Curious Bends – Warren Anderson, handheld malaria detectors, ancient Indian science and more

1. Warren Anderson, who faced one of history’s worst industrial disasters, is dead

“After he became chairman and chief executive in 1982, he improved productivity and sales, and acquired several companies, including STP Oil. Ecologists said Union Carbide began shaking off the reputation as a polluter that had long dogged it. Mr. Anderson ruled over an empire with 700 plants in more than three dozen countries. Then came Bhopal. For the first time in his life, Mr. Anderson couldn’t sleep; at one point he holed up for a week at a hotel in Stamford, Conn. He and his wife, Lillian, spent evenings reading newspaper articles about the tragedy to each other. When they went to restaurants, he was afraid to be seen laughing because people “might not think it was appropriate,” he told The Times.” (5 min read, The New York Times)

2. A handheld device that detects malaria in 30 minutes

““The algorithms we have developed run on a smartphone-like platform and do this evaluation automatically. It doesn’t require the intervention of a skilled technician. While the qualitative test results can be known instantaneously, quantitative parasitemia levels are assessed and displayed in about 30 minutes,” said Gorthi. The scientists also believe that this portable handheld device can be modified for diagnosing other diseases as well.” (3 min read, LiveMint)

3. Modern food retailing has struggled to win customers from India’s old-fashioned merchants

“In large part it is because supermarkets are not a compelling draw in terms of price and service. Most shoppers in India buy dairy products, vegetables and fruit either daily or every two to three days, and the traditional trade has a lock on these frequent purchases, according to research by the Boston Consulting Group (BCG). Its hold weakens a bit (and the appeal of supermarkets correspondingly tightens) on rich consumers and for less regular purchases: packaged foods; soaps, detergents and other groceries; and staples, such as rice and grains (see chart). But in general even affluent consumers prefer traditional stores, because they are closer to home, are usually open longer and offer credit to familiar customers. Many will deliver free of charge.” (6 min read, The Economist)

4. The Prime Minister and early Indian science

“Mr Modi’s claims are an inversion of the logic of faith; he is asserting that the supernatural, in this case the elephant-headed god, Ganesh, is not an instance of divine magic but the consequence of human technology. He is, if you like, offering us a secular explanation for a deity in the Hindu pantheon. If this is a reasonable characterization of his claims, then the closest parallel to the Prime Minister’s thinking is to be found not in the religious beliefs of other political figures, but in the speculative theories of Erich von Daniken. Von Daniken was an enormously successful Swiss writer in the 60s and 70s who wrote a series of best-selling books based on a single conceit: the idea that the artefacts of ancient civilisation were littered with signs that pre-historical human societies were raised from their primitive state by intelligent extraterrestrials” (7 min read, NDTV)

5. For ‘Clean India’ to work, the country needs to solve its waste disposal problem

“In addition, Delhi’s four landfill sites extend over 164 acres, when the current requirement is nearly four times the available area – 650 acres, according to a 2011 report by the Central Pollution Control Board. “Even if people learn to dump their garbage at the dhalaos [a small garbage dump typically servicing a few streets of a neighbourhood], how will that help if thedhalaos can’t be emptied, since there are barely any space left in landfills,” Narain asked.” (4 min read, Scroll.in)

Chart of the week

“The death penalty divides public opinion in America and has mostly ended in Europe. But around the world, the number of places that carry out capital punishment and the number of people killed is rising. Executions took place in 22 countries last year, according to Amnesty International, a human-rights lobby. In America there were 39 executions—more than the known number of executions in Yemen, Sudan or Somalia. Countries whose gallows had been left unused for long periods put prisoners to death, notably Indonesia (for the first time in four years), Kuwait (in six years) and Nigeria (in seven years).” The Economist has more.

Countries which carried out the death penalty in 2013

Malaria vaccine

Several vaccines for malaria have been developed over the past few decades, but none offer complete protection. Now, for the first time, US researchers have developed a vaccine that protects 100% of those given five doses of the vaccine.

New malaria vaccine the first to offer complete protection, The Conversation, 8 August 2013. Also on Ars Technica and The Hindu.

