Waiting to Exhale... But Don't Hold Your Breath

| Aug 1, 1998

Before eating lunch at a restaurant, Jim loads his foil packs of insulin into a device about the size of a large flashlight. He then presses a button which releases a cloud of insulin into the clear chamber of the device. He takes a slow, deep draw of powdered insulin into his lungs.

Is this a scene from some futuristic sci-fi movie? Not quite. In fact, two California companies hope inhalable insulin will replace insulin injections in less than a decade.

Currently, Inhale Therapeutic Systems (ITS) of San Carlos and Aradigm Corporation of Hayward are developing inhalable insulin devices. Both companies have the backing of powerful pharmaceutical companies to help them market and develop their products. ITS is working in conjunction with the New York based Pfizer Inc. and Aradigm Corp. is developing its AERx Diabetes Management System with the Danish pharmaceutical company Novo Nordisk.


Injections Not Over

North Carolina resident, Ann Boles, first used ITS' inhalable insulin device in a four-month clinical trial last year, then asked to continue using it after the study had ended. Boles, who has had type 1 diabetes for five years, takes her inhalable insulin three times a day before each meal.

It is important to note, however, that inhalable insulin hasn't entirely freed people with diabetes from injections. At night Boles still takes a bedtime insulin injection and she must prick herself four to five times a day in order to test her blood sugars.

Despite this fact, Boles is pleased with the inhalable insulin.

"Three less injections a day still makes a big difference to me," she says.


Similarities and Big Differences

Both companies use regular insulin packaged in foil blister packs which is absorbed in the deep lung. Similar to the way oxygen is absorbed into the bloodstream, the insulin is rapidly absorbed through a layer of tiny air sacks in the lungs called alveoli. This rapid absorption causes regular insulin to function as quickly as lispro.

In a study conducted by Aradigm, principal investigator, Stephen Farr, PhD, compared injected Humalog against inhaled Humalog. Farr found that the absorption time was the same.

Richard Thompson, former co-founder and president of LifeScan and now CEO and president of Aradigm reports that phase I clinical trials have shown that this rapid-acting insulin delivery allows for greater mealtime flexibility.

"These results show that inhaled insulin lowers blood sugar faster than injections of regular insulin and it is similar to Humalog," says Thompson. "This is important to patients because it will make taking mealtime insulin easier to do in the future."


Easy-to-Use or Ungainly?

Will users of inhalable insulin be forced to wear bandoliers loaded down with silver foil insulin packs? Will they leave trails of silver foil in their wake? Both companies emphatically say "no". They claim their inhalable insulin devices are easy to load and a user does not have to load countless packs of insulin. "It should take less than five minutes," says Bukar.

Ann Boles agrees. "I've had no problem loading the insulin packs."

Boles thinks that inhalable insulin will be especially effective for the elderly and those who have vision problems because the insulin packs are color coded according to dosage. "I like that you don't have to measure anything and it doesn't have to be stored in the refrigerator."

The only complaint Boles has about ITS' device is the size, which is roughly that of a large flashlight.

"You can't fit it in a small purse with your meter," says Boles. "And I often wonder how men will feel about carrying something so big around."

Despite the size, Boles thinks it's still worth it. "You weigh it against carrying syringes and vials of insulin and it's really not that much different," she adds.


How the Companies Differ

The two companies have followed different paths in the dosing and production of their insulin.

Aradigm Corporation uses a sterile liquid aerosol insulin which it packages in 5, 10 and 15 unit packs.

ITS uses a dry powdered insulin packaged in one and three milligram packs. A one-milligram pack equals three units and a three-milligram pack equals six units of insulin.

Why milligrams instead of units? A person using inhalable insulin must use roughly ten times as much insulin as they would inject.

Julie Bukar, RD, MBA, director of ITS' clinical studies says its concentrated powdered insulin will lessen the amount of packs a user will have to load. And that changing from units to milligrams should not be a problem for most people with diabetes.

"This form of measurement is easy to get used to," says Bukar. "It hasn't caused any confusion."

Not surprisingly, both companies debate as to which type of insulin is more effective: powdered or liquid aerosol insulin?

Reid Rubsamen, MD, founder and vice president of Aradigm Corporation, points out that liquid aerosol is sterile so that it doesn't encourage the growth of microbes plus users have more control over dosing. And in addition each packet has its own individual lazer drilled nozzle, using a technology similar to that used in ink jet printer nozzles.

And like ITS' insulin, the liquid aerosol insulin is also more concentrated than insulin in vials. "The trick is to make sure you deliver the drug in one or two breaths and the patient isn't generating a giant trail of packets behind them as they take the doses," says Rubsamen.

"Patients can program in partial doses on the front of the device," says Rubsamen. "You can use just part of a packet."

Rubsamen says the remaining portion of the packet cannot be reused, however. "Discarding small amounts of insulin won't have a big effect on the economics," he says.

Neither company has an idea of how much their insulin will cost yet.

However, Rubsamen concedes that the insulin will probably cost more. "Any kind of unit dose of liquid or powdered insulin will be associated with more cost than multiple dose vials of insulin."

One positive feature of these new forms of insulin is their longevity. Aradigm's insulin can be used effectively for up to two years if refrigerated and can last for a month unrefrigerated.

