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Pharma's David and Goliath in race to produce insulin pill

By Bill Berkrot

(Reuters) - An insulin pill, long desired by diabetes doctors and patients but abandoned as not physically viable, could be available by the end of this decade as a tiny Israeli company races a Danish pharmaceutical giant to be first with what could be a multibillion-dollar product.

In the pharma industry's equivalent of a David and Goliath story, the companies at the forefront are Novo Nordisk, the world's largest seller of insulin products with a market value of about $74 billion, and Oramed Pharmaceuticals Inc, with a market value of only $50 million and headquartered in Jerusalem, where the biblical David held court.

The concept of oral insulin as a way to relieve people with type 1 diabetes of several daily injections has been around since the 1930s. It was left for dead because as a protein composed of amino acids, insulin is destroyed by enzymes in the digestive system before it can do any good.

While skepticism over a viable insulin pill remains high, Novo and Oramed believe they have come up with solutions that will allow enough insulin to survive the onslaught of digestive juices.

"We've built technologies and we've seen from studies in animals and early human trials that this may not be as impossible as decades of research had indicated previously," said Peter Kurtzhals, Novo's head of diabetes research.

If all goes well, Novo believes its oral insulin could be available by the end of this decade or early next decade.

Oramed's program is ahead of Novo's. It has begun enrolling patients in Phase II, or midstage, clinical trials, while Novo has yet to begin Phase II testing.

The brains behind Oramed's oral insulin is the chief executive's mother, Miriam Kidron, who laid the groundwork with years of diabetes research at Hadassah-Hebrew University Medical Center. "She's the chief scientist. I just went for the ride to do the business side," said Oramed CEO Nadav Kidron.

"My mother said it could be commercial but Hadassah won't be able to fund it," Kidron recalled. "I took the IP from Hadassah and started Oramed. Since then, we've been moving it forward."

Regardless of who wins the race, Kidron said, "there must be an oral insulin. This is going to be a huge market." He sees the market potential to be at least $7 billion a year.

Novo said this week the global market for diabetes tablets could be worth more than $18 billion a year.

That is because the focus for oral insulin has shifted to the ballooning health crisis of type 2 diabetes, a progressive disease often caused by obesity. An estimated 90 to 95 percent of the more than 370 million people living with diabetes worldwide suffer from type 2, according to the International Diabetes Federation. It projects that could climb to 552 million by 2030.

GBI Research forecast the global market for type 2 diabetes treatments reaching nearly $40 billion by 2019.

"Even though there are other anti-diabetic agents and more coming in, ultimately all (type 2) patients with diabetes, if they live long enough, will need insulin," said Novo's Kurtzhals.

There is still a long way to go for Nova or Oramed to receive regulatory approval. The companies must prove the worth of their oral preparations with large clinical trials and demonstrate no heart problems or other major side effects.

Other than injections, no other insulin preparations have been shown to be satisfactorily safe and effective, doctors said. Past failures of alternative delivery systems include Pfizer Inc's abandonment in 2007 of its inhaled insulin product.

"I'm not going to hold my breath on this one," said Dr. Robert Ratner, chief science and medical officer for the American Diabetes Association (ADA).

"It would be an important contribution to the therapeutic armamentarium. But there are still great limitations in our ability to get the insulin absorbed and control how much insulin gets absorbed," Ratner said.

Other treatments being tried include nasal spray and a skin patch, which lack some of the potential advantages of an oral insulin.

A MORE NATURAL APPROACH

Insulin injections were introduced commercially as a life-saving treatment for diabetes in 1923 by Eli Lilly and Co. Novo has also sold insulin products for some 90 years.

While insulin is naturally produced in the pancreas and then goes to the liver, injected insulin circulates throughout the body before it gets there. The main attractiveness of an insulin pill, if it works, is that any absorbed insulin would go directly to the liver from the digestive tract.

"It is a much more natural physiological approach," said Dr. Joel Zonszein, director of the Clinical Diabetes Center at Montefiore Medical Center in New York.

Some doctors believe high levels of insulin circulating through the rest of the body may increase health risks.

Since the digestive system can break down insulin in a matter of seconds, both Novo and Oramed's approaches for their insulin pills involve protective coatings and molecular tweaks or added ingredients to help enough insulin be absorbed to provide effective glycemic control. That involves giving large enough doses of insulin so that some 90 percent can be destroyed without sacrificing efficacy.

Novo believes it has designed a more stable molecule than natural insulin that can slow the time of degradation to minutes. "And if you can do that, maybe it's sufficient time for absorption to take place," Kurtzhals said.

"Risk is still high for this type of project. But the chance of success has gone up quite dramatically in our own minds compared to what it was originally," he said.

Oramed has introduced a protease inhibitor and another tweak designed to protect and enhance absorption of its oral insulin.

Kidron sees oral insulin as an opportunity to save billions of dollars in healthcare costs by helping to delay the myriad complications associated with type 2 diabetes.

"If we give insulin earlier on, we're going to give the pancreas a rest," Kidron explained. "We could reduce the complications, such as blindness and amputations."

He likens earlier treatment with an insulin pill to Pfizer's Lipitor, which became the most profitable drug in history by preventing serious heart problems.

Dr. Jason Gaglia, a top researcher at Harvard Medical School's Joslin Diabetes Center, said an oral insulin could be used to better control overnight blood sugar.

"If you could give it in an oral pill that is just hitting the liver, it would be wonderful," he said. "If people take this pill at dinner time, they're not going to have this excess glucose production overnight and it will be really good for getting those morning blood sugars down."

INSULIN STIGMA

Persuading patients to take insulin earlier in their disease could take some work, however. Some doctors now see a stigma surrounding the need for insulin - rather than needles, which have become much smaller and less painful - as a possible impediment to its acceptance by those with type 2 diabetes.

Patients may see insulin as an indication they are sicker than they perceive themselves to be, or associate it with a relative who got insulin late in the disease only to see their health deteriorate, doctors said.

"We need to do some education to convince people that insulin is a therapy like any other and it's very effective," said Dr. Elizabeth Seaquist, a member of the Endocrine Society who is in line to become a future ADA president.

The riskiness of the project and the number of years it will take to come to fruition is likely a reason Oramed's market value remains relatively small. The shares are trading for just over $6 and the CEO is the largest shareholder.

The company, which is also developing oral versions of other injectable drugs, plans to take its insulin through Phase II testing and then find a partner with deep pockets to conduct large, expensive Phase III trials and market the drug.

Kidron see no shortage of potential partners among Japanese drugmakers, U.S. companies with diabetes sales forces, or even Novo Nordisk - a scenario in which Goliath could simply buy David's slingshot.

"Novo is in a different league from anyone else out there," Kidron says with admiration. "I look up to them."

(Reporting by Bill Berkrot; Editing by Edward Tobin, Tiffany Wu and Grant McCool)

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