Mumbai pharma plans new drugs for all

Nicholas Piramal, India’s number two pharma company, is ignoring generics and relying on R&D. First in the pipeline: a new low-cost cancer drug.

When the Director of Nicholas Piramal speaks of a global market, she means it – drugs affordable for five billion people. Moreover she’s reversed the brain drain, and attracted successful Indian research scientists back home from Western Big Pharma. She aims to use R&D to make the first totally Indian pharmaceutical. Here RealHealthNews talks to her, and to several of her staff, including the Head of Pharmaceutical R&D – recently recruited home from Merck. We ask him to tell us his story, and with him and others investigate the plans for R&D at his new company.

(Mar 06)

Nicholas Piramal India Limited in Mumbai – an outgrowth of a famous old textile business that has extensive real estate throughout the ‘maximum city’ – is forging a new path for pharmaceutical R&D in India: for Piramal it won’t be cheap generic copies of molecules researched and developed in the West, but brand new chemical entities for a foreseen multi-trillion dollar Asian pharmaceuticals market – and for poorer markets worldwide.

Already Nicholas Piramal has reached the number two position in Indian pharma, behind the massive generics company Ranbaxy, and even Ranbaxy is now stressing indigenous R&D – in the face of last year’s Indian patent law which brings India into line with the West for all new drugs.

So what’s happening? Why are Indian scientists returning? And with some of the world’s poverty literally on its doorstep, is Indian pharma now about to turn its back? To get an inside view, RealHealthNews decided to paint a quick sketch of R&D at Nicholas Piramal.

We first talked in Mumbai at Forum 9 of the Global Forum for Health Research to Swati Piramal, MD, graduate of Harvard School of Public Health and Director of the company, about her goals. Totally up-beat about the potential for Indian pharmaceuticals, she predicted she could create a new cancer drug – called NP-276 and already in Phase I/II clinical trials in Canada “with no bad news yet” – for US$ 50 million, one tenth to one twentieth the going rate among multinationals of some US$ 500 million to US$ 1 billion.

If it succeeds, the market price will be correspondingly low too, “lower than everyone else in the world”, she told RealHealthNews later (Februrary 2006). “Of course there are lots of ways you can do the accounting, including the costs of failure, and we haven’t yet succeeded making a new drug go global – but that’s our goal. I’m willing to be wrong by 100%, so on the outside it will be US$ 100 million.”

So will such a drug be available therefore to a wider, and poorer, market? “Exactly” said Piramal. “We are saying that there are five billion people in the world who do not have access to drugs that cost US$ 1 billion to create. We feel they are our market.” How can she do it? She is creating a “reverse brain drain” among scientist émigrés, she said, and could offer scientists better conditions of work and life than in the US.

One of those returned émigrés is Maneesh Nerurkar, Head of Pharmaceutical R&D. We talked to him in a beautiful laboratory, full of modern art. We might have been on the West Coast of the United States, with the Pacific rollers nearby, but this was Mumbai, and the ocean was Indian.

RHN:What’s your story, Maneesh?

Maneesh Nerurkar: I grew up in a small town in India called Indore in Madhya Pradesh – right smack in the centre of India between Bombay and Delhi. I was born into a rather affluent family – with the luxury of libraries, international travel and all that. So I was very lucky. However my parents had begun quite poor, and my father had managed to go to America to study, and returned to become a pioneer in chemical synthesis in India.

The whole ‘active pharmaceutical ingredient’ thing in India is due to some of the efforts my father made in the 1960s. India is probably [the world’s] leading manufacturer of drugs – but not in the finished dosage form, in chemical ingredients. And he helped make India realise that it can do this as a business… He and Ranbaxy’s owner were colleagues for a time.

So even though I grew up in a small town I was exposed to all these modern ideas. But they had down-to-earth values and made sure we children were not overwhelmed by the money and become materialistic. In fact I always want to be a paediatrician, and I studied hard, did well and went to Indore medical school. But there was rampant nepotism – in the first examinations, all the top people were somehow related to the professor. It was really a bad situation - I was extremely frustrated. But my father said if you want an absolutely unbiased academic environment, try America. So I quit medical college and studied pharmacy, and fundamental pharmaceutical chemistry at Kansas, which then and perhaps still is one of the foremost institutions in that field. My belief is that if you understand physical chemistry then everything else becomes relatively easy!

