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

Reuters

By Bill Berkrot

Oct 9 (Reuters) - An insulin pill, long desired by diabetesdoctors and patients but abandoned as not physically viable,could be available by the end of this decade as a tiny Israelicompany races a Danish pharmaceutical giant to be first withwhat could be a multibillion-dollar product.

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

The concept of oral insulin as a way to relieve people withtype 1 diabetes of several daily injections has been aroundsince the 1930s. It was left for dead because as a proteincomposed of amino acids, insulin is destroyed by enzymes in thedigestive 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 thatwill allow enough insulin to survive the onslaught of digestivejuices.

"We've built technologies and we've seen from studies inanimals and early human trials that this may not be asimpossible 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 beavailable by the end of this decade or early next decade.

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

The brains behind Oramed's oral insulin is the chiefexecutive's mother, Miriam Kidron, who laid the groundwork withyears of diabetes research at Hadassah-Hebrew University MedicalCenter. "She's the chief scientist. I just went for the ride todo the business side," said Oramed CEO Nadav Kidron.

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

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

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

That is because the focus for oral insulin has shifted tothe ballooning health crisis of type 2 diabetes, a progressivedisease often caused by obesity. An estimated 90 to 95 percentof the more than 370 million people living with diabetesworldwide suffer from type 2, according to the InternationalDiabetes Federation. It projects that could climb to 552 millionby 2030.

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

"Even though there are other anti-diabetic agents and morecoming in, ultimately all (type 2) patients with diabetes, ifthey live long enough, will need insulin," said Novo'sKurtzhals.

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

Other than injections, no other insulin preparations havebeen shown to be satisfactorily safe and effective, doctorssaid. Past failures of alternative delivery systems includePfizer Inc's abandonment in 2007 of its inhaled insulinproduct.

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

"It would be an important contribution to the therapeuticarmamentarium. But there are still great limitations in ourability to get the insulin absorbed and control how much insulingets absorbed," Ratner said.

Other treatments being tried include nasal spray and a skinpatch, which lack some of the potential advantages of an oralinsulin.

A MORE NATURAL APPROACH

Insulin injections were introduced commercially as alife-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 thengoes to the liver, injected insulin circulates throughout thebody before it gets there. The main attractiveness of an insulinpill, if it works, is that any absorbed insulin would godirectly 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 atMontefiore Medical Center in New York.

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

Since the digestive system can break down insulin in amatter of seconds, both Novo and Oramed's approaches for theirinsulin pills involve protective coatings and molecular tweaksor added ingredients to help enough insulin be absorbed toprovide effective glycemic control. That involves giving largeenough doses of insulin so that some 90 percent can be destroyedwithout sacrificing efficacy.

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

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

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

Kidron sees oral insulin as an opportunity to save billionsof dollars in healthcare costs by helping to delay the myriadcomplications associated with type 2 diabetes.

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

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

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

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

INSULIN STIGMA

Persuading patients to take insulin earlier in their diseasecould take some work, however. Some doctors now see a stigmasurrounding the need for insulin - rather than needles, whichhave become much smaller and less painful - as a possibleimpediment to its acceptance by those with type 2 diabetes.

Patients may see insulin as an indication they are sickerthan they perceive themselves to be, or associate it with arelative who got insulin late in the disease only to see theirhealth deteriorate, doctors said.

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

The riskiness of the project and the number of years it willtake to come to fruition is likely a reason Oramed's marketvalue remains relatively small. The shares are trading for justover $6 and the CEO is the largest shareholder.

The company, which is also developing oral versions of otherinjectable drugs, plans to take its insulin through Phase IItesting and then find a partner with deep pockets to conductlarge, expensive Phase III trials and market the drug.

Kidron see no shortage of potential partners among Japanesedrugmakers, U.S. companies with diabetes sales forces, or evenNovo Nordisk - a scenario in which Goliath could simply buyDavid's slingshot.

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

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