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.
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.That is a far cry from the days when India and reverse engineering were synonymous. With a compulsion to respect not just process patents but also product patents, drug discovery and development have become the key for survival and growth of pharmaceutical companies based here. It is a road less traveled.
“If we can make this [drug] work, it will make us a billion dollar company,” said Kiran Mazumdar-shaw, Chairman and Managing Director of Biocon. “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.
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. “It [IN105] 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.”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 clinical trials 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.
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,” Dr. Shaw said. “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,” she said.
“We have paid millions of rupees for a bunch of papers,” Dr. Suryanarayan said. “It’s a great asset provided you know how to translate them into drugs.” And at a time when India is taking baby steps in drug discovery and development, acquiring the IPs of Nobex has helped Biocon to cut short the time required for taking drugs from the laboratory to the market. Interestingly, some pressing compulsions have come up for Biocon following this acquisition. “We should now see if someone is infringing our patents,” he underlined, “earlier we were being scrutinised for infringement.”