key: cord-0902521-ci3k93j2
authors: Bartfai, Tamas; Lees, Graham V
title: Chapter 05 Therapeutic areas Strategically important diseases of the future
date: 2013-12-31
journal: The Future of Drug Discovery
DOI: 10.1016/b978-0-12-407180-3.00005-2
sha: d4e09f74aaef372e1d8e33b049de26b0eaa236b8
doc_id: 902521
cord_uid: ci3k93j2

Abstract Society and industry—still the only provider of approved medicine—share the desire to treat important diseases. Governments too, since some diseases’ high prevalence affect the economic output of society. Yet the decisions as to which drugs will be developed are strictly in private hands. The risks required to treat some really important, and often increasingly prevalent, diseases mean that the desires of society and the industry are diverging. This is not boding well for our society. The understanding and willingness of governments to step in as a partner and financier is not apparent. Will governments recognize their role in this? Since the economic cost of these diseases, in terms of reduced productivity and medical costs to treat the disease, is enormous, understanding should be forthcoming. Government has invested for many decades in an enormous program of cancer research, which now shows dividends. The importance of further government investment in basic research is apparent when industry does not want to or cannot anymore afford it. As Big Pharma drops out of important therapeutic areas, it is not promising to assume that government can step in to the vacancy. There has to be a serious effort to find a formula by which the government gently or not so gently forces the industry to continue its efforts because it is so important. Perhaps the most important of these neglected diseases is Alzheimer’s disease (AD) because of its dehumanizing nature and its predictably massively increasing prevalence. Yet, none of the currently approved Alzheimer drugs can be used to prevent, cure, or even significantly slow the progression of this disease. It is predicted that by 2030 50% of the over 80s will have the disease. Almost 100% of people with an inheritable trait will develop the disease unless we succeed in finding a preventive therapy. Only recently has a preventive trial been announced. It is often thought that insulin-dependent diabetes is a well-treated disease and needs no further diagnostic and drug development efforts. This could not be further from the truth. The long-term complications of insulin-treated diabetes add to the economic burden, especially as the growth in prevalence of the disease expands with the waistlines of the world’s population. Three hundred million may have type 2 diabetes by 2030. Pharmaceutical control of weight loss has so far been vexed by serious side effects. When it comes to diabetes drugs, we start to recognize that the control of blood glucose can be further improved; the biggest contribution is not by drugs, but by self-diagnosis with point of care glucose measuring devices. Morphine is still the most effective medicine against pain. It has been around for 5,000 years and we haven’t come up with anything better. But it can be ineffective against neuropathic pain and cancer pain. New pain medicines are difficult to find because of the subjective measurement and poor animal models. Since many current pain killers are abused, there are other hurdles. Despite the many difficulties, society needs new pain killers at the same time that notable pharma are pulling out, despite the economic opportunity. Drugs against cancer have had many high-profile and expensive failures in recent years, with all major companies having at least one failed candidate. Biotech companies have made much progress, however, and they are either collaborating with or being taken over by Big Pharma. Oncology drug development has been crucially enabled by decades of government investment. The key is the many characterized drug targets that other disease areas do not have. Government intervention in oncology and HIV provide the model for treatment of AD, neuropathic pain, and schizophrenia, among other therapeutic areas. Increasing governmental direct funding of translational research is not the solution many hope it will be.

Two large epidemics are slowly encompassing the whole world, not only Africa: obesity/type 2 diabetes and Alzheimer's disease (AD). These epidemics threaten abrupt and almost unstoppable reorganization of the economy and societal structures unless we bring them under medical and pharmacological control. The obesity/diabetes epidemic is going to affect countries like China and India dramatically, while countries with an aging population like Japan, Germany, and the UK will be hit by the consequences of AD the hardest. Models of the consequences show that up to 15% of the work force will be involved in the 24/7 care of AD patients. These trends should be shaking governments into action.

The health economics that deal with the economic effects of disease burden and the effects of healthcare cost in society is, together with the study of public health, becoming increasingly important in political discourse in all countries; there are superb books on the topic from different political viewpoints. We will only deal with aspects of these important branches of the economy and of medicine that affect the choices of pharmaceutical companies.

Companies try to look forward 10-12 years and to foresee not only the biology and epidemiology, but also the economic and political landscape at the time when any new drug would enter clinical practice, would be paid for, and should start to produce revenue.