Julie Bukar, says ITS' powdered insulin prevents the growth of microbes and it can be used effectively for up to a year without being refrigerated.

The devices will also need to be cleaned at least once a week.


Encouraging Results Announced

At the recent June ADA sessions in Chicago, the head of Inhale Therapeutic System's phase II clinical trials on type 1s, Jay Skyler, MD, announced encouraging HbA1c results.

"...The inhaled insulin performed as well as the subcutaneous regimen when levels of HbA1c ... over the prior two to three months, were examined," said Skyler, professor of medicine at the University of Miami.

Seventy subjects with type 1 took either insulin injections or inhaled insulin for three months. The injection group continued with two to three injections a day, while the group who inhaled insulin took one to two inhalations of insulin before each meal. The inhalable group also injected one long-acting insulin dose at bedtime.

According to the studies, the group who injected insulin had an average HbA1c of 7.7% after three months; the inhaled group averaged at 7.8% after three months.

Phase II studies were also conducted on people with type 2. The head of the type 2 study, William Cefalu, MD, found almost identical results.

"We saw improvements in blood glucose control in both groups, with the changes in hemoglobin A1c virtually identical," said Cefalu, Associate Professor of Medicine at the University of Vermont College of Medicine in Burlington.


Illness Effects

Will the insulin be properly absorbed into the lungs if the user smokes, has a cold or suffers from some other respiratory ailment?

Both Thompson, CEO of Aradigm and Julie Bukar, director of ITS' clinical studies are confident that it shouldn't be a problem. Both plan on studying the effects on users with colds and other respiratory ailments in the next phase of their clinical trials.

Ann Boles has used ITS' inhalable insulin device in the past when she had a cold.

"Initially I was worried that it wouldn't work. But I didn't have any problems getting all of my insulin," she says.

Thompson points out that, as long as the user has a continuous inhalation, the insulin will go to the surfaces of the lungs and be absorbed.

Aradigm's device facilitates the proper breathing by showing a red or a green light to cue the user when she has inhaled correctly. The device will not release the insulin until the user inhales properly.

"This helps minimize the variability," said Thompson. "This will be an advantage for people with respiratory ailments like asthma."

Thompson only speculates this will be the case, however, he admits that there is no data to prove this yet.


Age Range

Could inhalable insulin be a dream come true for children with diabetes? Possibly, if your child is over six; For younger children probably not. Both companies think it would be difficult to guide a small child into taking the proper deep inhalation in order to absorb all of the insulin.

Bukar says Inhale's device can be used in children as young as six. The company plans on making 0.5 mg packs (equals 1.5 units) for children's doses in the near future.

Aradigm is confident that its device will work for teens but has not tested on younger children as of yet.


How the Devices Differ

Inhale Therapeutic System's device does not require batteries. Instead it works on air compression.

"It's similar along the lines of an air gun," says Bukar. "You pump it until the chamber compresses with air, then press a release button that breaks apart the insulin packs." The chamber then fills with a fine insulin powder which the user inhales.

Aradigm's device works on batteries. "Our AERx device is rechargeable like a laptop computer," explains Thompson.

The device also contains a microprocessor which releases the automatic vapor of liquid insulin when the user takes the proper deep inhalation. Thompson says dialing up a dose is simple.

"Say you need 12 units for lunchtime. You choose the 15 unit pack and load it into the device which recognizes that it is a 15 unit dose," said Thompson. "It then asks you how much you need and you choose 12 units."


When Can You Get One?

Both companies must complete all three phases of clinical trials before they can apply to the Food and Drug Administration for approval. Currently ITS is ahead and approaching phase III clinical trials, which will involve a study of 1,000 patients this fall. This study will mimic the postmarketing environment. If successful, Inhale hopes it product will be on the market in two to three years.

Aradigm is approaching phase II trials this fall and is more hesitant to predict when its product will be available. "It's hard to say how long it will take," says Rubsamen. "We have to finish the three trials first and then file with the FDA. Luckily, the FDA has been supportive of inhaled insulin which helps."



In the past, several novel approaches of insulin delivery have been investigated from suppositories to nasal spray. All were found ineffective. Insulin in pill form was destroyed by stomach acids and sniffing insulin through the nose was sidelined by irritated nasal passages and erratic absorption. Suppositories were nixed for obvious reasons.

Currently, the worldwide insulin market including drugs and syringes is estimated to be greater than $2.9 billion.

The pharmaceutical industry giant Pfizer has already spent $15 million developing Inhale's inhalable insulin device. Novo Nordisk will sink up to $ 85 million into developing Aradigm's inhalable insulin device. No doubt, their investments will be well worth it if inhalable insulin becomes a viable alternative to injections.

In a recent San Francisco Chronicle article, stock analyst, Peter Ginsberg at Piper Jaffray in Minneapolis estimated that inhalable insulin sales could equal anywhere from $500 million to $ 1 billion a year.


Just Around the Corner

People with diabetes are all too aware that an innovation "just around the corner" could be several miles down the road. Still, if Ann Boles is any indication, people with diabetes are willing to wait and pay the higher prices if it will free them from the sting of insulin injections.

"I can't imagine someone with diabetes not being excited about inhalable insulin," says Boles. "It's a wonderful breakthrough."

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