Friday, March 23, 2007

 

Bacteria-eating Virus--new antibiotic

Nature’s Medicine

Set to hit the market within a year, Bangalore-born Gangagen’s natural bacteria killer could spell the end for antibiotics
P. Hari

Few businessmen would spend a lot of time talking about a harmless virus. But this virus, called a phage, kills bacteria that are dangerous to human beings. You could use it as a drug, if we knew how to tame it and get it to the right place. Some institutions and a few companies have tried to do it for decades, but with limited success. But now, an Indian-founded company seems to have achieved just that. Within a year, it will launch the first, phage-based antibacterial drug in the world.

Born in Bangalore, registered in Delaware, US and with an office in the Silicon Valley, Gangagen is still an oddity among technology companies. Few companies would be brave enough to bet an entire business on phages. It was born when J.Ramachandran, after retiring from Bangalore-based AstraZeneca R&D, decided to take up a challenge that everybody had left unfinished: conquer the mighty bacteria. It was a brainwave while watching a programme on the BBC. He knew nothing about phages when he set up the company. He still got $2 million (Rs 8.8 crore) from Silicon Valley-based ICF Ventures.

Ramachandran got scientists excited about his venture. In Ottawa, Canada, where he set up a subsidiary, he got some very experienced hands. Michel Chretien, well-known physician and brother of former Canadian prime minister Jean, became the chairman. Rainer Engelhardt, scientist and entrepreneur, became the president of the Ottawa company. Kishore Murthy, biologist and experienced phage researcher, became the chief scientific officer. This team, along with a few more scientists in Bangalore, took Ramachandran’s initial ideas and developed them into veterinary applications. Its first drug, to treat Escherichia Coli in cattle, is in advanced clinical trials. Between them and few other friends and board members, they also managed to raise substantial funds.

After ICF Ventures, most venture capitalists did not share the excitement of their scientists. Gangagen also refused to do services till it finished developing its product. Yet, its team managed to raise money after the initial rounds: $1.9 million in 2003 from board members and other initial investors; $2.5 million (Rs 11 crore) in early 2006 from a few more investors; and $4.5 million (Rs 19.8 crore) in September 2006 from several other individuals. What puzzled VCs was that Gangagen had no drug in the conventional sense.

Old Science, New Techniques


The Russians, during the time of Stalin, were the first to use phages to treat infected wounds. Even now, former Soviet Union countries use phages for therapy. The Tbilisi Institute in Georgia is a specialist institution for researching phage therapy. But the method has not caught on worldwide because of several scientific and business reasons. There is no commercial phage product that can treat bacterial infections either in humans or animals. Gangagen’s would be the first. And it aims to treat the problem at the source.

The gut of a cow is a reservoir of E.Coli 0157:H7. The cattle do not fall ill, but the bacterium runs amok when it emerges from the animals. The dung of cattle is rich in E.Coli, which seeps into the ground water. It also contaminates vegetables when dung is used as manure. When the cattle are slaughtered, the bacteria contaminate the meat, which is a major source of infection in developed countries. If you could eliminate E.Coli from cattle, you could also reduce the chances of infection in humans. Gangagen had patented some ingenious methods of using phages to treat humans, but those will come later. Veterinary applications are easier from a regulatory point of view.

It is not as if other companies had not tried to treat cattle using phages. OmniLytics, a company based in Utah, has a formulation that is sprayed on the skin of the animal. This method does work to an extent, but cannot kill the bacteria inside the animal’s body. Gangagen has developed pellets mixed with the feed — using a patented method — that take the phages directly to the source. The pellets are stable inside the cow’s stomach, but release the phages when inside the intestine, where they wipe out the E.Coli. The phages are so selective that they kill only E.Coli 0157:H7, leaving other bacteria alone. Says Ramachandran: “The best thing about phage therapy is the specificity. Unlike antibiotics, phages do not kill useful bacteria.”

Gangagen has tried the method in about 80 animals. The pellets are given every day to the cattle one week before slaughter. Thus, their guts are cleaned of E.Coli by the time they are killed. By the end of the year, it would have conducted trials on 400 animals. It is also developing phage-based products to treat salmonella and campylobacter infections, both common in the dairy industry. The veterinary market for treating infections is large. In North America alone, the dairy industry loses over $3 billion a year due to infections. Around $5 billion is spent on treating antibiotic-resistant infections in domestic animals.

Gangagen has tied up with Elanco Animal Health, a division of Eli Lilly Canada, to market the veterinary product all over the world. Incidentally, Eli Lilly was the first company in the world — in the 1930s — to pursue phage therapy. It later gave up because the method was not scientifically and commercially viable at that time.

