The great Indian cancer drug rush

The great Indian cancer drug rush

Bangalore: Over the past year, India’s large pharmaceutical firms have started working towards having enough cancer-fighting drugs in their product pipeline, reflecting a global trend where companies are rushing to tap a market that is estimated to touch $57.6 billion (Rs2.3 trillion) in sales by 2010, according to market research firm IMS Health.

To the companies, such a pipeline could mean higher revenues and profits. To cancer patients in the country, it could mean affordable drugs.

Some of the firms have expanded their existing oncology divisions. Others have made fresh strategic investments. Still, analysts say companies will not find it easy to reap profits—in a market that is growing at double-digit rates—because market forces will push down the prices of me-too drugs with modest survival rates.

According to Karan Singh, a partner at consulting firm Bain & Co.’s New Delhi office, firms are focusing on oncology because of higher realization (or profit margins) on the drugs. “But as competition increases, only drugs that can prove true survival benefits can command premium pricing."

Singh says companies will not be able to justify “historical pricing" and that to be successful, they “will need (to do) more than rushing a me-too compound to the market". Over the next five-seven years, patents on several cancer drugs will expire, resulting in the consequent rush of generics or off-patent drugs, and the fall in prices.

However, because a large number of current therapies in cancer aren’t any good, there’s room for improvement. Most of these therapies use traditional cytotoxic drugs—ones that fight cancer by killing tumour cells—which wreak havoc on the healthy cells of the body, sometimes causing side effects as lethal as the disease itself. And, most research is being done to find newer and better ways to fight the condition, not prevent it. “Most of the world is working on antibodies, with a handful interested in vaccines," says Harish Iyer, head of research at Biocon Ltd in Bangalore.

Biocon is working on an antibody-derived cancer vaccine with its Cuban partner, CIMAB Institute.

Inside the pipeline

Companies are tight-lipped about what’s cooking in their research departments in terms of cancer drugs, but most of them do seem to be developing traditional small-molecule drugs, largely generics; tinkering with existing drugs to deliver them in a new form; testing monoclonal antibodies; or developing therapeutic proteins. A small-molecule drug is one with a molecular weight between 300 and 700 atomic mass unit (amus); each amu is one-16th the mass of an Oxygen atom. Monoclonal antibodies are those produced by one variety of immune cells and they are used to activate the patient’s immune system into fighting the cancer cells. Therapeutic proteins are those developed in laboratories to fight diseases such as cancer and HIV/AIDS.

Iyer says although it is easy to develop small-molecule drugs and establish their efficacy, they come with the threat of long-term toxicity, or being dangerous to users if used for a long time. However, most traditional drugs, including small-molecule ones, fail safety tests. In contrast, biotech drugs rarely do because of their molecular specificity, or specific impact of the drug.

“We’ve looked long and hard at small molecule and decided to not go that path," says Iyer. Besides the already approved BIOMAb (MAb stands for monoclonal antibody and all such drugs usually have names ending in this), the monoclonal antibody for neck and head cancer, Biocon has another antibody applicable to cancer, but the company is currently testing it for auto-immune diseases, he adds.

Nicholas Piramal India Ltd (NPIL) has three new chemical entities (NCEs) for cancer, all small-molecules derived from natural products. It is the first Indian company with an investigational new drug application for a cancer drug with the US Food and Drug Administration (FDA), that country’s drug regulator. NPIL’s P-276, an injectable, is a new molecule for multiple myeloma (a deadly form of blood cancer), which enters phase-I clinical trial at four sites in the US in the next two months and is slated for launch around 2010.

“Our second molecule is an oral compound of P-276 indicated for blood cancer," say Swati Piramal, director, strategic alliances and communications, at NPIL.

Piramal adds that it is not easy to develop new cancer drugs because clinical trials take a long time to be completed as they have to watch whether the cancer recurs.

The firm with one of the largest anti-cancer drug portfolios in India is Dabur Pharma Ltd, which entered the oncology area in 1993—it has 15 products in its pipeline. Many of these are generics meant for Indian and global markets.

“From there we’ll take it to the new drug delivery systems. We launched Nanoxel earlier this year, which uses nano-particles to deliver the popular chemotherapy drug paclitaxel, and we’ll next use liposomes (a double-walled, artificially-made vesicle made of natural products like phospholipids and cholesterol) as the delivery vehicle," says Surendra Tyagi, chief scientific officer at Dabur Research Foundation in Noida, who believes the nano-tech-liposome platform used by Dabur can be applied to many drugs.

