Post-Genomic Drug Development. Is Pharma Ready?

Hard on the heels of the June 2000 announcement that the human genome sequence was completed came a wide array of articles on genomics' impact on drug discovery and development. Suddenly, previously inconspicuous areas of research, from genetics to gene-based medicine, took on new meaning and purpose. This article outlines the complex emerging genomics landscape, its implications for the future of R&D, and the potential bottlenecks that pharma companies must overcome before they can reap the benefits of the expected discovery revolution to come.

Scientific Framework

Beginning with the understanding that the genome is essentially an instructional framework for the production of proteins that handle the human body's key functions, scientists are exploring advances that will unravel the complexity of the human body in general, and an individual's response to drugs in particular. That involves several genomics-related areas:

Proteomics. Using high-throughput screening, scientists elucidate protein functions to define patterns of protein expression in cells and tissues. They then use those proteins to characterize the functional cellular processes of healthy and diseased cells and the impact of pharmaceutical intervention on those processes.

Pharmacogenomics. Researchers identify variant genes that affect response to drugs as well as disease susceptibility genes representing potential new drug targets, and they focus therapies on smaller patient subpopulations characterized by distinct genetic profiles. Single nucleotide polymorphisms (SNPs) are base pair differences in the genome. Scientists believe that the human genome has about ten million SNPs and that they dictate the majority of individual differences among humans. Some of the top pharma companies, together with IBM and Motorola, have formed a consortium to map 300,000 SNPs in the human genome. They hope to correlate them with disease susceptibility and drug response so they can estimate disease risk, design treatment strategy, and guide clinical trials.

Enabling technologies. Significant developments in proteomics and pharmacogenomics are being fueled by major advances in high-throughput screening and other enabling technologies. The 9 July 2001 issue of C&EN magazine reports that Harvard scientists are developing a full-length expression-ready FLEX-gene repository that would express proteins by an automated technique called recombinational cloning. The system will be used to study how proteins, hundreds or thousands at a time, function-the same way that the pharma industry studies small molecules using combinatorial chemistry, high-throughput screening, and characterization methodologies. Those enabling technologies are expected to flood the industry's pipeline with validated drug targets.

Diagnostics. Scientists have warned that the current 500 biologic targets will eventually increase to 10,000-75,000, providing an opportunity to develop an infinite number of drugs, with varying efficacy and side effect profiles. Those targets-disease proteins, enzymes, nuclear receptors, and genes-will be used for both diagnosis and therapy. Conventional diagnostic tools based on polymerase chain reaction and new clinical sensors being developed to identify specific proteins and DNA sequences in biological samples are expected to boost progress in the diagnostics arena.

Bioinformatics. The discipline of creating new knowledge from existing data includes the development and testing of software to analyze the data. This information-capturing medium is moving towards the transformation and dissemination of data and knowledge useful for diagnosis and therapy. An important outcome will be ease of accessibility to the targets for drug and diagnostics screening, most of which are likely to be available publicly.

Pharmacokinetics. This is the study of how long it takes for the body to absorb, distribute, excrete, and metabolize drugs.

Pharmacodynamics. Analyzing how a drug performs in the body over a period of time is equally important.

Made to Order

With the integrated view of the human body made possible by post-genomics discoveries, it is inevitable that future diagnostics will lead to personalized treatments for every individual. (See "Post-Genomics Playing Field.") Several in-depth articles describing those genomics-related areas have already come to that conclusion. Even Newsweek, in its June 2001 article, "Made to Order Medicines," noted the possibility.

Post-Genomic Playing Field: The integration of genetic, diagnostic, and technical disciplines holds tremendous promise for drug discovery.

Yet, believing industry's estimates that it costs an average of $800 million to produce a marketable drug, some argue that the market for personalized medicines will be marginal and that, to sustain double-digit growth expectations, blockbusters must be the way of pharma's future. That conclusion may seem reasonable, given the requirement for lengthy clinical trials and a regulatory system not geared for personalized medicines, but there is sufficient evidence suggesting that the seeds of personalized medicine have already been sown.

Genentech's herceptin (trastuzumab), a monoclonal antibody, was the first therapy approved by FDA to target a specific genetic defect shown to play a role in the development of cancer. Genaissance Pharmaceuticals, which applies population genomics, informatics, and clinical data to the development of personalized medicines, is conducting clinical trials with already marketed cholesterol-lowering statins. The company's aim is to link specific genetic markers to clinical response so physicians can decide which cholesterol-lowering product to prescribe for each patient based on his or her genetic make-up. Its goals are to improve the efficacy and side-effect profile of each product and to market its diagnostic kit.

Abbott and Genset have formed an alliance to market SNP markers to use in clinical trials to detect and weed out unresponsive patients. Further, they are developing a diagnostic test to screen patients for their susceptibility to liver toxicity, which occurs in 3 percent of patients taking Zyflo (zileuton). As a corollary to the Genaissance trials, it is reasonable to expect screening of patients based on genetic markers at the outset of future clinical trials, considering that the emerging genomics landscape will lean toward public accessibility of both diagnostic and therapeutic targets.

