Here's more on Targretin and diabetes:
Beyond Sulfonylureas
The New Drugs for Blood Glucose Control
By Rick Mendosa
Life is getting more complicated for people with type 2 diabetes and the doctors who treat them.
But that's good. If you think you and your doctor have a lot of glucose-lowering drugs to choose
from now, hang onto your hat as we look at what the biotech companies are developing.
Until 1995, the sulfonylurea class of drugs was the only choice other than insulin for treating type 2
diabetes. Certainly you had a choice of brand, but they all work the same way, by squeezing more
insulin out of your beta cells and improving insulin's ability to get glucose into the rest of your body.
Sulfonylurea drugs include Glucotrol (glipizide) and DiaBeta, Glynase, and Micronase (glyburide).
The explosion of drugs available for controlling blood glucose began when Glucophage (metformin)
became available in 1995, quickly followed by Precose (acarbose). Bristol-Myers Squibb's
Glucophage works differently from the sulfonylureas by keeping the liver from making too much
sugar. Bayer Corporation's Precose, a third class of drugs, slows carbohydrate digestion.
The fourth choice hit the market a year ago. Parke-Davis's Rezulin (troglitazone) makes the body
more sensitive to its insulin. In spite of reports of liver damage in some people, the drug continues to
be available here with warnings that people who use it need very frequent liver tests.
Rezulin remains on the market here because it works well for most folks. In one study, average
levels of HbA1c dropped 1.4 percent. For example, if you have an HbA1c level of 8, you might
expect it to come down to 6.4.
Rezulin works even better in combination with a sulfonylurea. In fact, "Any one of these drugs can be
used in combination with any other," says Dr. William W. Quick, a board-certified endocrinologist
practicing near Kansas City. "The research studies are a bit stronger for some of the combinations
than they are for others, but out here in clinical practice we use all the combinations."
"Vegetable soup" is what Dr. Quick calls the choices open to him and his type 2 patients. "We can
add any of several different ingredients and come up with a slightly a slightly different flavor for
individualized therapy with the drugs that are available now. I am very impressed that we are doing a
heck of a lot better than we did in the past when we had just one flavor to our soup."
PRANDIN
Now, a fifth class of drugs hit the market in April, when Novo Nordisk and Schering-Plough jointly
launched Prandin (regaglinide). It works by stimulating insulin secretion from the beta cells and differs
from earlier drugs both in its structure and how it is eliminated. It needs to be taken just before each
meal because it is so fast-acting.
Prandin may be even more effective than Rezulin. It reduced HbA1c levels by 2.1 percent in one
study reported in the package insert that will come with the drug.
Beyond Prandin, there is an explosion of research on glucose control drugs. "As someone who has
had diabetes for 48 years, I don't think that I have ever seen a more exciting time," says Dr. Keith
Campbell, associate dean and professor of pharmacy practice at Washington State University
College of Pharmacy and a Certified Diabetes Educator.
ERGOSET
The glucose control drug probably closest to market after Prandin is Ergoset. The FDA is
considering its approval after receiving a New Drug Application from its manufacturer, Ergo Science
Corporation, in October.
"We are probably looking at an early 1999 launch," says Donna LaVoie, Ergo Science's executive
director, corporate communications and investor relations. Johnson & Johnson will market Ergoset
under the terms of a multimillion dollar deal the two companies signed this February.
Ergoset is a low-dose and fast-acting formulation of bromocriptine, which doctors have prescribed
for years in a different form to treat Parkinson's disease. Unlike other diabetes control drugs that
work at the gut level, Ergoset's action is through the brain, resetting the body's clock that regulates
daily metabolic activity.
Studies of Ergoset show an average drop in HbA1c of 1.04 percent. But unlike other studies, that's a
measure only of the patients who responded well to it, excluding the 36 percent who didn't.
The drug also has a lipid-lowering effect and is in Phase II trials for obesity. And that's another
problem in understanding its effectiveness. Since patients on Ergoset lose weight, there's a question
whether it lowers HbA1c directly or because of weight loss, says Dr. Dan Baker, director of drug
information at Washington State University in Spokane.
"It is an interesting product, and it will be useful," he believes. He notes that two other weight-control
drugs close to market may also help people with diabetes reduce their blood glucose, Meridia and
Xenical (see following table).
TARGRETIN
Like Ergoset, Targretin's original target was another disease. And like Ergo Science, Targretin's
developer has a powerful corporate alliance that is some indication of the likelihood the drug will
actually come to market.
Ligand Pharmaceuticals developed Targretin to fight certain cancers, but serendipitously discovered
that it is also an insulin sensitizer. Ligand has licensed marketing rights to Eli Lilly and Company for
$99 million.
"Targretin is a Vitamin A derivative," says Henry Niman, an associate professor in the University of
Pittsburgh's epidemiology department and the scientific founder of Ligand's parent company.
The drug is in phase II trials for diabetes and probably won't be on the market until three to four
years from now, he says. "In animals it worked great. It was as effective as one of the second
generation compounds in Rezulin's class, which are even more effective than Rezulin itself." It also
reduced triglyceride levels.
BRL 49653
The second generation compound Dr. Niman is talking about is BRL 49653. SmithKline Beecham,
which developed the drug says that it is an insulin sensitizer and is in Phase III trials.
Beyond that, the company releases little additional information. "It's frustrating to us in pharmacy and
in medicine to project what is going to happen in the future with drug therapy," Dr. Campbell says.
"For almost every new drug that comes out there is almost nothing in the scientific literature until
about the time the FDA recommends it for approval."
SP-134101
Among all the other drugs now in clinical and preclinical trials to reduce blood glucose levels perhaps
the most interesting is SP-134101, which Shaman Pharmaceuticals is developing. The drug just
started Phase I trials and probably won't hit the market until about 2003, according to Vice
President J. D. Haldeman.
What makes SP-134101 exciting is that it is the first of 21 compounds the company found in tropical
plants that lower blood glucose levels in animal models. "SP-134101 comes from a plant that grows
in the southeastern part of the U.S. and Mexico," she says. "We will be isolating it directly from the
plant."
DRUG PROBLEMS
Even if all of these drugs prove effective in reducing blood glucose, that's not the end of the story. "I
consider effectiveness as only a minor factor in my decision-making," Dr. Quick says. "Other factors
to consider include cost, side effects, rules about time of administration, taste and other eccentricities
of the pill, and contraindications."
He emphasizes that these issues affect how well patients use these drugs. And as Dr. Campbell
points out, little of this information will be available until just before they come on the market. Stay
tuned.
An edited version of this article appeared as "Beyond Sulfonylureas" in Diabetes Wellness
Letter, May 1998, pages 1-4.
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