So I then worked at Merck, in West Point Pennsylvania – it’s had a lot of bad press over Vioxx [a controversial osteoarthritis drug] but in my opinion it’s absolutely the best pharmaceutical company in the world.

RHN:Best in what sense?

MN: It has the finest scientists in the world; and even from an ethical point of view, their emphasis on safety was so high that we used to say “if it makes it through Merck, it will make it through the US Food and Drug Administration (FDA).

So I really flourished in that environment. You are surrounded day in and day out by really really smart and intelligent people, far smarter than you are! So you can’t stagnate. But all through that I knew that I wanted to go back to India and do something for India. It was only a question of timing.

RHN:Was that an idealistic motive?

MN: It was more to do with giving something back to the country. I’ll be honest, it was not to take care of the poor or anything like that. I just wanted to do something good for the country, because America has everything. Obviously selfishly there’s a lot more one could do there, but I’d always had India in mind. The only thing that held me back was that I thoroughly enjoyed working at Merck!”

RHN:And the salaries are good too.

MN: Well these days, they can be reasonably good here too, for some positions. That was not the main consideration. Because I could have changed jobs in America many times and got higher salaries, but the work environment at Merck was fantastic. Every day I wanted to get up and go to work!

RHN:So you also needed an exciting place to come back to. How did you find this post at Nicholas Piramal?

MN: I asked my father to e-mail me a list of companies. He did so – and this company wasn’t one of them. Because it’s a relatively new company, started in 1988, and all the big companies he remembered were from much earlier.

So I wrote to them, and came and interviewed with most of them. I wanted to stay near Mumbai, as that’s where my parents were. I was literally about to sign with one in Mumbai, when I got a call from Nicholas Piramal. They’d heard of me from American contacts. I said I think I’ve already decided on a post. But they persuaded me to meet the Chief Scientific Officer (CSO), Somesh Sharma, and was heavily impressed, unbelievably impressed by him. He’d lived in the US for 35 years, so that made it easy – he understood my style of working, and my thoughts, which would most likely be very different from people who had worked only in India: it’s a very different work culture.

Secondly I could see in half an hour that he was very very bright. You need to respect your boss for something. But I said I’m committed to go to this other post, it’s difficult for me the change. He insisted, but I said no. Then when I got home I got a call from Ajay Piramal, the Chief Executive Officer (CEO) himself, saying he wanted to meet me. I was so flattered that the guy who runs such a huge organization values this position enough – obviously he didn’t know me – that he makes sure he gets someone his CSO is saying is the right person.

So I met him the next morning, and one of the things I liked was that he laid immense pride and value on becoming the first to put a purely Indian molecule on the market. And of all the things he said this one sentence grabbed me more than anything.

The second thing he said that I remember was to name the scientific advisory board – I didn’t know them, but he was proud of them and their thinking, and one was an Albert Lasker Medical Research award-winner etc., and this was so different from the usual Indian approach – where the boss is the one making all the decisions. But he said no, everything is being driven by the CSO, reporting to a scientific body. So it is all very neat, clean and clear. So I liked that also.

Money we didn’t talk about! But let me be clear, you need money! Mumbai is not a cheap place to live. Housing is very dear and many other things are rising by the day. Some things cost more than in America! But I was not seeking more money. They matched the other company’s offer. If one wants to do that one can go on forever. Every company wants to pay you five Rupees more than the other.

The hardest job was to get education for my daughter. But Swati Piramal personally gave us a lot of useful advice and got me in touch with the best schools in Mumbai. I valued her empathetic approach. So I joined.

Now, every day I hope that I can reproduce the Merck culture here. That’s what I tell all the people who report to me – that I want to create Nicholas Piramal as a mini-Merck.

Investing in people is very important. We expect to reach 400 people in 2006. 10% of our scientists have experience abroad.

RHN:How did you build the team?

MN: Somesh [the CSO] has concluded it’s very difficult to get biologists in India. The hurdle is not chemistry at all, it’s biology.

Ramani Aiyer, Head of Strategic Planning, R&D, expands on this:

Ramani Aiyer: Anything that’s development type work, whether it’s chemistry or pharmacology or the pharmaceutical R&D process, I think we have pretty good strengths. But what we don’t have is strength in [biological] discovery. So discoveries where you really have to understand biology are all challenges.

