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Reaching epic proportions

By Andrew Humphreys andrew.humphreys@ubm.com

From 2012 through 2035, the number of people with diabetes is forecasted to rise from 382 million to 592 million. According to the International Diabetes Federation (IDF), the amount of individuals with type 2 diabetes has grown in every country. Diabetes is the No. 7 cause of death as well as a leading cause of kidney failure, non-traumatic lower-limb amputation and new cases of blindness in the United States. During 2013, an estimated 5.1 million individuals will have died from diabetes-related complications. Additionally, there are roughly 175 million undiagnosed cases of diabetes. Per the most-recent version of the IDF’s Diabetes Atlas, $548 billion was spent on the disease during 2013.

According to a 2013 report from PhRMA, there are more than 450 medicines in clinical development for leading chronic diseases affecting seniors. Diabetes accounts for 140-plus of that product total, well ahead of the other leading categories: arthritis, Alzheimer’s, heart disease, COPD and depression.
Anti-diabetes products are expected to be the No. 2 therapy area (after oncology) in terms of global prescription and OTC sales in 2018 at more than $60 billion after totaling $36.3 billion in 2012, per an

EvaluatePharma June 2013 report. According to the analysis, the 2018 diabetes market will be paced by Januvia and Janumet (combined $9.28 billion), Lantus ($8.12 billion), NovoLog/NovoRapid ($4.94 billion), Victoza ($4.07 billion), and Levemir ($2.52 billion).

The dipeptidyl peptidase-4 inhibitors Januvia and Janumet are marketed by Merck. DPP-4 inhibitors represent a class of prescription drugs 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. Januvia (sitagliptin phosphate) was launched in the United States during October 2006. Janumet, which combines Januvia with metformin hydrochloride in one tablet for treating type 2 diabetes, won U.S. approval on March 30, 2007. FDA in February 2012 granted clearance to once-daily Janumet XR, which combines sitagliptin and extended-release metformin.

For the first nine months of 2013, Merck reported worldwide sales of $2.88 billion for Januvia (down 2 percent year-over-year) and $1.33 billion for Janumet (up 10 percent). The main compound patent for sitagliptin is scheduled to expire in the United States in 2022, and the product’s salt patent is protected in the United States until 2026.

Sanofi’s once-a-day Lantus (insulin glargine) is one of the top-selling prescription medicines globally. Marketed in more than 120 countries, Lantus is the best-selling insulin brand in terms of sales and units worldwide. A long-acting analog of human insulin, the drug offers improved pharmacokinetic and pharmacodynamic profile. 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.

Lantus generated global sales of €4.2 billion ($5.4 billion) during the first three quarters of 2013, up 20 percent. The product’s sales are projected to peak at €5.79 billion ($7.44 billion) during 2014, according to Sanford C. Bernstein analysts. Lantus’ compound patent is due to expire in the United States during August 2014, and in most of Western Europe as well as Japan in November 2014. A six-month pediatric exclusivity extension was granted in the United States (February 2015) and European Union (May 2015).

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

NovoLog/NovoRapid exceeded $2 billion in yearly sales in each of 2010, 2011 and 2012, and already attained that mark as of the first nine months of 2013 at DKr12.39 billion ($2.14 billion). Containing insulin aspart, NovoRapid was launched in the European Union during 1999 and NovoLog debuted in the U.S. arena during September 2001. NovoLog’s U.S. compound patent expires in 2014 and the formulation patent is protected until 2017. The compound patent has expired in Germany, France, the United Kingdom, China and Japan.

The human glucagon-like peptide-1 (GLP-1) analog Victoza has an amino acid sequence 97% similar to endogenous human GLP-1. Like natural GLP-1, Victoza (liraglutide) acts by stimulating the beta cells to release insulin and suppressing glucagon secretion from the alpha cells only when blood sugar levels are high. Due to this glucose-dependent mechanism of action, the drug is associated with a low rate of hypoglycemia. Victoza also reduces body weight and body fat mass via mechanisms involving reduced appetite and lowered food intake. The medicine debuted in the European Union during 2009 and is marketed in 60-plus countries. Victoza gained regulatory clearance in the United States and Japan in January 2010 for adults with type 2 diabetes.

Victoza generated sales of DKr5.99 billion ($1.03 billion) during 2011 and DKr9.5 billion ($1.64 billion) in 2012. For the first nine months of 2013, the product’s sales amounted to DKr8.4 billion ($1.45 billion), with sales up 28 percent in local currencies and 24 percent in Danish kroner. According to Novo Nordisk, Victoza holds the worldwide market share leadership in the GLP-1 segment with a 70 percent value market share as of October 2013 versus 66 percent during 2012.