The development of drugs to prevent, or at least to treat, these strategically important diseases constitutes from society's view the most important task for the industry, yet today in all countries' pharmaceutical industry even vaccine production is in strictly private hands and the in what drugs to develop is restricted to the trickle of funds devoted as charity to organizations working on diseases predominantly afflicting poor populations, such as malaria, leishmaniasis, sleeping sickness, and MDR-TB, which is now shared by all of Asia and prevalent in countries like Russia, China, and India.

The drugs that will treat these large diseases also potentially represent the largest incomes. Yet, because some of the diseases represent large drug development risks, even over the unusually high risk the whole industry carries, the big companies are abandoning work in some of these disease areas. The declining interest in AD and pain are examples. This does not bode well for our society.

The understanding and willingness of governments to step in as a partner and financier or limiter of liabilities is not apparent when it comes to the several large and potentially very profitable diseases we are discussing. Governments have always been involved as regulators and distributors, and have previously been involved in the development of some pediatric vaccines and drugs, for example, to control outbreaks or treat epidemics of infectious diseases. These increasingly neglected diseases are just as important for our society as are the infectious diseases.

Among these large strategically important therapeutic areas/diseases that affect very large numbers of patients and have large human and economic costs are the following: Of the diseases listed, only type 2 diabetes is being adequately addressed by resources of the industry. For the rest, we are not doing very well. While progress in the treatment of cancers, especially leukemias and breast cancer and in the past 2 years melanoma and non-small cell lung cancer, has been substantial, it is thanks to government-funded basic research since the 1960s. 78 Because of this large long-term investment, scientists are aware of many drug targets and thus the industry, which largely dropped its own basic research by the end of the 1990s, makes steady progress. Each of these areas will be discussed in purely economic terms because, along with having disease-specific aspects, they also provide some very general points of view about the development of pharmaceuticals, about the interplay between government and private industry, and about the importance of government investment in basic research when industry does not want to or cannot anymore afford it.

The most important example is AD. This neurodegenerative disease, which leads to cognitive decline, loss of memory, and inability to recognize faces or names, is, in short, one of the most horrible diseases in many senses. Many argue that all our humanity depends on our memories, and our memories determine who we are. When we lose these we are losing ourselves.

Although Alois Alzheimer diagnosed the first patient more than 100 years ago, AD has not been an important issue of research or of healthcare discussions, and certainly was not discussed in terms of a major threat to society as it is recognized today. The reason for this is that the major risk factor for AD is age. When the average life span of the population was 50-60 years, the frequency of AD was relatively low. Since definitive diagnosis still requires postmortem neuropathological examination of the brain, not many cases were identified. In contrast, the prediction for the United States is that in 2030 every second person aged 80 or above will have AD. The proportion of these people in Japan and the whole Western world is rapidly increasing.

What it really means is that up to 10% or more of the 2030 population in Japan, North America, and Europe may suffer from AD, and this is now being modeled by think tanks and insurers everywhere. Taking care of an Alzheimer patient, if they are taken care of individually, requires three full-time working persons each working 8 hours per day. This translates to a very large proportion of the productive labor force being devoted to taking care of patients with advanced AD, who cannot themselves be relied upon for the most elementary of functions. This is only the economic consideration. The societal implication is huge; there is currently a shortage of care givers. 79

The 2011 estimate is that $600 billion is being spent on taking care of AD

patients. Yet there is no drug available that prevents or cures the disease, or even significantly modifies the rate of progression of the disease. The only drugs today approved are giving a relatively small-although in large trials statistically significant-slowing of the loss of cognitive function in mild to moderate AD and in one case are approved to treat moderate to severe AD. Memantine (Namenda from Forest Laboratories) is a 30-year-old German drug (from Merz) originally used for neuropathic pain treatment. It produces very small changes in the rate of decline in already seriously demented patients. It is liked because of its relative safety, not its efficacy. The total number of approved, available drugs is five and none of them can be used to prevent, cure, or even significantly slow the progression of this disease.

