Among the Biotech Conventioneers

A dispatch on the value of failed drugs, new vaccines against superbugs, and the prospect of a molecular stethoscope.

Fifteen thousand conventioneers are gathering this week at the Washington, D.C., convention center for the Biotechnology Industry Organization's annual convention to talk science, deals, and policy. At such sprawling meeting, a reporter can only get glimpse of what is going on in this vast industry. But many of the most interesting sessions and conversations revolved around ways to insure that future medicines are better targeted, more personalized, and faster to market.

The keynote talk by National Institutes of Health director Francis Collins was my first event. Collins began by touting his proposal to create the new National Center for Advancing Translational Science, (NCATS) (which I have critiqued earlier). Collins noted that the drug discovery process is "painful, slow, expensive, and failure-filled." He added that the drug discovery process experiences a 98 percent failure rate and takes about 14 years to get a new drug to the bedsides of patients.

Despite the dismal state of drug discovery now, Collins was rather upbeat about the future. Genomics, the study of genes and their function, is being used to identify disease-related biochemical pathways in human cells and tissues. New drugs can be developed to target and correct the malfunction of these pathways. Collins noted that researchers have already identified the underlying molecular bases of more than 4,000 disorders, mostly rare single gene disorders.

The advent of cheap whole genome sequencing will make it increasingly possible for researchers to identify the combinations of genes that affect a person's risk of more common diseases such as diabetes, heart disease, and cancer. Collins pointed out that 44 gene variants that contribute to a patient's risk of diabetes have been identified and it turns out that six of them are already drug targets. Collins also cited the case of the PCSK9 gene, one variant of which significantly lowers its carriers' level of LDL "bad" cholesterol, cutting their risk of heart disease in half. Clearly, drug companies would like to find out what this gene variant does with an eye toward developing a treatment for those of us who are not so fortunate as to have inherited it.

Toxicity is the most common reason for drug development failure. Collins outlined vision in which researchers would forget about testing new compounds in animals and instead test them in organ-like structures called organoids created from differentiated human embryonic and iPS stem cells. Collins even suggested that new drugs could be tested for efficacy using stem cells derived from patients with genetic disorders. In addition, Phase Zero trials dose a small number of subjects with tiny amounts of new well-characterized compounds to check for toxicity and to find out if the compounds actually hit their therapeutic targets. The goal is to weed out compounds that don't work in humans early and so speed up drug discovery.

Collins also talked about a new initiative for rescuing and repurposing already-approved drugs and abandoned compounds. Drug companies have lots of data about thousands of compounds that did not work out for various reasons. However, these compounds might work on new targets and pathways being identified by researchers now. As example, Collins pointed out that the first successful anti-HIV pharmaceutical, AZT, was originally a failed cancer drug. In April, Collins convened a meeting of representatives from the NIH, pharmaceutical companies, and academia to discuss how to collaborate to rescue and repurpose compounds. As a first step, the NIH has now set up a new the NIH Chemical Genomics Center Pharmaceutical Collection database of compounds that have been approved for human use.

I next dropped by a breakout session on "Vaccines vs. Superbugs." Hospitals are breeding superbugs, i.e., very toxic versions of bacteria like Staphylococcus aureus (MRSA) and Clostridium difficile, and fungi such as Candida albicans. Hospital-acquired infections are a big and growing problem. A 2002 study estimated that there were 1.7 million hospital-acquired infections [PDF], and as many 99,000 patient deaths associated with those infections. Preventing such infections could save as much $45 billion [PDF] in direct costs each year. A 2009 study of infections in intensive care units (ICU) around the world found that 51 percent of patients were infected and infected ICU patients were more than twice as likely to die than non-infected patients, 25 percent versus 11 percent. Increasingly, these pathogens are developing resistance to antibiotics and antifungals used to control them. So what to do?

