Drug discovery and development is no more a less-trodden path for the Indian pharma industry. No wonder if select pharmaceutical players dare to challenge and transform the image of an industry, which currently triumphs in process chemistry, in the coming years.
If indications are true, several big, medium players already threw the hats on the ring by effecting sharp hikes in their R&D budget and many more are aggressively readying themselves for the big plunge, thanks to the product patent regime which is on the threshold.
Generally compared to a high risk gamble, the pursuit for new chemical entities (NCEs) is so far a terrain restricted to the Big Pharma. The cost of taking a molecule from the lab to the market place is estimated at an average US $ 800 million. (This is apparently double the size of the largest Indian player.) Here, the stakes are too high. You screen 10,000 compounds and only 250 of them succeed even for pre-clinical stage. Out of which only a handful reaches clinical testing. And very few, perhaps a single molecule, finally make it to the market.
Yet, the returns in this gamble can be amazingly huge if that single molecule hits high by turning out to be a blockbuster. The success will bring in a fortune. A windfall. Nevertheless, if you lose, you lose to the pit. This is the intrinsic paradox in NCE research. Only those who possessed the daring and the resource could ever think of discovery research.
No doubt, dearth of big money or lack of infrastructure pinch Indian players from entering the odyssey of drug discovery. Still, a rich pool of scientific talent and proven records in diverse research fields make them potential contenders for the great discovery race. And none can escape the clear signal - slow but steady emergence of NCE research-friendly community in the Indian pharma.
Dr Reddy's, the pioneer in Indian drug discovery research, who spends around 7.6 per cent of its revenue has recently raised it R&D spend by 79 per cent to Rs 1,375 million. The focus has been in the therapeutic areas of metabolic disorders, cancer, inflammation and bacterial infection. The company has already out-licensed three molecules DRF 2725, DRF 2593 in diabetes and DRF 4158 in cancer to MNCs for development. However, DRF 2725 was discontinued by Novo Nordisk at a late phase and DRF 4158 was returned to the company by Novartis. A couple of new leads DRF 4832 an HDL elevator and DRF 1644 for cancer are currently under development in Europe. DRF MDX 8, a treatment for metabolic disorders has been licensed to Novartis.
India's biggest drugmaker, Ranbaxy Laboratories, too is headed in the same direction. With urology, anti-infective, respiratory, anti-inflammatory and metabolic disorders as focus areas, the company has already filed a new drug application (NDA) for benign prostate hyperplasia (BPH) therapy RBx 9001. RBx2258, a selective 1µ antagonist for BPH is licensed to Schwarz Pharma AG, Germany and a VLA4 antagonist for bronchial asthma RBx 7796 has received permission from DCGI to carryout phase II studies. The antibacterial RBx 7644 is another candidate which is currently in phase I studies in UK. Other molecules which are under early stages of discovery are: RBx 9841, RBx 10146 for overactive bladder; RBx 11160, an anti-malarial and RBx 6198 for BPH.
To support research programmes, Ranbaxy has a number of collaborative networking with National Academic Institutions/ Universities (CSIR, DST etc.), International Research Institutions and Universities (USA, UK etc).
Recently, Ranbaxy announced a joint R&D venture with GlaxoSmithKline to share their respective resources and expertise. GSK will have the exclusive commercialisation responsibilities worldwide, while Ranbaxy will take the lead in India.
The Mumbai-based Wockhardt Ltd, which spends around 6 per cent of the sales turnover has also earmarked a considerable proportion of the fund for new drug discovery, has anti-infectives, antibiotics and anti-bacterials as thrust areas. The early phase trials of its first NCE WCK-771 has been found effective in methicillin and vancomycin resistant infections. The other anti-infectives WCK-1152, WCK-1456 have also reportedly found promising against respiratory infections.
Nicholas Piramal India Ltd's R&D budget in 1998-99 was Rs 24.6 crores (5.7 per cent of turnover) which came down to Rs.9.2 crores in 1999-2000 (two per cent of turnover). The company has committed four per cent of its sales to R&D expenditure in 2002-03. Two of its NCEs, the anti-cancer IM-962, a joint research initiative with a US company and Aablaquin, a product licensed from CDRI, are undergoing clinical trials and the company feels that atleast three of its five NCEs currently under research should reach clinical trial stage this year.
Lupin's research in NCEs uses not only the customary chemical synthesis route but also herbal based leads in anti-migraine, anti-TB therapies. It filed an IND for migraine therapy for intra-nasal administration in 2002. The company has also identified 3 compounds that have demonstrated significant in vitro and in vivo activity against sensitive and resistant strains of M.tuberculosis. Pre-clinical studies are in progress. Lupin is expected to start clinical studies for its psoriasis drug once DCGI approves its NDA which was filed last year. This plant based drug lead has been developed in association with the Lucknow-based Central Drug Research Institute and the Chandigarh-based National Institute of Pharmaceutical Education and Research (NIPER), Chandigarh.
Torrent Pharmaceuticals Limited (TPL), the flagship company of Ahmedabad-based Torrent group has licensed a cardiac NCE, Cardace to Novartis. It is said to have invested over Rs 100 crore for R&D and has shortlisled a few potential leads in anti-arrhythmic, AGE Breaker, DPP-IV Inhibitors, peptidase inhibitors, HSP upregulators and PTP-1B inhibitors.
Evidently, an increased, vigourous activity in basic drug research is visible in madcap players as well. For instance, the Mumbai-based Glenmark targets PDE4 inhibitors and beta3 agonists for asthma and obesity categories. Over the past 3 years the company has identified several lead candidates including GRC 3015, GRC 3566, GRC 3590 and GRC 3785 as therapies for asthma and COPD and GRC 1087 against obesity/diabetes. The leads are said to be in different stages of pre-clinical development.
Likewise, Orchid Chemicals and Pharmaceuticals Ltd, Chennai's drug discovery programme has also been formally announced recently through screening a number of compounds in anti-infective and pain management segments.
Many more big to midsize companies who are into formulation/NDDS research like Sun Pharma has announced NCEs as the highest priority area in the immediate future. Sun spends nearly 4 per cent of its turnover to a total of Rs 1857 has set aside Rs 40 cr investment towards projects in NCE and novel drug delivery systems.
Despite all these efforts towards NCE research, a certain section of the industry is still feel sceptical about the future of drug discovery in the country. A little dose of chemistry along with a bit of toxicity studies alone won't make the highly complex, skill-intensive, infrastructure-oriented drug discovery process, they opine. ``Some companies claim in-house R&D expertise. Very few companies can aspire to have such in-house expertise. How's clinical research possible without real-time patients or in-hospital environs?'' asks a leading clinical pharmacologist from Mumbai.
According to him, not only for the mandated clinical studies but for the pre-clinical evaluation also we don't have the right sort of infrastructure or the regulatory environment. A lead molecule requires to be studied in higher animals like primates to assess its toxicity profile. Study in higher forms of animals is not allowed so far, in India. Without mandated toxicity/ safety data our NDAs would not get legitimacy in the regulated markets.
There is no quick-fix solution or shortcuts for the lengthy, years long process of drug discovery. We have to have the right kind of corporate mindset. Several of our companies are forced to turn to basic research as they see no other option to survive in the post-GATT era. Such experiments without adequate expertise will fail fast. This is perhaps the reason why many of our companies miserably fail to obtain approval for clinical studies for their in-house molecules even in our own country, he concludes.