By David N. Leff

Science Editor

Biotech start-ups and big pharma companies alike are redoubling — and combining — their efforts to make oral insulin a reality.

Early this year, Emisphere Technologies Inc., of Hawthorne, N.Y., which specializes in orally delivered drugs, signed a $60 million deal with Eli Lilly and Co., of Indianapolis, to develop oral forms of two "as-yet-undisclosed" endocrine proteins. Lilly, of course, is one of the world's two leading purveyors of injectable insulin — the daily lifesaver for millions of diabetics. (See BioWorld Today, Feb. 28, 1997, p. 1.)

And in October, Lilly — which commercialized insulin in 1923 — negotiated a $190 million-plus agreement with Ligand Pharmaceuticals Inc., of San Diego, for Oral Targretin, a non-insulin diabetes-control agent, now in preclinical trials. (See BioWorld Today, Oct. 21, 1997, p. 1.)

Just last month, Aradigm Corp., of Hayward, Calif., received U.S. Patent No. 5,672,581, for pulmonary delivery of insulin formulations, "so diabetics can manage their mealtime glucose using insulin, without needles." (See BioWorld Today, Nov. 4, 1997, p. 5.)

"I am not aware of any oral insulin work in humans," Michael Flynn, president and research and development director of Cortecs International Ltd., told BioWorld Today. "Almost everything seems to work in animals," he observed, "but when you get to diabetic patients, it doesn't seem to. I'm not aware of any other groups than ours with results in humans at the moment."

Cortecs, an Anglo-American company, has just completed an as-yet-unpublished Phase II clinical trial of its orally ingestable insulin, trademarked Macrulin.

"It was carried out this autumn in the Netherlands," Flynn said, "under contract from Cortecs to the Dutch Pharma-Bio Research International BV, in Zuiderlaren.

"Six patients with Type II diabetes," he continued, "entered and completed the multiple crossover study. Each participant, while in the fasting state, received each of four different treatments in a single dose: either placebo or oral insulin — Macrulin — at three graduated dosages. After six hours," Flynn went on, "we measured levels of glucose, insulin and insulin C-peptide.

"We were looking for a very gentle reduction of blood glucose over the course of the experiment," the Cortecs executive recounted. "Observations continued during six hours, until the patients were fed. The results showed what we expected — a dose-related fall in blood glucose, which continued over the six hours. This was accompanied by an increase in the circulating insulin levels in peripheral blood.

"We had three objectives," Flynn pointed out: "Can we get the insulin in? Are we sure that when it gets in it has a biological effect? And is that effect due to the orally ingested peptide, not to some other effect, such as endogenous insulin induction?"

Study Tested Oral Delivery Method

The trial's main purpose, he added, "was to get insulin from the intestine via the portal vein to the liver, where the hormone is supposed to act. We wanted to avoid what happens with the injected insulin, where 80 percent of it acts in the periphery."

The reasoning behind this goal was, "If we can get it to the liver, we could probably achieve better control, particularly the increase in body weight that occurs when you put a Type II diabetic on insulin. Also, hopefully, avoid hypoglycemia."

To discern these effects, the Cortecs diabetologists scrutinized the insulin C-peptide values, "because we didn't know if on a single dose the patients could actually get a fall in glucose levels. But they did, so we were lucky." (C-peptide is the 30-amino-acid precursor chain that is removed when proinsulin's A and B chains unite to form the functional hormone.)

"But the main thing," Flynn went on, "was to get the oral insulin into the bloodstream and see if it had a biological effect. We measured this by the insulin-to-C-peptide ratio, and got good effects as well."

Macrulin's next challenge, as Flynn put it: "Does this have a practical application in diabetes patients?" Cortecs will address this issue during the first half of 1998, when it repeats the initial Phase II trial with a pair of new studies. "The next Phase II's first stage," Flynn predicted, "will be repeated doses, rather than single. And the second stage should be a real investigation of efficacy."

He foresees the first of these trials taking place in the U.K.; the second "within Europe, probably."

During the first half of next year, Cortecs also plans to do "a similar but not-quite-identical study in patients with Type I diabetes."

How Cortecs' Ingestable Insulin Works

"Macrulin," Flynn explained, "is a liquid inside an enteric-coated soft-gelatine capsule. It is designed to be given three times a day, between meals. The insulin used in trials so far was porcine," he added, "but we hope to move during 1998 to the recombinant human version."

Here is how he described the oral formulation's mode of action:

"We have developed a technology that enables a hydrophilic molecule to virtually dissolve in an oil. What we do is coat the insulin peptide with an amphiphile — an amphipathic molecule. This is a chemical substance that can dissolve either in an oil or in water; it has both a lipophilic and a hydrophilic pole.

"The hydrophilic part," Flynn continued, "is linked to the peptide, and the lipophilic part to the oil. So it forms what appears to be a totally clear solution of the peptide. One can use a whole variety of oils and amphiphiles to make this kind of formulation. However, the type of oil that one employs very much influences what happens to the insulin in the body.

"One type of oil would ensure that the peptide will cross the epithelial barrier of the upper gastrointestinal tract. We have demonstrated this first of all in in vitro studies, then in vivo — normally using pigs. By electron microscopy you can see how it is crossing the epithelial barrier. This technology," he pointed out, "also avoids uptake in the upper intestine, where it could interact with the Peyer's patches to cause a destructive immune response.

"In the Macrulin preparation, we ensure that the insulin crosses the epithelial barrier at the upper end, in the jejunum, far north of the Peyer's patches."

Cortecs' president concluded by making the point that "the purpose of this just-completed clinical trial was really proof of principle for oral insulin delivery, not for the treatment of diabetes. The last thing I would want is a flood of diabetics thinking that next year they're going to have oral insulin. That's a few years away — if everything goes well." *

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