The New Drug Hunters

Whether you are a bow hunter studying the forest for signs that this is the perfect location to set up your stand to await the appearance of a trophy buck, or a mushroomer looking for evidence of the right kind of decaying tree to alert you that coveted morels are nearby, or a lawyer pouring through dusty law books seeking that perfect precedent to win your case, successful hunters all share the trait of having an intimate, almost intuitive knowledge of their prey. Drug hunters are no different. They strive to understand the underlying physiology and biochemistry that ultimately manifest as symptoms of a particular disease, and seek targets that they can use their knowledge and experience to exploit for developing new therapies.

There have been several articles in recent months reporting on efforts to expand the available armamentarium we can deploy against diseases. The Pew Trust initiates a “roadmap” aiming to break barriers to finding new antibiotics; a British group reports a tabulation of new genetic targets for treating cancer. I have been particularly interested in a couple of articles by Robert Plenge. On his blog page he wrote in April about connecting known human biology with target selection to identify the most useful path toward developing a therapeutic. That post was followed up this month with a publication in Science Translation Medicine where he expanded on those ideas.

As pointed out by Plenge, the history of pharmaceutical drug discovery has been one where correlation leads to a lot of investment in screening. While in the field of infectious disease, enzyme targets yield cures, in most other human disease, drug targets don’t always line up with a true cure. Even supposed cures (for example, insulin for diabetes) account for a symptom (depletion of insulin) without actually addressing the underlying cause (e.g. development of insulin insensitivity in Type II diabetes). In his recent article, Plenge outlines some examples where a genetic understanding of the disease has led to more accurately targeted therapeutics. But I am uncertain, as in this recent report mapping new genes for autism, that expanding gene targets from 65 to 2,500 makes development of effective therapeutics more likely.

I cannot count the number of conversations I have had during my big pharma career where a drug target was lauded for its “druggability.” Certainly potent pharmacophores can be found to modulate GPCRs, tyrosine kinases, transporters and other similar cellular targets. But, for all the pharmacological effectiveness, translation to clinical utility has often been modest at best. Part of the problem is that nature has evolved numerous genetically similar signal transduction systems, making selectivity very difficult to achieve. This in turn results in undesirable off-target side effects. But certainly another dimension of the problem is that the druggable targets are actually downstream of the biochemical perturbation that is resulting in the disease.

The recent news that a drug targeting a new mechanism to treat Alzheimer’s disease (tau protein) failed in Phase 3 emphasizes the point that Plenge makes in his article: To advance development of effective therapeutics, we have to focus directly on causation, not on symptomatic sequelae. The challenge for drug discoverers is not a lack of potential targets but a willingness to expand the definition of what is druggable. Exploring new classes of drug targets will certainly require inventiveness in assay development. Perhaps assays focused on expression of specific GPCR targets are ultimately less useful than those that judiciously combine phenotype and target, where an investment in understanding the connection between the biochemical phenotype and consequent physiological perturbation yields new, effective therapeutics. Fifteen years ago, when Aurora and the CF Foundation undertook the development of drugs targeting the known genetic cause of cystic fibrosis, the CFTR, many in the field were skeptical that such a drug could be effective since the target was not a conventional druggable protein. Yet now Vertex has two drugs on the market specifically modulating CFTR function making profound changes on the lives of patients. There are other examples of new targets being explored in early stages of drug discovery. Perhaps we finally are at a stage where the investment in understanding the true cause of a disease won’t frighten drug hunters away from the novelty of the target. The only result of this new era of drug hunting will be improving the health of millions of patients.

History may not repeat, but it rhymes.

I have heard it said “History doesn’t repeat, but it rhymes.” As we enter a period of great flux and change in the pharmaceutical industry, can we observe any lessons from the past that at least provide some harmony to the decisions we are making today?

