Jackie Chaline needs four shots of insulin a day to survive. The 66-year-old Frenchwoman, who was diagnosed with diabetes 16 years ago, says switching to a pill would be a form of liberation.
“Swallowing a tablet would make such a difference,” says Chaline, a former public transport agent who has gotten about 9,000 insulin shots in the past seven years.
Novo Nordisk A/S (NOVOB) is trying to make Chaline’s wish, and those of millions more like her, come true. Vying with other drugmakers to develop what could be one of the biggest blockbuster drugs in years, the company is spending at least $2 billion to make an insulin pill hardy enough to cheat the body’s own defense mechanisms and deliver insulin to the bloodstream.
“The odds of making it were a million to one five years ago,” says Novo Chief Science Officer Mads Krogsgaard Thomsen. “Are we getting closer to a 50-50 scenario? Absolutely.”
If successful, an insulin pill could reach peak sales of from $5 billion to $10 billion, estimates Vincent Meunier, an analyst at Exane BNP Paribas in Paris.
“It would be one of the biggest drugs of all time,” Meunier says, though for now, it’s still “in the realm of science fiction.”
Novo executives say research is moving along. One new clinical study began earlier this month. Diabetics currently must inject insulin to prevent sugar from pooling in their blood. A successful pill must be hardy enough to withstand acid attacks during digestion and nimble enough to pass the filter of the gut wall to reach its first target, the liver.
“It’s a big effort, because it’s so difficult,” Thomsen says. “If things are difficult, you either make them big or you don’t make them.”
Diabetes, caused by a lack of insulin needed to convert blood sugar into energy, affects 366 million people worldwide, killing one every seven seconds, the International Diabetes Federation estimates.
A tablet wouldn’t replace injections entirely because it’s likely to be used only in patients whose bodies can still produce some insulin, according to Thomsen. Instead, the drug would allow diabetics to get treated earlier because doctors wouldn’t wait to prescribe a pill like they do with injections.
“If this were to work, it would be huge,” says Spyros Mezitis, an endocrinologist at Lenox Hill Hospital in New York. “We would get more people on insulin. It would be a lot easier to use.”
Hiding in Bathrooms
Jackie Chaline, who suffers from Type 2 diabetes, the most common form, says she resisted the switch to insulin for fear of injections. Seven years later, she still finds it painful at times. When she eats out, she ducks into bathrooms to spare others the sight of the needle. She also has to rotate between her arms, belly and thighs to find undamaged skin. Swallowing a pill would “change everything,” she says.
So far, Novo’s experimental long-acting insulin pill has been tested on rats, beagle dogs and more than 100 human volunteers. One version of the medicine, dubbed NN1953, has “successfully completed” a first round of clinical tests, in which people took the tablet once, the Danish company said on Feb. 2 when it reported full-year earnings.
The tests are being conducted at the Profil Institute for Metabolic Research near Dusseldorf, Germany, Thomsen said. The company wouldn’t comment further. An earlier version, known as NN1952, was abandoned after failing early tests.
Cheating Mother Nature
Chief Executive Officer Lars Soerensen kicked off the pill hunt six years ago. A corporate magazine displayed in the company’s waiting lounge devotes two pages to Novo’s “search for the Holy Grail,” with pictures of scientists at work.
Novo, the world’s biggest producer of insulin, needs new products to fight competition from France’s Sanofi (SAN) and Indianapolis-based Eli Lilly & Co. (LLY:US) The company is waiting for U.S. regulators to approve a new, long-acting injectable insulin called degludec, intended to wrest market share from Sanofi’s best-selling Lantus. First-quarter earnings missed estimates, hurt by slower-than-expected sales of Victoza, also a medicine for diabetics, and NovoSeven, a hemophilia treatment.
When swallowed, insulin embarks on a journey that takes it through the stomach and the intestines, where it faces the assault of acids and enzymes. It must then cross the gut wall, usually accessible only to smaller particles known as amino- acids, to reach the bloodstream and travel to the liver.
“The gut should make sure you don’t get toxic material into your body,” says Thomsen, sketching the product’s travel route on the board of a conference room at Novo’s headquarters in Bagsvaerd, Denmark. “You have to cheat Mother Nature.”
‘The Real Thing’
To tackle the challenge, Novo has been bringing together its own scientists, experienced in insulin engineering, and external researchers who are experts in tablet formulation.
New hires include Nazaneen Pourkavoos, who helped develop an extended-release version of Janumet, a pill that combines the Januvia diabetes treatment with an older drug known as metformin, for Merck & Co. (MRK:US)
Pourkavoos, whose role is to find a formulation that can cross the gut barrier, works with Thomas Kjeldsen, a 23-year Novo Nordisk veteran who likes to carry the experimental tablet around like a baby -- and speaks of it in the same adoring tone.
“This is the real thing,” he says with a grin, holding up the oval white pill prototype. “It’s fascinating. You think about the insulin pens, the needles, and then you look at this. It explains all the efforts.”
The challenges aren’t over once the insulin crosses the gut wall. Researchers must extend the hormone’s ability to stay in the bloodstream and boost its capacity to be absorbed by the body, a concept known as bio-availability, according to Thomsen. Novo has already found a way to give insulin more staying power and it’s searching for ways to further increase bio- availability, he said.
Finally, scientists must avert absorption swings caused by the vagaries of human digestion. On days when the patient suffers a bout of diarrhea for example, the pill’s passage through the bowels may be too quick to allow proper insulin absorption. Novo says the once-daily tablet should give patients enough of an insulin buffer to guard against hypoglycemia, a state of dangerously low blood-sugar levels.
A handful of smaller companies, including Diasome Pharmaceuticals Inc. of Conshohocken, Pennsylvania, Jerusalem- based Oramed Pharmaceuticals Inc. (ORMP:US) and Diabetology Ltd of Jersey, in the Channel Islands, have tried to solve the problem, some only to abandon efforts. Biocon Ltd. (BIOS) from Bangalore, India, said last month it’s looking for a partner to further develop its oral insulin program, which is in advanced tests.
“Previous attempts never worked,” Meunier points out.
Novo will be able to tell which oral insulin candidate is ready for mid-stage clinical development by the end of next year, Thomsen said.
“I would be extremely surprised if they were successful,” said Nick Turner, an analyst for Mirabaud Securities in London. Others point to difficulties of a different kind.
An insulin pill could be “cannibalistic of their existing business,” says Alistair Campbell, an analyst at Berenberg Bank in London. Still, “the risk is someone else could develop a pill, so the fact they are leading the way on oral insulin is, from a defensive point of view, good news for them.”
Soerensen, who has spent three decades at Novo, jokingly warned researchers he won’t retire until they succeed in making an insulin tablet. On Feb. 2, the company said the 57-year-old CEO’s contract had been extended by three years to 2019.
“When we started this, I thought it was going to be very, very difficult,” says Lars Fogh Iversen, who heads the company’s diabetes protein engineering unit. “Now I am really confident we will crack this one.”
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