India’s new anti-malarial drug

Indian pharmaceutical firm Ranbaxy has launched the drug Synriam, which it claims will prove a more efficient and simpler treatment for malaria. With its affordable price, Synriam may well be a step towards achieving the WHO’s goal of eradicating malaria by 2050, but Ranbaxy cannot take all the credit for it.

Ranbaxy launches new anti-malarial Synriam – Chemistry World, 3 May 2012

A list of main references for the article is here.

The story behind Ranbaxy’s new anti-malarial drug

From the previous post about Ranbaxy’s new anti-malarial drug, we know that Synriam is a fixed-dose combination of two known molecules, arterolane maleate and piperquine phosphate. The highlight of the media coverage has been to call this India’s first new drug, which isn’t entirely correct. What makes Synriam special, though, is that it is the first ever drug based on arterolane, a cheaper and better alternative to what is currently available.

Before we look at arterolane, let’s take a quick look at malaria and anti-malarial drugs. According to a World Health Organization (WHO) report, every year 250 million new cases of malaria are reported and it causes 800,000 deaths. It is the biggest killer among the diseases that affect children less than 5-years of age. Anti-malarial drugs have existed for over 300 years, but it is only in the last century that there has been a rise in drug-resistance among the parasites responsible for the disease. This spurred research into developing new drugs and therapies.

One key finding from the increased attention that malaria received was the role of combination therapy. It was found that a judicious combination of drugs could help delay the development of resistance to drugs. To ensure that the new drugs that have been developed do not develop resistance, according to WHO guidelines, the artemisinin class of drugs must always be used in combination with other drugs. Arterolane falls in that class.

Funded by a Swiss non-profit, Medicines for Malaria Venture (MMV), arterolane (codenamed OZ277) was revealed in 2004 in a paper published in Nature. It was developed as part of a collaborative drug discovery project that consisted of researchers in the US, the UK, Switzerland and Australia. The aim of the project was to discover a new chemical entity (NCE) that could overcome the limitations of artemisinin, a widely-used antimalarial drug.

Among the many limitations of artemisinin is its price. It is produced from a plant-based source, making it an expensive solution to a poor man’s disease. Arterolane, on the other hand, can be synthesised from commercial chemicals and more cheaply (As a side, arterolane also has one of the funkiest chemical structures among drug molecules). With this molecule, MMV had achieved its goals of finding an NCE with desired qualities, but without further development through clinical trials, it would not have become a marketable drug. That is when Ranbaxy entered the scene. MMV tied up with Ranbaxy in 2003 and supported the development of the drug up until 2007.

According to LiveMint, MMV decided to stop funding the project after it reviewed preliminary data and other portfolio priorities. According to results that were presented at a conference in 2006, MMV found that results of Ranbaxy’s trials were not very satisfactory compared to other drug candidates available in the agency’s many collaborative projects. By this time, Ranbaxy had spent about $16 million. Despite losing MMV’s support, it planned to continue the development of the drug.

The IP-related issues surrounding arterolane remain unclear. In a conversation with Jonathan Vennerstrom, who led the study that was published in Nature, I was told that MMV owns the patent for arterolane (see here and here). By 2007, given that MMV had lost interest in arterolane might mean that it licensed the molecule to Ranbaxy at a low price.

Looking at the lack of confidence that MMV showed in the drug, in 2007, Ranbaxy was taking a risk by continuing research because there was no guarantee that the final clinical trials would be successful. It deserves credit to have been brave enough to plough in a further $15 million (of which $1 million came from the Department of Science Technology) to bring Synriam to the market. Whether they did that to avoid losses or because they truly believed that Synriam was going to be successful, I am not sure.

The drug is claimed to be more effective than any other drug currently available. The recommended dosage is one pill a day for three days, which is less than other for other drugs. Ranbaxy has also ensured that the price remains low at Rs. 130 for the three-day treatment. It is interesting to note that this is much cheaper than Cipla’s Mefliam Plus, which is priced at Rs. 300. Ranbaxy gets more points also because Mefliam Plus is a combination of artesunate and mefloquine, both of which are known molecules that have been used in different fixed-dose combinations previously.

Although Synriam does not qualify as ‘India’s first new drug’ (because none of its active ingredients were wholly developed in India), Ranbaxy deserves credit for being the first Indian pharmaceutical company to launch an NCE before it was launched anywhere else in the world.

