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Pharmacogenomics

Managing Editor

Smart drugs emphasize prognosis over diagnosis

School is in, and pharmacogenomics may just be the "cheat sheet" that can make doctors and drugs smarter by providing the blueprint which unlocks the answers to problems associated with administering drugs and patient response.

Once again, it seems, we are led to tout the beginning of a new development in biotechnology which can revolutionize drug discovery. Only this time, the novel topic of interest has the credibility of being in clinical trials, on the market and showing valid results for problematic areas that have long plagued the drug development industry.

The completed mapping of the human genome has affected no area of drug discovery more profoundly than the pharmacogenomics segment. There is a great need to find a solution to the problems of underserved patients, misdiagnoses, adverse drug reactions (ADRs) and ineffective therapeutics.

Medicine has traditionally been prescribed on a "one size fits all" model that could not consider the individual heritable constitution of each patient, since there were only limited methods of diagnostic validation to genetically distinguish vital traits that expose a patient's vulnerability to grave, or mortal, side effects.

According to Food and Drug Administration (FDA) statistics, more than 100,000 people in the U.S. die each year from injurious responses to drugs that were correctly prescribed by a physician. Additionally, more that 2.2 million people endure acute, though not fatal, side effects. Worldwide, BioWorld estimates those figures increase to 200,000 deaths and more than 4.5 million suffering serious side effects, principally attributable to a lack of available data that could allow medical and research professionals to ascertain a patient's genetic propensities for a range of factors, including tolerance, vulnerability and rejection.

DNA has proven itself as a catalyst in the drug development cycle by enabling mired research programs to advance, based on data that identifies the distinguishing genetic traits of individuals and groups. Without the benefit of a genetic profile, doctors can only theorize on the causes of ADRs in patients. Armed with a pharmacogenetic profile, physicians can identify genetic predispositions in patients that greatly reduce risk and afford the opportunity to deliver customized therapies that address only what is necessary. This allows scientists, physicians, biotechnology researchers and pharmaceutical providers to engage in therapeutic development endeavors that aspire to cure, rather than treat. The technology will more than likely prove to be a valuable resource for doctors, if pharmacogenomics research is successful in developing and delivering drugs to market that prevent diseases prior to their onset, rather than treating them post-diagnosis.

Pharmacogenomics has the capacity to not only predict susceptibility to maladies, but is also capable of creating therapeutics tailored to an individual's specific genetic profile. This equates to a preemptive treatment approach in drug development, a field that has been defined from its inception by its primarily reactive methodology.

Personalizing the blockbuster model

The dynamics of the successful blockbuster model usually spell enormous financial windfalls for drug-makers; however, there are also several negative aspects associated with that system. Blockbuster drugs can bring ruinous effects when things go bad.

The category of "when things go bad" can include drugs that provide only a scattershot effectiveness among the general patient base, spur large lawsuits or induce adverse patient reactions as grave as death.

Blockbuster drugs may be appropriate for a broad range of the population, but they are never effective across the complete populace and don't address the fact that patients are individuals. Most products launches are leaps of faith in which companies hope the extent of any reaction issues is limited to a lack of patient response, rather than an ADR scenario. Unique genetic make-ups predispose characteristics such as reaction, susceptibility and compatibility, indicating a need for "tweaking" therapeutics to include personalized applications in order to obtain maximum efficacy and minimal rejection or misdiagnosis.

Success stories

A major concern regarding pharmacogenomics is that it may not be able to support a blockbuster archetype, since targeting individuals and population subsets, rather than the masses, significantly reduces the opportunity for profit, unless pharmacogenomic drugs are marketed as highly expensive "designer" drugs.

That theory is challenged by the factual accomplishment of pharmacogenomics drug success stories. In June 2005, the FDA approved BiDil, a drug for the treatment of heart failure in self-identified black patients, signaling progress in the development of a sound personalized medicine market. BiDil is marketed by NitroMed Inc. of Lexington, MA.

BiDil's approval was partially based on the positive results of the African-American Heart Failure Trial (A-HeFT), a clinical study, co-sponsored by the Association of Black Cardiologists, which involved 1,050 self-identified black patients with severe heart failure who had already been treated with the best available therapy, but showed no therapeutic benefit. Two previous clinical trials of BiDil conducted in the general population of severe heart failure patients found no benefit for the group, but suggested a benefit from BiDil in black patients, based on their ethnic genetic profiles.

Patients on BiDil experienced a 43 percent reduction in mortality and a 39 percent decrease in hospitalization for heart failure compared to placebo results, and a significant decline in their heart failure symptoms. These results were so confirmatory that the A-HeFT was halted prematurely in July 2004 and the data was submitted to seek new drug approval from the FDA.

Dr. Robert Temple, FDA Associate Director of Medical Policy, stated in the news release announcing the approval, "This approval of a drug to treat severe heart failure in a self-identified black population is a striking example of how a treatment can benefit some patients even if it does not help all patients. The information presented to the FDA clearly showed that blacks suffering from heart failure will now have an additional safe and effective option for treating their condition."

In January 2005, months before the drug was approved, the American Heart Association ranked BiDil and the A-HeFT number 2 on its top 10 list of achievements in the field of cardiovascular medicine for 2004. FDA approval and public acceptance were relegated to implicit formalities, because the validity of the therapeutic was all but assured earlier in clinical trials by the near-perfect genetic profiling results provided by pharmacogenomics technology.