Gangagen, however, has solved these problems with some recent research and patents. The major scientific problem is that phages kill bacteria and then come out of them in amounts numbering in the hundreds of thousands, and scattering bacterial toxins in the process. The commercial problem was that phages were known long ago — one cannot get patents on old knowledge. Gangagen, however, found a new technique, which stops the phage from coming out of the bacterium after it kills it. It was then granted a few more patents, including one to use the phage as a vaccine. Gangagen had solved both the commercial and scientific problems in one stroke.

The End Of Antibiotics?


Sometime next year, Gangagen could start human trials on topical applications of phages. A specific target is the bacterium staphylococcus, an antibiotic-resistant bacteria that causes smoldering infections in wounds, particularly when acquired from hospitals. Staph, as this bacterium is usually called, lives in our nasal cavities and is a major cause of infection after surgery. Use of nasal sprays a few days before surgery could eliminate the problem. To keep the costs down, Gangagen had not used its patented genetically-engineered phages on the veterinary product. But human applications would necessitate the use of its genetically-engineered phages that kill the bacteria but not scatter the toxins.

Antibiotics were once considered magic bullets to cure any infection. However, it is now apparent that humans are losing the battle against bacteria. Phages are nature’s own cure, which is preferable even in animals. Says Tim Guichon, managing partner, Feedlot Health Management Services in Alberta, Canada: “There is a feeling among the public that large-scale use of antibiotics in animals increases the chances of resistance in human infections as well.” If phage therapy becomes widespread in a decade, Gangagen would almost certainly be the pioneer.

Wednesday, March 21, 2007

 

NRI doctors return home

Times of India

Sujata Dutta Sachdeva

His first tryst with India happened five years ago. That's when he came to meet friends and deliver guest lectures in Chennai and Vellore. Little did Dr Hassan Tehrani know that in a few years he would give up a flourishing career as cardiac and endovascular surgeon in the University of Miami and Jackson Memorial Hospital and relocate to Gurgaon, which he did two months ago. He's joined Artemis Health Science (AHS) as a consultant surgeon.

Interestingly, this 39-year-old British citizen, is not alone. Many foreign and NRI doctors are now making a beeline for India and wanting to relocate here to gain the India experience. AHS claims it is getting enquiries from foreign doctors in the US and EU who want to visit the facility and then take a final decision on India.

Tehrani had never imagined that one day he would be assisting in setting up a hospital in India. "Initially, I was sceptical, but a couple of trips later, I saw it as a lifetime opportunity. And my mind was made up," he says. Of course, his wife, a doctor herself too saw it as a great opportunity and challenge.




He realised that if he stayed on in the US, he would be doing the same kind of work even after a decade. It didn't challenge him anymore. "There was little room for personal growth. I wanted to do much more than just treating patients," he asserts. He feels India could offer him that challenge. "The sheer number of patients and cases one handles here is in itself a challenge," says Tehrani.

The situation is much the same in other hospitals too. Dr Shabnam Singh who handles physician recruitment at Max Healthcare, says,"We get many enquiries from foreign doctors who are interested in coming to India. In fact, one of our ads for a surgeon had 20% non-Indian applicants." In fact, in the last three months, a senior NRI dentist, a plastic surgeon and a cardio-vascular surgeon have joined the hospital.

This reverse brain-drain began in the the last five years when many NRI doctors came back by choice. Singh says 10% doctors at Max Healthcare are such cases. For decades, India had watched many of its best-educated doctors shift abroad in search of degrees and mega bucks, never to come back. But now, with talent returning to India, the implications for a developing country like ours is potentially huge.

Dr Vivek Raj, a gastroenterologist with Max Healthcare, says doctors return for both personal and professional reasons. He himself came back in June to join Max after spending 18 years in the US. And despite doing quite well at the University of Arkansas, Little Rock, he began to feel bored like Tehrani. "For the last three years, I wanted to come back as I couldn't imagine doing the same thing for years together. Also, I wanted to translate what I had learnt abroad here."

Though there are the usual explanations about wanting to return to their roots, be close to aging parents and wanting kids to imbibe Indian values, there are other reasons for the prodigals returning.

Experts say it also has to do with the growing economy. After IT, the healthcare sector is now poised for a big leap.
Moolah is being pumped in by MNCs and Indian companies for new R&D centres and super-speciality hospitals. This makes it easier for NRI doctors to make a choice, as they know they can get the same working environment and equivalent infrastructure as they had abroad.

