‘Synthetic chemistry is ahead of biological sciences in India’

Merck Research Laboratories, the research arm of Merck & Co, Inc employing close to 10,000 people in research, carries out global R&D in wide therapeutic areas and had a research budget of $2.8 billion in 2002. With a third of group sales coming from projects discovered outside MRL, it has well delineated process of partnering and doing research with top R&D firms. Dr Lewis R Mandel, a biochemist and pharmacist from Columbia University joined MRL in 1964 and retired as VP for External Scientific Affairs recently. Now Director, Academic Programmes, Dr Mandel was recently in India looking for prospective external growth opportunities for MRL when N V Ramamurthy of Express Pharma Pulse caught up with him to elicit his views on Indian research and issues related to R&D in general. Excerpts:

Now that you have completed your trip to India and interacted with scientists, what are your first impressions about pharmaceutical research in India?

Clearly, the scientific and intellectual capabilities in India are high. I was particularly impressed with the fact that many of the laboratories are moving toward novel drug discovery for new chemical and biologic entities, rather than just focusing on generics in one form or another. There seems to be an entrepreneurial spirit among the scientific community to participate in the discovery of breakthrough drugs; background and talent are being put into place and, with the forth-coming change in patent law, pharmaceutical research in India will work toward becoming competitive with the rest of the world. India is doing a good job in improving existing molecules and mechanisms, but the greater challenge is to identify totally new molecules and mechanisms, in order to achieve breakthroughs in therapy for human health.

What are your observations about our strengths in synthetic chemistry?

Synthetic chemistry appears to be ahead of the biological sciences in India. However, as noted above, there seems to be a disproportionate level of effort directed towards developing analogs and derivatives of known molecules rather than seeking totally new structures with novel pharmacophores. On the development side, the skill set appears to be very high in the areas of process chemistry, synthesis of active pharmaceutical ingredients, and branded generics.

You’ve said that MRL does research with an in-depth and agonizing analysis and that the strategy of doing R&D is different from others. Could you elaborate with examples?

In terms of our research strategy, the focus of Merck Research Laboratories (MRL) is on the conduct of innovative research. That is, our focus is on discovering and developing new therapeutic targets and agents which will lead to the development of breakthrough medicines.

In order to do this, we hire for scientific excellence. We also have detailed peer review of all projects, both new and ongoing, and the peer review process includes both internal and external review, for example with outside scientific consultants or with our Board of Scientific Advisors. Finally, in addition to striving to develop novel therapies with potency and selectivity for the desired target, our researchers also insist on ensuring the safety of all new molecules. In all that we do, we follow the George Merck ethic “We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear.” George W. Merck, Dec. 1, 1950. To highlight the arduous process of drug development, I will outline a few examples of programs that experienced some setbacks along the way, but ultimately resulted in success.

Among the stories included in this category are those of Mevacor and Zocor, amongst the first HMG-CoA reductase inhibitors/statins, the angiotensin converting enzyme inhibitors (ACEIs) Vasotec and Prinivil, and the leukotriene D4 antagonist (LTD4) Singulair. The development programs for each of these successful products were of heroic proportions.

In the case of the statins, we were advised by an outside party of a toxicity that occurred with their molecule that would carry over to ours; years of research ruled out this possibility and Mevacor, followed by Zocor, successfully emerged. In the case of ACEIs, the aim was to generate a superior molecule by eliminating potential side effects associated with the chemical structures of earlier drugs; we succeeding in doing this with the introduction of Vasotec. Finally, the LTD4 antagonist programme, which emanated from one of our smaller laboratories (thus, an example that size is not pivotal to success), experienced numerous challenges; nevertheless, the researchers working on this important programme believed in the target, persevered and now te marketplace has Singulair, a very important therapy for the treatment of asthma, and now allergic rhinitis.

In considering molecules discovered outside MRL, we undertake a detailed due diligence review of all available data before committing to license the entity. Examples of successful licensed-in products include Cozaar, Fosamax, and Prilosec. The identification and subsequent development of Fosamax was largely due to the diligence of a Merck researcher, the leader of our world class bone biology group in our Pennsylvania laboratories. In addition to focusing on our internal research efforts, this particular researcher was also keeping abreast of external research and identified a drug in early development from a small European pharmaceutical company. Following a careful due diligence review, the molecule was licensed in to Merck and an in depth research and development programme ensued, ultimately leading to the marketing of the first bisphosphonate for the treatment of osteoporosis. In the area of hypertension, as part of our continual efforts to achieve excellence in our research efforts, we capitalized on an opportunity from Dupont to develop one of the first compounds known to target angiotensin II. Following a significant joint effort, Cozaar, an angiotensin II antagonist, was successfully marketed. Finally, in the course of our assessment of the product portfolio of a major European pharmaceutical company, we identified the first known proton pump inhibitor, an alternative to and advancement over the H2 blockers for the treatment of gastrointestinal disorders, such as ulcer, gastroesophageal reflux disease (GERD or heartburn), and other conditions involving excessive stomach acid production. Development efforts led to the development of Prilosec, the first marketed proton pump inhibitor.

