New drugs offer help; won’t halt huge rise in Diabetes

Even with the advent of health awareness campaigns to draw attention to the health problems associated with diabetes, the global* prevalence of diabetes is expected to climb to over 50 million by 2012. However a new report by independent market analyst Datamonitor** expects significant developments in the field of diabetes therapy. According to the report, by 2012, at least three new key classes of drugs to treat diabetes will have entered the market, with the most promising being Novartis’s LAF-237 and Eli Lilly’s exenatide LAR.  According to Datamonitor forecasts, both drugs will acquire blockbuster status by 2012, amassing total sales in excess of $3 billion, says Datamonitor Endocrinology analyst Nick Karachalias.

Huge societal cost

Datamonitor estimates that there are 38m diabetic people in the US , Japan , France , Germany , Italy , Spain and the UK , with almost half residing in the US. Despite increasing health awareness campaigns and attempts to slow down the startling increase in diabetes rates, Datamonitor predicts that the prevalence of diabetes will increase to over 50m by 2012, Karachalias says. “Health complications and comorbidities associated with diabetes are a huge drain on national health services around the world. Based on statistics from an ADA (American Diabetes Association) report, in 2002, the direct medical and indirect expenditures in the US attributable to diabetes were estimated at $132 billion.”

Despite the presence of well tried and liked compounds for the treatment of diabetes (insulin, metformin and sulfonylureas) and the recent introduction of new classes such as thiazolidinediones (TZDs), alpha glucosidase inhibitors (AGIs) and prandial glucose regulators (PGRs), there are still important unmet needs in the treatment of diabetes. Due to the high unmet need, diabetes represents a lucrative market for R&D investment, Karachalias says. “Datamonitor has identified seven new classes of compounds currently under development. Of these classes, three present the most interest, Glucagon-Like Peptide -1 (GLP-1) agonists, Dipeptidyl Peptidase IV (DPPIV) inhibitors and dual Peroxisome Proliferator Activator Receptor (PPAR) agonists.”

New drugs promising

Two of the most promising drugs in the pharmaceutical pipeline are Eli Lilly’s exenatide and exenatide LAR, which are expected to be launched in 2005 and 2007, respectively. The drugs belong to the class of GLP-1 agonists, have been successful in clinical trials for diabetes and appear to have a good safety profile. The main issue with these agents is their mode of administration, namely they will have to be injected, Karachalias says. “This fact may pose a problem with the uptake of exenatide and the subsequent patient compliance to therapy. However, exenatide LAR promises to solve this problem with its long acting release formulation, which means that the patients will only have to inject themselves with the agent once per week or once per month.”

“Datamonitor forecasts that sales of exenatide will remain relatively low to $81m by 2012, while exenatide LAR will reach $1,557m in the same time period.”

Another very promising drug in the pipeline is LAF-237, which is being developed by Novartis and is currently undergoing Phase III trials. LAF-237 belongs to the class of DPPIV inhibitors and is exploiting the same basic biochemical pathway as GLP-1 agonists. However, its main difference and main advantage is the fact that unlike GLP-1, it can be orally administered, Karachalias says. “This fact is expected to boost its uptake and benefit patient compliance. It is predicted that LAF-237 will be launched by 2007 and will reach sales of $1,869m by 2012.”

Lifestyle changes needed

"Although the influx of new drug classes is definitely good news for both pharmaceutical companies and diabetics, none of the new drugs will be the answer to the growing diabetes problem. Lifestyle changes are still needed in order to prevent the development of the disease and slow its progression. The development of even more potent agents, with the ability to maintain their efficacy over prolonged periods of time, with excellent safety and side-effects profiles will remain crucial to combating diabetes," he says.

Dual PPAR agonists were once hailed as the next big development in the treatment of diabetes. However the recent withdrawal of many leading agents following safety concerns has prompted the FDA to request additional safety data before considering the approval of any such compounds, Karachalias says. “This development will severely delay the progress of dual PPAR analogs. As a result even the leading compound in this class, BMS and Merck and Co’s muraglitazar is not expected to exceed $500m of peak sales.”

Data Indicate That Lilly's Ruboxistaurin May Have A Potentially Beneficial Effect on Diabetes-Induced Eye Disease

 - Confirmatory Phase 3 Clinical Trials Are Ongoing

Eli Lilly and Company's (NYSE: LLY) investigational compound ruboxistaurin may reduce vision loss from diabetes-induced eye disease, according to new analyses of previously reported data presented at the 2004 Joint Meeting of the American Academy of Ophthalmology and the European Society of Ophthalmology in New Orleans , La.

