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Insulin Analogs

Genetic Engineering for Diabetes Control

By David Mendosa

Last Update: January 16, 2001

While work on oral insulin is getting lots of attention in the press, drug companies are more quietly bringing to market new designer insulins that provide greater blood sugar control with fewer problems.

‘It’s a new paradigm.’

Researchers have succeeded in genetically engineering these new insulins by changing the order of the amino acids that make up human insulin. Because of this, the insulin molecules interact with each other differently, changing how our bodies absorb these new insulins.

Known as insulin analogs, these new drugs give us the opportunity to fine-tune their use. An insulin analog that can be taken immediately before eating to cover a meal's glucose load is already available. On the near horizon are other fast-acting insulins as well as complementary insulins that promise to cover daily basal needs.

Rapid Acting Insulin Analogs
The first insulin analog to hit the market was insulin lispro, sold by Eli Lilly and Company as Humalog. In June 1996 the U.S. Food and Drug Administration approved its use in the United States.

It's called lispro because in this insulin analog, two amino acids, lysine and proline have different positions on the beta chain of the insulin molecule than they do in regular human insulin. This change in the position affects how the insulin molecules interact, resulting in faster absorption from the injection site and quicker onset of action than regular insulin.

Insulin lispro starts lowering blood glucose more quickly and has a shorter duration of action than regular human insulin. While regular insulin works best when given from 30 minutes to an hour before a meal, insulin lispro should be given within 15 minutes of eating.

Being able to take your insulin just before a meal means that you are much more likely to know exactly when and what you will be eating. This means that it's easier to judge the dose needed to cover the meal.

An important implication of this is less hypoglycemia among people with type 1 diabetes who maintain tight control. A study of 199 type 1 patients reported last year in the journal Diabetes Care found that use of insulin lispro resulted in "a significant decrease in severe hypoglycemic episodes and coma."

While insulin lispro is the only insulin analog sold anywhere today, this is likely to change soon as insulin manufacturers rush other insulin analogs to the market. Three companies manufacture almost all of the world's insulin supply.

Lilly has the lion's share—about 80 percent—of the U.S. insulin market, but the Danish pharmaceutical giant Novo Nordisk A/S has the largest share worldwide. A third company, Hoechst Marion Roussel AG, the pharmaceutical subsidiary of Germany's Hoechst AG, doesn't yet sell any insulin in the United States but has about 8 percent of the worldwide market.

Novo Nordisk just submitted a New Drug Application to the Food and Drug Administration in September for its rapid-acting insulin analog. Formally known as insulin aspart, it's called NovoRapid outside the United States and went by the name Asp(B28) in early trials.

It's called insulin aspart because the amino acid, aspartic acid, has been substituted for proline at position 28 on the beta chain, says John Whisnant, vice president drug development for Novo Nordisk Pharmaceuticals Inc. in Princeton, New Jersey. "It's one amino acid different from regular human insulin. If you change insulin by one amino acid, its absorption is faster but it is still insulin."

In practice that's no small difference. Unlike all regular insulins—and even lispro—people don't have to take it before they eat.

"They can wait until they actually are eating," Whisnant says. "That makes an enormous difference to people whose schedules are erratic or not precise."

The old paradigm, Whisnant says, was that you had to take your insulin before your meal, which meant that once you inject your insulin you better sit down and eat. "You ate food to cover insulin instead of the converse. So it's a new paradigm now."

Insulin aspart will "give you a nice peak within about 30 minutes" and cover the two-hour period after a meal, Whisnant says. "You don't get much tail with these drugs. Because of the rapid onset, the action curve drops pretty fast, and you don't have that lingering tail of action four or five hours leter that you get with regular insulin and which sometimes gives you hypoglycemia."

The rapid onset of insulin aspart would indicate that you might even be able to take it just after a meal. "We didn't do the study that way," Whisnant explains, "but the kenetics would predict that you could."

When will insulin aspart be on the market here? "I am not allowed to say that," Whisnant responded. "But you can pretty much predict that it will happen sometime next year."

Long-Acting Insulin Analogs
As exciting as these new rapid-acting insulins are for covering meals, there's still something missing. And that is a truly long-acting depot insulin to cover basal requirements.

"Basal is the term used for the slow steady release of insulin needed to control blood sugar between meals and during the night. It is what keeps body cells supplied with energy and able to keep working when no food is being ingested," explains R. Keith Campbell, associate dean and professor of pharmacy practice at Washington State University College of Pharmacy in Pullman, Washington. "A normal pancreas should put out about a basal unit of insulin every hour to handle the glucose produced by the liver between meals. And when you eat, it should put out a supplement or a bolus of insulin to handle the carbohydrates. A depot insulin is one you inject that can act as a basal insulin."

While some rather long-acting insulins available today are called basal insulins, they have less than a 24-hour steady effect and have some peaks and valleys in their action profile. But two long-acting insulin analogs in development promise to be real depot insulins.

Novo Nordisk has "a very good one" called NN304 in clinical trials, Whisnant says. Rather than being a molecule substitution like other insulin analogs, "we took regular human recombinant insulin and attached a little fat to it to change its solubility. It's the change in solubility that prolongs absorption and extends its tail of action."

NN304 is not ready for submission yet to the FDA, he says.

But another long-acting insulin analog from the third player in the world insulin market is generating a lot of excitement.

Hoechst Marion Roussel is developing Lantus® (insulin glargine, formerly HOE901), which, Campbell says, will be next most important insulin development following the introduction of lispro two years ago.

"That is because it lasts for 24 hours," he says. "It doesn't have peaks and valleys, so it truly is a basal depot insulin, and that should be very beneficial. The bad news about it is that it is not mixable with other insulins, so people may have to take an extra shot to use it."

The fact that insulin glargine can't be mixed with other insulins would be bad news only in an ideal world, believes Eberhard Draeger, global project leader and senior director of Hoechst Marion Roussel Inc. in Bridgewater, New Jersey. It has the advantage, he says, of being given at once daily at bedtime, providing a fixed regime that patients can easily follow.

Insulin glargine differs from human insulin in three amino acids, slowing down its release and reducing its solubility in the blood. Phase III clinical studies are currently ongoing, and Hoechst Marion Roussel expects to make a U.S. submission next year. It should be available on the U.S. market in 2000, Draeger says.

When insulin glargine and perhaps other long-acting insulin analogs become available, people with diabetes will be able to combine a true basal insulin with a rapid-acting insulin like lispro or aspart with their meals. Draeger believes that this promises to be our best weapon yet for really tight control, thereby reducing the onset and severity of eye, kidney, and nerve complications. 

This article originally appeared in Diabetes Wellness Letter, November 1998, pages 1-3.

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