Class warfare 2013

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Pharmaceutical and biotechnology companies are fighting for diabetes market share via a variety of established and new innovative medicines.

U.S. biopharma research companies are developing more than 200 innovative new medicines to help the nearly 26 Americans affected by diabetes. These drugs – which are in clinical development or undergoing FDA regulatory review – include more than 30 for type 1 diabetes, about 130 for type 2, and 60-plus drugs for diabetes-related conditions, according to the Pharmaceutical Research and Manufacturers of America (PhRMA).

One in 10 U.S. adults has diabetes and up to one-third could face the disease by 2050 if trends continue, per the Centers for Disease Control and Prevention. Prevalence is expected to grow sharply for different reasons, including an aging population more likely to develop type 2 diabetes, an increase in minority groups at high risk for the disease, and longer lifespans among diabetes patients. If left untreated, diabetes can result in severe health problems and complications, including heart disease, stroke, vision loss and amputation. Diabetes was estimated to cost the United States $245 billion during 2012.

Leaders of the pack

Lantus has become one of the world’s best-selling prescription medicines for any therapeutic indication. Marketed by Sanofi, Lantus generated 2012 sales of EUR4.96 billion ($6.38 billion), up 26.7 percent on a reported basis versus the 2011 amount. This is the No. 1 selling insulin brand in terms of sales and units worldwide, and is marketed in more than 120 countries. The three leading countries for sales of Lantus during 2012 were the United States, France, and Japan.

Composed of insulin glargine, Lantus is a long-acting analog of human insulin. The product offers improved pharmacokinetic and pharmacodynamic profile. The drug is indicated for once-daily subcutaneous administration in treating adult patients with type 2 diabetes mellitus who require basal insulin for the control of hyperglycemia; and for adult and pediatric patients 2 years and older with type 1 diabetes mellitus. A label extension for pediatric use was granted in the European Union during 2012.

Lantus is the most studied basal insulin with more than a decade of clinical evidence in diabetes treatment and a well-established safety profile. The medicine can be administered subcutaneously via syringes or specific pens including:

• Lantus SoloSTAR is a pre-filled disposable pen available in more than 120 countries. This is the only disposable pen that unites a low injection force, up to 80 units per injection, and ease-of-use.
• ClikSTAR is a reusable insulin pen first approved by health regulators during 2009 in the European Union and Canada. ClikSTAR is marketed in 30-plus countries.
• AllSTAR is the first state-of-the-art, re-usable insulin pen developed especially for people with diabetes in emerging markets, indicated for use with Sanofi’s insulin portfolio. AllSTAR is available in India, and Sanofi plans to make AllSTAR accessible to other emerging markets.

The compound patent for Lantus is set to expire in the United States in August 2014, and in most of Western Europe as well as Japan during November 2014. A six-month pediatric exclusivity extension was granted in the United States (February 2015), and was pending clearance in the European Union (May 2015).

Lantus sales are forecasted to peak at EUR5.79 billion ($7.44 billion) during 2014, according to Sanford C. Bernstein analysts.

Another diabetes brand in 2012 that generated more than 23 percent year-over-year growth worldwide was Januvia/Glactiv/Tesavel. The dipeptidyl peptidase-4 (DPP-4) inhibitor is available for the treatment of type 2 diabetes. Containing sitagliptin phosphate, Merck markets the active chemical around the world under the brand name Januvia.

Januvia entered the U.S. arena in October 2006. DPP-4 inhibitors represent a class of prescription medications that improve blood sugar control in patients with type 2 diabetes by enhancing a natural body system known as incretin, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas.

Whitehouse Station, N.J.-based Merck reported Januvia 2012 sales of $4.09 billion, compared to $3.32 billion during 2011. Sitagliptin is also marketed in Japan by Ono Pharmaceutical under the trade name Glactiv, and in Spain by Almirall via the brand name Tesavel. Including sales reported by all three companies, branded sitagliptin sales totaled about $4.51 billion in 2012 and $3.67 billion for 2011.

Merck’s blockbuster Janumet combines Januvia with metformin hydrochloride in one tablet for treating type 2 diabetes. Sitagliptin plus metformin is marketed in Spain by Almirall as Efficib. The oral antihyperglycemic agent targets all three key defects of type 2 diabetes. Janumet gained U.S. marketing clearance on March 30, 2007, less than six months after FDA approval was granted for Januvia. Januvia/Efficib produced worldwide sales of about $1.72 billion in 2012 and $1.41 billion during 2011, with the majority of those amounts accounted for by Janumet.