Another on-the-market success story is Herceptin (trastuzumab), a unique biologic therapeutic for breast cancer in women. Herceptin, from Genentech Inc., approved in September 1998, is a humanized antibody prescribed for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Research establishes that women afflicted with HER2-positive metastatic breast cancer experience a more aggressive disease, more grave recovery prospects, greater probability of recurrence and approximately half the life expectancy of women with HER2-negative breast cancer.

According to statistics released by the American Cancer Society, 211,240 women in the U.S. will be found to have invasive breast cancer in 2005. About 40,410 women will die from the disease this year. There are more than 2 million women living in the U.S. who have been diagnosed and treated for breast cancer.

Genentech estimates 25 percent to 30 percent of the women with metastatic breast cancer have tumors that overexpress HER2 and may be candidates for Herceptin, which is designed to target and block the function of HER2 protein overexpression. Herceptin is the biggest selling pharmacogenomics drug, with $483.2 million in sales in 2004. Its closest competitor in the near future will be BiDil, released only months ago and still building a patient base.

Herceptin is demonstrating potential to expand into other applications, reaching a greater number of patients and increasing its curative and pecuniary value. The drug is in two Phase III adjuvant clinical trials in which it has been shown to reduce the likelihood of cancer recurrence by 52 percent when it is combined with chemotherapy in HER2-positive metastatic breast cancer patients. The trials evaluate the combined treatment versus treatment with only chemotherapy.

Edith Perez, M.D., professor of medicine at the Mayo Clinic in Jacksonville, FL, and the lead investigator in one of the two Herceptin trials says the results are impressive and endorses the life-saving advantage of HER2 diagnostic tests for all women diagnosed with any form of breast cancer.

"The reduction in disease recurrence observed in these trials was the largest improvement I've seen in breast cancer clinical research. Herceptin plus chemotherapy can potentially stop or delay early-stage HER2-positive breast cancer from relapsing. These trials also underscore the importance for every woman diagnosed with breast cancer to receive a HER2 test," said Perez in a May 2005 press release statement for the announcement of the trial results.

Genentech Inc. is engaged in discussion with the FDA about filing a supplemental Biologics License (sBLA) for Herceptin in the adjuvant indication.

Pharmacogenomics is being used increasingly in the laboratory to assist in the drug development process. In use now is the cytochrome P450 (CYP) family of liver enzymes which is responsible for breaking down more than 30 different classes of drugs. DNA variations in genes that code for these enzymes can induce their ability to metabolize certain drugs. Less active or inactive forms of CYP enzymes that are unable to break down and efficiently eliminate drugs from the body can trigger drug overdoses in patients. Genetic tests are being implemented in clinical trials by researchers to evaluate distinctions in cytochrome P450 genes to screen and observe patients. Also, many pharmaceutical companies screen their chemical compounds in order to monitor and evaluate how well they are broken down by variant types of CYP enzymes.

Another enzyme, thiopurine methyltransferase (TPMT), performs an essential role in the chemotherapy treatment of common childhood leukemia by deconstructing a class of therapeutic compounds called thiopurines. A moderate percentage of Caucasians have genetic variants that prevent them from producing an active form of this protein, This leads to elevated toxic levels of thiopurines in the patient because the dormant form of TPMT is incapable of breaking down the drug. To avoid this, doctors can create a genetic test to screen patients for this defect, and monitor the TPMT activity to determine a suitable thiopurine dosage.

Such advances in enzyme research will increasingly augment researchers in distinguishing individuals who are likely to experience adverse reactions to medicines without having to use potentially dangerous methods of trial and error which cause unnecessary pain and suffering to patients.

Ethics: discrimination and misuse can also be personalized

Principal ethical issues in pharmacogenomics involve the invasion of privacy and ownership rights of genetic information. This area is very problematic because there are so many ways to collect, distribute and misuse genetic data.

People leave conduits for accessing their genetic profiles in almost every location they occupy during the course of routine daily activities. Your garbage can contain many items which can be used to collect DNA samples. Other channels include dinner utensils used at a restaurant, interpersonal contact, computer keyboards, doorknobs, pencils, tissues, toothpicks and clothes. A complete list of mediums suitable for harboring and conveying DNA suitable for sampling could take up pages. There is little chance that an individual can plausibly control the exposure of his own DNA to external sources. Personal medical records can be destroyed and there are legislative penalties for misuse of such, but genetic information sources can't be eradicated in a shredder and can outlive their owners by centuries. Currently, there is negligible regulatory and punitive consequence for misuse.

The increasing research and medical application uses of genomic data may add to growing concerns regarding ethical matters, as there may be just as much potential for harm as there is to help.

People enrolling in genetic studies must sign waivers giving consent for their own genetic makeup to be studied; however, they are also revealing private information regarding the genetic histories of family members who may not have given permission and possibly have no idea of the implicated involvement the enrollee's decision has on them. It is not possible to study the enrollee's profile without exposing information relative to offspring, parents or other blood relatives.

As more physicians and researchers employ pharmacogenomic technologies to address disease treatments, they are working in a largely uncharted area, in which there are no nationally defined rules yet to assign or regulate responsibility for ownership, storage, sharing and management of genetic data.

