If India’s presence in the world of generic drugs is well established, its efforts to gain a foothold in the field of novel medicines are still very much a work in progress - an Indian-discovered new molecule has yet to receive marketing approval anywhere in the world.
The desire to see this happen is widely held by the country’s researchers, more and more of whom are being employed in the search for just this in labs of both foreign and domestic companies. It is no doubt only a matter of time and many are predicting significant advances in the next five years, although it appears unlikely that a truly novel agent will make it to a Western market in this time frame. Still, when the first approval happens the event will certainly represent a significant climb up the value chain for India’s pharmaceutical industry.
With vast knowledge of small molecule manufacture and chemistry gained from years of copying novel compounds derived elsewhere, India’s generic drug developers have been applying this knowledge to new discoveries for some time. This includes most of the established Indian drug developers like Glenmark Pharmaceuticals, Zydus Cadila and Lupin, which have been active in this space for around a decade.
Small start ups are also now emerging; Connexios Life Sciences and Incozen Therapeutics a couple of recent examples.
Considering it can take 15 years for a new molecule to reach the market, it is perhaps not surprising that these efforts have yet to generate a success story. A few molecules have made it into later stage development and there are increasing numbers approaching this stage, but the final regulatory barrier has yet to be breached, either within India or beyond.
“India is growing strongly in drug development and will make a major foray in the next five years in new chemical entities,” predicts Sham Nikam, vice president of global discovery for Nycomed (EP Vantage Interview - Nycomed planting deep roots in India, November 2, 2010).
The ever growing number of Indian companies taking this goal seriously means this prediction could well come true. And in a sign of growing activity and interest, Bio, the world’s largest biotechnology trade organisation, held its first partnering conference in India this year.
Others, however, are more circumspect, particularly when it comes to succeeding in getting a novel product approved in the US or Europe.
“In Indian markets it will perhaps take five years, but in the regulated markets it might take more,” says Chirag Talati, pharma analyst for Execution Noble.
Much of the really novel work on interesting targets, which would be more attractive to take to Western markets, is still very early stage, he says.
Innovation comes on a sliding scale and most Indian research is being conducted into well characterised modes of action – a lower risk strategy certainly not restricted to this region. This prompts a certain amount of criticism of the country’s pipeline, as being heavily focused on lower value, “me-too” molecules, but there are definitely signs that Indian research is becoming more ambitious.
Glenmark, for example, was one of the first Indian firms to invest in novel research and has gradually become much more ambitious, says Dr Neelima Joshi, vice president of the company’s R&D operations."
Initially when we got into drug discovery nine years ago we were exclusively working on clinically proven targets. There would be molecules well ahead of us in late stage, with data on safety and efficacy, so we would have benchmark compounds to compare.
“Based on that we gained a lot of internal knowledge and subsequently moved into less explored targets, where there was some literature and information on biology and chemistry, but nothing in clinical development. Now we are exploring totally unprecedented targets where there is nothing in pre-clinical stage,” she says.
This strategy has helped Glenmark successfully find partners for compounds emerging from its research labs, most recently with Sanofi-Aventis. Earlier this year the French pharma giant bought rights to its vanilloid receptor antagonist programme, for chronic pain, in a deal worth up to $325m. The most advanced candidate is in phase I.
Dr Joshi says that the five deals the company has struck over novel molecules during the last decade has brought in $140m. Based outside Mumbai, the firm’s state-of-the art facility employs 200 scientists conducting all aspects of pre-clinical work, a significant scale of activity that has been enthusiastically backed by Glenmark’s chief executive and founder, Glenn Saldanha.
No other Indian firm has managed to out-license as successfully as Glenmark, but pipelines and potential are building.
Zydus Cadila, for example, has a pipeline of eight clinical candidates, the most advanced is in phase III trials in dyslipidaemia, a PPAR alpha-gamma agonist called ZYH1. The company is focusing on metabolic disorders and pain and, like Glenmark, has no plans as yet to take these products to external markets itself, aiming to partner at a late stage of development.
Pankaj Patel, Zydus Cadila’s chairman and managing director, agrees that getting an Indian-discovered medicine to market will bring recognition, but says quality is still important.
“Obviously for any pharmaceutical company the goal ultimately is to sell its own products, it’s a dream, and we think we can become a fully integrated pharmaceutical company,” he says. “But my objective is not to be first but to be the company who has a significant product,” he says.
Dr Kamal K. Sharma, managing director of Lupin, another traditionally generic firm investing in novel R&D, describes this move as “natural progression”.
“If we are a technologically strong company, then it’s natural progression to move up the value chain. You are strong in organic synthesis, then you are strong in formulation development, then formulation technology and delivery, then the logical end is new chemical entities,” he says.
Perhaps the best example of this move up the value chain can be seen at Piramal Healthcare, which earlier this year sold its core branded generics business to Abbott Laboratories for a huge $2.12bn upfront. The standalone Piramal Life Sciences is now a pure R&D outfit, boasting several phase II candidates in oncology, inflammation and anti-infectives and deals with Eli Lilly and Merck & Co.
The asymmetry of this deal – an Indian generics giant focusing on innovation by selling its commodity business to a traditional brand-focused Western healthcare company – neatly encapsulates two distinct global strategies, and it will be interesting to see if they both bear fruit.
Novelty still in its infancy
At the same time as India’s traditional generics players are dipping a toe in the R&D world, the country is also seeing more start-ups. And here some of the really innovative work is going on.
Bangalore-based Connexios, for example, has developed a translational network biology platform to help it identify new targets in metabolic diseases, and their small molecule modulators. The company is also working on existing targets, and it is likely to reveal more details on its lead candidate shortly, a GPR 40 agonist. Few are working on this target; only Takeda has a candidate in the clinic, according to Suri Venkatachalam, chief executive and founder.
He says the company is working on filing an IND in the US, but wants to find a partner to take the compound into the clinic. This would bring in some non-dilutive funds to the company, which has so far been backed by an investment firm, Nadathur Holdings.
Mr Venkatachalam is optimistic that India’s time in novel medicines is coming, but also acknowledges that work has only really just begun.
“Companies are only now beginning to commit resources to really novel R&D,” he says. “It will be tough for many Indian organisations to change the mindset from generics and contract-lead research to proprietary novel research.”
Big challenges no doubt remain, not least the lack of structures in place that encourage the type of early stage entrepreneurship and innovation seen in the US and Europe. Mr Talati of Execution Noble agrees that the industry is still really in its infancy in India.
“We are seeing an increase in activity, but I can’t say it is growing by leaps and bounds. There are quite a few issues, there are no systems in place where Indian academia can develop something and then license it to industry, and the culture of innovation in academia is not really present,” he says.
On top of this, finding funding is tough, with few Indian venture capital firms willing to invest in early stage, high risk drug development.
All of which means the first Indian-discovered new chemical entity to reach patients is unlikely to represent a huge medical breakthrough, and it could well be launched outside the really lucrative markets of Europe and the US. But progress is being made at all levels of innovation, and the country’s journey up the small molecule value chain is gathering momentum.