In Exubera's Shadow: Generex Bets Oral Spray Is Next Big Thing for Diabetics

As companies bail out of the inhaled insulin business -- most recently Pfizer, which lost $2.8 billion before throwing Exubera overboard -- one small firm believes there is an alternative to pills, injections and inhalers.

Generex, a Worcester, Mass.-based company, believes there's an opportunity for insulin delivery in a liquid spray. It isn't inhaled into the lungs, however -- the spray is directed at the lining of the mouth where the insulin is absorbed. The company's product, Oral-Lyn, is approved in Ecuador and India (where it is marketed by Shreya), and is in phase III trials for approval in the U.S.

I spoke with Dr. Gerald Bernstein (pictured), a former president of the American Diabetes Association and now Generex's vp of medical affairs, about why he believes Ora-Lyn won't meet the same fate as Exubera. Our questions and answers have been edited for flow.

BNET: What's wrong with inhaled insulin? It seems like a good idea in principle, no injections. Bernstein: The biggest thing that's wrong is utilizing the fragile alveoli membranes to transport proteins. It's basically, biologically, been designed to transport gases and not solid molecules and almost all pharmacology to the lungs is exactly that, delivery to the lungs not through the lungs. It was very apparent going back 10 years that only a small percentage of the endocrine community was at all interested in the use of a pulmonary insulin product. There were people in the scientific community who were concerned about the impact on [cancer] growth factors because of the insulin that was delivered, 20 percent got into the alveoli and the other 80 percent sat in the bronchial system, so was there an implied risk. There were six lung cancer cases that were found in the Exubera group. There's no proof that [Exubera was to blame] but the fact is clinicians weren't willing to take that chance.

BNET: With Oral-Lyn, insulin is absorbed through the mouth. If absorbing insulin through the inner cheek is such a good idea, why hasn't anyone else thought of it before? Bernstein: There's an extensive literature on peptide and small proteins and trying to have them absorb through the mouth, but the fact is that it's not easy. Although people have been writing about it, nobody has taken it far enough to have a model of predictability. When you get into larger molecules they don't regularly cross, but Oral-Lyn has the right combination of ingredients prepared in the right way to allow it to predictively penetrate.

BNET: What exactly is in Oral-Lyn? Bernstein: It's human regular insulin, it's put into a liquid formulation [with a spray propellant]. The formulation results in tiny bubbles called micelles that are greater than seven microns and therefore cannot go into the lungs. So in no way, fashion or form does this parallel a pulmonary insulin product. The product is sprayed into the mouth. Once it gets through the superficial layer [inside the mouth] the number of blood vessels is so rich it goes right into the bloodstream. It's very simple, it's very fast. When it's finished it doesn't hang out. For people with diabetes that's very important because if you don't have extra insulin hanging around, you reduce the risk of low blood glucose. And finally it's delivered with an asthma-like device. So it's very familiar to doctors and patients. There's no intimidation to people using it. No one will know you have diabetes, which is very important.

BNET: I'll bet it tastes disgusting. Bernstein: It actually has no taste. What you get is a cold sensation from the propellant. When you spray you literally start eating the next minute. It will peak in 30 minutes. And most important it's finished in two hours without a tail. The lack of a tail reduces the risk of low blood sugar or hypoglycemia. Because it's so fast you have the flexibility -- maybe you want a dessert, you can spray again. We recommend that the person splits the dose and sprays half at the start of the meal and half right after. It turns out to be more efficient that way.

BNET: How does it perform in terms of A1C, the yardstick glucose measurement for diabetes? Bernstein: In our early studies in type 2 diabetes it showed that when Oral-Lyn was added to a failing regimen it reduced the A1C by as much as 1%. By anybody's standard that's superb.

BNET: Did it bring A1C down to 6.5 percent? That's the gold standard. Many diabetics have A1C at 9 percent and above. Bernstein: What we looked for was, can it bring the A1C down equal to or better than other forms of bolus insulin, such as regular, Novolog, Humalog, and Apidra? We've shown that, but we haven't done a specific study where the endpoint was a low A1C. In our studies to date the A1C has come down but it wasn't the specific endpoint. Non-inferiority is what we've been aiming for because that's what the FDA requires.

BNET: What about side effects? Bernstein: It's extremely safe by all the studies that have been done [so far], including two years in animal tests. We haven't seen allergic reaction. The lining of the mouth hasn't shown any abnormalities. The buccal mucosa is an extra-tough and resilient tissue, it's beaten up all the time. People bite themselves or burn themselves. Whatever doesn't get absorbed is going to go to the stomach. Now the insulin molecule is unprotected and therefore it will be denatured by the acid and then broken down. There are no side effects. It's like eating a piece of meat.

BNET: What are the limits to the device? Bernstein: Each puff represents one unit to the body. If someone requires 10 units they would require 10 puffs. It can range from four or five and up. My own feeling is, once you begin heading through more than 15 units that's too many puffs, I think people would get tired of doing that.

BNET: If this product is so good, why haven't you been acquired or given a marketing deal by a major pharma company? Bernstein: Certainly everybody looks at us and has contacted us but that's [not my decision]. There were a couple of things that were inhibitors early on. The simplicity of Oral-Lyn was very disarming, especially with the huge cloud that pulmonary insulin put over the whole sector of alternative delivery. The handful of abstracts and presentations that might have come from Generex were completely overshadowed by Pfizer.