States was 5.3 million, and a similar number applies to Western Europe, but, including the nondiagnosed patients, the total is estimated at some 30% higher. Where do we stand with the development of drugs to be used in the therapy of AD patients? The scientific background is such that in this disease there are both sporadic forms, accounting for 99.8% of cases, and clear familial (or inherited) forms, which is to say, cases that have an early onset of disease at about 40 to 45 years based on a genetic predisposition; these account for 0.2% of cases. There are several other genetic vulnerabilities identified. A very frequently occurring vulnerability is being a carrier of a protein isoform called ApoE4. One can carry two of these gene copies when one is homozygotic. One can carry one ApoE4 and one ApoE3, which is more common in the population, when one is heterozygotic. But, the vulnerability for AD is significantly higher in the Genome Project's parallel study, 83 and Jim Watson, 84 the co-discoverer of double helix. 85 In the first case, Venter's sequence showed increased risk of AD 86 and in the second case the ApoE3/4 encoding sequence was omitted from Watson's data at the specific request of Dr. Watson. He did not want to know if he were susceptible to an incurable disease to which a grandmother had succumbed. 87 Interestingly, the cost of the Human Genome Project was $3 billion over 13 years, Venter's sequence cost some $100 million, and Watson's was variously reported at $1-2 million in 2-4 months. 88 The costs are dropping in a dramatic manner: Complete Genomics, Life Technologies, and Illumina have disclosed that from January 2012 they will provide a full genome sequence for anyone for $1,000. We have yet to start a discussion about what cognitively happens to individuals carrying both the ApoE3 and ApoE4 genes-one from each parent-as their age increases.

There are more serious, but luckily less frequent, genetic causes of AD, such as the "Swedish" and "Dutch" mutations in the amyloid precursor protein. These mutations and mutations in another associated protein, presenilin, and a combination of these mutations lead, in a small group of people, to very early onset (about 40 years of age) rapid progression AD. These patients, who will have "familial forms of AD," make up a small portion, 0.1-0.2%, of all AD patients. Most of the AD patients endure the sporadic form, yet the discovery of patients with familial AD suggests the possibility of highly focused trials for AD preventive medicines in a group whose risk is very high. Almost 100% will develop the disease unless we succeed in finding a preventive therapy.

It is worth explaining that in diseases where there is a large sporadic group of patients yet a small "familial group" or "genetically determined group" the understanding of the familial forms had great importance, in almost all cases, for finding treatments for the sporadic cases. This is because when people with familial disease are treated, we are fairly sure of the causative mechanism. It may be compared to the increasing introduction of companion diagnostics in oncology: treating those who have a genetic cause of the tumor improves responder rates from 5% to over 60%. 89 Yet we have great difficulties in finding any (preventive AD) trials involving family members of patients who have or have died from familial AD. The patient associations that "organize" these individuals have good lists of who would be eligible, but basic research and pharma have failed these people and missed this opportunity for two reasons. One is pure greed: "Why wait 4-5 years to show in familial cases that a therapy works, and then do another 4-5-year study in the real market representing sporadic patients?" goes the argument. It is added that "it is hard to recruit for familial case clinical trial," which does not seem to be true, or it has to do with the second factor: the drugs we so far have put into trial are associated with such bad side effects that it is hard to convince people presently fully healthy, even if they know that they are likely to have early AD, to endure the side effects for an uncertain delay of the onset or for the prevention of the disease. We need to improve science and pharmacy, and we need governments, not NGOs, to pay for the more focused trials. 90 89 See Chapter 08. 90 See also Chapter 11, where we may reveal that our argument is vindicated: one trial, designed in the way we recommend, is now being conducted. For those readers who wish to "fast forward" you should look, for example, at http://www.multivu.com/mnr/56128-banner-alzheimer-s-institute-genentech-nihprevention-trial-genetics It is important that in the new healthcare legislation in the United States, upheld by the Supreme Court in June 2012, one cannot be excluded or penalized for a pre-existing condition or a genetic predisposition. This will become more and more important, especially as genome sequences are becoming affordable as part of diagnostics, not just as a research tool.

In general, the presence of genetic forms of the disease accelerates the understanding of the disease and indirectly accelerates the development of drugs to treat the disease. This is also the case with AD. The early onset disease has been linked to mutations in the metabolism of the amyloid precursor protein leading to the appearance of amyloid plaques. 