And the reason is that India hasn’t had a history of discovery for the last 30 years. That was the result of our 1970s patent law. Until the 1970s the country was dominated by [foreign] multinational companies, and there was no indigenous pharmaceutical industry. So the government decided to develop it by banning product patents and recognizing only process patents... That’s primarily responsible for the growth of Indian pharma. It was a government strategy.

However, this strategy killed innovation, except in processes, said Aiyer. But now the revision of India’s patent laws in 2005 to include intellectual property in products will bring R&D to the fore, he believes.

RA: It’s really exciting. If you look at oncology, our first molecule, NP-276, is a CDK4 inhibitor, which inhibits the cell cycle. The neat thing about this is that it is very specific to cancer cells, which is the new paradigm. The target in inflammation is TNF alpha, but what we’re doing here is that rather than looking at TNF alpha blocking, like Enbrel and Remicade, we are looking at inhibition of TNF alpha production. And we are looking at small molecules, not biologicals.

Then in diabetes – we want to look at very specific, focused insulin sensitizers; and in infectious diseases we are looking at an exciting antibacterial [which is active against MRSA, methicillin-resistant Staphylococcus aureus], we have an exciting antifungal too but we can’t do everything at once.

And we’ve in-licensed a technology from Canada to make vaccines. There are several components in a vaccine; the antigen of course, which is the immunogenic portion; we also need an adjuvant, which boosts the immune response; and we need some vehicle in which this thing can be delivered. All are very important. This novel technology has the characteristics of both a vehicle and a very good adjuvant.

RHN:So as well as basic discovery you could also in-license an antigen and put it in this vehicle.

RA: That’s right. So we are sourcing for antigens. Marry the two, and we’ve got something.

So that’s our integrated drug discovery approach. We are not in the business of target identification and validation. But we do have chemistry, isolation of products going into lead optimization, and a strong cheminformatics group, with a couple of mathematicians who trained in maths and statistics but dabbled in chemistry. Our rigour of analysis comes from them, applying computational techniques – in-silico techniques – to look at chemicals and predict how they’ll behave on a particular target. And we have pharmacology, with all the pre-clinical studies.

We have about 12 different programmes, and I expect several entities to be in IND territory [the step before clinical trials] in 2006.

We also have a lot of collaboration. There are a lot of pockets of excellence in Indian academia, and we want to tap into our own backyard – because clearly we can’t discover everything ourselves.

So we have a collaboration with a university in Chennai, looking at Southern Indian medicinal plants for anti-inflammatory drugs. Likewise we have very exciting work looking at novel targets in antifungals. We’re looking at DNA in fungi that won’t overlap DNA in humans, and therefore probably won’t be toxic, if you make a molecule to inhibit it.

I said we don’t do target discovery but this is an exception. So we are dabbling in serious biology by funding some of these academia – so over the next five years we are hoping to build some capability.

And we want to start an in-house teaching programme, to support post-graduate education. So we are talking to local universities about affiliation as a centre for PhD and post-doctoral programmes. So some of our senior scientists would become adjunct or affiliate professors, under whom people can do PhDs.

That way we can retain very bright people who join us for an MSc but then leave and go abroad to do a PhD. If we can offer that here we can retain them. We’ll do the same thing with post-doctoral fellows. It’s our contribution to the country.

Then in the laboratory, Sunil Deshmukh – a senior scientist responsible for microbiological activity – told RealHealthNews where many of the new molecules were coming from: Indian flora.

Sunil Deshmukh: We collect them from high altitude to ground level North to South, in altogether different climates, from hot springs, dung, rivers, marine water, historic monuments, anthills, mines – everywhere. I personally believe a lot of bioactive compounds will come from marine water.

We’ve already got 50’000 micro-organisms, 5’000 endemic plant extracts,

17’000 fungi – tropical countries are not well-explored for them, so there are many new species to find.”

RHN:Who collects these?

A lady colleague, Shilpa Verekar, spoke up.

Shilpa Verekar: We do – we personally go out. I’m from Madhya Pradesh, with experience of screening against micro-organisms, at Masters level. I dropped my CV in everywhere and was very lucky to get here. I think this is a fantastic environment to work in. You work on a lot of new things, the people are cooperative, from senior to junior there’s transparency.

Sunil Deshmukh: Yes, you can approach our CSO without any appointment…”

Shilpa Verekar: “That’s the best part. It’s not your qualification or seniority that matters, it’s what work you put in. Our CSO values people for their work. That encourages us.” RW

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