Timothy Cooke, the CEO of NovaDigm Therapeutics is developing a vaccine which would actually immunize against both MRSA and Candida. Cooke noted that on average it takes 12 to 14 days from the time of admission to an ICU to acquire an infection. In a Phase 1 trial, Novadigm's vaccine produced a robust immune response in 40 healthy adults in two weeks. If the vaccine proves out, patients might be vaccinated immediately upon being admitted to an ICU.

Ginamarie Foglia, the director of clinical development at vaccine developer Sanofi Pasteur, talked about the problem of Clostridium difficile infections. Some 300,000 hospitalized patients get it every year. C. diff causes diarrhea and infection often occurs after a patient has been taking an antimicrobial drug which kills off the "good bacteria" in her gut. In some patients C. diff can so inflame her colon that it micro-perforates and starts leaking into her body. The Sanofi vaccine is now in a Phase 2 trial with a vaccine that targets the toxins made by the bacterium.

I ended the day with a panel discussion featuring the heads of research for several biotech and pharmaceutical companies who were musing on the question: "What is the Future of Innovative Medicines in Our Industry's Pipeline?" The panelists included Doug Williams from Biogen Idec, Moncef Slaoui from GlaxoSmithKline (GSK), Tom Daniel from Celgene, and Charles Homcy from Third Rock Ventures. What counts as innovative medicine?

The panel tried to make a distinction between innovative change and incremental change. As an example of innovation, Biogen's Williams suggested the case of increasing the half-lives of Factor 8 and Factor 9 hemophilia medicines. From a patient's point of view, this would mean shifting from injecting themselves every two days to every four days. This would likely increase compliance and result in fewer silent bleeds which damage various joints. On the other hand, to my mind, new gene therapy research in mice reported just this week in which the defective hemophilia gene is precisely edited out and replaced points to a truly innovative breakthrough.

GSK's Slaoui argued that innovation occurs only when the science is ripe. Every 5 to 6 years, his company engages in what he called "therapeutic rebalancing" by looking broadly at recent research results to see if promising new drug targets had been identified. One example how science ripens is recent findings about the Warburg effect in cancer. In 1931, German physiologist Otto Warburg won the Nobel Prize for his work on the glucose metabolism of cancer cells. It is only recently, however, that researchers have begun to tease apart the precise changes that occur in cancer metabolic pathways. Third Rock Ventures partner Homcy noted that new research has found that all solid tumors switch on the same metabolic enzymes used by fetal cells to promote rapid growth. Based on this, the biotech startup Agios is trying to uncover new targets for anti-cancer drugs.

In the past, lots of medicines have been developed to treat the symptoms of disease. Slaoui argued that in the future medicines will increasingly target the underlying physiological processes that produce illness. Consequently the way that diseases are described will change from citing symptoms to detailing their specific pathophysiology. Homcy strongly agreed with Slaoui. Homcy asserted that our disease categories are way too crude. Rheumatoid arthritis is not one disease, it's many diseases. Effective treatments will have to be tailored to each patient's version of it.

According to Homcy, what's needed are new ways to define diseases using a "molecular stethoscope." Homcy pointed out that everyone in the room already was experiencing some pathophysiological process, perhaps their kidney function is declining, or plaque is accumulating in their arteries. By the time that symptoms arise, most of the damage has already been done. A future molecular stethoscope would be a suite of tests that can identify the onset of pathological processes in each patient and allow early intervention to correct whatever is going wrong.

Homcy cited the example of Foundation Medicine (a startup in which his venture group has invested) which aims to look at each patient's cancer genome as it evolves. Over time cancers become resistant to treatments, and Foundation Medicine's goal is to identify early on in each patient how this resistance is developing and deploy new treatments ahead the evolving tumors.

I will be hanging out with the biotech conventioneers for the next couple of days and blogging more of what I find out, with a focus on developments in personalized medicine.

Ronald Bailey is Reason's science correspondent. His book Liberation Biology: The Scientific and Moral Case for the Biotech Revolution is now available from Prometheus Books.