During February 2012, U.S. regulators approved the type 2 diabetes medication Janumet XR, which brings together sitagliptin and extended-release metformin. Janumet XR provides a convenient once-a-day treatment option for health-care providers and patients who need assistance to control their blood sugar.

The main compound patent for sitagliptin is scheduled to expire in the United States in 2022. The drug’s salt patent is protected in the United States until 2026. In 2018, the sitagliptin franchise of products is expected to be the best-selling worldwide for any therapeutic indication at more than $9.7 billion.

NovoLog/NovoRapid exceeded $2 billion in yearly sales for the third consecutive calendar term during 2012. After producing DKr12.8 billion ($2.21 billion) in 2011 global sales, the 2012 total amounted to DKr15.69 billion ($2.71 billion). Composed of insulin aspart, NovoRapid was introduced in the European Union in 1999 and NovoLog entered the U.S. marketplace during September 2001.

According to the Denmark company Novo Nordisk, NovoLog/NovoRapid is the world’s most widely used rapid-acting insulin for use at mealtimes. For patients with type 2 diabetes who have uncontrolled blood glucose levels while on a basal insulin, intensification with the product helps attain and maintain treatment goals. NovoLog/NovoRapid is used by patients with type 1 and type 2 diabetes.

NovoLog’s compound patent in the United States expires during 2014 and the formulation patent is protected until 2017. The compound patent has expired in Germany, France, the United Kingdom, China and Japan. EvaluatePharma analysts have projected NovoLog/NovoRapid to rank as the world’s No. 3 diabetes medicine during 2018 with sales of $4.93 billion and an 8.5 percent share of the worldwide market.

Arrival of the SGLT2 inhibitors

The next wave of new diabetes drugs expected to follow the market success of the DPP-4 inhibitors are the sodium glucose co-transporter 2 inhibitors. The kidneys of individuals with type 2 diabetes reabsorb greater amounts of glucose back into the body compared to non-diabetic people, which may lead to elevated glucose levels. Acting as significant carriers, SGLT2s block the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.

In late March 2013, the Food and Drug Administration approved the first SGLT2 inhibitor to reach the U.S. market: Invokana. Containing the active chemical canagliflozin, Invokana is available to improve glycemic control in adults with type 2 diabetes. This is the only oral, once-daily medication available in the United States offering improved glycemic control, while also demonstrating reduced body weight and systolic blood pressure in clinical studies.

“Patients with type 2 diabetes struggle managing their blood sugar, and nearly half of adults with type 2 diabetes do not achieve recommended levels of glucose control, increasing their risks for potentially life-threatening complications,” noted Richard Aguilar, M.D., medical director of Diabetes Nation and Diabetes Care Foundation, a non-profit organization dedicated to improving diabetes care. “Invokana is thought to work differently than other currently available medicines because it reduces blood glucose by acting on the kidneys as a ‘glucuretic,’ increasing the loss of glucose in the urine. What has historically been viewed as a sign of diabetes – glucose in the urine – may also reflect the efficacy of a new and unique approach to treatment.”

Janssen Pharmaceuticals and its affiliates have rights to Invokana via a license deal with Mitsubishi Tanabe Pharma. Janssen and other Johnson & Johnson companies hold marketing rights in North America, South America, Europe, the Middle East, Africa, Australia, New Zealand, and parts of Asia.

The path to reach the U.S. marketplace was not an easy one for Invokana. Reportedly, more patients on a 300-milligram dose of the drug had to drop out of J&J’s CANVAS trial of 4,330 patients with type 2 diabetes at risk of heart disease versus those on placebo due to adverse events. Patients taking the medication demonstrated higher increases in cholesterol levels and hypoglycemia, while other conditions such as urinary tract infections and increased urination were additionally more common among patients on Invokana. Those safety data were included in the U.S. and European filings for market clearance of canagliflozin.

On the other hand, in a Phase III study of patients with type 2 diabetes not controlled with metformin plus sulfonylurea, adding canagliflozin improved glycemic control better than adding Januvia; though genital fungal infections were a common side effect. These results were published online April 5, 2013, in Diabetes Care.