Most states have some law against genetic-based bias in health insurance and there are currently 33 states with measures in place to prevent workplace discrimination, but work to enact federal regulations has stalled, according to BioWorld research.

If a doctor is allowed to give genetic profile data to insurance companies, either directly upon request, in the course of diagnosis reports or for pre-authorization submissions-just as they are with other types of personal patient information, there are latent implications for patients and their families to consider.

There is the potential for insurance discrimination if, for example, insurers can acquire data about a father from testing conducted on the daughter. If insurance carriers know the genetic probability of individuals to manifest disease before policies are granted, it could result in the equivalent of pharmacogenomic insurance premiums, personalized in cost to fit your profile. It could be applied much like a credit score is used by lenders to assign rates. A medical premium could reflect an increased cost for a disease you may never acquire, even though you carry a flawed gene. Denial of coverage, based on probability of disease is also a potential risk.

Employment discrimination is another potential area of concern. With the projections of individual genetic test kits coming on the market soon, employers could consider administering genetic profile screens alongside blood and drug tests to weed out undesirable job-seekers and employees. A person could be denied employment based on genetic susceptibilities to obesity, alcoholism, headaches, menstrual illness and other such conditions capable of being interpreted as prejudicial risks.

Manipulation of the genetic code through by addition or subtraction of genes to enhance or replace defective or missing counterparts, creating a class of super athletes, is looming as a dubious offshoot of pharmacogenomics.

The same technology that could repair diseased muscles could soon produce stronger, faster and more agile sports competitors capable of feats never thought possible. The technique, called gene doping, has only been used in the laboratory environment so far, but the prospect of it finding its way—legally or otherwise—into professional, amateur and personal circles prompted the World Anti-Doping Agency, which governs Olympic drug testing, to establish a committee in February 2005 to monitor its status.

Gene therapy is regulated in many developed countries where clinical trials are taking place, including the United States, Great Britain, Australia Japan, China and Germany. The World Anti-Doping Agency has gene treatments on its prohibited list of applications. Given the perceived benefits available for competitive edge and the steroid abuse escapades of athletes who disregard the illegal aspect of that drug, the potential for widespread abuse of gene doping is still a realistic prospect.

Financial stakes, the pressure to succeed and a societal obsession with appearance and performance are factors fueling the concerns that gene doping will one day become a corrupting element in sports. The dilemma will be that illegal gene manipulation will not only render a new form of cheating, but will create an undetectable one. Unlike steroids, which can be identified through blood and urine tests, the technology for determining alterations in the human genetic code is still unrefined and inexact.

H. Lee Sweeney, a physiologist at the University of Pennsylvania, has used gene transplantation in the laboratory to create rodents with abnormally developed physiques. After injecting the mice with a gene known to stimulate a protein that promotes muscle growth, the mice grew muscles that were as much as 30 percent bigger than normal, even though the rodents were sedentary. Sweeney's work addresses muscle-wasting disorders and is researching and developing ways to regenerate muscle, increase its strength and protect it from degradation. The research of Sweeney, as well as that of others conducting similar studies, if successful, will conceivably enter clinical trials eventually and foster increased illegal interest along the way.

Government support facilitates advancement

The acting chief of the FDA, appointed in September 2005, insinuates a favorable environment ahead for genomic-based technologies such as pharmacogenomics, by stating he expects to be presiding over a transformation in medicine, as scientists come to understand diseases in a more detailed way that could improve doctors' ability to treat patients.

Dr. Andrew C. von Eschenbach, named by President George W. Bush as the temporary chief of the regulatory agency, said that molecular-level investigation of diseases is poised to redefine modern health care.

Speaking in September 2005 in Washington D.C. at the FDA news conference to introduce the appointee, von Eschenbach said he expects to prepare the FDA for that transformation. Physicians treat illnesses now based on how well other people have responded to a particular treatment. Soon, they will develop a tailored treatment built around definite knowledge of the patient, the treatment and the disease, he said.

"We are discovering so much about diseases like cancer at the molecular level," he said. "Much of what we have done has been based on a model of empiricism, but soon doctors will be able to intervene with medical treatments more effectively matched to a specific patient's illness."

In March 2005, acknowledging the growth and potential of the market, the FDA issued the Guidance for Industry Pharmacogenomic Data Submissions (www.fda.gov/CDER/GUIDANCE/6400fnl.htm) to facilitate the scientific advancement of pharmacogenomics through the regulatory process and to support the use of pharmacogenomic data in drug development.

The guidance presents counsel to companies submitting investigational new drug applications, new drug applications, and biologics license applications. The procedural document gives recommendations on when to submit pharmacogenomic data during the drug or biological drug product development and review processes, what format and content to provide for submissions, and how and when the data will be used in regulatory decision making.

The document clearly recognizes and supports pharmacogenomics as a viable technology, and such procedurals issued in the past usually portend the onset of clinical trial activity and ensuing regulatory submissions in the relative industry.

In March 2004, The National Institutes of Health (NIH) released an announcement report, Health Disparities in NIDDK Diseases. The report discusses the diseases that have been identified as National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) priorities and explains a program which will award grants for research to address those maladies. The diseases include diabetes, obesity, nutrition-related disorders, hepatitis C, sickle cell disease, H. pylori infection, kidney disease, gallbladder disease, and metabolic, gastrointestinal, hepatic and renal complications from HIV infection.

