Here's the NY Times article on future diabetes treatments:
January 17, 1998
Drug Makers at Threshold of New
Diabetes Therapy
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By LAWRENCE M. FISHER
SAN FRANCISCO -- Few medical breakthroughs have been as
dramatic as the 1921 discovery of insulin, which changed diabetes
from a death sentence to a survivable disease.
But diabetes and its complications remain a huge
health problem. Now, a host of biotechnology
companies are racing to develop new therapies
that ultimately aim to go beyond merely treating
symptoms to attacking the cause of the disease,
in which the pancreas shuts down or fails to
produce the correct amount of the insulin
hormone, causing dangerously high blood-sugar
levels.
For many patients, frequent injections of insulin
may soon be only a memory.
Many diabetes patients could have the option
within two to three years of inhaling insulin rather
than giving themselves injections. But not long
after that, if all goes well, new oral drugs could
postpone or even prevent the need for some to
use insulin.
A new genetically engineered hormone could serve as a useful
supplement to insulin. Meanwhile, other drugs in the advanced stages of
development take aim at the complications that most afflict diabetics:
kidney failure, nerve damage, heart disease and blindness.
While the insulin market is dominated by two giants -- Eli Lilly & Co. of
Indianapolis, and Novo Nordisk AS of Denmark -- many new therapies
are the work of start-up companies. But these small concerns have been
able to trade their expertise in the complex biology of the disease for
lucrative partnerships with big drug companies, raising hundreds of
millions of dollars in research money from companies like Lilly, Pfizer Inc.
and Johnson & Johnson.
The need for new diabetes therapies was underscored late last year when
Glaxo Wellcome PLC halted British sales of troglitazone, an oral drug,
after it caused six deaths worldwide through liver damage.
Troglitazone, which Glaxo had licensed from Sankyo Co. of Japan,
remains on sale in the United States, where it is produced and marketed
by Warner-Lambert Co. under the name Rezulin. Officials of the Food
and Drug Administration and executives of Warner-Lambert say the
drug's benefits outweigh its risks.
"New science allows us to investigate specific pathways of the disease,
but we are still at a very early stage in our understanding of diabetes,"
said Viren Mehta, an analyst with Mehta Partners, a biopharmaceuticals
research firm in New York.
Some diabetics are resistant to insulin. Troglitazone, he said, is the first to
mitigate that resistance, "but even that is not well understood." Despite the
uncertainty and worries about adverse side effects, he expects
troglitazone and related drugs to generate several billion dollars in annual
sales before too long.
Troglitazone caused liver problems in fewer than 2 percent of patients, a
toxicity common to several successful drugs. But biotechnology
executives say both the drug's success and its problems highlight the
opportunity for a new drug with similar or greater effectiveness but fewer
side effects.
At $1,400 a year per patient, troglitazone set
a benchmark for what the health-care system
will pay for an innovative drug. With several
million patients for such a drug in the United
States alone, it could easily command
domestic sales of $1 billion a year.
Of the new drugs, closest to market is
Ergoset, from Ergo Science Corp. of
Charlestown, Mass. It is awaiting FDA
approval. Ergoset is a low-dose, fast-release
oral formulation of bromocriptine, a drug
previously approved by the FDA to treat
Parkinson's disease.
In clinical trials, Ergoset was at least as good
as existing oral drugs in regulating blood sugar;
side effects were limited to transient nausea,
nasal congestion and low energy.
Another promising drug originally aimed at a different disease is Targretin,
which Ligand Pharmaceuticals Inc. of San Diego has been testing against
various cancers.
When a lower dose of the drug was found effective in clinical trials against
one type of diabetes, Ligand licensed it to Lilly for $99 million in equity
and research financing, with a possible $75 million in additional payments
if the drug is successful. Targretin is in the second of the three stages of
clinical trials typical for new drugs.
Although the discovery of Targretin's role in managing diabetes was in
part serendipitous, it is in fact the first in a new class of drugs that
intervene directly between insulin and the proteins it interacts with inside
cells to regulate blood glucose.
"We can not only treat the disease, but in certain animal models we can
delay or prevent the onset of diabetes," said Richard Ligand's senior
director of research into drugs known as retinoids, which work within
individual cells.
Also working in this area of research is
Metabolex Inc. of Hayward, Calif.,
which has a broad program in
partnership with Abbott Laboratories of
Abbott Park, Ill.
More recently, Cell Therapeutics Inc. of
Seattle, and the City of Hope National
Medical Center agreed to form a joint
venture to seek out and develop a new
class of drugs that have the potential to
block destructive oxygen-carrying
molecules that attack the pancreas,
cause resistance to insulin and may
contribute to some serious side effects
of diabetes.