Pharma powers AstraZeneca and Bristol-Myers Squibb have thus far been unsuccessful in bringing to the U.S. market their own SGLT2 inhibitor: dapagliflozin. The regulatory filing for this drug was accepted for FDA review in March 2011. Three months later, the regulatory agency’s Endocrinologic and Metabolic Drugs Advisory Committee voted against approval of dapagliflozin. During January 2012, FDA issued a complete response letter regarding the new drug application for the novel compound for treating type 2 diabetes in adults. The letter requested clinical-trial data from continuing studies, and potentially information from new trials. A refiling of the NDA is expected to occur during 2013.

AstraZeneca and BMS were able to gain EU regulatory clearance for the drug in November 2012, marking the first approval anywhere for a SGLT2 inhibitor. The EU approval of dapagliflozin – branded as Forxiga – was based on the results of a broad clinical study program that included 11 double-blind, randomized, placebo-controlled Phase III trials assessing the safety and efficacy of the drug as a once-daily oral therapy. The 11 studies consisted of 5,693 patients globally with type 2 diabetes, including 3,939 patients treated with Forxiga. A higher percentage of individuals with type 2 diabetes treated with Forxiga versus placebo achieved the goal of HbA1c < 7%. The extensive clinical development program showed that Forxiga had a positive benefit-risk profile, with a low risk of hypoglycemia, across a broad range of patient populations. Researchers found other benefits, including reductions in body weight and systolic blood pressure in double-blind, randomized, placebo-controlled clinical trials.

Dapagliflozin was discovered by New York-based Bristol-Myers Squibb. BMS and AstraZeneca of London entered into a collaboration during January 2007 to research, develop and commercialize select investigational medicines for type 2 diabetes. The Bristol-Myers Squibb/AstraZeneca diabetes collaboration is committed to worldwide patient care and improving patient outcomes in treating type 2 diabetes. The portfolio of type 2 diabetes products developed as a part of the BMS/AstraZeneca collaboration includes the first-in-class SGLT2 inhibitor Forxiga, as well as the DPP4 inhibitors Onglyza (saxagliptin) and Kombiglyze XR/Komboglyze (saxagliptin and metformin HCl extended-release fixed-dose combination).

Onglyza was introduced in the United States in August 2009 and Kombiglyze XR debuted on the U.S. market during January 2011. Komboglyze was approved for EU marketing on Nov. 29, 2011. The Onglyza and Kombiglyze XR product line breached the billion-dollar sales barrier for the first time during 2012. After generating combined sales of $684 million in 2011, the products brought in $1.03 billion for 2012.

During August 2012, Bristol-Myers Squibb completed the acquisition of Amylin Pharmaceuticals. Bristol-Myers Squibb and AstraZeneca proceeded to expand their existing alliance in diabetes to incorporate Amylin’s portfolio of diabetes medications. The products included the glucagon-like peptide-1 receptor agonists and first-in-class meds Byetta (exenatide injection) and Bydureon (exenatide extended-release for injectable suspension).

Byetta was launched in the United States in June 2005. Byetta injection was the first in a new class of type 2 diabetes drugs known as incretin mimetics. The GLP-1 receptor agonist was jointly promoted in the United States by Eli Lilly and Amylin until Nov. 30, 2011. At that time, Amylin took over the drug’s marketing in that territory.

Bydureon was cleared for approval in Europe in June 2011 and the United States during January 2012 for treating type 2 diabetes. Bydureon is the first once-weekly treatment for type 2 diabetes.

The Amylin acquisition also brought in the mimetic Symlin (pramlintide acetate injection), which is marketed in the United States for treating type 1 and type 2 diabetes patients with inadequate glycemic control on meal-time insulin. Symlin is a synthetic analog of human amylin, which is a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period.

Eli Lilly and Amylin amicably terminated their joint collaboration during November 2011 for exenatide and started to transition worldwide responsibility for the exenatide franchise to Amylin, beginning in the United States and targeting the transition for all markets by year-end 2013. BMS and AstraZeneca are working to transition non-U.S. countries in which Lilly markets and sells exenatide into the expanded Bristol-Myers Squibb and AstraZeneca alliance.

Another top 15 pharma company partnership for developing diabetes medicines exists between Eli Lilly and Boehringer Ingelheim. During first-quarter 2013, EU health authorities accepted for review the marketing authorization application for empagliflozin as a treatment for type 2 diabetes (T2D) in adults. The NDA filing is awaiting acceptance by FDA. A regulatory submission in Japan is anticipated for 2013.

