February 1, 2013 (Vol. 33, No. 3)

Firms Use a Range of Strategies to Exploit a Market Expected to Grow to $157B by 2017

The global type 2 diabetes market is heating up, as obesity increases and incidents of diabetes approach epidemic proportions globally. Although more than 40 diabetes therapeutics are approved for type 2 diabetes, there are high levels of unmet need, creating opportunities for companies in the secondary and tertiary treatment segments that address such complications as cardiovascular disease, peripheral neuropathy, and blindness. Rapid expansion for the global diabetes market is expected during at least the next decade.

“There’s a lot of work today around preventing complications. Mostly, drug development companies are focusing on neurosalvage, cardiovascular protection, and lipid management, all of which help prevent complications,” according to T. Forcht Dagi, M.D., MPH, DMedSc, professor, Harvard Medical School and Queens University, Belfast, Northern Ireland, and partner at HLM Venture Partners.

“Researchers are working to balance the risk of hypo- and hyperglycemia, to produce improved, long-lasting effects, and to enable self-correction.” Those goals are leading researchers to investigate new pumps for type 2 diabetes, as well as to investigate the complexities of the disease, including its environmental components, he says.

The global market for diabetes therapeutics and diagnostics (including devices for diagnosis and monitoring, as well as therapeutic agents) is expected to climb from $110 billion in 2011 to nearly $157 billion by 2017, according to BCC Research. The compounded annual growth rate is expected to increase by 4.7% in North America, by 5.7% in Europe, and by 6.6% in Asia.

“All the action is in type 2 diabetes,” Donny Wong, Ph.D., director of metabolic disorders research at Decision Resources, says. The G7 countries alone account for $26 billion in revenue from diabetes drug sales. “In 10 years, the G7 market is expected to surpass $49 billion, and global sales will exceed $80 billion.” Decision Resources reports 20 drugs in Phase III trials and 27 drugs in Phase II trials for type 2 diabetes. “The first line of therapy remains metformin, which has been in use 50 years in Europe and 20 years in the U.S. The competitive action is in the second- and third-line spaces.”

Diabetes Market by Region, Through 2017 ($ Millions)

SGLT-2 Inhibitors

In the past seven years, two novel drug classes have been introduced—SGLT-2 inhibitors and GLP-1 receptor agonists. Of novel therapeutics, the SGLT-2 inhibitors are among the most exciting because they cause patients to excrete extra glucose through the urinary system, Dr. Wong says. Normally, 99% of filtered glucose is reabsorbed by the kidney, thanks to sodium-glucose co-transporters (SGLT). Therefore, SGLT-2 inhibitors offer another opportunity to improve glycemic control.

“Studies have shown that patients taking SGLT-2 inhibitors also lose some weight—approximately 2–3 kilograms per year. The downside is that because the drugs work through the urinary tract, they also increase the risk of urinary tract infections, which is a particular risk factor in the elderly.”

The SGLT-2 inhibitor market is dominated by two collaborations. Both show clinical benefit and few side effects. “Bristol-Myers Squibb/AstraZeneca’s SGLT-2 inhibitor, dapagliflozin (Forxiga™), was delayed for launch, but is expected to be introduced in 2013 in the EU and probably in 2014 in the U.S.,” Dr. Wong says. In the U.S. market, Johnson & Johnson/Mitsubishi Tanabe Pharma’s canagliflozin probably will be first to launch. “The clinical trials data look quite similar,” he adds.

In January, Boehringer Ingelheim and Eli Lilly trumpeted topline Phase III results showing that once-daily 10 and 25 mg dosages of empagliflozin met the trial’s primary efficacy endpoint, namely significant change in HbA1c from baseline compared to placebo. U.S. and EU filings are expected in 2013. GlaxoSmithKline (GSK) also has an SGLT-2 inhibitor in Phase I trials.

GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists, a new drug class introduced in 2005, also are interesting. “Insulin corrects one hormonal defect. GLP-1 corrects the other,” Dr. Wong points out. By administering GLP-1 therapeutics, physicians can administer less insulin for the same effect, lower the risk of hyperglycemia, and prevent the associated weight gain.

Bristol-Myers Squibb/AstraZeneca’s Byetta® (exenatide) and Novo Nordisk’s Victoza® (liraglutide) were first-to-market. Now, they are being challenged by versions with improved delivery schedules. “It’s a tradeoff between efficacy and efficiency,” notes Lauren Migliore, equity analyst, Morningstar.