Levemir was first approved by EU health authorities in June 2004, and the diabetes medicine made its U.S. debut during March 2006. Available for once-daily use for people with type 1 and 2 diabetes, Levemir provides glucose control with a favorable weight profile. Following its FDA clearance during 2012 for use in children ages 2–5 years, Levemir became the modern long-acting basal insulin offering treatment to the broadest range of U.S. and EU patients.

Levemir sales reached DKr7.68 billion ($1.33 billion) during 2011 and DKr9.79 billion ($1.69 billion) for 2012. The product attained sales of DKr8.4 billion ($1.45 billion) for the first three quarters of 2013, increasing 22 percent in local currencies and 18 percent in Danish kroner.

Pipeline prospects
Novo Nordisk in May 2013 filed for EU regulatory clearance of a new medicine that would further bolster the company’s market-leading diabetes arsenal. IDegLira was submitted for approval to the European Medicines Agency for the treatment of people with type 2 diabetes. The combination product consists of the once-daily new-generation basal insulin analog Tresiba (insulin degludec) and once-a-day Victoza with an ultra-long duration of action.

Results from an EU Phase III randomized controlled trial showed that IDegLira significantly improves glycemic control in patients with type 2 diabetes mellitus compared with either drug alone. The fixed-ratio combination therapy, which was administered to patients inadequately controlled on the oral agents metformin and pioglitazone, was also demonstrated to have a low risk for hypoglycemia, weight gain, and gastrointestinal side effects. Pioglitazone is the active chemical in Actos, the former annual multi-billion sales generator marketed by Takeda Pharmaceutical and Lilly.

Tresiba is cleared for marketing in Europe and Japan. During February 2013, FDA said large-scale cardiovascular studies would be necessary before insulin degludec can be approved in the United States.

“Tresiba is an ultra-long-acting insulin with a duration of action beyond that of Lantus, the most popular once-daily insulin from Sanofi,” comments Frost & Sullivan Life Sciences Senior Industry Analyst Debbie Toscano. “The combination of this next-gen insulin with liraglutide has shown clinical data superior to any diabetes product, and stands an excellent chance of reaching blockbuster status, leveraging the well-known highly effective therapeutic approach of insulin and GLP-1 therapy.”

Another anticipated pipeline prospect taking longer than expected to reach the U.S. marketplace is Lyxumia (lixisenatide). During September 2013, Sanofi decided to withdraw Lyxumia’s New Drug Application to FDA. That decision followed dialog with FDA regarding its proposed process for the review of interim data. Sanofi believes that potential public disclosure of early interim data, even with safeguards, could potentially compromise the integrity of the continuing ELIXA study. Sanofi’s decision was not related to safety issues or deficiencies in the New Drug Application for Lyxumia.

The ELIXA study, which started during 2010, continues as planned and is fully enrolled. Complete results are expected to be available 15 months after the NDA withdrawal announcement. Sanofi expect to refile the NDA for lixisenatide with U.S. regulators during 2015 following completion of the ELIXA cardiovascular outcomes study.

Some industry experts contend that Lyxumia’s delayed potential U.S. market entry could ultimately help the new drug compound’s eventual market success with the accompaniment of more robust study data. “This trial is very important to Sanofi, not only because of the tough FDA regulations, but also because one of the main opportunities in the type 2 diabetes market is the development of a drug that addresses not only glycemic control but also cardiovascular complications,” comments Valentina Gburcik, Ph.D., an analyst for GlobalData.

Lixisenatide represents a new-generation version of the blockbuster brand Lantus. Lixisenatide is the first once-daily prandial GLP-1 receptor agonist for treating adults with type 2 diabetes mellitus. The medicine was accepted for marketing review by FDA and was granted clearance by the European Commission under the trade name Lyxumia in February 2013. Lixisenatide, which is in-licensed from Zealand Pharma, has been additionally approved for marketing in Australia, Japan, Brazil and Mexico for type 2 diabetes.

The initial U.S. NDA for lixisenatide was based on results from the GetGoal clinical program. Through this program lixisenatide demonstrated significant reductions in HbA1c, a pronounced post-prandial glucose-lowering effect, and a beneficial effect on body weight in adult type 2 diabetics. GetGoal results showed that the product had a favorable safety and tolerability profile in most patients, and a limited risk of hypoglycemia.

Industry forecasters have projected lixisenatide global revenue of nearly 500 million euros in 2018. A late-stage clinical study of lixisenatide combined with Lantus remains on schedule to start during first-half 2014. Lantus is set to lose U.S. patent protection during 2015.