The start of each treatment is diagnosis of the disease. Today, AD diagnosis heavily relies on neuropsychology test batteries, which have 91 Confidence has not been improved by the poor results from Lilly's therapeutic antibody trial of solanezumab (see Chapter 06). become better and better. They are now able to detect mild cognitive impairments and early AD. But nobody really knows how much damage has already occurred in the brain when cognitive impairment becomes obvious to relatives, friends, and colleagues. It is, therefore, very important that 2011 has seen the clinical entry of several imaging agents. 92 When working well, these permit the visualization of amyloid plaques in the living brain, and might, therefore, be important in establishing whether a drug aimed at inhibiting the production of amyloid peptide is really successful in reducing the plaque load. It is, however, evident that nobody is bothered by carrying amyloid plaques. When it is conclusively shown that the amyloid plaque load predicts cognitive impairment, we will then be able to convince people who exhibit no cognitive evidence of AD to take drugs that prevent the formation of amyloid peptide and amyloid plaques. But then these drugs will have to be very, very "clean" with no or a very low incidence of serious side effects or even annoying side effects.

If we had succeeded in producing a drug candidate with a strong scientific rationale suggesting it would prevent AD, without major and minor side effects, then which people would be convinced to take it? Firstly, those with a very high risk of developing familial AD would take it, preferably before showing any symptoms. Later, those who, through aging and some first signs of mild cognitive impairment, appear to have the risk of developing AD in a few years would take it. Some of these candidates would have to be prepared to test this drug in trials that will take 3-5 years. The principle is very similar to the way we have convinced millions and millions of people to take the cholesterol-lowering statins. High cholesterol per se is not a disease, but it is a harbinger of many cardiovascular diseases. If amyloid peptide and amyloid plaques can be detected and shown more rigorously to be a harbinger of AD, then volunteers would be easier to find. But for this to happen one will need much cleaner and much safer Alzheimer drugs than those we presently have. 92 The approval for the imaging agent florbetapir (Amyvid) to image amyloid plaques from Avid-Lilly was, however, delayed over procedures of evaluation.

Based on earlier neuropsychological diagnosis, patients are selected for the clinical trials of proposed Alzheimer drugs. These trials are becoming longer and longer. The reason for this is that we are entering into these trials based on the success of neuropsychological assessment that now captures early Alzheimer patients, in ever milder forms of the disease.

The first Alzheimer drug clinical trials in moderate to severe patients could show that the first class of drugs, the acetylcholine esterase inhibitors (AChEIs), could slow the decline of cognitive abilities significantly after a 6-12 month treatment (trial) period. The latest trials with AChEIs have, however, taken 18 months to show a significant difference in cognitive decline between drug-treated and placebo patients. The milder, and earlier the AD cases enrolled into the trials, the longer we have to dose the drug to show a significant difference in the cognitive performance between drug-treated and placebo patients. This is a clear recognition by pharma that, in order to show efficacy, they will need longer trials. These are a major expenditure, but, more importantly, the results are further and further away from what affects the stock price in the 2-3-year period upon which present pharma executives focus or are obliged to focus.

Another issue regarding Alzheimer patients and clinical trials is that the average age of these persons is above 65 and they suffer from a great number of other diseases, for which they are also being treated. This means that the drugs to be used in Alzheimer therapy have to be devoid of interactions with a very, very large number of drugs. It also means that because of age and other diseases, a relatively large number of these people will drop out of the trial or may die during the 18-or 24-month length of the trial. This means that these trials, at least at phase 3, will have to be very long and very large. The industry has conducted such long and large trials in cardiovascular disease and in type 2 diabetes. However, most large and long trials-usually post marketing, i.e., post approval, phase 4 trials-are carried out by governmental agencies in the UK, United

States, and so forth. But the repeated failure of Alzheimer drugs over the last 10 years is making more and more companies silently withdraw from the effort to develop therapeutic agents for the treatment of AD, which would slow disease progression, prevent the disease, or cure the disease. This is understandable from the point of view of profit within organizations, but it is not acceptable for our society. As we recognize AD as a serious risk for our society, we cannot afford to give up trying to make drugs that achieve effective treatment. Today, there are no seriously capable organizations except the pharma industry to develop such a drug.

So, when they withdraw, openly or silently, and are permitted so to do, we will end up with the horrific prospect of every second over 80-year-old citizen suffering from AD, but not being offered any kind of treatment that would help the patient, the family, and society as a whole.

When we say that the only seriously capable complex, sophisticated large organizations to develop therapeutics are the pharmaceutical companies, we are not disregarding the expensive efforts governmentsupported institutions, such as the National Institutes of Health (NIH) and

corresponding European institutions, put into what they call translational research, that is, research that is directed toward affecting medical practice.