Novo Nordisk, one of the biggest suppliers of insulin, submitted an NDA in November for Tresiba® (degludec), which offers extended dosing but increases cardiovascular risks. Another developing option, semaglutide (NN9535), offers once-weekly dosing. Plans to begin Phase III trials were announced in June 2012. When it is commercialized, “it is expected to generate $1 billion in sales,” Migliore notes.

Already, Eli Lilly’s once-weekly GLP-1 therapeutic, dulaglutide, is garnering favorable Phase III trial results. The company plans to file for marketing approval in the first quarter of 2013. GSK is developing the GLP-1 agonist, albiglutide, now in Phase III trials. GSK also has an IL18 monoclonal antibody in Phase I trials for type 2 diabetes and inflammatory bowel disease, and an ileal bile acid transfer inhibitor for type 2 diabetes also in Phase I trials.

NovoNordisk is actively investigating insulin/GLP-1 receptor agonist combinations, delivering its long-lasting insulin Tresiba with liraglutide in a single dose. Trade named Ryzodeg®, it combines insulin degludec and insulin aspart to treat type 1 and type 2 diabetes. It received positive reviews from the European regulators in October 2012 and by Japanese regulators in December 2012.

“Some physicians are prescribing insulin and GLP1 receptors separately for the same patients. “It remains to be seen whether they can be combined into one injection. If so, it would be a major achievement,” Dr. Wong says.

DPP-IV Inhibitors

Merck’s Januvia/Xelevia (sitagliptin) was first in class in 2006. Now, Takeda/Furiex’ Nesina (alogliptin), which was delayed, and Boehringer Ingelheim/Eli Lilly’s Tradjenta/Trajenta/Trazenta™ (linagliptin) are both seeking to challenge it. Industry-wide, however, “The DPP-IV products look virtually identical,” Dr. Wong says. Nonetheless, Decision Resources predicts that the class will experience strong growth during the next decade.

Combinations are also being developed with DPP-IV. In March 2012, Boehringer Ingelheim and Eli Lilly released Jentadueto™ in the U.S. to help glycemic control in adults. It combines linagliptin and metformin in one tablet that may be taken twice daily.

Biosimilar Insulin

“Most biosimilars developers are targeting arthritis or oncology,” Dr. Wong says, but a few are looking at insulin, in anticipation of Sanofi Aventis’ patent for Lantus® (insulin glargine) expiring in 2015. Eli Lilly, for example, is working on a Lantus biosimilar. Lilly also is developing a PEGylated version of its own short-acting insulin, Humalog®. In Phase II trials, early results support once-daily administration and show weight loss in patients.

Noninjectable Delivery

Companies also are developing noninjection delivery mechanisms. For example, Intarcia Therapeutics is developing a GLP-1 receptor agonist implant, ITCA-650. This small osmotic pump is implanted subcutaneously and delivers therapeutics for nearly one year. In November, the company raised $210 million in financing, enabling global Phase III trials to begin the first quarter of 2013.

MannKind is developing an inhaled insulin that is expected to enter in the market in one to one-and-a-half years. According to Dr. Wong, “MannKind’s therapy works in the lungs so, over time, it may cause problems. It also works as a growth factor, so there is resistance to giving it to children.” MannKind also is developing an inhaled GLP-1 therapy using its Technosphere inhalation technology known as MKC253. Patients taking MKC253 do not develop the nausea and other side effects typically associated with GLP-1 analogs.

Diabetes therapies are well-reimbursed, but there is increasing pressure to limit costs and for new therapies to demonstrate strong clinical benefits. “GLP-1, for example, is the most expensive drug class in the diabetes market and faced hurdles when used as a latent therapy,” Dr. Wong says. Additionally, since 2007, the FDA mandates that diabetes therapies be evaluated for cardiovascular risk.

Intarcia Therapeutics’ delivery system is a matchstick-sized device consisting of a cylindrical titanium alloy reservoir. Once inserted under the skin, water from the extracellular fluid enters the device at one end, by diffusing through a semi-permeable membrane directly into a salt osmotic engine that expands to drive a piston at a controlled rate of travel. This forces the drug formulation to be released in a slow and consistent fashion through the exit port, or diffusion moderator, at the other end of the device.

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