The failing heart: a new therapeutic approach

Heart failure is one of major cause of death among people both in developed and developing countries. After 40 years of age, the lifetime risk of developing heart failure is 20% for both women and men. In its most common manifestation, heart failure is marked by a decrease in cardiac contractility and called systolic heart failure. To preserve cardiac output, the body increases sympathetic tone and activates neurohormonal pathways (a cascade of intracellular events occurring inside the cardiac muscle cells). These compensatory mechanisms can, however, accelerate the decline of cardiac systolic function. Patients die because of progressive weakening of the heart leading to cardiac remodelling, which further weakens it and can also cause deadly arrhythmias (irregular heartbeat or abnormal heart rhythm). Therefore a group of scientists thought that if the failing heart could be strengthened, the outcome might be more favorable. This group of researchers working at Cytokinetics, Inc., San Francisco, CA, a pharmaceutical company, recently published their exciting and very promising findings about  a small-molecule drug — omecamtiv mecarbil — that selectively enhances the activity of the motor protein myosin, the main force-generating protein of the heart.

Let us first understand the underlying mechanism of heartbeat. The sarcoplasmic reticulum (a organelle inside the striated muscle cell), major functions of which is to  release calcium ions (Ca²⁺) into the cytoplasm of the heart-muscle cells in a synchronized manner  as shown in following figure (Source: Bers & Harris, Nature 2011, 473; 36–39). The Ca²⁺ activates myofilaments — organized structures in the cytoplasm composed of interlocked (like the fingers of folded hands) filaments of either actin or myosin proteins. On activation, each myosin filament simultaneously grabs and pulls on an actin filament, in a process that uses the cellular energy molecule ATP. The coordinated contractile activity of the myofilaments develops the forceful muscle contraction that ejects blood from the heart. In heart failure, a reduced amount of Ca²⁺ is available for release by the sarcoplasmic reticulum, contributing to weaker myofilament activation and contraction.     

First line of drugs to teat heart failures were, inotropic drugs —that enhance contraction at a given ventricular volume — by enhancing the Ca²⁺ signal that activates contraction. But many of these drugs actually overload cardiac muscle cells with Ca²⁺, increasing both energy consumption and the risk of arrhythmias and therefore worsen a patient's prognosis. Now these drugs are not that widely used these days. Most widely used type of drugs to treat patients with chronic heart failure are β-blockers, ACE inhibitors, and ARBs, which are not inotropic drugs. These drugs block neurohumoral signalling by adrenergic and renin–angiotensin pathways. Heart failure is accompanied by a neurohumoral storm that activates these pathways by fuelling progressive remodelling and dysfunction. Thus blocking these pathways can slow the progress of heart failure. However, these drugs also increase heart rate and myocardial oxygen consumption and can produce arrhythmias and hypotension or low blood pressure, which contributes to higher mortality.

Dr. Fady Malik and co-investigators hypothesized that directly activating the contractility of the cardiac sarcomere (the smallest functional unit of cardiac muscle fiber) would improve cardiac performance while avoiding the adverse effects of indirect mechanisms. The sarcomere is made up of interdigitating thin and thick filaments. Myosin, the main component of the thick filament, uses chemical energy derived from ATP hydrolysis to produce force for contraction. Myosin motors act upon thin filaments composed of actin and the troponin-tropomyosin regulatory complex. In resting muscle, the free calcium concentration is low, and the regulatory proteins prevent myosin from interacting with actin. During each heartbeat, calcium is released transiently from the sarcoplasmic reticulum into the cytoplasm, where it binds to troponin and allows myosin to interact with actin filaments and to produce contraction. The muscle relaxes as calcium is removed from the cytoplasm.

In this report recently published in Science, (2011, 331 (6023): 1439-1443) this team established that omecamtiv mecarbil — also an inotropic drug — increases heartbeat strength by selectively enhancing the ability of the myosin molecule to generate force (see above figure). They demonstrated that omecamtiv mecarbil enhances cardiac output without changing the level of consumption of oxygen and ATP (molecular unit of cellular/chemical energy) by the heart. As the heart weakens, it receives less nutritive, oxygen-rich blood (that is, the heart pumps blood through its own coronary arteries), which further limits cardiac contraction. By augmenting force while avoiding extra energetic costs, omecamtiv mecarbil increases the apparent efficiency of cardiac contraction and preserves the energy supply–demand balance.

Though tested in a dog model of heart failure, omecamtiv mecarbil holds lot of promises as a selective activator of cardiac myosin, and a rare example of a drug whose action depends on activation rather than inhibition of an enzyme, an approach that may have broader application for therapeutic intervention. Further studies in patients with heart failure will eventually define the clinical benefit and risk profile of cardiac myosin activation in a condition that is still marked by substantial rates of mortality and morbidity. Also this drug gives a new direction of research in which more drugs need to be developed to activate cardiac myosin as a new therapeutic approach to treat heart failure conditions.

For details, please read the article:
http://www.sciencemag.org/content/331/6023/1439.full

Economics of drug development

A friend of mine recently quipped that pharmaceutical companies make lot of profit and also they put high price tag on their products than the real cost on the name of research and development. Obviously, this gentleman was completely oblivious of the procedure of drug development. Though, I do not want to go into the details of the politics and economics of drug development, however, I thought it was good idea to let people know the basics of drug development.

