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.

Sparking young minds

Last year I helped organise a science essay writing competition in my high school. This year, with the help of teachers, a similar competition was organised at Rasbihari International School in Nashik (where I also gave a talk earlier this year). The topic for the students this year was ‘A scientific discovery or invention that changed the world.’

Selected essays that I read had covered these subjects: aeroplanes, electricity, E=mc^2, medicine, space, and computers. Among those the winners of this year’s competition are:

  1. Vaishnavi Maniyar
  2. Saloni Lodha
  3. Shruti Tarle

You can read the essays by clicking on their names. My criteria for judging these essays was imagination, accuracy, flow of ideas, and use of language. The winners are being given the following books:

  1. What Einstein Told His Cook – Robert  L. Wolke
  2. How to Fossilise your Hamster – Mick O’Hare
  3. Why Can’t Elephants Jump – the New Scientist

I am grateful to Piyushee Amrite, Suchitra Sarda, my mum and others who helped organise this. The school has agreed to hold this competition annually, and I am looking forward to reading more such interesting essays.

On Speaking

I have a fear of public speaking. It is not a debilitating phobia, but when I have to speak to an audience I prefer to have time for preparation (not just for practicing but also to gather some courage). Even with that preparation, it turns out, I say “um” a lot and get a little thrown off by unintended pauses.

As a writer, I decided that I need to get better at speaking. Any effort put into bettering my speaking abilities will only help me improve my writing skills, I thought. After reading Paul Graham’s essay on Writing and Speaking, I have changed my mind. I still want to get better at speaking but not as much as I want to get better at writing. Here’s why:

Having good ideas is most of writing well. If you know what you’re talking about, you can say it in the plainest words and you’ll be perceived as having a good style. With speaking it’s the opposite: having good ideas is an alarmingly small component of being a good speaker.

Getting better at speaking needs improving your showman skills more than your thinking skills. It is true that remarkably good speakers don’t memorise their speeches. They have few points, written down or mentally noted, on which they expand while speaking. To do that the speaker relies on ideas that he has previously thought of in some depth. A certain amount of clarity in thought is needed to be able to speak well, but it would be rare to refine ideas and rarer to think of new ones while giving a speech.

It is more important for a good speaker to engage the audience which can be done through not just good ideas but also anecdotes and jokes. The speaker can tap into mob psychology which make jokes seem funnier in an audience than alone. Graham hasn’t taken it too far when he says:

As you decrease the intelligence of the audience, being a good speaker is increasingly a matter of being a good bullshitter. That’s true in writing too of course, but the descent is steeper with talks.

So are talks useless? Graham says:

They’re certainly inferior to the written word as a source of ideas. But that’s not all that talks are good for. When I go to a talk, it’s usually because I’m interested in the speaker. Listening to a talk is the closest most of us can get to having a conversation with someone like the president, who doesn’t have time to meet individually with all the people who want to meet him.

Talks are also good at motivating me to do things. It’s probably no coincidence that so many famous speakers are described as motivational speakers. That may be what public speaking is really for. It’s probably what it was originally for.

This lamentation has been about public speaking, of course. One man talking others listening without much engagement from the audience. I’m a fan of another form of speaking which involves engagement – conversations, that is. Many of which have led to the most fascinating learning experiences. With the right set of people, conversations can go to bizarre places and still feel familiar.

Some of the best conversations are those without structure. They tend to flow with an aim to seek the truth, but remain content in not reaching the end. They can sometimes feel like a mental dance involving two or more. Rhythm is set by the pace of thoughts, music by the ideas and notes by the words.

Conversing, like public speaking, requires the ability to communicate with clarity, but beyond that it also needs additional skills such as engaging conversational partners without being overbearing, redirecting the flow of ideas but allowing others to do the same, and creating an atmosphere that encourages new ideas.

Good conversations leave me with the feeling that I get after enjoying a fantastic meal. Instead of a good aftertaste, I am left with some very satisfying thoughts. They also come with a bag of goodies that contain new ideas and new perspectives.

Even with all that love for conversations, I don’t treat them as my way out of a difficult problem. Sometimes two or more brains with the same amount of motivation are able to solve problems that either brain alone would find unsolvable, but synchronisation of that kind leading to synergistic effects rarely happens in conversations.

So when a friend of mine said, “I think by talking about things”, I had my eyebrows raised. She tends to use another person as a mental stage to begin the thought process. Speaking to her, it seems, is thinking. I find that odd and limiting, but that might be an extreme case.

Therapists ask patients to ‘speak’ their mind. Talk therapy is powerful and is known to release chemicals in the brain altering, very literally, the state of a person’s mind. Therapists enable a conversation with oneself by removing mental blocks and/or directing the flow of thoughts in the right direction.

Speaking may be a good way out of difficult emotional problems but it isn’t the best tool for problem solving. Speaking can be uplifting to the depressed and invigorating to the dull. It can be a motivational tool or a way to admire heroes. It can also be a thinking tool in difficult scenarios, but for problem-solving and a daily dose of new ideas writing is a better option.

