Complications

Amgen’s Alexander Kamb explains why cancer may be more genetically complex than we originally believed.

“There is obviously a role for business experts and creativity on the business side, but if you actually treat an unmet medical need, the commercial success will follow”
-Alexander Kamb

In 2007, Alexander Kamb co-authored an article for Nature entitled, ‘Why is cancer drug discovery so difficult?’ highlighting the difficulties of cancer drug discovery. As he explains, it is a lot more difficult than originally thought five or ten yeas ago, when drugs such as Herceptin came on to the market in a buzz of hype. The drugs made huge differences for patients, in some cases were effectively curative, and received responses unlike any before. This is what set the precedent of cancer drug discovery as ‘easy’.

“All the investment in research over the last 30 years or so is beginning to pay dividends and we understand a lot about cancer, and so now we can be much more predictive in what we do. We can predict if we inhibit this target, attack this part of the cancer cell that predicatively it will die and the patient will survive.

“What has unfolded in the last few years is actually not as simple as that and in fact the view that cancer might be a kind of simple disease genetically – with a few changes that convert a normal cell to a dangerous cancer cell, in some cases that’s true, but it’s a limited number of cases and the most lethal cases. For the most widespread cases like colorectal cancer, prostate, breast and lung and so forth, the disease when you look more closely is actually genetically very complex, with minimally dozens and possibly hundreds of genetic cases. So taking that information now and deciding what we will do with that complexity is our challenge and it’s fair to say we don’t yet understand how we will tackle that problem,” says Kamb.

Biological challenges
Kamb, who is Executive Director of Oncology at Amgen, explains that one of the greatest challenges currently facing his team is the question of determining which tumors will respond to a given drug and which won’t.

“In some cases we can do that. We can predict, which is a very powerful thing to be able to do. You keep patients from being exposed to drugs that might be harmful and have no benefit, and today the challenge is not technical, it’s biological.

“K-ras is one of the cases, and there are only a few, where you really can ascribe non-response of a tumor to a particular mutation acquired by the tumor during its development. So these are mutations that you don’t inherit, the tumor actually develops these by mutation and they benefit the tumor so they take over, so that when it’s fully formed is composed of cells that have this mutation. That mutation actually blocks response to a drug that targets the EGF receptor, which is a protein present on normal cells but also on these tumors. 

“Some tumors appear to depend at least depend in part on EGF receptor and K-ras mutations essentially short-circuit that need, so tumors that contain K-ras mutations don’t respond. What we’d like to do is to generalize that further and find simple predictors of non-response – you can exclude patients at least from treatment with drugs that usually carry some kind of risk and more importantly would be to be able to understand why the subset of tumors that have wild type K-ras do respond. Only a subset of tumors that have wild type are normal K-ras gene respond to these drugs, and we really don’t have any idea why. So that’s one of the mysteries and one of the challenges we face, and a lot of people are working hard to try to understand that,” he says.

The technologies underpinning these developments are biological, with a lot to choose form. There are many different ways of carrying out the development: multi-plexing techniques, different methods of measuring biological substances and so on. It is done very precisely and to a varying degree of expense.

Personalized medicine
Kamb explains how the methods of drug discovery are relatively straightforward, it is understanding the biological substances and their behavioral change in the disease state versus their normal state that is challenging. Kamb decrees the ultimate solution for this to be personalized medicine.

“Cancer as we’ve learned in the last few years has many, many mutations that it acquires in its natural history as it develops, and understanding that complexity is very, very challenging. As we move forward and try to understand it we will employ a lot of these technologies that are merging. It’s not magic. 

“These are genes that are inactivated in some cases and activated in others. They are parts of a very little machine, a cell, but it’s a very complex machine and it’s hard to study.  It will take time and if nothing else we will make incremental progress; the safe thing to predict is incremental progress in the coming years.”

Instrumental to drug discovery are imaging techniques – in determining sizes of tumors and growth change over time. This is one of the methods used to discern whether a drug is working, through noninvasive MRIs or x-rays to image the tumor and follow its behavior. This is one of the fundamentals in the clinic, and Kamb explains that this is developing, as new technologies are coming online with the ability to monitor those tumors that are a little more specific.