The announcement offers topics for investigation which would merit funding. One topic promotes research to identify genes and subsequent therapies that might affect development and function of micro- and macro-vascular complications in diverse populations. Another recommendation of the program is to identify and investigate genetic modifiers that phenotypically express sickle cell disease.

These proposed pharmacogenomics solutions convey the receptiveness of the government to facilitate the advancement of innovative technologies that address a specific populace. The NIH program offers the NIH research Project Grant R01 and the Exploratory/Development Research Grant R21 for feasibility demonstration and the utilization of preliminary data-testing technology research that represents an apparent departure from current traditional research. Much of the language in the report refers to the importance of studying and implementing genetic data for development of personalized therapy.

More on the program announcement and grant qualification details can be found at http://grants.nih.gov/grants/guide/pa-files/PA-04-074.html. Submission deadline is March 1, 2007.

In February 2005, a version of the Genetic Privacy Act, a bill to prevent genetic-based insurance or employment discrimination cleared the U.S. Senate, 98-0, and a movement is taking place to bring it up for vote in the House of Representatives before year's end.

Former House Speaker Newt Gingrich, in October 2005, endorsed passage of the bill during an address at a gathering on Capitol Hill. In speaking to several House members, Gingrich concurred with other speakers in noting that "people have every right to be worried about genetic discrimination."

Public and private sector activity imply the market's direction

A number of companies are incorporating personalized medicine into their agendas in various applications ranging from diagnostics to drug development. This is unlike similar technologies, such as RNAi, in which it may be more problematic to develop a therapeutic program from start-up without licensing a pioneering patent. Industry events are also increasingly featuring pharmacogenomics, personalized medicine and related diagnostics biomarker applications as agenda topics and news regarding the subject is consistently abundant on media outlets.

According to BioWorld research, conference and meeting events for pharmacogenomics topics have increased 100 percent over the last four years. Such events can serve as a barometer on the progress of an industry.

Genzyme Corp. announced in September 2005 the commercial availability of a new laboratory test, the EFGR mutation Assay, to identify patients likely to respond to therapy for non-small-cell-lung cancer (NSCLC). The test reveals the presence of epidermal growth factor receptor (EGFR) mutations in patients with NSCLC. Those mutations have been shown in research to demonstrate a beneficial therapeutic relationship with particular drugs used in treating the deadly cancer.

According to Mara Aspinall, president of Genzyme Genetics, the division responsible for developing these tests, this and other targeted diagnostics for cancer are indicative of a growing trend to assist physicians in determining the best treatment course for patients as soon after a diagnosis is made as possible.

"With this test, the rationale for prescribing specific lung cancer therapies may be individualized and we can help physicians and patients choose the best treatment possible," she said in an interview with Medical Device Daily. "This is personalized medicine in action."

Clinical studies of first-line drugs in the indication are ongoing. Mutation testing may allow these drugs to achieve approved indications for first-line use in NSCLC patients who have the EGFR mutations and are, therefore, more likely to respond to these therapies, Aspinall said,

"Up to 20 percent of patients with NSCLC test positive for the EGFR mutation. For these patients, physicians now have additional information to decide how aggressively and when they should use these other targeted treatments," she added.

Tests such as this, Aspinall said, allow the physician to have more data and not be forced into subjecting cancer patients to undue trial-and-error treatments. Using the trial-and-error approach, she said, costs not only in economical terms, but also costs patients in terms of needless added toxicity.

Collaborative activity creates DxRx

There may not be news of as many mega-deals occurring in pharmacogenomics as one might traditionally anticipate in a progressively active market, but there is an explanation. Unlike the RNAi industry, in which big pharma buys and licenses its way in, the trend in pharmacogenomics reveals the big players with deep pockets are developing in-house DNA prognosis programs and applying their own biomarker data and tools to their pharmacogenomics, and traditional, drug development candidates.

This doesn't preclude M&A activity, as some mid-size and smaller companies are combining resources from attuned genomics technologies to form partnerships and entities that can exploit what each technology has in order to create advanced pipelines. Most of this action is between diagnostics companies seeking to share in a bonafide revenue-generating drug program, and drug development businesses looking to advance pipelines and shorten clinical trial schedules. There has been activity involving diagnostics companies buying specialized diagnostics businesses that operate in niche markets, such as personalized medicine applications.

A new technology which merges diagnostics with therapeutics has been expanding under the pharmacogenomics umbrella: theranostics. This drug development method, also known as Dx/Rx, represents the development of diagnostic tests to identify which patients are most appropriate for a drug and to provide instantaneous data on the drug's effectiveness.

Theranostics is a technology certainly grounded in a collaboration model. It typifies a drug founded on diagnostic data and monitored with the same throughout its treatment cycle. It features on-the-spot and extremely accurate DNA-based diagnostics that detect disease, calculate a patient's reaction or indicate specific patient subpopulations for targeted treatment. The data is utilized to compose personalized therapeutics.