All these efforts are aimed at developing oral drugs for Type 2 diabetes,
once commonly called adult-onset diabetes. There are about 7.5 million
people in the United States for whom Type 2 diabetes has been
diagnosed and roughly 7.5 million more who are believed to have the
disease even though it has not been diagnosed.
Type 2 diabetics produce insulin, but their bodies have somehow become
resistant to it. Initially, many are treated with a combination of low-sugar
diet, exercise and oral medications like Orinase, which has been around
for decades. Most, however, must eventually inject insulin that is
manufactured from recombinant DNA or produced from animals -- most
often pigs.
Oral therapies have already surpassed insulin injections, and they are
growing fast. IMS America, a company that tracks sales of
pharmaceutical drugs, predicts that sales of oral therapies will triple to
$3.5 billion by 2002.
Patients with Type 1 diabetes, once commonly known as juvenile
diabetes, must take multiple insulin shots every day to survive. About
750,000 people in the United States have Type 1 diabetes, a disease in
which the body mistakenly destroys the beta cells in the pancreas that
produce insulin. There are no oral therapies for Type 1 diabetes.
Partly because it affects fewer patients, and partly because it is largely
controlled by insulin, Type 1 diabetes has attracted fewer companies. But
several are working on encapsulated pancreas cells from animal or human
donors, in hopes of eliminating the daily injections by creating a
sustainable source of insulin that could evade the immune system. Others
are trying to develop genetically engineered animals that could serve as
pancreas donors. Both efforts are a long way from fruition.
Closer to market, Amylin Pharmaceuticals Inc. of La Jolla, Calif., was
formed in 1987 to develop a genetically engineered version of the
hormone amylin, which is normally produced in the same pancreas cells
as insulin. Type 1 diabetics do not produce amylin on their own, either.
"In biotech, the majority of the big successes have been hormones," said
Howard Greene Jr., Amylin's chairman and co-founder. "If you have a
hormone deficiency, with a syringe and subcutaneous delivery, you're in
business." Amylin calls the drug Pramlintide.
Unlike insulin, amylin plays a role in the body that is not well understood,
but researchers who have worked with the drug say it should help
diabetics control their glucose levels without side effects like weight gain,
increased cholesterol and sudden drops in blood sugar. But in clinical
trials, Pramlintide has produced only modest results in Type 1 diabetics
and failed to help the more numerous Type 2 diabetics.
Greene attributed these equivocal findings to uncontrolled variations
within the trial. On the positive side, he noted that the drug has shown few
side effects.
He said that Amylin, and its partner, Johnson & Johnson of New
Brunswick, N.J., which has already invested $155 million in developing
Pramlintide, will proceed with four additional trials, with hopes of
demonstrating that it is safe and effective enough to lead to a possible
FDA filing in late 1999 or 2000.
While a huge study of diabetics in the early 1990s clearly demonstrated
the importance of tight maintenance of blood sugar levels in avoiding the
onset of complications, such control is difficult to maintain. An inhalable
insulin could prompt Type 2 diabetics not using the drug to start, and
encourage Type 1 diabetics to use it more often.
Inhale Therapeutic Systems, a small company based in Mountain View,
Calif., has developed a dry, powdered insulin that can be stored at room
temperature and can be inhaled rather than injected. Inhale has licensed
the system to Pfizer.
"We have confirmed that we can achieve levels of insulin similar to and as
reproducible as those with subcutaneous injections," said George Milne,
president of central research for Pfizer in New York. Pfizer hopes to file
for FDA approval in 1999.
In the absence of a cure, some companies are taking a pragmatic
approach. Shaman Pharmaceuticals Inc. of South San Francisco recently
began clinical trials of a compound based on a tropical plant that has been
used by indigenous cultures to treat the symptoms of Type 2 diabetes.
Alteon Pharmaceuticals Inc. of Ramsey, N.J., has focused on the
complications caused by high blood sugar and recently joined forces with
Genentech Inc. of San Francisco, a unit of Roche Holding and a pioneer
in biotechnology, to further develop a new drug, Pimagedine, which is in
late-stage trials for the treatment of diabetic kidney disease.
With the rapid development of molecular biology and immunology in the
last decade, "now there is a huge data base and technological base that
makes possible things that were inconceivable even five years ago," said
Michael Brownlee, co-director of diabetes research at the Albert Einstein
College of Medicine in New York and an adviser to Alteon.
"I've been pessimistic about making major advances, because I didn't
think the technology was there; now I'm enthusiastic," he said. "We're on
the threshold." |