Neonatologist and paediatrician Dr Raghuram Mallaiah came back three years ago when he was offered a chance to set-up the neonatologoy centre at Fortis Hospital, Delhi. "As a medical student I had wanted to change things radically, but opportunities were limited then. So when I was offered a challenge to set up the centre, I took it up. But made it clear that I would return only if all the equipment required to set up the unit and make it world-class, was in place," he says. He has no regrets.

Orthopaedic surgeon Dr Sanjay Sarup has a similar explanation. He had always wanted to return after gaining training abroad. But after spending a decade abroad, when he got an offer to create a specialist department of paediatric orthopaedics at Max, he jumped at the offer. "It was a new field in India and I felt I could create the same standards I had in the UK."




But for doctors such as Tehrani and Dr Kushagra Katariya, a noted cardiac surgeon who gave up his job as associate professor, University of Miami to join AHS as CEO, it also meant being able to focus more on research. With growing medical litigation and restrictions on clinical research, doctors in the US are practising more of defensive research, they feel. "Funders who have deep pockets have realised it's taking more time to get results there, while the costs are prohibitive," says Katariya. "India is becoming the frontier of healthcare research. That's why NRI and foreign doctors are flocking here."

In fact, both friends moved here with the same objective — to do more bedside application. "We want to create cutting edge research, not follow what's been created elsewhere," says Tehrani.

Katariya went to the US with just four suitcases, a few dollars in his pocket and a huge determination to succeed. "But when I decided to return, everyone thought I was a fool to run after a dream. But I knew what I wanted," he says confidently. Ofcourse, the move from south beach Miami to the heat in Gurgaon was not easy for this doctors family. But they are happy to be back.

Ofcourse, all the returnees knew that remuneration here could never match up with what they got abroad. Nor would quality of life be the same, but they were willing to make the compromise.

"Goals change as time goes by. And it takes a certain mindset to understand the opportunity. Indeed, in the West, it's much easier to earn your salary and enjoy it. But as long as you can live comfortably here, you should take up every opportunity as a challenge," explains Katariya. Anyway, as Sarup says, it’s challenges that make life worth living.

But what if their Indian dream doesn't work out the way they want it to and they want to return? Tehrani says he came to India with an open-ended contract,"My wife is expected to join me in a few months. I have not come on a sabbatical, nor do I have a back-up plan. I know it has to be successful," he asserts.

It's obvious there is no looking back for them. India is where the action is and they would rather be a part of it than watch from miles away.

Sunday, March 18, 2007

 

Ranbaxy in the US market

TOI

Rupali Mukherjee

Pharma major Ranbaxy Laboratories is expected to mop up nearly $2 billion in sales by launching generic versions of four block-buster drugs, including atorvastatin (Lipitor) over the next five-six years.

The block-buster molecules including atorvastatin (lipitor), pioglitazone (actos), valacyclovir (valtrex) and tamsulosin (flomax), are expected to be launched in US during 2007-2012, subject to the requisite legal and regulatory approvals.

At present, the company has 20 First-to-File (FTF) products that command a market size of over $26 billion (at innovator brand prices) with nine under litigation. The first-to-file status is granted to the first generic company which files the abbreviated new drug application (ANDA) with a Para IV certification. The first-to-file benefit allows 180 days of exclusivity in the US market to the company.

Ranbaxy CEO and MD, Malvinder Singh said, "The potential first-to-file molecules present a sizeable opportunity, and offer significant commercial upside to our organic growth plans". The company has filed 197 ANDAs with the US FDA, of which 121 have been approved, while 76 are pending. Cumulative value of 76 pending ANDAs is valued around $50 billion (at innovator brand prices).



Domestic generic companies like Ranbaxy and Dr Reddy's have become aggressive in challenging blockbuster drugs from MNCs through Para IV filing of their ANDAs in the US and Europe. They are eyeing huge revenues which they can earn from the 180-day market exclusivity.

Singh added: Our strategy on litigations is a considered one where we bring to bear our innovative R&D capabilities to develop generic alternative and litigate against patents which are weak in our opinion. We challenge them based on the fact that we believe, after due consideration and careful study, that they are invalid or not infringed.

Ranbaxy has developed a robust product flow, and plans to launch new products with a focus on products comprising vanilla generics, niche/value-added products, complex technology products & first to file (Para IV) products. US is the most important market for the drug major, and contributed $380 million to the total global sales of $1340 million in 2006.

Analysts say that the company is expected to launch one first-to-file product every year, with the first one to be launched next year. Last year, the company launched simvastatin tablets (80mg) with a 180-day exclusivity in the US. The product has garnered over 50% share of the generics market and notched up around $70 million in sales.

Recently, Ranbaxy has got involved in a litigation against Pfizer to launch the generic version of cholesterol and blood pressure medicine, Caduet. Pfizer has filed a complaint in the federal court in Delaware, saying that the copy would infringe patents that expire in 2010. Sales of the Caduet totalled $325 million last year.

