Innovate or die

How to survive the 21st century

Like the Sword of Damocles, innovation is hanging over the pharmaceutical industry’s head. R&D costs are soaring, numbers of new drug approvals are decreasing, pricing pressure for prescription drugs is growing stronger and regulatory and compliance requirements are becoming stricter. If you want to make it in this new pharmaceutical environment, innovation is imperative. So how has the industry responded? Julia Puppe asks Michel DeWilde and Mark Fidock.

Sanofi Pasteur’s outlook for 2007 is good. The vaccine business, which is anticipated to outpace the growth of pharmaceuticals, attracts more and more interest. In the last two years, the company has grown by almost 50 percent. This was driven by growth in virtually every business segment, with flu being the biggest driver.

Flu is something that Michel DeWilde, Sanofi Pasteur’s Executive Vice President, Research and Development, is particularly excited about. According to the World Health Organization, the next flu pandemic is likely to result in one to 2.3 million hospitalizations and 280,000 to 650,000 deaths in industrialized nations alone, with an even more devastating impact in developing countries.

Preparing for a flu pandemic

“We are by far the largest flu producer in the world, which is about 50 percent of the market. One characteristic of our business is our products’ relatively long lifecycle. Optimizing lifecycles is very important in case of the flu,” says DeWilde, who has already demonstrated that his company could improve product effectiveness in the elderly, who need it most. “We have actually developed a new way to administer the vaccine altogether. We call it micro-injection. Through this approach, we have been able to significantly improve the product performance,” DeWilde points out.

The number of targets in vaccine R&D is limited, and so are ways to go about it. Vaccine R&D does not rely on anything like isotope spinning, DeWilde explains, or large laboratories of compounds. “We need a different approach to find our new compounds, which is mostly based on a thorough understanding of the genesis of the microbes we are dealing with. Immunology is a major aspect of it.”

The current flu pandemic threat makes it even more important for companies such as Sanofi Pasteur to improve innovation levels and bring new drugs through the pipeline quicker. A lot of the innovation in this field, however, is done by academia. Identifying the most promising potential and bringing it in-house is a challenge. DeWilde emphasizes: “A very important aspect for us is to make sure we can identify opportunities very early on. Organizationally, we need to be set up to scan the environment as effectively as possible to identify everything that is going on out there.”

In the future, Sanofi Pasteur will concentrate on capitalizing innovation in other parts of the world. Innovation does not yet come from less developed countries but products, DeWilde believes, can be effectively developed there. In terms of prospect, he is pleased that the members of an advisory committee to the FDA voted that Pentacel, Sanofi Pasteur’s combination vaccine for use in pediatric patients, is both safe and efficacious. “We expect to launch it towards the middle of the year, which will contribute to further growth,” says DeWilde with a confident nod.

Utilizing biomarkers in drug development

Pfizer is currently downsizing rather than growing – at least physically. The world’s largest pharmaceutical company is creating a smaller and more flexible organization whilst maintaining the same level of investment in science and the pipeline. The result will see a more streamlined and focused R&D organization that will enhance innovation and draw on the company’s scale and resource to deliver new medicines more quickly.

In 2007, Mark Fidock, Senior Principle Scientist, Biomarkers and Translational Biology Department at Pfizer, is focused on developing biomarkers for proof of pharmacology purposes. “Our aim is for all programs across our portfolio to have a biomarker associated with them, so that we can ensure that when they are first given to patients, we have tested the mechanism and can make the appropriate decisions based on that data,” Fidock says.

To utilize biomarkers in early clinical drug development, Pfizer is using a multitude of different techniques to identify molecules or processes that have changed, along with the target modulation. “For example, a target biomarker will give us a means to quantify the level of compound that reaches its biological target in patients. For that, we would use a technique such as receptor occupancy, which would enable us to correlate the occupancy of the receptor to its animal model or its efficacy outcome, so that we would know what percentage occupancy is required to obtain the desired outcome. We can use that to drive the project forward,” explains Fidock, who is looking at using receptor occupancy as a lead-in to doing positron emission tomography (PET) studies. “These are becoming increasingly popular because of their high translatability to the clinic, which provides even better decision-making data.

Leaving the molecular field, Fidock believes electroencephalographs (EEGs), which look at sleep patterns, are as important as a translatable biomarker. “This is a really good method to use because it also translates well,” says Fidock, adding: “In preclinical testing, if you see a change in the sleep pattern or some modulation of the EEG spectra, there is good evidence to suggest that it may translate to humans.”

A long list of novel approaches

Another technology that Fidock predicts will be key in terms of understanding new targets as they come forward is genomics. “We’re now starting to explore uncharted waters in our exploration of new drug targets, which poses lots of unanswered questions. We’re looking to deploy a host of new technologies to gain as much knowledge as we can about them”.

There are, of course, quite a few challenges that need to be overcome for the promise of pharmacogenomics to be fully realized. For Fidock, these include ensuring sufficient statistical power through the clinical trial design and collecting bio fluids in an appropriate way to enable genetic association studies to be achieved. In response to the challenges, Pfizer has invested in a bio bank to save samples and maintain their integrity. This enables the company to conduct genetic association studies at the beginning of or during clinical trials, or even retrospectively. Ultimately this could lead towards more closely targeted medicines.

Pfizer’s response to innovation, it seems, is to embrace it rather than fear it – which is the only true way forward. Novel technologies are exciting and the list of innovative approaches is long. In the future, although it will likely take several years for them to be fully implemented, Fidock foresees two technologies that hold big potential for Pfizer. One of them is using advanced mass spectrometry in a variety of biofluids to enable novel biomarker discovery. The second technology is the application of microRNAs. “This will lead to advances in being able to associate a biomarker with the effects of a particular compound. Analyses of microRNAs are being established in the area of oncology. Exploring how they could be used outside the oncology field,” Fidock concludes, “is something we would consider in the future”.

Experts at WHO and elsewhere believe that the world is now closer to another influenza pandemic than at any time since 1968, when the last of the previous century's three pandemics occurred. WHO uses a series of six phases of pandemic alert as a system for informing the world of the seriousness of the threat and of the need to launch progressively more intense preparedness activities.

The designation of phases, including decisions on when to move from one phase to another, is made by the Director-General of WHO. Changes from one phase to another are triggered by several factors, which include the epidemiological behavior of the disease and the characteristics of circulating viruses.

The world is presently in phase 3: a new influenza virus subtype is causing disease in humans, but is not yet spreading efficiently and sustainably among humans.
Source: World Health Organization

• Proteins are the building blocks of all living cells. The type of cell, its function, and the timing of its death are determined by which proteins are produced in the cell, and at what quantities and time they are produced. However, the proteins are the end product of a complex process, which begins with the genetic code present in DNA.
• Before a protein is expressed, or produced, relevant parts of the DNA are copied into a messenger RNA. Each messenger RNA holds a code with instructions on how to build a specific protein using a process called translation. Although one messenger RNA molecule is capable of translating hundreds of thousands of protein molecules, the number it actually produces is regulated by microRNAs.?
• MicroRNAs are small, single-stranded forms of RNA (~22 nucleotides in length) that are generated from endogenous hairpin-shaped transcripts encoded in the genomes of humans, animals, plants and viruses. We now know that microRNAs are one of the largest gene families, consisting of hundreds or, in higher life forms, more than a thousand.
• MicroRNAs regulate protein production in a process known as base pairing – in which complementary codes found on microRNAs bind to the corresponding mRNAs much like a lock and key. This process leads to inhibition of protein translation and, in some cases, to degradation of the mRNA itself.
  Source: www.rosettagenomics.com