Orwellian gobbledygook

Too often we try to hide ourselves behind big words that don’t mean much. It is unfortunate that we find it very hard to follow the simple advice: Say it as you see it.

Andreas Kluth of the Economist calls all this Orwellian gobbledygook because it was George Orwell who pointed out in his famous essay Politics and the English language that, “The whole tendency of modern prose is away from concreteness”.

Kluth believes the two reasons we do this are:

1. Laziness: Speaking or writing clearly takes enormous effort.

2. Fear or cowardice: If you write clearly you use strong words which can offend somebody, and that is something you will not want to do.

How does epigenetics shape life?

Identical twins, despite being biologically identical at birth, grow up to become unique individuals. Sure they may have a lot more things in common than two randomly picked individuals, yet there are many characteristics which belong only to one or the other. If the twins have the exact same DNA, then what is that makes them different?

The common answer to this question is it’s the environment that they live in which shapes them differently. Researchers have found that such environmental factors cause chemical modifications to the genome without affecting the nucleotide sequence, leading to the unique characteristics that we observe. This field of research is called epigenetics, and beyond the DNA, it’s what shapes our lives.

Rat mothers nurture their pups by licking and grooming. Researchers in Canada studying epigenetic changes found that rats whose mothers licked them more than normal expressed hundreds of genes differently from those who were licked less than normal. These differences were consistent and predictable, and led to a number of behavioural changes among the rats, including one where highly licked rats’ response to stress was a lot better than the less‐licked rats’.

Epigenetic changes don’t just occur through environmental factors but are also a different form of inheritance, one that doesn’t have to suffer from the randomness of natural selection. The licking of the rat encodes specific information onto her pup’s DNA without modifying to the sequence of base pairs. Mom’s behaviour programs the pup’s DNA in a way that will make it more likely to succeed. Such information is stored in the DNA in many ways, one of which is through DNA methylation. Through this process methyl groups are attached on to the DNA, and their attachment at specific positions leads to genes being turned on or off. This makes epigenetic changes reversible. For example, you can take a low‐nutured rat, inject its brain with a drug that removes methyl groups, and make it act like a high‐nurtured rat.

DNA methylation also plays a key role in cell division and cancer cells are known to divide faster than normal cells. Researchers in the US have developed drugs to interfere with DNA methylation as a treatment for cancer. They use molecules that mimic cytosine, one of the four bases of DNA. In cell replication, the fake cytosine swaps places with real cytosine in the growing stand of DNA, which then in turn traps DNA methyltransferase. When used in low enough doses, the drug allows the formation of the cell but with less methylated DNA. These drugs are currently being used to treat myelodysplastic syndrome, a prelukemia condition.

As Brona McVittie says, like the conductor of an orchestra controls the performance of musicians, epigenetic factors govern how the cell plays the notes in DNA. A better understanding of these factors has the potential of revolutionising evolutionary and developmental biology, thus affecting practices from medicine to agriculture.

Further reading:

  1. Learn Genetics, The University of Utah
  2. Introduction to epigenetics from Science magazine
  3. More ways to fight cancer through epigenetics, The Economist
Image credit: SciShark

On being creative

This week’s Brain Picking’s newsletter brought to my attention this gem of a talk on creativity by John Cleese of the Monty Python fame. Of particular interest to readers of this blog should be a quote from the talk:

Keep your mind gently round the subject you ponder. You can daydream, of course. But keep bringing your mind back [on to it], just like meditation. Because – and this is the extraordinary thing about creativity – if you just keep your mind resting against the subject in a friendly but persistent way, sooner or later you will get a reward from your unconscious self. Probably in the shower later or breakfast the next morning, but suddenly you are rewarded and, out of the blue, a new thought appears mysteriously. If you have put in the pondering time, first.

In short, persistent contemplation is very important to be creative. The importance of creativity in any profession cannot be overstated and such nuggets of gold should not pass through our mental sieves. Thinking about something with purposeful intent requires effort but with practice it becomes a habit.

Cleese says, “Creativity is not a talent. It is a way of operating.” Persistent contemplation is one way to operate to be creative, but that alone may not be enough.

In another fascinating talk that John Cleese gave on creativity, almost two decades later, he reminds us, in a rather funny way, that our ideas come from our unconscious. He calls our unconscious mind a tortoise – one that hides in its shell unless the right conditions are created to allow it to come out. To create those conditions, Cleese asks us to create boundaries of space and time. By space, he means, not just the physical surroundings but also the mental ones which allow the tortoise to come out and play without distractions.

The most profound insight to be gained from the talk comes right at the end when Cleese reveals a profound discover he made about life. He says, “To know how good you are at something requires the same skills as it requires to be good at that thing.” Applying which he finds that those people who have no idea about what they are doing have no idea that they have no idea about what they are doing.”