Chris Anderson

Solid vision, adequate funding, and support of basic science all play a role in bringing a new drug to market.

Innovation in the pharmaceutical industry is not rare. Even less rare are the nine-of-ten potential new therapeutics that fail to move from clinical trials to market. But how does one convert innovation to market in the pharmaceutical space?

“If one sees things no one else has seen, or think thoughts no one else has thought or if you use a new method or approach that no one else has used before, there is a good chance it is an innovative contribution,” said Barry Berkowitz, CEO of Bessor Pharma and moderator of the panel discussion “Translating Disruptive Innovations into Products: Successfully Blazing New Trail in Stem Cells, RNA, and Epigenetics-based Therapeutics” held Wednesday morning at BIO 2014 in San Diego.

But innovation is not enough. If it takes a village to raise a child, it takes a combination of venture capitalists, academic researchers, and pharmaceutical partners among others to help bring a promising compound or biologic through clinical trials and to market. And by the time a product comes to market, its age is truly that of an adolescent looking to make his or her mark on the world. As Berkowitz noted, the average time from discovery to drug approval averages 17 years. More groundbreaking therapeutics take even longer—often more than 20 years.

The Road to Approval

It’s hard to argue that the performance of the pharmaceutical industry in bringing drugs to market hasn’t been declining. According to Stanley Crooke, founder and CEO of Isis Pharmaceuticals, in the late 1960s, pharma successfully brought to market 30 new products for every $1 billion spent in research and development. Today, the number has dropped to .3 per $1 billion. “The industry had done an abysmal job of effectively investing in new, disruptive, more efficient drug development projects,” Crooke said in the panel discussion.

That noted, Isis has successfully developed a broad pipeline of therapeutic candidates using its RNA-targeted and antisense technologies. Isis also exemplifies the long—and often costly—road to gaining approvals for new therapies. To date, the 25-year-old company has just one approved drug, but another 20 in Phase II or Phase III trials with an array of pharmaceutical partners across multiple indications.

To reach this point, however, took a strong vision—what Crooke described as “a galvanic presentation of the dream and the value proposition” of the company’s antisense technology. Because antisense as a chemical class has class generic behaviors, “I felt antisense could be more effective and more efficient in the discovery stage and, more importantly, in the development stage,” he added.

The way Crooke sees it, Isis is one of the companies redefining diseases into molecular pathological terms, and that, as those terms become actionable, they become targets of drug discovery and development. As an example of how this redefinition can inform discovery and development, he detailed how the understanding of psoriasis has evolved from that of a localized condition to one that is more systemic. “Psoriasis today is a set of transcriptomic signatures that can be measured. You can identify the early factors that seem to contribute to the beginning of the disease, those that are associated with in-stage disease, and you can identify transcriptomic changes that define response,” he said.

While the transcriptome identifies potential individual drug targets, it also provides an opportunity to subdivide the disease in patients with a molecular cause. “And if we subdivide those patients and focused our drugs on those causes and patients, we should be able to create high value. So it is subdividing these diseases that is exciting,” Crooke added.

Funding the Pipeline

While Crooke painted a picture of a very constricted pipeline of new products in his presentation, Kim Kamdar, a partner with venture capital firm Domain Associates, sees the glass as more than half full. “Despite the difficulties, I think as an industry we are managing to get drugs approved,” Kamdar said. “I think we are in one of the best periods right now regarding both the quality of biomedical science and also its potential translatability into therapeutics.”

As Kamdar sees it, the market is on the cusp of seeing more and more new molecular entities receive fast-track approval or first-in-class designation due to a number of breakthroughs over the past ten years.

“New modalities in biopharma, whether it is monoclonal antibodies, antisense, gene therapies, cancer therapies or RNAi, all tend to go through this period of initial exuberance, followed by a decade of near irrelevance, followed by some kind of Renaissance, and sometimes some success,” she noted.

But getting there for small startups requires not just a potential breakthrough, but financial backing, especially since many of the innovations in science come from small, venture-backed companies. The key for these companies, she said, is how to keep the money flowing.

Crooke noted there among the four phases of innovation on the path to a marketable drug, first there is “wild enthusiasm, so take advantage of it and get money. Then there will be disappointments and delays and you’ll need more money,” he said.

One company backed by Domain is Syndax Pharmaceuticals, which is one of a number of companies that are advancing epigenetic therapies for a broad range of indications. The success of Syndax and its lead candidate entinostat, an epigenetic therapy for treatment-resistant cancers, could make it easier for similar firms to garner funding for their program.

But Kamdar admitted venture capital firms sometimes aren’t able to provide capital early on for great innovations. “The hardest part about this is there is this (funding) gap and I think people recognize that there is great science happening in academic settings and early science,” she said. The problem arises since VCs usually need to provide a return for their limited partners within five to seven years and most early-stage scientists can’t provide returns within that time.

But according to Lawrence Goldstein, director of the University of California, San Diego Stem Cell Program, these scientists, often from academia, are key players in the collaborations that bring new drugs to market.

“Human diseases are ultimately very difficult, and to solve them you need basic scientists such as myself, who use molecular biology, cell biology, and now stem cells,” he said. “You need chemists—antisense would never have advanced without incredible chemistry to modify the backbones to make them more stable; and of course modulating epigenetics requires very diverse chemistry and biophysics expertise to understand what is going on.”

Stem cells are a bit behind antisense and epigenetics in terms of producing therapies, but their potential and value are well understood, and Goldstein hopes that stem cell therapies can eventually reduce the 90 percent failure rate in clinical trials. Stem cells also serve a role both as a drug discovery engine and for future therapeutics as well.

But funding here is also a problem. And where VCs dare not go, Goldstein thinks there is a need for federal and state governments to step in, in order to keep innovation from public institutions and academia flowing. Unfortunately, the track record for public funding of basic research is not encouraging. He noted that in the U.S. annual spending on caring for people with Alzheimer’s disease is between $200 million and $400 million each year. “That’s like spending $1,000 to fix the damage from a leak in your roof, but only two dollars each year to try to find the leak,” he said.

This is all the more reason that, when VCs fund a company, they make the right picks as often as they can. “Why is it important and why do we need to get this right?” Kamdar asked. “Because while it is hard to fund innovation, the costs of treating chronic diseases is astronomical and it is increasing. The only way we have to actually tap into these kinds of problems is by having innovative science that is funded.”

Chris Anderson ([email protected]) is the former chief editor of Drug Discovery News, which he helped launch in 2005.



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