Translational research, which is the modern equivalent of applied research, is an increasingly important part of their task. However, in retrospect, one can today clearly state that these organizations have It is clear that the NIH and its international counterparts bear huge responsibility for the "real" science in AD. When one compares funds poured into HIV/AIDS and cancer research to those put into AD, one is shocked. It is clear that funding initiatives can bring large numbers of scientists to work on a problem, and that it is what we badly need.

Instead, AD research is conducted by a small club; this we cannot afford. Therefore, it is not a promising route to let private industry back out of trying to develop Alzheimer drugs, saying: "it's too hard; it's too risky; it's too slow; it's too expensive," and assume that governments will step in to the vacancy. There has to be a serious effort to find a formula by which governments, gently or not so gently, force the industry to continue its effort in developing Alzheimer drugs. Intervention can come from tax breaks or other incentives, as well as somewhat punitive legislation for pharma to release data from programs they have dropped, in order to support this highly risky activity because it is so important. We have seen how U.S. and other governments can enhance and semi-force the development and production of antidotes to biological weapons, and how it can incentivize and encourage the production of vaccines.

AD is not as acute as bird flu or the risk of a bioterrorist attack, but it is as, or more, threatening for the individual and for our society.

The first biological to be used on a large scale was insulin, albeit preceded by some vaccines and antidotes to snake toxins, and so forth. The first clinical trial of insulin involved one patient: a child.

We often forget this. As discussed earlier, production of insulin is now made with recombinant technology in bacteria or yeast. The three major producers, Novo Nordisk, Lilly, and Sanofi-Aventis, are producing both acutely active and delayed, slowly, or long-acting depot or retard insulin preparations.

One may think that insulin-dependent diabetes is, therefore, a well- on to a balance, see for themselves whether the drug is efficacious. The fallacies of these trials are many, however. While it is relatively easy to achieve a 5-10% weight loss in the first 6-8 weeks, it is very hard to keep it over 12 months. This is why the FDA now insists that drugs that might be approved achieve and maintain a 5% or higher weight loss over a 12-month treatment because less than that is not clinically meaningful.

Also, drug treatment is not comparable to other ways of achieving dramatic weight loss such as bariatric surgery, itself not without dangers.

Surgery is, however, very expensive and not acceptable or appropriate for every patient, but bariatric surgery can produce a 30% or higher weight loss that remains after 12 months.

Home Products until it turned out that a large number of patients develop valvulopathy-changes in the heart valve-as a result of taking this drug.

As this is an irreversible disease state leading to death in many cases, The development of weight loss drugs is very attractive but very difficult; the last 3 years have seen the industry bringing forward compounds or combinations of compounds that showed efficacy of 6-10% weight loss over 12 months, but which contributed to an increase in social isolation, suicidal ideation, and suicides. It forced the FDA to demand that companies specifically examine these side effects, and it finally asked its outside academic-clinical experts whether obesity is such a life-threatening condition that we should permit the taking of drugs that might significantly increase suicidality. The answer was no; we have to be able to find drugs that achieve the same weight loss without these serious side effects.

Other weight loss drugs have shown large increases in blood pressure and heart rate, and were deemed not safe. Presently, the industry is wondering if it is possible to make a truly safe obesity drug, while several biotechs are hampered by their financial inability to afford the long cardiovascular safety study rightly requested by the FDA.

But, unlike in the case of AD, the industry is not abandoning the area because it seems that the development of these drugs is easier in the sense that the scientific basis to fight obesity is better understood, and that the chance of proving that one has an efficacious safe drug is better than achieving the same in AD. In particular, the efficacy of the drug is shown and seen by the patients themselves within weeks. The other problem is maintaining this efficacy. It is so clear that there is a great desire in our world to achieve the ideal body weight determined by fashion and by health advisories of a body mass index (BMI) around 22-24. Despite a period of 3 years of efficacious drugs not being approved because they

were not safe enough, it is less likely that the industry will abandon its search for obesity drugs.

When it comes to diabetes drugs, we start to recognize that the control of blood glucose can be further improved. The biggest contribution to improved control is not by drugs, but by continuous, daily, or repeated daily self-diagnosis of high blood glucose levels. These levels can be measured at home using the glucose meters developed in the last In summary, it has to be said that the impact of the fight against obesity as a major risk factor for type 2 diabetes cannot be overstated.