In another example, through its challenge of Pfizers patent on cholestrol lowering drug, Lipitor, Ranbaxy has been able to bring forward the launch of the generic version by 15 months with 180 days exclusivity in US . Analysts say that an estimated $70 billion worth of branded products are expected to go off-patent between 2007-11.

Sunday, March 04, 2007

 

Oral Insulin

End of 2008 may well bring about a paradigm shift in the way diabetes is treated, if every thing goes well with human clinical trials. The driver that may engender this is oral insulin. Taking insulin through the oral route, unlike injecting it, which is the conventional method, has many advantages; mimicking the way the human body uses insulin to control glucose is by far the greatest advantage.

The Phase I clinical trials on humans are about to begin in a month's time. And it would be done in India and abroad by a biopharmaceutical company based in Bangalore — Biocon Limited.

Biocon and Nobex Corporation


Of vital significance is that Biocon would fully own the patent of the drug when it is commercialised. Biocon got full ownership of oral insulin and other programmes with the acquisition of the U.S. based company Nobex Corporation. The two companies had entered into a joint venture in 2004, but following Nobex's bankruptcy Biocon has acquired most of its patents. Biocon has named its oral insulin drug IN-105.

Oral insulin is just one of the many potential applications of the intellectual property (IP) assets of Nobex. "We have acquired 300 patents that have been granted or applied for by Nobex," said Kiran Mazumdar-Shaw, Chairman and Managing Director of Biocon. "This is the first time an Indian company has acquired another for IPs. Many don't understand the significance of it. Biocon has now become the largest patent holder by doubling the number of patents."

"If we can make this [drug] work, it will make us a billion dollar company," said Dr. Shaw. "And it will have the `Made in India' label."

Dr. Shaw was in Chennai recently to attend an Indo-Swedish symposium organised by the Madras Diabetes Research Foundation, Chennai and the Karolinska Institute, Sweden.

But what is it that gives efficacious oral insulin the potential to turn into a blockbuster drug? "It mimics the way insulin works naturally in humans," said Shrikumar Suryanarayan, President (Research and Development), Biocon. "It gets into the liver [past the stomach and intestines] through the portal vein and then to the muscles in the periphery. In the case of injection, it is the reverse — from the periphery to the liver."

While pancreas is where insulin is produced, liver is where glucose is stored as glucogen and released into the body as glucose as and when needed. "When the liver shuts off glucose production depends on the amount of insulin present in the liver," explained Dr. V. Mohan, Chairman, Dr. Mohan's Diabetes Specialty Centre, Chennai.

Advantage of Oral Insulin


Liver produces more glucose when fasting and in the postprandial condition, insulin signals the liver to shut off and stop producing glucose. So by making oral insulin available to the liver through the stomach, the drug will be able to achieve better glucose control. "Oral insulin is theoretically far superior to injection," Dr. Mohan emphasised, "injections are not the right way to control blood glucose."

If the oral route is indeed far superior, then why has no drug become commercially available? The biggest challenge is to make oral insulin escape destruction in the stomach before becoming available in the liver and the rest of the body. There are various other unknown variables — the time when the drug has to be taken and the effect of various foods on the drug's ability to escape destruction, to name a few.

Biocon's oral insulin candidate has polymers added at specific locations in the B chain of the insulin to prevent insulin from getting destroyed in the stomach. "IN-105 was found to be more bioactive than HIM2 in animals," said Dr. Suryanarayan, "and this could be due to several factors — better resistance to enzymatic digestion or improved absorption in the stomach or intestine... It is difficult to distinguish the contribution of each of these to the final bioactivity in an in-vivo system."


Human Clinical trials


HIM2, a first generation oral insulin licensed to Glaxo by Nobex, showed positive results in human clinical trials. It was found that the digestive enzymes did not destroy oral insulin. "... HIM2 is as effective as subcutaneous insulin in controlling postprandial glycemia ... " noted a paper published in Diabetes Care in 2003. The subjects studied were those with Type II diabetes. HIM2 was not commercialised though.

Dr. Suryanarayan expects the second-generation oral insulin candidate to be tested to perform better than HIM2 as it has higher specific activity. Phase I human clinical trials of IN-105 would be carried out in India and abroad. Measuring the amount of insulin in blood would be done in India. "But what I want to know is the level of insulin that would be required to switch off the liver [from producing glucose]," explained Dr. Suryanarayan. This part of the trial would be done abroad. Phase II would be started once the safety of the drug is established.

The Hindu
R. Prasad

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