The pharma industries and contract research organizations have employed more than 10 million PhD, MS and BS candidates. The cost of their salaries, chemicals for the projects, additional maintenance costs, documentations, phase I and phase II trials, will lead to a huge expense over $90 billion each year. Worldwide industries have to bear these expenses and they have to earn whatsoever invested in the market by selling potent drugs. This rich source of funding and talents for R&D, phenomenal knowledge of drug substrates isolated from medicinal plants, scientific knowledge of new therapies, and rational drug design using small molecules will figure the pharmaceutical targets.
About 8000 potential protein/antibody therapeutics are naturally present inside human body. Approximately 218 of the synthesized synthetic molecules already present in the market, roughly 100 of the targets went under advanced clinical development. Many of talents from pharma and biotech sectors guessed 500-800 new mechanisms of disease and exposed them to journals. Despite of new drugs flow into the markets, their reduced medical activity, disease burden, environmental pollutions, agonizing human population even in developed countries. Each year by the efforts of public and private sectors, five of drug molecules with novel mechanism pushed into market. Still the 'big cures' have not been discovered yet. Neurological damage (either as a result of accident or stroke), Alzheimer's disease, chronic heart failure, chronic obstructive pulmonary disease, many cancers, obesity and other chronic conditions have no treatment options. Whatever discovery is done day, today is for the low lying fruits while difficult targets left untouched. Even big pharma companies pumping drugs with modification of old drug to the same disease without investing into difficult targets.
R&D costs and risk raise
The risk associated with novel 'druggable' targets is substantial and the investment in taking many targets forward until end is very high or their manufacture tactic in bulk is expensive. CCR5 receptor antagonist discovered by genomic clinical rationalization on AIDS which lead to development of maraviroc, bcr-abl kinase inhibitor Gleevec developed by checking kinase activity in leukaemia patients. Nav 1.7 blockers under R&D developed by checking pain sensing gene human Nav 1.7. CETP inhibitor (torcetrapib, Pfizer) failed due to safety but discovery is based on genomical expression.
Limitations for disease, where medicine unmet
Around 50 neuroprotective drugs were tested between 1995-99 for stroke, none of which demonstrated any efficiency despite promising preclinical results. An average of $8000 per patient out of 74000 people for stroke trials equalled $6 billion total cost lead without discovering a novel medicine for it! This clearly shows by the limited understanding and complexity of the pathophysiological processes that leads to neurological damage after a stroke, the possible irreversibility of some of these processes. The limited understanding of primary pharmacology-driven side effects combined with non-predictive animal models all contributed to these failures. The compounding factor is the animal model and human setting, including brain penetration was poorly understood or not investigated properly. Currently new imaging technologies shed some lights on receptor occupancy and possible pharmacological drug effects. But the cost and failures on these directions lead big pharmas to rethink their discovery.
In contrast to stroke, now, there is a range of targeted therapies emerging for various oncology (cancer) therapy. Gleevec and Mylotarg for leukaemia, Herceptin for breast cancer still it is obvious requirement of more efficient medicines in this field. Unlike stroke cancer has a clear genetic component and indeed is caused by changes in gene function. The number of clinical cancer studies is amazing, 3500 open and 15000 closed cancer trials are carried out. The National Cancer Institute itself put $5 billion in the research and 650 medicines are under development stage.
Shifting expectations
Few diseases are complex to treat with medicine, for example cystic fibrosis (CF) which effecting one out of 2500 new born in the world. It is due to defective function of the pancreas and chronic obstruction and infection of the lungs. The defective gene is delta FS08 accounts for 70% cases regulating chloride ion channel. The early diagnosis have played best role in its treatment.
Pricing, medical expenses
The cost of medicine is also a major factor in existing therapies. Although pricing of 'miracle drugs' in cancer therapies created problem in the market. Most of these drugs given to patients admitted into hospital, so cost of admission, cost of doctor, nurses and infrastructures of hospitals burdens the people. The newer drugs are patent protected, which automatically make them more expensive. For example few of them used as combination of drugs for ex Herceptin breast cancer and Avastin for colon cancer. Due to the raise in personalise medicine which are found higher cost still it is not reached to poor, so unaffordable to many people.
Potential R&D solutions, knowledge and new technologies
Why all the targets not been converted into useful medicines? Until in 1990's Chris Lipinski introduced seminal article describing physiochemical properties (rule of five), there were no prediction for 'druggable' and ' nondruggable' compounds, due to this concept the discovery of drugs taken faster track. This concept easied the drug permability into the body. Rennin is a complex target, many attempts failed to find a small molecular inhibitor. Finally, Novartis discovered a hidden binding pocket and prepared Aliskiren which is then acted as high-affinity inhibitors. Many of the drugs are 'hard won' discoveries. AstraZeneca appeared to be successful with their thrombin inhibitor Exanta (ximelagatran) which was approved in Europe in 2004 and withdrawn due to liver damage, short half-life and noncompliance with wafarin (therapy point). The well established protein and antibody therapeutics, the emerging field of RNA interference technology, stem cell therapies improved medication. Few targets cannot be modulated by small molecules due to physicochemical properties of the binding site, but made them availability by therapeutic vaccines.
In conclusion drug companies today are struggling with many issues. Lack of innovation and an obsession of commercial value still pharma industries did not delivered cures to society expected. More funds have been 'lost ' by the private enterprises through the pursuit of difficult diseases in high medical need areas such as 'stroke'. Nowadays new approaches like antibody and protein therapeutics shed light on treatment of difficult targets. Emerging technologies are therapeutic and prophylactic vaccines, based on new delivery platforms promised more in tackling diseases that are difficult targets and they also could reduce the cost of innovative new therapies. New discovery need to hold following points:
Need a mechanism oriented drugs discovery where it does not cause major unwanted side effects.
Need to find a right target molecule having little or no off-target toxicity.
(The author is scientific manager with Syngene International Ltd, Bangalore)