amounts of money.
- 3.Given that the former villages have produced and no doubt will continue to produce more targets whose “hitting” could significantly ameliorate various diseases of the skin, how can the interest of the latter villages be piqued sufficiently to unleash the large amounts of capital needed to bring such a drug to market? That’s really the big question. Two types of answers come to mind.
- i.In the case of melanoma, and increasingly for psoriasis, the market opportunity is perceived as being large enough to develop drugs whose first indication is dermatologic, although many would consider melanoma once it has left the skin an oncologic rather than a dermatologic disease. Can we find more dermatologic markets (numbers of patients × possible profit per patient) that are large enough that their targeting would justify the large amounts of capital that would have to be spent to develop new drugs specifically for those targets? In the case of the healing of chronic wounds and of the safe amelioration of eczema, the answer clearly would be affirmative. Perhaps this also might be the case for several orphan disease drugs with primarily skin manifestations because orphan diseases, at least for the time being, can command high prices per patient treated, and their path to approval may be less costly. But for the great majority of conditions to be found in any dermatologic text, the answer clearly is negative.
- ii.In the case of hedgehog inhibitors for BCCs, it seems highly unlikely that the monies ever would have been spent were it to have been known that BCCs, and only a small subset of them (“advanced” or metastatic), would be the only market for the new drugs. The BCC drug came along on the coattails of anticipated indications for pancreatic, colorectal, and other cancers. This is a time-honored path for new dermatologic drugs (ie, using a drug developed for some other indication for a skin problem)—consider aminopterin and methotrexate decades ago and etanercept and other tumor necrosis factor inhibitors more recently for psoriasis, brimonidine for a red face, and steroids for almost everything. Could we repurpose newer drugs (or even old standbys) developed and utilized for other ailments for skin problems? Presumably to do so we would need to think more seriously about identifying such drug-skin targets and to institute a more structured approach to the problem. One example comes from the hedgehog inhibitor field. An in vitro targeted assay by Philip Beachy, then at Hopkins, of a large number of FDA-approved drugs identified both in vitro and in vivo (at least in our Ptch1+/- mice) antihedgehog/anti-BCC activity of itraconazole unrelated to its antifungal activity (Kim et al., 2010,Kim et al., 2013). Investigation of its anti-HH efficacy in humans, including its anti-prostate cancer efficacy, is under way. Its potency is considerably less than that of vismodegib and other “professional” hedgehog inhibitors but if we did not have the latter, perhaps it could have served as an at least partially effective anti-BCC treatment. The regulatory and financial hurdles blocking repurposing of an old drug are far lower than are those blocking development of a new drug. Are there more such in vitro screens of already approved drugs that might unearth yet other, even more useful surprises?
- 4.I have been extraordinarily fortunate to have seen work that our lab has done actually lead to something useful for patients. How many people get to work on the identification of the molecular basis of a disease and then lead the clinical trial of the first drug to replace the function of the defective gene? What underlies that good fortune, beyond a very healthy dose of good luck? I could have skipped the Cleveland trip and not have read about RB; Matt could have called someone else; we could have worked on a disease for which the identification of the mutant gene did not lead so clearly to a drug. Indeed, our own findings of keratin gene mutations in epidermolysis bullosa simplex have not enabled a therapy. Part of it clearly depends on my having been surrounded from the start by very good individuals. Because of the example set by my family, I grew up expecting to become a clinical scholar in an era in which the phrase “balanced life” had not yet been coined and never felt that work was drudgery. And my lab at the San Francisco General Hospital for 35 years was adjacent to that of Y.W. Kan, a pioneer in applying molecular biology to clinical problems; he was kind enough to teach us the fundamentals of this then-arcane field. More broadly, being immersed even half-time in a vibrant research university gave me exposure to new ideas and the sense that if these guys could employ new approaches, maybe so could I. Part of it depended on having the freedom to travel. For many years I was not only a faithful attendee at the meetings of the Society for Investigative Dermatology but also the sole card-carrying dermatologist at the annual meeting of the American Society for Human Genetics. Because of this, in 1980 I was, along with Alain Hovnanian, one of the two persons on the planet who knew something about two particular fields of knowledge—family linkage analysis and Mendelian diseases of the skin. And part of it was because I had both a clinical practice and a lab that allowed me to approach whatever problem I wanted so that I could fantasize about how wonderful it would be if someday I could go to some far off country and see on the druggist’s shelf a drug whose development I had touched, even peripherally. It happened, and the patients are even happier than I am. Now if only we can convert remission into cure!
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The author states no conflict of interest.
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