Theranostics exceed the role of conventional diagnostic services and products used only to screen or verify the presence of a disease. Theranostics can also calculate the probability of disease, analyze the attributes of disease, categorize patients, monitor therapeutic response and maintain and deliver real-time data for those factors. These functions can be applied in the drug development stage during clinical trials, as well as in the offices of trained physicians and staff during actual treatment schedules with a marketed therapeutic.

The value of theranostics is not in question, as the technology has proven itself in clinical trials and even participated in the success of marketed drugs. The debate on DxRx centers on whether the technology can support an industry on its own as a hybrid model or only function through partnering collaborations as an integrative development tool on the front-end of pharmaceutical drug discovery processes.

The successful hybrid model would require stalwart companies, such as Genzyme or Pfizer Inc., with internal diagnostics and therapeutics divisions already in place, to work together for the duration of a clinical trial schedule. Otherwise, the scenario would necessitate a collaborative R&D venture. Acquisition would also be an option that renders immediate full-range DxRx capability.

Pharmacogenomics outside the U.S.

There are few surprises here. As is the case in most major emerging biotechnology market pursuits, the U.S. will lead the way in research and development of pharmacogenomics endeavors, based primarily on the intrinsic strength and vitality of its drug development market. Although pharmacogenomics is not as risky a venture as, say, pre-2001 genomics, the U.S. market can contend with challenges more confidently than its European counterparts. The European sector, following the lead of the UK, will be deliberate in its entry into the market. BioWorld projects this ponderous approach will further downgrade the European genomics market and additionally consign that segment to U.S. domination.

Diagnostics, a major component in the sector's mechanism, is just as developed in European and Asian nations as it is in the U.S.; however, the American diagnostics industry, because of its proximity to and heavy participation in the Human Genome Project, appears to have paid closer attention to the progress and subsequent completion of that enterprise. This factor may be the reason U.S. pharmaceutical, biotechnology and diagnostics companies were more prepared and equipped to immediately exploit the technology.

The oversight of European companies to capitalize on the forefront of pharmacogenomics opportunities will be damaging, and it was also avoidable. It represents one of the lesser risks that the market can make in attempting to emerge from its 21st Century slump. Generally, diagnostics companies have most of the resources needed to partake in the DxRx, testing, forensics and pharmacogenetics disciplines; however, that advantage is not being fully utilized in Europe. The UK is aggressive in the forensics market, but is failing to capitalize on the compatible technologies of personalized medicine.

In September 2005, the Royal Society, the UK's National Academy of Science that advises the government on scientific issues, rejected the theory that the Human Genome Project propelled genomics research into an advanced stage capable of putting drugs on the market in the near future.

In its report, Personalised Medicines: Hopes and Realities, the Royal Society said it believes personalized medicine will not be a prevalent industry that produces marketable drugs for up to two more decades, due to a general lack of understanding about how genetics relate to the causes of diseases.

Sir David Weatherall, chair of the advisory committee, said, "We need to lay the groundwork now if we are ever to realize the potential of personalized medicines. With the NHS expected to spend 11 billion on drugs in 2005-6, there is a need to invest in gathering data on how genes influence drug response in the patient population. This is to try and reduce the risk of adverse reactions and to target drugs so they are only given to the patients for whom they will be most effective."

Whitehall said, "Personalized medicines show promise but they have undoubtedly been over-hyped. With the human genome sequenced, some people are expecting personalized medicines within a few years, but the reality is still many years away. There are some examples around today, but the complex multiple causes of diseases mean it will be at least 15 to 20 years before a patient's genetic make-up is a major factor in determining which drugs they are prescribed."

In contrast, in 1998, the U.S. National Academy of Sciences published Evaluating Human Genetic Diversity, assessing pharmacogenomics technologies as viable mechanisms for innovative medical research and products.

There was enough advance notice of the impending 2003 project completion for international companies to make preparations to capitalize on the human genome data, but the European industry was hesitant to act. The biotechnology industry was stalled in its post-boom phase around the beginning of this century, in which markets outside the U.S. were particularly affected and reluctant to take on the risk of dramatically altering existing agendas.

The immediate, provisional ambiguity over just what to do with the human genome mapping cultivated international anxiety, but the domestic markets adapted and built upon the newly acquired data while the non-U.S. markets took a wait-and-see approach.

Forecast: Does target size matter enough to restrict market growth?

The technology is poised to expand, due to its ability to easily assimilate into existing therapeutics delivery paradigms and its well-regarded potential-as well as proven ability-to reduce diagnosis and prescription errors.

Physicians and medical insurers stand to benefit from a prominent reduction in ADRs which can inflate the number of medical malpractice lawsuits and the cost of relative insurance premiums. For this reason, pharmacogenomics is increasingly gaining the support of the insurance industry which pays for 84 percent of all diagnostic tests in the U. S. annually. Genetics testing is widely covered as an essential benefit and pharmacogenomics drugs such as BiDil and Herceptin are included on the formulary lists of the major carriers, validating their effectiveness and increasing their market value. It is more economically feasible for the insurance industry to endorse a policy of co-payment for personalized medicines prescriptions than to subsidize ADR lawsuit awards.

Drug developers and investors can gain opportunity from a market that addresses an underserved medical need in ADRs. Patients who have endured negative effects or unproductive outcomes from mass-prescribed drugs will regain consumer confidence in therapeutics that are developed from their own genetic profile data and tailored to their individual needs.