This was published as a guest post on SpicyIP’s blog. SpicyIP aims to be a leading repository of resources pertaining to Indian intellectual property (IP) law and policy.

Has India’s new anti-malarial drug really been ‘indigenously’ developed?

I woke up to the news that Ranbaxy India has launched it’s first indigenously developed drug: Synriam. A drug for malaria treatment, it is a combination consisting of arterolane maleate 150 mg and piperaquine phosphate 750 mg. I was pleased to hear that India’s drug discovery initiatives had matured enough to produce new drugs and that the drug companies were acting very responsibly by working on a poor man’s disease. Naturally, I dug into the story a little more.

Ranbaxy’s press release (which is where most news sources have got their information from) claims:

  1. Synriam has been approved by Drug Controller General of India (DCGI) for marketing in India and conforms to the recommendations of the World Health Organization (WHO) for using combination therapy in malaria.
  2. Synriam has a high cure rate of 95%.
  3. Phase III clinical trials were conducted in India, Bangladesh and Thailand.
  4. Dose regimen is better than anything out there. Three pills over three days.

So far so good. Out of curiosity I looked up the chemical structure of arterolane and was surprised to see that it features both an ozonide and an adamantane group in it. In all my synthetic organic chemistry work, I hadn’t seen a drug like that. After all, organic ozonides (3 oxygen atoms in a 5-atom ring) are more explosive than organic peroxides (R-O-O-R)!

It turned out that Derek Lowe of the famous In the Pipeline blog had written about arterolane in 2009. At the time it was in Phase III trial, which I assumed were the trials that Ranbaxy was conducting. But it turned out that arterolane was developed by a collaboration between researchers in the US, the UK, Switzerland and Australia who were funded by the World Health Organization and Medicines for Malaria Venture (a Swiss non-profit). They published this work in Nature in 2004 and further SAR (Structure Activity Relationship) studies in J Med Chem in 2010.

So Ranbaxy did not develop the drug from scratch? But the press release quotes Arun Sawhney, CEO and Managing Director of Ranbaxy which misleads people to think so: “It is indeed gratifying to see that Ranbaxy’s scientists have been able to gift our great nation its first new drug, to treat malaria, a disease endemic to our part of the world. This is a historic day for science and technology in India as well as for the pharmaceutical industry in the country. Today, India joins the elite and exclusive club of nations of the world that have demonstrated the capability of developing a new drug”.

So Ranbaxy mixes a known active compound (piperaquine) with a new compound that someone else found to be active (arterolane) and claims that they developed a new drug? In an interview in LiveMint, Sawhney says, “Ranbaxy spent around $30 million on Synriam and the contribution from DST [India’s Department of Science & Technology] was Rs.5 crore. The drug went through several phases of development since the project began in 2003. We did not look at this as a commercial development. Instead, this is a CSR [Corporate Social Responsibility] venture for us.” That’s a give away because developing a new drug from scratch has to cost more than $30 million + Rs.50 million. Why wasn’t this put in the press release?

The initial high that I got from the news that Ranbaxy launches first ‘made in India’ drug just got murdered. India is yet to see a drug that it has ‘indigenously’ developed. I am sure that Synriam will do a lot of good for India and the many developing nations that suffer from a malaria epidemic, but it will be because of a ‘made in India’ drug not one that has been ‘developed in India’. It’s a shame that Ranbaxy did not acknowledge that the development of arterolane was funded by WHO and that their scientist have worked on developing a combination of two compounds both of which weren’t developed in their lab. They should make it clear that they are claiming the combination to be a ‘new drug’, not the molecules that make up the combination.

Like an Apple product says, “Made in China. Designed in California.”, Synriam should say, “Made in India. Developed by WHO + MMV + Ranbaxy.”

UPDATE: Vidya Krishnan, LiveMint reporter who covered this story, answered my question about patentability. She said that Ranbaxy has a joint patent with the Government of India for the ‘unique’ combination that they have developed, not for arterolane itself.

UPDATE 2: I spoke to the lead author of the Nature and J Med Chem paper Jonathan Vennerstrom who confirmed that MMV holds the patent for arterolane and has licensed it to Ranbaxy since 2003. Thus, the clinical trials mentioned in both the papers were Ranbaxy’s work even though arterolane was developed by other researchers.