The problems of finding efficacious and safe obesity drugs are great, both practically and theoretically, because eating is so deeply and intricately programmed in our brain. So many processes of mental well-being are controlled by parts of the neuronal circuits that control repeated, pleasurable activities such as eating. Nevertheless, it is clear that here the industry continues to stand at the gates of the FDA with new drugs and drug combinations that can achieve significant weight loss.

A comparison of surgical procedures such as bariatric surgery to drug treatment is an important one. Those who work for insurance companies and major health plans calculate the risk-benefit ratios of major surgeries.

One often finds that bariatric surgery is only recommended for those who are relatively young and who are enormously difficult to treat with drugs, diet, and exercise. Whether this will change with improvements in surgical procedures or not is hard to foresee. But it is clear that many patients will prefer any available oral or injectable drug if it comes close to the efficacy of the weight loss produced by a surgery where today mortality is over 1%.

Morphine is one of our oldest drugs. The ancient Egyptians called it "God's own medicine." This was not because of its marvelous pain-killing

properties, but because it effectively stops diarrhea, which is one of non-morphine-type pain drugs is gabapentin. Gabapentin is a more than $2 billion-selling drug that in its clinical trial reduced pain from an average of somewhat above "7" to an average of "4," not to zero. The FDA suggests that patients may be recruited for pain trials if they assess their own pain to be above "4." This means that even after having taken the best available drug many patients would still be eligible to enroll in a new trial for a painkiller.

Current practical treatment of pain may use multiple drugs. Physicians and patients learn to use several drugs to achieve some pain relief. The biggest problem is not that our basic pain research is lacking in effort, but that the animal models, in which we try to assess the efficacy of new pain medications, are not very reliable. Therefore, many clinical trials that were initiated after successful animal experiments have failed. There are additional big problems with developing new pain medications. This includes the potential for misuse of painkillers. People take them recreationally rather than because they have pain. Often these drugs, which were made for oral use, are being ground up and injected intravenously when their effect is much faster and much more robust in the brain, sometimes causing deadly accidents. So, whoever tries to introduce a novel serious painkiller has to prove or has to safeguard against abuse potential. This is difficult.

Painkillers are also the most often overdosed drugs. Patients in pain start taking the recommended dose then readily take more or more often when the pain does not abate. Therefore, these drugs have to be very safe even at 5 to 10 times the recommended dose. Another problem of many painkillers is their interaction with alcohol.

Despite these inherent difficulties, we cannot stop trying. In many ways Neurontin by Parke-Davis (now Pfizer), which is now more than 18 years old. It was approved in 1994 and has spawned many generic forms such as Fanatrex, Gabarone, Gralise, Nupentin, and so forth. Those who work in pain clinics are using a mixture of dedicated painkillers, antiinflammatory drugs, tricyclic antidepressants, and anti-epileptic drugs to treat neuropathic pain, but their success is very limited.

In the 1970s and 1980s, the 20 large pharma companies, of which today exist less than 10 because of mergers and acquisitions, were not very interested in the area of oncology. The argument was that cancer, leukemias and solid tumors, are often discovered too late to do anything and that many cancers will not be treated easily because breast cancer, prostate cancer, lung cancer, renal carcinoma, pancreatic cancer, and so on, are clearly different diseases of different organs that will require completely different medications; therefore, the market is very fragmented. So, not only are the patients diagnosed late but there are also too few patients for each cancer form, maybe with the exception of some leukemias and lymphomas (see Table 5 .3). However, it turns out we knew too little about some of the underlying cellular pathways and that certain controls of the cell division that runs amok in cancer are general in many cell types; thus, there will be carry over from developing a drug for one cancer indication (see the section "Effective governmental & societal intervention"). We were too organ focused, and not focused on cellular pathways.

In any clinical trial, the industry would not want to use, as the comparison, the most commonly used chemotherapy: the cytotoxic agents. These nucleotide analogs are still among the most efficacious cancer drugs, but with terrible side effects like hair loss, nausea, and weight loss. They are still used frequently, and these are drugs that are very cheap to make and very cheap to buy. This has shaken some of the best-selling cancer drugs such as bevacizumab (Roche-Genentech's Avastin), which has been approved for treatment of non-small cell lung carcinoma and for colorectal cancer, but which has failed to show efficacy in breast cancer. This also may be initiating a possible re-evaluation of the original approval in non-small cell carcinoma, thereby endangering one of the best-selling cancer drugs from Roche.

