October 1, 2005 (Vol. 25, No. 17)
New Oral Drugs Promise Better Convenience and Tolerance
Type 2 diabetes is a growing epidemic with an estimated 18.2 million people affected in the U.S. and 194 million worldwide as of 2002. Prevalence has increased steadily in the past 20 years, and over one million new cases are diagnosed anually. This increase in type 2 diabetes in adults over age 40 accounts for over 90% of all diabetes cases, across all demographics and is believed to be associated with obesity.
Diabetes is the fifth leading cause of death by disease and costs about $132 billion a year in direct and indirect medical expenses. Medical expenditures are expected to double over the next ten years.
Type 2 diabetes is a progressive disease that begins with insulin resistance, a disorder in which the cells are unable to utilize insulin effectively. Eventually the pancreas loses its ability to produce insulin, the disease progresses, and patients require a combination of oral anti-diabetic drugs and insulin to control glucose levels.
Current treatments, however, do not satisfactorily control glucose levels, which is the primary purpose, nor do they prevent complications. Research is under way to determine whether weight reduction and increased physical activity could effectively slow the progression of the disease.
There are currently several classes of drugs on the market, including insulin, for treatment of diabetes with total worldwide revenues in the $20B range.
According to Medco Health Solutions in their 2005 Drug Trend Report, endocrine disorders and diabetes will be 10% of all therapeutic categories in 20052007. Diabetes as a category of drugs will account for 5% of the market in the same time frame.
Sanford C. Bernstein & Co. analysts Gbola Amusa, M.D., and Devesh Gandhi, M.D., estimate that total worldwide revenues for current branded diabetes drugs exceeded $12B in 2004. U.S. sales are growing at 15% annually, compared to the 6% annual, overall industry growth. Recently launched branded oral drugs plus new drugs in the pipeline will reverse the declining market share for branded drugs. It will also increase insulin sales, which are currently $6B worldwide, at a 10% rate.
Sanford C. Bernstein estimates that the top six companies in the diabetes pharmaceutical marketNovartis, Merck, Eli Lilly, GlaxoSmithKline, Takeda Pharmaceuticals, and Sanofi-Aventiswill have revenues from new products in the $18 billion range by 2011.
Two of the most commonly used classes of oral drugs for treating type 2 diabetes are metformins (class Biguanides), which lowers glucose produced by the liver, and sulfonylureas, which spurs the pancreas to produce more insulin. These drug classes are primarily generics but are also produced under the Sanofi-Aventis brand.
The leading branded oral therapeutic product is Avandia, marketed by GSK, with U.S.revenues forecasted at about $1.7B. Avandia (rosiglitazone) is an insulin sensitizer
Lilly is a major player, with Morgan Stanley forecasting revenues of about $3.1B for treatment of diabetes in 2005. Its products include Humalog, Humalin, Humatrope, and Actos (pioglitazone).
Takeda Pharmaceutical, partnered with Lilly, manufactures Actos (forecasted $1.6B U.S. in 2005), a new class of oral drugs linked to PPARS genes that impacts not only insulin metabolism but also obesity and cardiovascular diseases. Lilly also partnered with Amylin Pharmaceuticals (San Diego) and recently introduced Byetta, which is expected to grow rapidly over the next five years.
New Products for Treatment
Amylin Pharmaceuticals has been the premier speculative stock for potential blockbuster therapeutics in the treatment of diabetes. During the last weeks of August its stock soared, after positive results were reported on from a Phase II trial for Byetta long acting release (Byetta LAR) with weekly dosing. Amylins stock reached an all-time high of 33 on August 31.
Byetta (exenatide) is an injectable drug that has been on the market since April; it represents a new class of drugs called incretin mimetics. This class mimics the human incretin hormone, glucagons-like-peptide-1 (GLP-1).
In the small 15-week trial, mid-point results showed that patients did lose weight and showed improvement in controlling glucose levels. The ongoing Phase II randomized, placebo-controlled, double blind study includes 45 subjects with type 2 diabetes who could not achieve adequate glucose control using diet and exercise with or without metformin.
Amylin also partnered with Alkermes (Cambridge, Massachusetts), which integrated its Medisorb drug delivery technology in Byetta LAR.
Speculation on the efficacy of Amylin exenatide products in development began with increased trading volume off its June 2005 low. Amylin raised $152 million through the sale of over five million shares of common stock at the end of August with Goldman Sachs as the sole underwriter.