Empagliflozin has been studied for the reduction of blood glucose levels in adults with T2D. As a SGLT2 inhibitor, the drug has been demonstrated to reduce blood glucose by removing excess glucose independently of beta cell function and insulin resistance. Analysts from Sanford C. Bernstein have predicted that Lilly’s share of 2020 global sales for empagliflozin will total $676 million.

Boehringer Ingelheim and Eli Lilly during January 2011 announced their alliance in the area of diabetes. The partnership is focused on several compounds representing a few of the largest treatment classes. This collaboration unites Boehringer Ingelheim’s (BI) solid track record of research-driven innovation and Lilly’s innovative research, experience, and pioneering history in diabetes. The companies are committed to the care of patients with diabetes and are concentrated on patient needs.

Tradjenta/Trajenta/Trazenta (linagliptin) is one of the drug compounds from the BI/Lilly partnership to reach the marketplace. The drug was approved for marketing by U.S., EU and Japan health regulators during 2011 for the treatment of adults with type 2 diabetes. Linagliptin was the first DPP-4 inhibitor approved at one dosage strength (5 mg, once daily) for adults with type 2 diabetes, without any need for dose adjustments. The drug is primarily excreted unmetabolized through bile and gut, thus no dose adjustment is necessary in adult patients with kidney or liver impairment.

Tradjenta can be used as monotherapy or in conjunction with other commonly prescribed medications for type 2 diabetes: metformin, sulfonylurea or pioglitazone (the latter is marketed as the blockbuster brand Actos). The product has shown reductions in hemoglobin A1C (HbA1c or A1C) levels up to 0.7 percent (compared to placebo). A1C is measured in individuals with diabetes to provide an index of blood sugar control for the previous two to three months.

Sanford C. Bernstein analysts have projected Lilly’s portion of Tradjenta worldwide sales in 2020 will reach $455 million.

The most recent diabetes alliance for the development of a SGLT2 inhibitor brings together two industry forces, Pfizer and Merck. Announced during late April 2013, the parties agreed on a global (excluding Japan) collaboration for the development and commercialization of Pfizer’s ertugliflozin. Also known by the product code PF-04971729, the investigational oral sodium glucose cotransporter inhibitor is being developed for treating type 2 diabetes. Phase III studies for the new drug compound are anticipated to launch during 2013.

Merck, via a subsidiary, and Pfizer will collaborate on the clinical development and commercialization of ertugliflozin and ertugliflozin-containing fixed-dose combos with metformin and Januvia tablets. Merck will continue to hold the rights to its existing portfolio of sitagliptin-containing medicines. Pfizer gained an up-front payment and milestones of $60 million and is eligible for other payments associated with the achievement of pre-specified future clinical, regulatory and commercial milestones. Merck and Pfizer will share potential revenues and certain costs on a 60/40 percent split.

“The diabetes alliance between two big pharma rivals, Pfizer and Merck & Co, is driven by a familiar desire to share the risk of developing drug classes facing increasing regulatory scrutiny that nevertheless target huge potential markets,” noted analysis from EP Vantage. “The deal gives Merck access to Pfizer’s SGLT2 inhibitor ertugliflozin, as well as putting in play its combination with Merck’s $4bn DPP-IV inhibitor, Januvia, and it will be interesting to see how other diabetes players respond. The deal is of immediate relevance to Boehringer Ingelheim’s alliance with Lilly, and to the U.S. biotech group Lexicon Pharmaceuticals.”

Lexicon of The Woodlands, Texas, is proceeding with preparations for the initiation of a new stage of clinical trials for LX4211. This oral, dual inhibitor of sodium glucose transporters 1 and 2 will be entering Phase III trials in type 2 diabetes and a Phase II study in type 1 diabetes. While SGLT2 is the transporter responsible for most of the glucose reabsorption performed by the kidney, SGLT1 is the main transporter responsible for glucose and galactose absorption in the gastrointestinal tract. Lexicon says LX411 is unique as the first dual inhibitor of SGLT1 and SGLT2 in clinical development for diabetes.

“Merck had been one of the likelier potential licensees for LX4211, and the big pharma group’s choice of a straight SGLT2 inhibitor does undermine Lexicon’s contention that dual 1 and 2 subtype inhibition improves tolerability,” according to EP Vantage analysis. “Nevertheless, Sanofi is a natural partner for LX4211.”