Nanoparticles and liposomes are essentially delivery systems that deliver drugs more precisely to the disease site for better efficacy and reduced side effects. For instance, a water soluble drug such as paclitaxel is normally coated in a castor oil solvent, cremophor, which is quite har-mful for the body. But coating paclitaxel in a nanoparticle, instead of cremophor, dramatically reduces the side effects.

Paclitaxel is one of the most popular chemotherapy drugs with a wide spectrum of anti-tumour activities and is currently used in ovarian, breast and lung cancers.

“This is a good way of retaining the benefits of old molecules while avoiding the side effects," says Tyagi. The company is now looking to do this with Aventis’ ovarian cancer drug Taxotere (docetaxel), which is similar to paclitaxel.

A few companies are also looking at biosimilars or generic versions of biotech drugs. However, the regulatory pathway for these in the US is still unclear, although Europe has started approving some.

Analysts claim price differentials between the original biotech drugs and biosimilar products will not be as high as in small-molecule generics because the manufacturing process is very complex and not many companies have the requisite capabilities.

Not a fan of biosimilars herself, Piramal says these are 100% more expensive than small-molecule generics. The conditions they are supposed to treat also “develop resistance (to them) much faster", she adds. Among the Indian firms following this route are Glenmark, Dr Reddy’s Laboratories and Biocon. Glenmark’s Swiss arm is conducting research on biosimilars that can be used to fight cancer. And Biocon plans to manufacture its G-CSF (granulocyte-colony stimulating factor)—a biosimilar of Amgen’s G-CSF product Neupogen—in Bangalore. A G-CSF is a protein that promotes growth of white blood cells and is one of the first few drugs to reduce infection-related morbidity in cancer patients.

The pricing equation

Most cancer drugs available in the market today provide modest benefits at an exorbitant price. As a result, says Bain’s Singh, both FDA and the European Medicines Agency, the European Union’s drug regulator, have suggested that clear survival benefits will become the new benchmarks in future regulatory approval. That means only drugs that promise better benefits get the regulatory nod.

“This is an indication for pharma companies to stop investing in me-too drugs," he says. Due to competition, Singh cautions, the cancer market in terms of profitability would be smaller than what it is now projected to be. Companies cannot assume the ability to price their drugs high especially because there will be more generics options from which patients can choose.

The drugs will become cheaper in India because “we have competition", says Biocon’s Iyer, but “it’ll never be pennies per person treatment". A cycle of Herceptin or Avastin (often taken for a year) costs anywhere between Rs10 lakh and Rs12 lakh. But Iyer estimates that once home-grown cancer drugs start rolling out, prices may come down by as much as 50%. Biocon’s BIOMAb, for instance, is priced at least 50% less than its closest rival Erbitux from ImClone Systems Inc. Access to these drugs, then, will largely depend on the extent of medical reimbursement in the country. Even after the prices come down, the drugs will need to be paid for or subsidized either by insurance schemes or state subsidies.

The Curie Centre of Oncology on the leafy south Bangalore campus of St John’s Medical College and Hospital sees about 300 new cancer patients a month. A third of these patients require new-age biotech cancer drugs such as Herceptin, MabThera, BIOMAb, Avastin or Tarceva—inhibitors that prolong life. Less than 15% of the people who need such drugs can actually afford them.

The rate of growth of cancer in the country has remained steady, but its incidence is being seen more commonly in people as young as 30, says Dr Ramachandra Reddy, professor of epidemiology at Bangalore’s Kidwai Memorial Institute of Oncology.

However, what is indeed alarming is the rate of growth in breast cancer in India, even as rates of cervical cancer have declined, he adds.

An ageing population, chan-ging lifestyles and rise of newer forms of cancer don’t make for a good prognosis. Pharma companies say it is unfair to expect them to reduce prices.

“Our ministers only talk of price control, why can’t they evolve some mechanism to subsidize expensive drugs," says Rama Mukherjee, the former head of R&D at Dabur Research Foundation who, with seven new molecules to her credit, set up Ara Healthcare in November to develop biotech drugs for cancer and diabetes.