In the next few years, the treatment of diabetes may change dramatically. If just some of the drugs in phase III trials
fulfill their current promise and reach market, we may see the following developments:
- For some patients on insulin, there might be no more shots; insulin will delivered via an inhaler similar to that used by
asthma patients.
- Fine-tuning of gut hormones will preserve beta cell function, arresting the natural progression of diabetes.
- One pill—with one active ingre-dient—will control plasma glucose levels and improve lipid profiles.
- It might be possible to directly stop or limit the damage to the eyes and kidneys caused by diabetes.
Pinch yourself. These things are really happening in diabetes therapy—and happening fast.
For years, patients with diabetes and the clinicians who treat them have agreed that the biggest drawback to starting insulin
therapy was the accompanying needle. For at least some patients, that is likely to change soon. On Sept. 8, a Food & Drug
Administration advisory committee recommended approval of Exubera (insulin [rDNA origin] powder for oral inhalation). The
Sanofi-Aventis group and Pfizer Inc. are developing Exubera jointly. Although the FDA is not bound by the recommendations
of the advisory committee, recommendations are usually followed, and Exubera will likely be approved in the very immediate
future.
If public enthusiasm is any indication, inhaled insulin could be the next blockbuster in diabetes therapy. Pfizer spokeswoman
Rebecca Hamm commented, "With Exubera being a treatment option that patients [in clinical trials] could choose, they were
much more willing to initiate insulin. We think that will have positive implications in patient outcomes down the line."
Exubera has been evaluated in more than 3,500 patients—some for over seven years—and has been found to have efficacy comparable
to injected insulin. Pfizer and Sanofi-Aventis are seeking approval for its use in the treatment of adult patients with Type
1 and Type 2 diabetes, but not children, and not smokers (so far, clinical trials have excluded smokers and people with underlying
lung disease). However, data show Exubera does not compromise healthy lung function. A pooled analysis of two one-year open-label
studies involving 627 patients with Type 2 diabetes found patients who added Exubera to their treatment regimen experienced
no clinically important effects on pulmonary function compared with patients treated solely with oral agents.
Exubera is designed to be inhaled through the mouth into the lungs using a proprietary inhalation device and powdered insulin
formulation developed by Nektar Therapeutics. It is quickly absorbed, mimicking the action of physiological insulin in reducing
postprandial blood sugar spiking.
Following close on the heels of Exubera is another inhaled insulin formulation that headed into phase III trials in mid-July:
Lilly's formulation of human insulin inhalation powder (HIIP) based on Alkermes' AIR pulmonary drug delivery technology. Phase
II results (released at the 41st Annual Meeting of the European Association for the Study of Diabetes, held in Athens in mid-September)
showed that patients using the Lilly/Alkermes inhaled insulin system achieved blood sugar levels similar to those of patients
treated with injected insulin, a hemoglobin A1c of 7.9 compared with 8.0 in the injected insulin group. Eighty percent of
patients in the study also preferred the Lilly/Alkermes inhaled insulin system at mealtime to injected insulin.
The new world of diabetes options is also likely to be accompanied by several "incretin enhancers." The basis for interest
in incretin enhancers, according to Michelle A. Baron, M.D., FACE, senior medical director, Novartis Pharmaceuticals, was
the observation that an oral glucose load triggers a greater insulin response than the same glucose load given intravenously—meaning
that something in the gut modulates the insulin response. Investigators have found several incretins that are responsible
for what has been termed the "incretin effect." One that has proven particularly interesting to pharmaceutical companies is
glucagon-like peptide-1 (GLP-1). Novartis decided to enhance incretin by developing an inhibitor for dipeptidyl peptidase-4
(DPP-IV), the enzyme that breaks GLP-1 down; the company developed vildagliptin (LAF237). Vildagliptin, which is administered
orally, is currently in phase III trials.