“The (Merck-Pfizer) collaboration underscores the heated race in the diabetes market and, in particular, to develop a new type of treatment that can avoid the sort of side effects that have raised questions about drugs that mimic a hormone called GLP-1 to stimulate natural insulin production,” commented Ed Silverman of Pharmalot. “Recently, different studies have generated concerns about not only pancreatitis, which is not a new potential side effect, but also the possibility that patients may develop pre-cancerous cellular changes. The findings have prompted watchdog groups to call for additional studies and, in one case, for the FDA to ban the drugs.”

According to a Johns Hopkins research report, individuals who take GLP-1 (glucagon-like peptide-1) based therapies to control blood sugar are twice as likely as those on other types of sugar-control medication to be hospitalized with pancreatitis. In an article posted online in JAMA Internal Medicine, the scientists say GLP-1 drugs are associated with an increased risk of hospitalization for acute pancreatitis. Sitagliptin and exenatide evidently may contribute to the formation of lesions in the pancreas and the proliferation of ducts in the organ, leading to wellsprings of inflammation.

Doctors and health authorities have been aware that pancreatitis could be a side effect of GLP-1 therapies, a risk that emerged in animal studies and reports to FDA. According to the Johns Hopkins investigators, their study is the first to accurately measure the strength of this risk in analyses that accounted for other pancreatitis risk factors, including gallstones, obesity and heavy alcohol usage.

Other promising pipeline prospects

Lilly’s diabetes product pipeline includes the GLP-1 analog dulaglutide as a once-weekly treatment. The Indianapolis company announced during April 2013 positive Phase III study results for the new drug candidate. Primary efficacy endpoints of non-inferiority to insulin glargine, as measured by the reduction of hemoglobin A1c (HbA1c) levels at the 1.5 mg dose, were met in the AWARD-2 and AWARD-4 trials. By meeting the primary endpoints, superiority for HbA1c lowering was examined. The dulaglutide 1.5 mg dose showed statistically superior reduction in HbA1c from baseline compared to insulin glargine at 52 weeks in patients with type 2 diabetes on metformin and glimeperide (AWARD-2). The dulaglutide 1.5 mg dose in conjunction with insulin lispro demonstrated statistically superior reduction in HbA1c from baseline versus insulin glargine in combination with insulin lispro at 26 weeks (AWARD-4).

Lilly revealed during October 2012 positive top-line results of three other completed Phase III studies: AWARD-1, AWARD-3 and AWARD-5. Primary efficacy endpoints, as measured by reduction in HbA1c at the 1.5 mg dose, were met in each of the trials. The five AWARD studies will support registration filings of dulaglutide, anticipated for 2013. Sanford C. Bernstein analysts have forecasted dulaglutide worldwide sales of $1.32 billion for 2020.

Sanofi is developing a GLP-1 receptor agonist as a next-generation version of its megabrand Lantus. Lixisenatide represents the first once-daily prandial GLP-1 receptor agonist for treating adults with type 2 diabetes mellitus. During February 2013, the drug was accepted for marketing review by FDA and was granted clearance by the European Commission under the trade name Lyxumia. In-licensed from Zealand Pharma, lixisenatide also has been approved for marketing in Mexico for type 2 diabetes.

The U.S. filing for lixisenatide is based on results from the GetGoal clinical program. Through this program, lixisenatide showed significant reductions in HbA1c, a pronounced post-prandial glucose (PPG)-lowering effect and a beneficial effect on body weight in adult patients with type 2 diabetes. GetGoal results demonstrated that the drug had a favorable safety and tolerability profile in most patients, as well as a limited risk of hypoglycemia.

Sanofi is additionally developing a new version of Lantus for type 1 and type 2 diabetes. During the third quarter of 2012, the Paris-based company launched four new Phase III trials evaluating the new formulation of insulin glargine. The first Phase III headline results in diabetes are expected during second-quarter 2013.

Sanford C. Bernstein analysts have projected worldwide 2020 sales of EUR889 million ($1.14 billion) for the new Lantus formulation and EUR442 million ($568 million) for lixisenatide.

Januvia is being developed by Merck as a one-tablet combination with atorvastatin for the treatment of diabetes and atherosclerosis. Atorvastatin is the main ingredient in Pfizer’s cholesterol therapy Lipitor, which was the top-selling prescription medicine globally during 2001-2011. Known by the product code MK-0431E, the sitagliptin/atorvastatin tablet is expected by Merck to be submitted for U.S. marketing clearance during 2014.