Other scenarios will strengthen the foundation for personalized medicine. Consider the following. A company decides to develop and market a diagnostic kit for a validated therapeutic target, for which another company plans to develop a new therapy. The first does so to demonstrate to the physicians and patients involved in the therapy's clinical trial that the patients' chances of success-in terms of efficacy and safety-would be greater if the diagnostic test were used for trial recruitment. Of course, the company getting approval for the diagnostic kit must first demonstrate the product's benefit through scientifically validated studies. Assuming they do so, the recruiting physician for the therapy's clinical trial will be morally obligated to use the diagnostic kit in his selection process. Patients would demand such testing to ensure a positive outcome for themselves. The company sponsoring the trial would be forced to comply.

Regardless of how pharma feels about it, personalized medicine will take root, especially considering that entrepreneurial companies will be competing for the patient pool. Companies ignoring that trend may be unable to keep up with the market's growth expectations for new therapies. In fact, a recent report from Boston Consulting Group titled "A Revolution in R&D-The Impact of Genomics," predicts that, by applying available genomics tools and technologies to the drug development process, the pharma industry could cut the cost of development by about a third. That gives further credence to the possibility of personalized medicine.

Because the blockbuster model has a proven track record, a more balanced scenario, in which the industry finds an equilibrium between blockbusters and personalized medicines, is a likely outcome. (See "Balancing Act.") Although the timeline will depend on how quickly companies tap the opportunities shaped by genomics and its related disciplines, a huge influx of candidates for discovery is imminent. But is the industry prepared for the onslaught?

Balancing Act; Pharma may be forced to adopt a new R&D model to meet market expectations for growth.

Benefits and Bottlenecks

To answer that question, one must review the preparedness of each key area in the R&D process: clinical trials, regulatory affairs, technical development, and the marketing and supply chain.

Clinical development. Clinical trial design is likely to become more complex, requiring the use of diagnostic markers and information accessible from bioinformatics. Pharmacokinetics and pharmacodynamics, now integral to clinical trial design, will become more predictable because of genetic screening, which makes clinical trial outcomes more predictable, requiring fewer patients and less time. So clinical development will not be a development bottleneck.

Regulatory affairs. Of course, regulations must evolve to cope with new developments. The consortia of regulatory bodies, industry, and academia should be able to move quickly to meet the new demands of the marketplace.

Take, for example, the required shelf-life of dosage forms based on the guidelines of the international commission on harmonization. One can envision, based on the ability to create personalized medicines, that patient populations and prognoses will be so well defined and predictable that medications will be in the supply chain for only a few months. In that case, it makes no sense to require a long product shelf life, thereby mandating revisions to ICH guidelines ensuring that products proven effective in clinical trials aren't delayed approval while the company conducts long shelf-life tests. Thus, in many instances, regulatory changes will be needed, but it will depend on the ingenuity of the consortia to provide reasonable guidelines, to keep the process from becoming a bottleneck.

Marketing. Marketing could be the biggest beneficiary of genomics-driven changes. The availability of accurate information from diagnostics, whose use would be validated during clinical trials, will make forecasting a thing of the past. Relatively accurate statistics of the disease, patient population, demographics, and other relevant information will be available to marketing departments.

Supply Chain. On the other hand, production processes must be robust. Technical experts will need to develop manufacturing processes that meet stringent requirements for flexibility in scale within equipment and plant constraints, allowing changeover from one product to another relatively quickly. With proper management and coordination, marketing and supply chain areas can be quickly adapted to new medicines.

Technical development. Small-molecule, protein/peptide, and gene-based therapies are the three categories to consider. Small molecule therapies have dominated the industry, and they will continue to do so. During the past few years, R&D has evolved to integrate the prediction of safety, disposition, and absorption properties of select candidates for further development.

The requirement for small molecule identification and development has been oral bioavailability. The ideal oral therapy requires a balance of properties that allows it to cross cell membranes and the epithelial lining of the gastrointestinal tract. Neutral or uncharged molecules that are lipophilic or lipid-loving can easily pass through membranes and also provide good interaction with receptors. But such molecules tend not to be water soluble, a requirement necessary for oral bioavailability. Many molecules that meet the criteria for therapeutic excellence in the lab fail to proceed into development and are either shelved or discontinued for lack of water solubility. Considering the influx of possible new genomics-based candidates, the solubilization issue is likely to become a major bottleneck. (See "Solubility Problem.")

Solubility Problem

On the other hand, a large number of protein-based-and all gene-based-drugs will require a dry powder formulation for improved stability as well as for targeted delivery. Lyophilization, commonly used for that purpose, is energy inefficient and poses capacity limitations. But an alternate processing technology supercritical fluid (SCF) has potential, because it creates particle sizes that can be tailored for pulmonary delivery or targeted directly to the genes.

By the Numbers

In February 2000, PhRMA reported that there were 369 biotechnology medicines in development. In May 2001 an In Vivo article about the protein production challenge reported 1,394 biotech medicines in development, an almost fourfold increase in the number of biotech medicines in one year. That number is expected to increase significantly.

Post genomics R&D promises to provide safe and efficacious medicines for individuals based on their genetic makeup. However, pharma companies will fulfill that promise only if they identify the potential bottlenecks-particularly those in the technical area-and find solutions. Big Pharma, therefore, needs to evaluate and invest in new and innovative technologies such as supercritical fluid processing technology.

Smaller companies have taken the lead in that arena. Inhale Therapeutics and Lavipharm have both acquired an SCF-based enterprise, Bradford Particle Design and Separex and Phasex, respectively. The industry's success in utilizing such innovative technology will depend on the willingness of major pharmaceutical companies to evaluate its potential. They will find much synergy through the integration of such technologies in their R&D programs.