Could you tell us a little about the nature of MRL’s worldwide licensing and external research networking and how it synergizes with internal R&D and overall objectives.

MRL has a worldwide external research networking operation to support licensing efforts. We have scientific liaisons in Japan (established 1973), Europe and Australia (both established 2002), and we mounted the Emerging Scientific Market Initiative for the rest of the world in the middle of 2001. We interact broadly with laboratories from industry, academia, and government. Our goals are to identify novel project and product opportunities, with the primary focus being new chemical entities (NCEs). Secondary focuses are new biologic entities (NBEs) and platform technologies.

From our experiences, we understand that both internal research and external opportunities can lead to the development of successful marketed products. External opportunities are viewed as a valuable source of new products; in fact, our yearly R&D objectives contain a significant number of licensing objectives. We realize that opportunities can come from both internal, innovative research and from external sources; we aim to capitalize on both sources to ensure the success of our overall R&D objectives. Our efforts are complimentary and are the foundation for success.

What are the types of licensing MRL normally gets into with external research teams?

MRL’s agreements range from the in-licensing of specific chemical and biologic entities through the establishment of joint ventures and all in-between. An example of a straightforward in-license is Kyorin’s PPAR alpha/gamma agonist KRP-297 (now known as MK-767), and an example of a joint venture is the work with Schering-Plough on a new cholesterol absorption inhibitor known as Zetia. We also work with our partners on a angle of enabling/platform technologies; these include formulation and drug delivery systems to optimize Merck products and product candidates, platforms to enhance our work in proteomics and genomics, and agreements to acquire samples of new molecules to populate our chemical compound repository.

I won’t ask why MNCs shied away from doing basic research in India during the process patent regime, but now in the changed scenario post-2005, don’t you think it makes immense sense for drug majors to invest resources here especially when there is no dearth of intellectual expertise and India additionally has a vast ethnic population as trial subjects that could be conducive to affordable clinical trials? There still appears to be hesitation.

We agree that it definitely makes sense for major pharmaceutical companies to begin to invest more resources in India. My 2003 visit to research-based organizations in India is evidence of our commitment. We recognize that the country has a patient population conducive to clinical trials. Unlike others, however, Merck does not have a current business presence in India. The environment will ultimately dictate the level of the investment. In 2005, policies which permit a climate more conducive to drug discovery and development, and the maintenance of innovation, will be in place; this can only enhance the level of research investment in India.

It is generally felt, in this part of the world, that the figure of $800 million for an R&D molecule is quite hyped. Isn’t there a good amount of cushioning of costs in inflating this figure? What according to you are the broad break up costs of this entire chain of discovery?

This figure comes from independent studies, conducted and ultimately published by outside organizations such as The Tufts University Center for the Study of Drug Development. According to a recent Tufts study, clinical trials are becoming larger and more complex. For example, the number of patients in a new drug trial has increased from approximately 1,300 in the early 1980s to more than 4,000 for a typical new medicine today. The number of medical procedures per patient in trials, such as blood tests and other measurements, are also on the rise. In addition, the drug discovery process now requires investment in costly new diagnostic technologies. On the positive side, new technologies should provide the best research organizations the tools they need to operate more efficiently.

What is your honest opinion about generic companies? Don’t they have a place in the pharmaceutical/healthcare scenario?

We support the use of generic medicines. They are important to patients who want to get the best value on prescription medicines.

However, our business strategy is based on developing breakthrough medicines that represent true advances in patient care and we defend our patents in accordance with the applicable patent laws.

The present product patent protection enhanced to 20 years (since 1995) and making available practically an entire global market in the beginning, enables any R&D firm to recover costs and make profits for future R&D investments also. Why then evergreening of patents and all the court battles against generic players? Should large pharma companies fritter away energies after having extracted the best out of that product?

Merck respects both the letter and the spirit of the patent laws. When Merck scientists develop inventions that make a real difference to patients, we defend them vigorously. However, Merck does not exploit the law simply to delay inexpensive generic medicines. To do so would be inconsistent with our values and erode the confidence of our customers in how we conduct our business. We support the use of generic medicines. They are important to patients who want to get the best value on prescription medicines. Our business strategy is based on developing breakthrough medicines that represent true advances in patient care.

With the foray of genomics and biotechnology, how do you see the future of drug discovery and the drug industry in the coming decades?

This is the most exciting time in the history of drug discovery, and the environment for innovation could never be better. With the advent of proteomics, genomics, and other biotechnologic tools, we believe the outlook for innovation is terrific. We will seek to establish relationships with partners throughout the world. We are optimistic that India will play an important roll in the discovery of novel drugs and their development for the myriad of unmet medical needs that remain.