 

The discovery and development of new drugs is a very lengthy and costly process. Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average, about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing.

In the research-based drug industry, research and development (R&D) decisions have very long-term ramifications, and the impact of market or public policy changes may not be fully realized for many years. Recently it has been estimated that the cost of bringing a new drug to market ranges up to 1.3 billion US dollars. Thomas Lönngren, former chief of European Medicines Agency (EMA) for almost 10 years, recently complained that of the estimated US$85 billion spent globally each year on drug research and development (R&D), around $60 billion was wasted while very few new drugs (some of them are still in question for their efficacy and toxicity) were produced. In the area of Cancer Research itself, currently, almost 900 novel cancer agents are undergoing investigation in more than 6,000 clinical trials. Owing to this large number of investigational agents, a critical lack of financial and patient resources significantly reduces the chances for adequate development of many of these agents. As a result, clinical drug developers require continual innovation in their approaches to best determine which drugs to develop further, in which patient population to test the novel agents, and how to maximize resources.

            Undoubtedly, drug discovery is a big challenge, as for every new drug that is approved on average $1 billion is spent on research, at least 10 years of development are required, and nine of every ten drugs fail. With the blockbuster pipeline drying up, increasing drug development costs, and higher regulatory standards for drug approval, innovation has become even more difficult. Also, the cost of a new drug has direct bearing on the organizational structure of innovation in pharmaceuticals. With the same context, it is important to note that higher real costs in research and development of drugs have been cited as one of the main reasons underlying the recent trend toward especially in last 3 years, more mergers of big pharmaceutical companies. According to Boston Consulting Group, which published their study in 2001, average 880 Million US dollars spent to develop one single drug, have following components of costs estimates:

Component                 Pre-approval Cost (in US $ Million)

Biology                                     370 (42%) –

Chemistry                                 160 (18%) –

Preclinical safety                        90 (10%) –

Overall preclinical                    620 (70%)

Clinical                                    260 (30%)                             

Total                                       880 (100%)

 

             We have reaped extraordinary benefits from the pharmacological revolution of the twentieth century. Diseases such as such as polio, diphtheria, and whooping cough have almost been eliminated in developed countries by extensive use of vaccines. Many fatal communicable diseases can be readily cured with antibiotics. Complex surgical procedures such as heart surgeries, organ transplants are now safely and effectively undertaken using modern anaesthetics. And drugs have improved the quality of life for many people with chronic diseases such hepatitis B, and C, vascular diseases, and diabetes, to an extent that would have been unthinkable in the first half of 20th century. Nevertheless, there remains massive unmet medical need in both developed and developing countries. For example, there is a growing requirement for effective vaccines against HIV/AIDs, malaria and tuberculosis. We have little to offer those with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease or Huntington’s disease. Current treatments for many psychiatric disorders leave much to be desired. And the outlook for patients with the most common advanced malignancies, such as lung, breast, prostate and colorectal cancers, is still poor.

             However, it must be acknowledged that most of the drug related R&D related research has been sponsored primarily by pharmaceutical industry in North America and Europe. Also, government agencies such as NIH and few others in Europe have been contributing significantly financially   towards new drug developments. However, it is a reality that people from developing countries are equally being benefitted by all the developments in biomedical sciences without investing their share of cost. It must be noted that the increasing cost of drug development is likely to promote the situation whereby companies invest only in the development of those new drugs that are expected to yield peak annual sales greater than US $500 million. It is also worth noting that completely novel drug development — that is, against unproven disease targets— poses a greater risk of failure than developing drugs against proven targets, which means the diseases whose mechanisms have been largely deciphered versus those which are still being explored. This provides additional incentive for companies to focus on improving on approaches that have been clinically and financially successful, and a disincentive to develop products for unmet medical needs. In summary, the fact that the discovery and development of a new drug now costs in excess of US $800 million, and is rising at an annual rate of 7.4% above general price inflation, raises concerns. If the pharmaceutical industry’s R&D efforts become concentrated solely on high-selling products, the outlook in many areas of pharmacotherapy — in particular those in which the risk of failure is high — is bleak. Not only will less common conditions be ignored, but many of the potential benefits of knowledge about advances in genomics will not be realized.

           With the advancement in genomics and proteomics, the future of pharmacotherapy in the twenty-first century should be bright. Our capabilities to meet unmet clinical need should be great. We are, though, in danger of jeopardizing this potential if we do not make every attempt to reduce the cost of drug development. It will not be easy; nor will it be uncontroversial. There will be political, social and legal challenges to be addressed. But if we do not work towards this goal, we will fail future patients, their families and society as a whole. And this will and should not be expected alone from pharmaceuticals. Governments in countries whose economy is booming such as China and India must ensure sufficient funding for research into new medicines, especially for curiosity-driven science. Basic research might not have an immediate effect on medical treatments, and because of the short-term nature of research based on academic review cycles and shareholder dividends it is always difficult to get adequate funding. However, history shows us that in many instances it is such “untargeted” research that has led to major scientific advances. Also, now this is high time when developing nations must realize their responsibility and share the costs of drug development by investing into biomedical research initiatives and forcing their local pharmaceutical companies into start new research and development efforts rather than let them flourish as only money making companies that make only generics.

a good article to read about scientific reputation

http://www.nature.com/news/2011/110506/full/news.2011.270.html