“For example, the metabolism of a tumor of interest and it’s reasonable to suppose, and in some cases this is documented, that if you interfere with cancer metabolism the cancer cell will respond. It will die or at least not grow, and so you can imagine using this kind of imaging as an early endpoint, something that you can ascertain earlier and in aggregate those benefits are added over many, many patients in many, many clinical trials that’s a significant savings in money and hopefully will increase our efficiency in the clinic.  Amgen has the capacity to do those kinds of things, metabolic testing in the clinic noninvasively as well as other imaging technologies. 

“One technology that’s also interesting has to do with understanding whether your drug actually interdicts or modulates the target that it’s designed against. This is pretty easy to test in vitro, in test tubes, maybe even in cultured cells or in animals. It’s obviously hard in humans because you can’t go poking around in humans and taking out tissue. So there are now noninvasive methods to do some of this, and those will be increasingly important.

Exploratory images have huge benefits, but it also has huge costs. Kamb notes that the costs within the business are getting even higher. “One would hope that by technology improvements, say much like the computer, Bill Gates was proud that the cost of personal computers was always coming down as their power was increasing and it’s not clear that that same trend will apply here,” he says. “It’s not clear, but that’s the hope that by imaging, by getting early reads on drug action in people, that you will save money and be more efficient, so ultimately there will be a cost savings.”

But whether the situation then ends up with technology providing the data and the cost coming down remain to be seen. As technology develops, where do the skill sets have to be in pharmaceuticals in moving forwards?

“This process is very complicated, even in terms of the practicality of making a drug there are many, many disciplines and expertise types that are required to do it successfully. It’s a long chain and each link has to hold, and so we in this industry have to rely on our colleagues who have expertise in lots of these areas and put together teams that are able to solve these problems. Human knowledge is increasing and our understanding of things is increasing and that means there are more things to worry about. 

Bureaucratic cost
“The more things we can see and monitor, generally speaking, the more we end up doing and the more it costs, but hopefully the better the results will be. As important as the technology is, the key thing is still the biology. People who can understand the biology have a vision, have ideas; those are the people that are much needed and are arguably in short supply,” he says.

The major pharma mergers have begun to formulate into actuality and a recent suggestion has formed that legal and marketing expertise at the very top is taking precedence over science. In so many words, Kamb agrees with this.

“I can’t speak for chief executives in pharmaceutical companies. Many of them are trained in the business world and of course it is a business – we are embedded in a financial system and we have to provide a return to investors, otherwise the business isn’t buyable. 

“There is obviously a role for business experts and creativity on the business side, but I think my view and the view of many of my colleagues is that if you actually treat an unmet medical need, the commercial success will follow. People, societies and individuals will always want to pay for their health. It’s one of the basics of life, food, shelter and health, and people that have my job, should focus on treating the disease and trying to do it in ways that have significant impacts. The business takes care of itself.”

During his time at Novartis, Kamb was noted for highlighting the pharma industry’s desperate need for molecules in 2000, and he still agrees nine years later. “One of the things that you hear if you’re at meetings is just about every presentation in the first slide shows the decline in productivity in the pharmaceutical industry,” he says.

“There’s no question that the trends are toward decreasing productivity and companies want drugs. They still have the resources to test them, but the supply is diminishing, so that creates an opportunity. It’s an opportunity inside the industry to try to address that and obviously an opportunity for entrepreneurs and other kinds of people who don’t necessarily have the taste for big pharmaceutical companies to make contributions.”

Kamb believes the economic situation to have affected the value of licensing deals; “There are certainly in recent history several cases where you look at it and raise your eyebrow and can’t help but think that some of these deals were overvalued, but that is a measure, if not desperation, but of the strong desire to get a hold of new technologies and new molecules, and of course the upside here is very, very high. Not only for patients who could get access to a new breakthrough medicine, but also on the business side those kinds of successes are rewarded.

“In part those high price tags were justified by this very favorable reward if the promise is fulfilled. I shouldn’t be forecasting what’s going to happen in terms of those price tags – there’s clearly still a strong appetite in the industry for good drugs. The question is, are we going to be looking more carefully? Are we going to be unwilling to take the risks that we used to pay to take those risks? That’s something that is in flux as a lot of things are now,” he concludes.

Alexander Kamb is the Executive Director of Oncology at Amgen.