Before pharmacogenomics became an option in predicting patient response, the primary tactic for an ADR to drug A was to recover, then try drug B, and continue the process until either the appropriate therapeutic was chosen or the patient revolted, or even expired, from one too many extreme rejections.

Keeping the cost of personalized drugs affordable may be a valid concern, considering that personalized medicine is the equivalent of a "designer" product. Whereas luxury items such as clothes and automobiles target audiences that can afford them, personalized therapeutics must target those who need them. That doesn't always mean they can afford them.

Diseases do discriminate in many cases, but the bias is genetically predisposed in situations which rely on personalized medicine as the best hope for treatment. Diseases do not target people who can necessarily afford to fight the illness, rather they often attack individuals or groups that have genetic idiosyncrasies which uniquely relegate them to an exclusive unit.

In the U.S., these groups are often racial and ethnic minorities, a subset that has traditionally been encumbered with issues relative to health care access and economics, according to the program announcement report, Health Disparities in NIDDK Diseases, released by the NIH.

The report states that many diseases disproportionately afflict minorities, including African-Americans, Hispanic Americans, American Indians and Alaska Natives. These groups are also generally disproportionately disconnected from America's wealth class, which may induce apprehension over the feasibility of addressing a market that may not have the end-user ability to support the investment made in it.

BioWorld concludes the issues related to limited target groups that amount to less than the general populace will not inhibit substantive growth and venture capital opportunity in the pharmacogenomics market. The disease applications addressed by the pharmacogenomics sector are relevant and ubiquitous enough to ensure a broad patient pool which can sustain an expanding market. Cancer, hypertension, arthritis, heart failure or other disease applications, even in exclusive groups like African-Americans or post-menopausal women, nevertheless represent relevance for at least hundreds of thousands of people and have the capacity for multimillion dollar revenue opportunities.

The success of drugs like BiDil and the integration of enzyme variant profiling in drug development are examples of the capability of personalized medicine to target a group, as opposed to the general population, in creating venture opportunities and flying in the face of the argument that targeting niche audiences restricts revenue opportunities. A blockbuster model can be realized from an ethnic, gender- or age-targeted drug.

It can be argued that many successful drugs are targeted to specific groups, rather than the entire population. For example, two of Pfizer's most profitable drugs are Viagra, which focuses on men with erectile dysfunction, and Rogaine, targeting men, usually of mature age, with hair loss. Other examples of drugs with niche appeal which have sustained huge revenue despite limited by-design applications include oral contraceptives, for women who wish to avoid pregnancy, and Glaxo-SmithKline's AZT, which applies to patients with HIV disease. Those drugs represent blockbusters that don't cover a broad swath of application across the entire market.

Pharmacogenomics drugs are just as capable of generating extraordinary revenue, since their target patient group, though limited by application, can still be substantial enough in number to support a blockbuster model.

According to the latest U.S. Census Bureau figures, the African-American population in the U.S. is approximately 36 million. Evaluation of data from the Census Bureau, the Centers for Disease Control and Prevention(CDC) and internal research, BioWorld estimates that 2 percent, or approximately 725,000, of that group may be genetically predisposed to be, at least, trait-carriers for heart disease. According to figures posted on its web site, NitroMed Inc. estimates that of the 5 million people in the U.S. suffering from heart disease, 750,000 African-Americans to-date are actively afflicted with the illness, and that number is expected to grow to approximately 900,000 persons by 2010.

These subjects constitute a niche group by definition, but also represent a large foundation which contains a significant market. Should BiDil generate hundreds of millions of dollars per year in revenue for NitroMed, it would become not only the first drug approved for racial populations, but a valid pharmacogenomics blockbuster drug.

The point is, even in such subpopulation applications, the stakes are still considerable, given that specific groups such as Hispanics, African-Americans, women, Alaskans and American Indians are still represented by enormous numbers which can definitely support a vigorous market.

The prospects for NitroMed's pharmacogenomics success are so optimistic that the company, in acknowledging the general disadvantage in health care access which African-Americans face, is offering the drug free to those who don't have insurance and live less than three times below the poverty level. The company will also sell the drug to others who lack drug benefits for $25-the equivalent of a minimum co-pay.

Such confidence is projected to reflect in a consistent market growth pattern that will make pharmacogenomics one of the genomics market leaders. Pharmacogenomics aspires to a new model of drug development that emphasizes "one size does not fit all" and advocates a departure from the traditional trial and error clinical process model to focus on preventing disease, rather than reacting to symptoms and effects.

Pharmacogenomics can also be a component factor within a traditional model, such as modifying an Amyotrophic lateral sclerosis (ALS) drug that is broadly administered across the population, to include the capacity to address additional or specific factors, such as Attention Deficit Disorder (ADD), hypertension, etc., or even target ancillary side effects in specific patients with special needs which were identified by genetic profiling data. Chemical components in a drug can be added, extracted or modified to customize its application and benefit.

Forecast redux: The blockbuster redefined

Several key drivers are in place to advance the pharmacogenomics market, and the most influential one may be the capability to increase the value of the most prized element of the financial side of drug development: the blockbuster.

Big pharma and biotech players are already participating in the pharmacogenomics sector by way of internal development programs and through agreements which combine genomics technologies from two or more companies to address underserved subjects.