The analyses showed that diabetic macular edema (DME) -- a serious manifestation of diabetic retinopathy that occurs when fluid builds up in the retina and causes swelling(1) -- was associated with lower visual acuity when it involved the center of the macula. The severity of central involvement was associated with the severity of vision loss, according to the analyses.

Patients who received 32 mg per day of ruboxistaurin appeared to have better visual acuities (better vision) at equivalent levels of involvement of the center of the macula than placebo-treated patients (data from a trial with approximately 63 patients per treatment group). In addition, there was a trend toward less progression of DME to involve the center of the macula in patients receiving 32 mg of ruboxistaurin (data from a trial with 170 patients per treatment group).

"A key to preventing vision loss from diabetic eye disease is to prevent macular edema from involving the center of the macula, where it affects the part of the retina that is most important for detailed vision," said Lloyd Paul Aiello, MD, PhD, associate director of the Beetham Eye Institute at The Joslin Diabetes Center , Harvard University Medical School . "These data suggest that ruboxistaurin may have the potential to decrease the progression of diabetic macular edema to involve the center of the macula. A Phase 3 clinical trial is underway to further explore these preliminary findings."

Details

These analyses involved data from two Phase 3 placebo-controlled trials of ruboxistaurin in patients with diabetic eye disease, one with a 30-month minimum duration and one with a three-year minimum duration. The trials enrolled a total of more than 900 patients with diabetic retinopathy and different degrees of DME. Over the course of the studies, patients had both their visual acuity and extent of DME measured at multiple visits.

One analysis examined 540 different concurrent determinations of visual acuity and distance of DME from the center of the macula in 122 eyes of patients receiving placebo treatment only. The results showed that visual acuity was close to normal in eyes with macular edema that did not involve the center of the macula (approximately 80 letters correct, equivalent to about 20/25 vision, on the ETDRS visual acuity protocol -- the standard measure used in visual acuity research). The visual acuity was significantly lower in eyes with macular edema that involved the center of the macula (approximately 65 letters correct, corresponding to about 20/50 vision, p < 0.001.).

 In a second analysis, patients (n=67) with eyes showing center involvement who were taking 32 mg per day of ruboxistaurin had higher average visual acuity than the eyes of placebo patients (n=61) -- 71 letters correct versus 60 letters, p < 0.01. This difference was not seen at lower doses of ruboxistaurin. In addition, there was a trend toward less progression of DME from outside of 500 microns to the center of the macula in patients taking 32 mg of ruboxistaurin (n=168) than in placebo-treated patients (n=176) -- 20 percent versus 31 percent, p = 0.083. This difference was not seen at lower doses of ruboxistaurin.

Findings from a previously conducted analysis of these two combined clinical trials showed that side effects were equally distributed among experimental and placebo groups and that ruboxistaurin was generally well tolerated by the patients. While no cause and effect relationship was established between ruboxistaurin and any event, the most common side effects seen in the trials were nasopharyngitis, headache, cough and hypertension.

About Diabetic Macular Edema

Diabetic macular edema is a manifestation of diabetic retinopathy that occurs when fluid buildup causes the macula, or the center of the retina, to swell. This can cause blurriness and vision loss.(2) Diabetic retinopathy, one of three major diabetic microvascular complications, affects the small blood vessels in a part of the eye called the retina.

Currently there is no prescription therapy in the United States or Europe approved to target the underlying process of microvascular damage that leads to diabetic retinopathy. Pre-clinical data show that ruboxistaurin, currently being investigated for treatment of diabetic retinopathy and other diabetic microvascular complications, is a specific inhibitor of PKC beta. PKC beta is an enzyme that has been implicated in the underlying process of microvascular damage.

1 American Diabetes Association, Diabetes Dictionary. Available at:

    http://www.diabetes.org/diabetesdictionary.jsp?pageID=3&exitDictionaryTo=

    Accessed August 9, 2004 .

 2 National Eye Institute, Diabetic Retinopathy: What You Should Know.

    Available at: http://www.nei.nih.gov/health/diabetic/retinopathy.asp.

    Accessed August 9, 2004 .

 (15/12/04)