Steven Harr, M.D., an analyst at Morgan Stanley, forecasts Amylin revenues of $125 million in 2005, with U.S. exenatide sales of $58 million. Dr. Harr forecasts Byetta (not including Byetta LAR) peak sales of over $1B and believes that Byetta LAR has multibillion dollar potential.
On September 9, the FDA advisory committee approved a new oral drug from Bristol Myers Squibb (Princeton, NJ) and Merck called Pargluva. This drug is a potential $3B blockbuster. The advisory committee, however, did not recommend it in combination with other oral drugs except metformins.
Pargluva is a new class of compounds called glitazars and is a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor). Activation of PPAR is associated with reduction of glucose levels, reductions in triglyceride levels, and increase in HDL levels.
Astra Zeneca is also developing a PPAR compound.
Therapeutic Devices – Inhalers ” & ” aaaa ‘
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One of the most significant therapeutic devices recently introduced for diabetes treatment is the insulin pump that Medtronic (Minneapolis) currently markets. Medtronic got the insulin pump through the acquisition of MiniMed, founded by Alfred Mann.
Manns new company, Mannkind (Valencia, CA) is in Phase III clinical trials with a device that will deliver insulin through dry powder (Technosphere) inhalation into the deep lung. Recently completed Phase IIb studies showed significant reductions in HbA1c levelthe most important diagnostic markerover a three-month period with no increased risk of hypoglycemia. The Technosphere product is designed to deliver insulin in a manner that approximates the first phase insulin spike normally seen in healthy individuals following a meal.
The FDA advisory committee voted 7-2 for approval of Exubera (r-DNA insulin), an inhalable rapid-acting dry powder for treatment of type 1 and type 2 diabetics, in September. Nektar Therapeutics (San Carlos, CA) with Pfizer (New York City) and Sanofi-Aventis as partners developed the proprietary inhalation device.
Although there were some safety concerns, such as potential lung function toxicity for patients with lung conditions such as asthma, Exubera is expected to offer convenience of use compared to injection and hence better compliance. Additional safety studies and data may be required prior to FDA approval.
Since only about 7% of all diabetics achieve their target numbers for blood glucose, cholesterol and blood pressure, earlier diagnosis, monitoring, and insulin delivery will be a growing market. Market potential for Exubera is in the $2B range, however Sanford Bernstein analysts project inhaled insulin sales of only $1.7B worldwide by 2011.
Diagnostic devices for monitoring insulin levels are a huge multibillion dollar market dominated by players such as Bayer (Leverkusen, Germany), Johnson and Johnson (New Brunswick, NJ) and Abbott (Abbott Park, IL). The holy grail of the next diagnostic product upgrade is to design a non-invasive device that eliminates finger pricks for daily blood testing.
The potential applications of stem cell therapy have been well chronicled in a variety of diseases. One important application would be tissue engineering to create cell lines for transplants. For example, the European Commission funded a $31 million project at the University of Liverpool in the U.K. to develop tissue cells from stem cells to treat diseases such as diabetes, heart failure, and chronic ulcers.
The stem cells could be used to replace pancreatic cells for treatment of type 1 diabetes. New sources of stem cells other than embryos are cells from the umbilical matrix and most recently Harvard researchers published on creating stem cells out of human skin tissue.
Scientists at the Joslin Diabetes Center, affiliated with Harvard Medical School, used DNA chip technology to discover a new gene implicated in type 2 diabetes. The researchers studied genes from type 2 diabetics that were altered in their expression of islet beta cells from the pancreas. They then showed in mouse studies that one of these genes called ARNT resulted in altered insulin secretions. This gene could possibly result in a new target for treatment of the disease. Joslin is also developing new islet cells from pancreatic duct cells harvested from human donor pancreatic tissue.
Vaccines for type 1 diabetes are at an early stage of research and development. The vaccine strategies involve treatment with DNA or antigens and are designed to prevent the bodys destruction of islet cells.
Advances in biotechnology will help create new therapies for diabetes. Drug delivery systems, such as pulmonary inhalers; peptide mimetics for identifying new drug targets; DNA chip arrays for genetic analysis and receptors; tissue engineering including stem cell creation for islet cell replacement: and transplant are among the most promising technologies advancing diabetes treatments.