My first encounter with insulin came when I was diagnosed with gestational diabetes. Being pregnant was hard for me. Being diagnosed with diabetes was harder. And learning how to cope with insulin therapy was the hardest part of all.
If you’ve never used insulin, or been around someone using it, you might think the worst part of the therapy is the injection. The injection is unpleasant, no doubt, but it isn’t the biggest downside to insulin therapy. The worst thing about insulin therapy, by far, is the hypoglycemia that often accompanies it.
So when I first heard about the work being done in Israel to create oral insulin, I thought it sounded great but I wasn’t over-the-top excited since what I’m waiting for is insulin that doesn’t cause hypoglycemia. Then I talked to the team at Oramed Pharmaceuticals in Jerusalem, where they believe they’ve successfully developed oral insulin for the treatment of type 2 diabetes, and I was floored. Not only has Oramed created oral insulin that’s shown good results in early trials, apparently, it doesn’t cause hypoglycemia.
Oramed was founded by a group of scientists from Jerusalem’s Hadassah Ein Kerem Medical Center. Dr. Miriam Kidron, who was part of that team, had been working for over twenty-five years on the development of oral insulin. In 2006, the team had a breakthrough when they figured out how to correctly work the technology that would enable oral insulin to be effective. At that time, Nadav Kidron, the son of Miriam Kidron, decided it was time to bring this product to the market. Together with his mother, he founded Oramed. “When the technological basis seemed sound, I readily enlisted myself to help leverage the years of research toward commercializing this concept as soon as possible,” said Nadav.
The development of oral insulin has been no simple task. “People have been dreaming about oral insulin since 1922,” Dr. Kidron said. Because insulin is a protein, it’s easily broken down by enzymes in the digestive tract, just like any protein we eat. An unprotected insulin tablet has no chance to do its job in the harsh environment of the gut. And furthermore, insulin is a very large molecule, meaning it can’t be easily absorbed through the gut wall and circulated to the tissues where it is needed.
To combat these problems, Oramed has come up with a platform technology which can work not only with insulin, but with other peptides, like GLP-1 analogues (Byetta and Victoza are two current GLP-1 analog drugs on the market.) Oramed’s technology provides protection against natural obstacles within the gastrointestinal tract, without jeopardizing the drug integrity and bioavailability. The formulation involves a simple blend of insulin with protective reagents, provided at precisely calibrated concentrations and ratios. Oramed’s drugs do not require any modification of active ingredients, so they can be administered in their natural state. Because the technology doesn’t require changing the insulin molecule, the pre-marketing regulatory processes is shorter.
Oramed’s platform technology begins with a soft gel capsule that’s coated with an “enteric coat,” which only disintegrates to allow for protein release once it reaches a region of pH typical to the small intestine. Thus, the capsule will not dissolve in the acidic and harsh environment of the stomach. Next, an absorption enhancer assists the insulin in crossing the gut wall where it is deposited into the liver via the portal vein. From there, the insulin enters the bloodstream, however, not before undergoing drug metabolism in the liver (first-pass metabolism). In the case of oral insulin, up to 80% is cleared by the liver during first-pass metabolism, while only a small amount spills over to the bloodstream. This process closely mimics that of natural insulin released from a healthy pancreas. It’s because of this primary insulin metabolism in the liver, that the risk of hypoglycemia is significantly reduced. (By comparison, when you inject insulin subcutaneously, 100% of the insulin enters the bloodstream.) According to Oramed, studies comparing insulin infusion into the portal vein versus infusion into the subcutaneous space suggest that portal insulin delivery is associated with improved glycemic control, reduced risk of hypoglycemia, and fewer glucose swings.
All of this sounds promising, but what about oral insulin in the day-to-day, practical sense? To find out how oral insulin will work for the patient, I talked to Tara Horn, Oramed’s Corporate Communications Director, who kindly answered some questions.
Can oral insulin replace both basal and rapid injectable insulins?
The current oral insulin formulation is released following a basal lag period, essential to allow for its passage through the gut and release only after reaching a specific pH, typical of the small intestine.
Does oral insulin work faster or slower than injectable insulin? Would be a once daily pill? A pill with each meal?
Oral insulin can only spring into action following the natural delay between administration and its breakdown and later absorption across the small intestine. The frequency of administration will depend on the indication at hand. Oramed capsules have been shown to effectively curb glucose excursions when delivered to volunteers with type 1 diabetes up to 90 minutes before a standard meal. At the same time, Oramed is pursuing application of a once daily, bedtime oral insulin formulation to combat impaired fasting glucose concentrations, common in pre-diabetes or early stages of the disease.
Do you expect oral insulin to be equally effective in type 1 and type 2 diabetics? How precise can the dosing of oral insulin be?
Oral insulin has proven equally effective in both type 1 and type 2 diabetes populations. Oral insulin dosing can be easily fine-tuned to match the broad interpatient response variability. For type 1 specifically, in the near future, our oral insulin will not be marketed to replace the insulin injection, but it will certainly foster glucose control and hopefully reduce the number of complications
Are there any side effects of oral insulin?
To date, Oramed’s oral insulin preparations have been evaluated in eight clinical studies, involving over 100 volunteers and over 1300 administrations. Apart from seven reports of mild hypoglycemia, reversed after drinking orange juice, no serious side effects have been reported. Due to its route of absorption, oral insulin is anticipated to significantly reduce the risk of hyperinsulinemia and hypoglycemia, tightly associated with injectable insulins.
Do you have any concerns about the long-term effects of oral insulin on the liver?
No, the liver is constantly exposed to insulin so this drug shouldn’t put any extra burden on it. We don’t predict it will.
What about oral GLP-1 therapy? Are you using the same technology? I believe you recently filed for a patent for a combined oral insulin/oral exenatide treatment. Can you tell us more about this?
We are using the same technology for the GLP-1 analog capsule. The patent is for an entirely new product which will combine insulin and GLP-1 analog in a single capsule.
If all goes well with clinical trials, how soon could oral insulin be on the market?
It will probably be a number of years until the oral insulin is on the market. The FDA approval process takes a very long time and it is hard for us to precisely predict when it will be available. However, outside of the U.S. and Europe it could be as soon as two or three years.
If and when oral insulin comes to market, it could mean big changes for the treatment of type 2 diabetes. “Injectable insulin is usually prescribed for type 2 diabetics only when oral medications fail,” said Horn. “We hope that oral insulin will be prescribed for patients with type 2 diabetes at an earlier stage than injectable insulin, in order to blunt further progression of the disease.”