Baron noted, "There are multiple things that enhancement of GLP-1 will do from a mechanistic standpoint. It improves insulin
secretion. It suppresses glucagon (so the liver is not releasing sugar when blood sugar is high after a meal). It lowers hemoglobin
A1c. It lowers fasting glucose as well as postprandial glucose and does so with a low incidence of hypoglycemia. Vildagliptin
is very well tolerated by patients thus far, and it has also been weight-neutral."
To Baron, though, one of the most exciting aspects of vildagliptin is that animal evidence suggests it can cause an increase
in the mass of the beta cells, the cells that produce insulin in the body. "There's a progressive deterioration of beta function
as well as mass in the patients who have diabetes." Beta cell deterioration causes diabetes to progress, necessitating additional
medications or higher doses to maintain glucose control. So if, in fact, vildagliptin were able to improve beta cell function
in humans, it would be a truly disease-modifying therapy that could change the natural course of diabetes.
Baron said, "We have a phase III clinical program that is looking at this drug in monotherapy as well as in combination with
commonly used antidiabetic drugs and insulin." Some phase III results are expected to be presented as early as June 2006.
On Sept. 8 the FDA advisory committee also recommended approval of Pargluva (muraglitazar) for use as monotherapy and in combination
with metformin. The committee voted against the combination of muraglitazar with a sulfonylurea, however. If approved, muragli-tazar
would become the first glitazar, a dual alpha/gamma peroxi-some proliferator-activated receptor (PPAR) agonist. Muraglitazar,
like other PPAR agonists, effectively reduces blood glucose levels, but it also reduces plasma triglycerides and increases
high-density lipo-proteins (HDL). Muraglitazar is in development by Bristol-Myers Squibb and Merck. Elliott Sigal, M.D., Ph.D.,
chief officer and president, Pharmaceutical Research Institute, Bristol-Myers Squibb, remarked, "Bristol-Myers Squibb and
Merck are encouraged by this recommendation."
Meanwhile, in addition to its phase III trials of inhaled insulin, Lilly has also been conducting phase III trials of ruboxistaurin
mesylate (proposed brand name, Arxxant), an orally available protein kinase C (PKC) beta inhibitor. PKC beta is an enzyme
that has been implicated in the processes leading to diabetic microvascular complications, including retinopathy, neuropathy,
and nephropathy. In early August, Lilly announced that phase III trials of ruboxistaurin in retinopathy had been completed
and that results supported the filing of a new drug application (NDA) for this indication. Before the end of 2005, Lilly is
planning to submit an NDA for retinopathy as the first indication for ruboxistaurin. Results of ruboxistaurin studies in nephropathy,
presented at the mid-September European Association for the Study of Diabetes meeting, were also promising. In patients being
treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) or both, the addition
of ruboxistaurin reduced albuminuria by 24%, compared with a nonsignificant 9% reduction in patients taking placebo. Trials
for nephropathy are continuing.
Trials for ruboxistaurin in neuropathy have been somewhat disappointing. Phase III trials, which were completed in early August,
failed to show sufficient efficacy in the treatment of sensory symptoms associated with diabetic peripheral neuropathy for
Lilly to pursue an indication for treatment of the sensory symptoms of neuropathy. However, company spokeswoman Marni Lemmons
commented, "We do still have an ongoing study—not in the symptoms but in the treatment of the underlying condition of diabetic
peripheral neuropathy."
Dainippon Pharmaceutical Ltd. also has a drug in its research pipeline for diabetes complications. Ranirestat (AS-3201) is
an aldose reductase inhibitor. It is said to be the first investigational drug to address the underlying cause of diabetic
sensorimotor polyneuropathy.
In addition to the drugs in development discussed above, a number of other diabetes drugs are moving forward in clinical trials.
Many have similar mechanisms of action to those overviewed here. But either they have not yet entered phase III trials or
research is still closely guarded by the manufacturer. The uniqueness of products moving through the diabetes pipeline right
now is remarkable. Major changes are on the horizon in diabetes treatment, and the horizon is not very far away.
Kathy Hitchens, Pharm.D. is a medical writer based in Indiana.
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