Several of the spectacular clinical trial failures of 2010 were in oncology (Table 5 .4), but so were three of the most spectacular successes (Table 5 .5). Oncology remains a highly successful area, both medically and economically, for pharmaceutical companies. We also saw the first new therapeutic modalities such as the antibody-drug conjugate (ADC) brentuximab vedotin (Seattle Genetics' Adcetris), approved in August 2011 for anaplastic large cell lymphoma (ALCL) and Hodgkin's lymphoma; many others are in trials.

There are 40 times as many drugs being tested for cancers than for schizophrenia. Why? In short, the explanation is government-sponsored basic research. Today oncology 94 is the most drug target-rich area, 94 Perhaps together with inflammation. The reason for the richness of drug targets in oncology is twofold. One is the decision by governments and NGOs, such as cancer societies, to engage large-scale sponsoring of basic research over several decades starting in the 1960s. Firstly, this research has shown that many molecular mechanisms are common in very different cancer forms. Therefore, even though on the surface prostate and ovarian cancer are clearly different and occurring in different genders, there are molecular pathway similarities.

Effective drugs may affect basic underlying mechanisms of the repair of DNA, or the formation of vasculature, which is needed to supply the tumor with blood, and so on. These putative drugs might be used to treat more than one cancer form. Secondly, the discoveries of drug targets in leukemias and then in solid tumors have accelerated as a result of major public spending. When considering the importance of this, one has to remember that until the 1960s the pharma industry had been responsible for the basic research in most areas of life sciences (except embryology), which was the foundation for most of the drug developments. Since the 1960s, government-sponsored research in physical and life sciences in the United States and Western Europe has increased (the "Sputnik effect") and has almost completely replaced the basic research efforts of big pharmaceutical companies. It is true that pharma spent $92 billion on research and development in 2009, but a very small portion, maybe $10 billion, of this was considered basic research. This is to be compared with the more than $60 billion spent annually on basic research by public and other sources. The NIH alone in the United States has a budget of over $30 billion.

The example of oncology shows that when politicians recognize the need either for popular or other reasons to support research, then they can initiate sustained and large-scale efforts that eventually produce scientific breakthroughs. HIV treatment is another area serving as a good example of the joint forces of patient interest groups, relatives of patients, celebrities, and governments to put pressure on a pharma industry that had not been in general very successful in developing antiviral agents. Yet, in the relatively short period of 20 years, HIV has switched from being a 100% deadly disease to a chronic disease that can be managed at several levels. This is one model, in which society can influence pharma by spending on basic research (to provide basic functional understanding and drug targets). Society would then rely on different sized companies, small ones first and bigger ones later, to pick up the scientific breakthroughs and apply them in the development of novel drugs. This is a very long-term, indirect way to find new drugs, but it has worked and it does not rely on specifying the commercial entities that will use the scientific results; instead it hopes that several will, and that they will do it in competition with one another.

There is also post-drug development encouragement and incentive by allocating NGO budgets to guarantee the purchase of a very large number of doses for developing countries. They exert a push-pull mechanism: the push on development and pull on production.

The examples of oncology and HIV cannot be underestimated. They are extremely important if we are not to give up work on Alzheimer therapies and on finding drugs against neuropathic pain and, for example, against schizophrenia, where the present drugs have relatively low response rates and are associated with severe metabolic side effects in many cases leading to early type 2 diabetes in young schizophrenics.

There are many good reasons to protect the freedom of researchers and not to direct all research, mostly because we really are not that good at predicting the truly innovative breakthroughs, many achieved through studying systems such as Escherichia coli, yeast, nematode worms, sea slugs, and fruit flies, and leading to cancer drugs. Nevertheless, one must not shy away from directing a much larger portion of the research budget to AD and antibiotics resistance than is happening presently. NIH and European research agencies already have large directed programs, but they are not large enough. Biotechs would be most helped if phase 2 and phase 3 clinical trials in AD were made possible with the partnership of government as an alternative to partnering to Big Pharma, which is currently not interested in these trials.

The diploid genome sequence of an individual human

The sequence of the human genome

Initial sequencing and analysis of the human genome

The complete genome of an individual by massively parallel DNA sequencing

A structure for deoxyribose nucleic acid