The origins of the modern pharmaceutical industry are very much founded on a similar entrepreneurial spirit that drives the current blossoming of new biotech companies. Visionaries like Charles Pfizer and Eli Lilly, leveraging mostly their own resources rather than venture capital, created an industry that truly changed the course of history. In the 19th century they had the luxury of rather longer timelines and different expectations of income growth, but these men took often quite humble technologies such as a better capsule maker and turned their companies into drug discovery power houses. Over the first 100 years these companies generally poured their profits back into R&D, identifying and developing compounds discovered by their own scientists. Of course there were some notable exceptions (such as the partnership that brought insulin to market) but the usual model was a go-it-alone approach to drug development.

Forty years ago developments in the academic world began to change this dynamic. The invention of the techniques of recombinant biology made it possible to cheaply turn natural proteins into drugs. The 1980s saw the first blossoming of these new biotech companies, and initially old pharma had a good collaborative relationship with the new biotechs. Whether through partnerships or occassionaly through acquisitions, big pharma was ready to join with biotechs to help bring their discoveries to market.

This changed in the 1990s when, with a slate of new drugs targeting large medical needs, pharma brought in unprecedented revenues. They used new molecular understanding of drug targets and combinatorial chemistry to massively industrialize the drug discovery process. But a consequence of this huge investment into internal R&D was to make it much harder for external drug discoverers to get lucrative partnerships. Though deals were done, it was very much a buyer’s market and one where big pharma often exhibited the NIH (Not Invented Here) syndrome.

But a funny thing happened in the first decade of the 21st century. All the billions invested by big pharma did not bear the expected fruit. As their blockbusters went off patent, the global drug companies became increasingly desperate for innovative drugs regardless of the source. Sometimes, in an effort to conserve resources, they even licensed their own programs to external startups, hoping that someone else’s investment could generate a de-risked asset they could add to their portfolio closer to launch. A buyer’s market very much became a seller’s market.

How do these history lessons inform our approach today? In many ways, the melody is still the same. Drug discovery still is an entrepreneurial enterprise. However, big pharma is shifting its business model, focusing resources on late stage clinical development and marketing while looking externally for innovative drugs to fill the pipeline. To feed big pharma’s appetite for new drugs, a new generation of entrepreneurs has stepped up, backed not only by VCs but also by Angel investors and other funding sources. In the past, VCs sought out investment opportunities, screening hundreds of proposals from independent entrepreneurs to find a potential breakthrough opportunity. Today, seeking to improve their chances for success, VCs increasingly are following two other models to fund starups. Several funds have assembled internal teams, reviewing diseases, mechansisms and modalities in consultation with experts to identify opportunities that they found themselves, often within internal incubators. These startups are frequently set up in partnership with big pharma, with an acquisition by the investing pharma sometimes baked into the business plan. Alternatively, syndicates are being assembled to create companies de novo with huge startup resources of hundreds of millions of dollars. Rather than using those sums to build multiple startups exploring a spectrum of diseases and treatments, they aim to create companies with the critical mass necessary to hopefully guarantee success with the technology upon which they are founded.

These two strategies: internal incubation or huge startup seeds have created an unexpected sense of déjà vu. With the large investments VCs are making into startups of their own creation, they risk playing the old tune that burdened pharma in the 1990s. Having invested in incubating their own ideas, VCs may be harder to convince that an investment in an external idea is worth it, a sort of new-era NIH syndrome. I think we are already seeing some evidence of this, with the focus on new investment in a very small number of geographical areas. If it wasn’t discovered in Boston, or at least willing to move to Boston, is it worth investing in?

It remains to be seen how the next stanza of the drug discovery epic poem will be written. Here’s hoping that old traps are avoided and contributions from any source of innovation continue to have a chance to join the chorus.

Welcome to the Blazing Star Pharma Advisors Blog

This blog will be a place for my regular (?)… occasional (?)… occasionally regular! musings on current events in the pharmaceutical/biotech industry. I hope you will find my comments interesting if not a little provocative. Follow my on Twitter (@martineglitis) to get alerts when I post.

Blazing Star Pharma Advisors

Martin A. Eglitis, Ph.D.