Partnering and merger activities are increasing, as diagnostics, therapeutics and genomics meld into a confluent market that is acting upon its potential to produce personalized therapeutics which anticipate predisposition to disease, avoid the unnecessary risk of trial and error treatments and shorten pipeline research cycles.

Diagnostics providers are experiencing increased demand for services to complement therapeutics agendas. In many case, the introduction of genetic profiling data into therapeutics pipeline candidates immediately augments progressive programs and takes the research to the next level.

Government is encouraging academic and corporate research by providing research funding and offering an encouraging environment in which to pursue pharmacogenomics product development. The Human Genome Project was initiated and funded by the government and is regarded by the scientific community as a boon for the research industry. The momentum it generated took a brief respite immediately after the human genome was mapped, but has caught its breath and come roaring back to energize research in various disease applications.

Various human, animal, mammal and plant genomes that can aid in human and agricultural clinical development applications are being mapped and sequenced. More than 400 types of genomes have been sequenced since the Human Genome Project was completed. These paradigms serve as comparative models on which research can be conducted and evaluated to learn from the distinctions and equivalences that define the assorted species.

In July 2005, the government of Mexico, in conjunction with Applied Biosystems Group and IBM's Healthcare and Life Sciences division, launched a project to map the genes of Mexicans. In addition to the mapping project, Mexico's National Institute of Genomic Medicine will work with Applied Biosystems Group on a pilot project to develop pharmacogenomics drugs for applications specific to Latin Americans and those of Latin American descent. Research will address indications for health problems such as diabetes, asthma and hypertension. Such large-scale endeavors can result in equally impressive financial reward and therapeutic value for a company and its pipeline.

Similar research is already underway or planned in Africa, Japan, Europe and the U.S., according to Mexican Health Secretary Julio Frenk, speaking at the ceremony announcing the project.

Other genomes that have been sequenced are chimpanzee, rice, rat, mouse, fruit fly and various bacteria. Discovering the function of genes in these applications will address many issues, including finding cures for human diseases, reviving endangered species and tackling world hunger through plant disease control.

According to research compiled by BioWorld, 40 percent to 45 percent of all biotechnology companies actively involved in human therapeutics or agricultural disciplines are engaged in some form of genomics technology, ranging from pharmacogenomics drug development to research tools to molecular diagnostics. Many of these programs are in clinical trials, while others are involved with front-end diagnostics testing which fosters pipeline discovery activity.

The predominant trend is DxRx partnering, as diagnostics companies and reagent businesses attach their testing and research tools to therapeutic candidates and marketed drugs in order to customize products for a particular genetic profile or to identify patient subtypes prone to negative response or impervious to treatment.

Participation in pharmacogenomics research by such big industry players as Genentech, Abbott Laboratories, Johnson & Johnson, Genzyme, Pfizer and Bristol-Myers Squibb gives notice of the technology's growing acceptance as a valid diagnostic tool and sound therapeutic venture. These companies, as well as an increasing number of others, are using pharmacogenomics to reap new indications and targets for existing therapeutics, re-focus stalled or inefficacious pipeline candidates and gain advantageous proprietary positions in niche markets.

Internal pharmacogenomics pipeline development programs are moving forward with the aid of pharmacogenomics, as companies with deep resources and stable footing are able to combine their own diagnostics testing capabilities with their therapeutics pipelines to generate new products or expand established drugs into additional applications.

Expect this trend to continue, as companies learn from lessons such as the Vioxx case that severely affected the image and revenues of Merck & Co. When a blockbuster fails, drug companies suffer just as much as they benefit when one succeeds. In August 2005, a jury awarded a $253 million verdict against Merck for the 2001 death of a patient who had been taking the painkiller Vioxx. Merck's troubles are likely to continue, as that is only the first of what are estimated to be perhaps thousands of suits against the company, potentially negating any revenue the drug may have brought in.

Vioxx, as illustrated in clinical trials, is regarded to be safe for the majority of patients, but the drug can dramatically increase the risk of blood clots for a subset of patients, and there is no diagnostic test to identify who is predisposed to experience an ADR from taking it. Genetic diagnostics and customized versions of the drug, in retrospect, would seem to have been well worth the effort, no matter how small the affected subset. If reducing or eliminating this risk alone is the sole benefit of personalized medicine, companies cannot afford to ignore its value.

The silver lining in every Vioxx situation is the opportunity for a remedy such as pharmacogenomics to offer a means of resolving a major problem. When a drug is pulled from the market, the affected company does not usually abandon it, but likely will attempt to correct what is wrong. Frequently, the cause of failure is ADR in a percentage of patients. Identifying the biomarker causing the immunity from efficacy and composing a remedy for the exception class is a pharmacogenomics process. Although only a low percentage of drugs are recalled, the consequences are so prohibitive that no company wants to be subjected to the ordeal, and if the situation is unavoidable, as quick a resolution as possible is sought. Embarking on preemptive subpopulation indication research programs to parallel the primary mass target drug development program may become standard procedure in an effort to prevent, or minimize, product recalls.

Biotechnology is an industry founded on innovation and risk, and still thrives on those principles. Even though big pharma relies on the biotechnology industry and can assign a big percentage of its recent successes to that prototype, it still is hesitant to change when such actions involve tinkering with the Holy Grail representing the blockbuster model.

