Making Strides

Fighting serious illness has been the ultimate aim of Amgen over its 28-year history. Having been ranked third in the biopharmaceutical industry in Fortune magazine’s 2007 list of ‘America’s Most Admired Companies’ Amgen maintains an enviable level of expertise in its R&D efforts.

Biomarkers in particular are proving to be an increasingly popular avenue for many biotechnology and pharmaceutical companies, who are turning to them in order to increase productivity and improve clinical trial success rates.

Amgen has been making great strides in this interesting sector. Some of the company’s recent findings include the fact that KRAS mutations could be used to identify patients who may not respond to treatment with Vectibix (panitumumab) monotherapy, the first fully human anti-epidermal growth factor receptor (EGFr) monoclonal antibody.

Alexander Kamb, Amgen’s Executive Director of Oncology, describes how the team would like to understand those cancers in the population with wild-type KRAS, which account for a substantial percentage. There is still only a subset of those who respond and Amgen would like to discover why this is so, along with markers that further differentiate this group: “It’s curious that it took so long to uncover this, because mutant KRAS has been around for almost three decades. The EGFr receptor is upstream of KRAS in the signaling pathway. It’s one of the best-studied signaling pathways in biology.

“In retrospect, it’s obvious that if you have an activating mutation in KRAS, it could short-circuit the therapeutic effect. It’s taken a lot of time, but at least we got there and it’s a notable success. There aren’t many successes of this type that you could point to and this underscores the fact that this is a tough business.”

The challenges ahead

Making predictions in biology and human physiology is, as Kamb points out, challenging. Many drug responses are likely to be polygenic, with quantitative traits having an impact on outcomes. “Lots of things contribute to how well you respond to a drug,” he says. “This makes things pretty hard to figure out. There will be some cases where there’s a big difference in response magnitude within the population. These ought to be simpler to elucidate. But for quantitative traits with more subtle differences, it’s likely to be a slog. For instance, it’s easy to track down the genetic basis for human dwarfism because the phenotype is extreme and monogenic. But for height variations within the normal range, controlled by many genes, the obstacles to genetic analysis are much, much higher.”

Working this out, by Kamb’s own admission, will take time: it’s a difficult task requiring incremental steps. Kamb hopes that more of the well-known cancer genes will be involved in controlling sensitivity to certain therapeutics, getting us a little closer to personalized medicine.

Kamb believes that the fundamental challenges in this area are in the biology, rather than the technology. In the area of biomarkers, although Kamb does not think the primary limitations are technical, he highlights the importance of having good data to work with. “There are a lot of diagnostics companies working in this area with great technology, substantial improvements over ten years ago,” he says. “So technology isn’t the problem. But if you use bad techniques then even having good analytical procedures is probably not going to help you. Ultimately though, the biggest challenges in this area are biological in nature. So many things contribute to drug response.”

Possible therapeutics of the future

What might revolutionize disease therapy in the future? The human genetics field has developed a great deal, to the extent that the next chapter will approach single nucleotide resolution. The big question is whether this is going to deliver a windfall of drug targets and predictive power. “I’m a little skeptical, but it’s worth doing. It’s something of great interest to me; the computational models, for example. But they haven’t yet proved themselves in terms of impacting drug discovery in a big way.”

Small interfering RNA (siRNA) is a potentially revolutionary area that Kamb believes holds much promise, despite needing to overcome some very significant hurdles in order to be useful therapeutically. “People may have underestimated the challenge,” he cautions. “If it were easy to get RNA into cells then you’d have RNA leaking out of them all the time, but you don’t.

“Cell membranes are designed to keep large macromolecules on one side of a membrane or the other, to exclude unwanted macromolecules like viruses and keep useful ones like protein and nucleic acid inside the cell. Getting a negatively charged, 10,000 Dalton molecule efficiently into a cell is not easy. Viruses can do it, and there are some protein toxins. However, these are highly evolved machines. They’re designed to defeat that barrier. It isn’t clear that we’re going to be able to do it easily, but still there’s a really high reward if we succeed.”

Protein therapy is another area that Kamb thinks is not thoroughly tapped out. He argues that medicinal chemistry is fairly mature in terms of the technologies associated with it. “But there’s more to do in protein therapeutics,” he declares. “Maybe putting them together with small molecules is something that we should think about.

“Certain diseases present their own specific challenges. In oncology, the problem is how to destroy cancerous cells while sparing normal cells. In many neurological disorders, drug developers have to deal with the blood/brain barrier, which poses a big problem, particularly with protein therapy. Again this is something you would think could be circumvented for therapeutic purposes.

“In inflammatory diseases, there are a lot of genes known to play a role, but it isn’t clear how to prioritize them. There are hundreds that affect immune system function, but which ones do you focus on? Which specific inflammatory diseases do you go into? These are the kinds of problems that we have to face.”

Risk/benefit tradeoffs

Safety is another area that is given a great deal of attention, particularly as there is so much concern from the public. Although Kamb is well aware of the implications, he also rightly points out that that most drugs carry some kind of risk. “The whole risk/benefit tradeoff sometimes gets forgotten, because there’s so much concern about risk that you start forgetting about the benefit. The fact that the risk/benefit equation isn’t being expressed or computed explicitly makes it harder to advance drugs that are going to have risks but also benefits. This is something that is going to be a drag on the industry. I’m not saying it’s inappropriate – risk is something that should be dealt with and thought about, but if you insist that all drugs be absolutely safe you’re almost certainly going to give up a lot of benefit for people who are sick.”

About Dr. Alexander Kamb

Dr. Kamb is Executive Director of Oncology at Amgen and also heads the Amgen Neurosciences group. After completing his studies, he worked in the biotechnology field for about 10 years, specializing in the genetics of cancer, and then in the pharmaceutical sector, where he led the Novartis Oncology Research Group.