That reluctance will not be an obstructive factor in the growth of pharmacogenomics, because the blockbuster model can actually be expanded to a larger patient base by personalizing therapeutics to include individuals or groups which are predetermined by genetic disposition to be unaffected or adversely affected by the primary composition of a particular drug.

In some cases, the inherent risks associated with the traditional blockbuster model will contribute to the appeal and growth of pharmacogenomics as a codicil to the primary target application. Best-sellers, with efficacy limited to about 50 percent of the mass indicated population, will be given an opportunity to address the needs of the unclaimed half with the expanded application(s) offered by pharmacogenomics secondary indications. Another intrinsic liability associated with the traditional blockbuster paradigm is the enormous fiscal and public image damage that occurs when a patient subset experiences serious or mortal ADRs that tend to draw the attention of the entire industry, investment community, media and regulatory powers. Those risks, along with the huge investment of developing and marketing a drug, creates a favorable scenario for derivative applications capable of reducing side effect hazards and increasing revenue generated by the drug in its primary composition.

BioWorld research garnered from industry sources and statistics concludes blockbuster drugs are efficacious in only about 50 percent of patients. Manipulating a therapeutic formulation to address the unique needs of those who cannot benefit from its principal composition can increase revenue by capturing that unattended group. The opportunity to boost revenue by as much as 50 percent will appeal to investors, especially in instances where a drug is already on the market and needs only diagnostic biomarker identification work and a moderate amount of therapeutic fine-tuning. In most cases, the investment will merit the reward. BioWorld deduces prevailing protocol in the future will include either concurrent or post-launch therapeutic tweaking, or secondary application research, of all blockbuster drugs in order to attend to the excluded patient base, minimize liability and grow revenue.

The value of the total pharmacogenomics market, at $787.2 million in 2006, is projected to increase to $1.308 billion in 2008, $1.862 billion in 2010, $2.609 billion in 2012 and $3.162 billion in 2014. Growth will be led by pharmacogenomics therapeutic applications of new drugs and existing drugs expanded into genetically specific subpopulations.

The pharmacogenomics application market, with a value of $720.4 million in 2006, is forecasted to grow to $1.2 billion in 2008, $1.7 billion in 2008, $2.4 billion in 2012 and $2.9 billion in 2014. This projection anticipates an average of at least one marketable pharmacogenomics-derived drug every two years over the span of the forecast period.

Therapeutics derived from pharmacogenetics applications, with a 2006 value of $30.2 million, is projected to increase to $47.1 million in 2008, $73.4 million in 2010, $73.9 million in 2012 and $84.1 million in 2014. The comparatively slow growth of pharmacogenetics reflects its smaller target patient base of individuals and small groups such as tribes, as compared to the larger ethnic, gender and geographic groups targeted by the pharmacogenomics applications market.

Diagnostics applications for all forms of pharmacogenomics testing and incorporation into therapeutics development programs, with a 2006 value of $37.6 million, is projected to increase to $47.1 million in 2008, $88.6 million in 2010, $129.4 million in 2012 and 178.3 million in 2014. This segment is projected to experience significant growth independent of the drugs-to-market factor, inasmuch as diagnostics propel all phases of the research process and will be used for post-launch tasks, such as monitoring and tracking efficacy and providing data for secondary indication and subtype patient groups.

Pharmacogenomics, for purposes of the BioWorld market forecast, refers to broader, but still genetically specific, groups. Pharmacogenetics, distinguished from pharmacogenomics as applications of personalized medicine development for individuals and small groups such as families or tribes, is a growing market which will deliver important products for its subjects, but will be the segment most affected by a limited patient base.

BioWorld concludes the growth of all sectors of the pharmacogenomics market will enhance the value of many peripheral technologies and services, such as point-of-care testing, bioinformatics, reagents and agricultural biotechnology, thus possessing the potential to become one of the leaders of the biotechnology sector by the end of the forecast period.

All diseases have a genetic component, whether inherited or derived from external sources such as viruses or toxins. The pharmaceutical industry-wide pursuit of products to treat or cure these diseases creates opportunities for pharmacogenomics in diagnostics and therapeutics programs in potentially most disease applications. BioWorld concludes the capability of pharmacogenomics to allow researchers to identify and attack flaws in genes contributing to or causing diseases will drive and sustain this progressive market throughout the forecast period.

As pharmacogenomics successes become evident in clinical applications that show significant declines in some of the biotechnology and pharmaceutical industries' biggest problem areas-ADRs, malpractice litigation and therapeutic ineffectiveness-companies will not be able to ignore its value and indemnity. Advances in resolution of those issues would merit the hype of innovation, and there is sufficient evidence that overcoming those issues is a reality currently taking place. The application of pharmacogenomic medicine has produced observable effectiveness in the reduction or elimination of ADRs and unresponsive outcomes. The technology's biggest role in litigation so far has been its reference as a practical method to clean up the mess that broad application drugs have wrought.

There is increasing evidence that the proven positive aspects and the revolutionary potential of pharmacogenomics have drug developers, physicians, patients, and regulators of one accord in advocating the advance of the technology. Such general concord that has everyone pushing in the same direction may deter some traditional drug development roadblocks and make it less problematic to facilitate the growth of this market.