Fasiglifam represents the industry’s first G protein-coupled receptor (GPR-40) agonist to reach late-stage clinical development. Fasiglifam is a novel, highly selective agonist of GPR-40, one of the G protein-coupled receptors expressed in pancreatic islet cells. The oral drug has the potential to be a safe and effective treatment for type 2 diabetes by selectively improving glucose-dependent insulin secretion with a low risk of inducing hypoglycemia and pancreatic exhaustion, unlike sulfonylurea or glinides.

The novel glucose dependent insulin secretagogue was discovered and is being developed by Takeda. The new molecular entity is undergoing Phase III trials in the United States, Europe, and Japan. GlobalData analysts say fasiglifam has the potential to be a compelling therapeutic option and will likely be investigated for use in combination therapy, given its unique mechanism of action.

A Phase III clinical will evaluate the efficacy and safety of fasiglifam in combination with Januvia. According to GlobalData analysis, this combination holds great potential due to each drug’s respective distinct mechanism of action, oral route of administration and good safety profile.

Another potential blockbuster opportunity in the diabetes pipeline is NewMet, a delayed-release formulation of generic metformin. As the gold standard oral diabetes therapeutic, metformin is the foundational treatment for type 2 diabetes. San Diego-based Elcelyx Therapeutics is developing the pharma product candidate NewMet for use by type 2 diabetes patients who have difficulty tolerating generic metformin or are contraindicated for its use.

NewMet offers best-in-class glucose control by reducing metformin’s gastro-intestinal side effects in a once-daily, low-dose tablet that does not require titration for initiation of treatment. Results from a randomized, 240-patient, multicenter U.S. Phase IIb clinical trial confirmed previous studies demonstrating that NewMet reduced fasting plasma glucose to a similar extent as generic metformin, but at plasma exposure levels previously shown to be as much as 65 percent lower than comparable doses of generic metformin.

According to Elcelyx, the company has not changed the way metformin works, but instead has discovered how metformin works and leverages this understanding to develop an improved product. Rather than acting via circulation, Elcelyx proposes that metformin works at the lower bowel to activate signals resulting in glucose regulation. NewMet targets the lower bowel, maintaining metformin’s glucose effect, but significantly reducing bioavailability, thus minimizing systemic exposure.

This improved safety and tolerability profile makes NewMet appropriate for individuals requiring the glucose control of metformin with reduced gastrointestinal side effects or the need for titration. Renally impaired patients contraindicated for metformin use may benefit from the product’s much lower exposure. Because NewMet can deliver a maximally effective dose of metformin, it is regarded as an ideal candidate for fixed-dose combos (FDC) with other oral anti-diabetes agents. Elcelyx says NewMet offers the potential to be the only metformin/DPP4i FDC with a full effective metformin dose in a once-daily formulation not needing titration.

“Elcelyx is developing their gut-targeted formulation of metformin based on their discovery of metformin’s mechanism of action in the gut,” Toscano states. “This new formulation promises to exert comparable efficacy with a much smaller dose and greatly improved tolerability since it stays in the gut and does not get absorbed systemically. Since this is a well-known drug that has been used and trusted for decades, it is highly likely to see strong uptake, but this will probably be highly dependent on a strong marketing campaign and we are anticipating a partnership with a large pharma to see it through.”

The biotech company Adocia announced in November 2013 the start of a Phase I/II study for a combination product consisting of the long-acting insulin glargine and the fast-acting insulin lispro. As mentioned previously, insulin glargine is the active ingredient in Lantus, the gold standard of long-acting insulin. Insulin lispro is the main chemical in Humalog, which is a member of one of Lilly’s blockbuster diabetes franchises.

This clinical study intends to show that the combination medicine could offer diabetic patients improved glycemic control versus a premix of insulin analog such as Humalog Mix, based on insulin lispro, or NovoMix, based on Novo Nordisk’s insulin aspart. Pharmacodynamic and pharmacokinetic profiles of the combination BioChaperone glargine/lispro will be compared to the pharmacodynamic and pharmacokinetic profiles of Humalog Mix in a cross-over design on diabetic patients under a euglycemic clamp.

Type 1 and type 2 diabetic patients in need of intensive insulin therapy have two treatment options: either a premix, which is a formulation of a single insulin with both fast and long actions, or a combination of a long-acting insulin and a fast-acting insulin. Premix products such as NovoMix and Humalog Mix ease daily life for diabetics, who can manage their glycemia using only one drug injected twice daily.

These premix blockbusters have been on the market for more than a decade, but they reportedly put patients at higher risk of hypoglycemia compared to separate injections of Lantus and a fast-acting analog insulin.

“There is a real need to provide patients using Lantus and a fast-acting insulin with the simplicity afforded by premix products, as well as to offer premix-using patients the greater medical efficacy obtained with Lantus, a real gold-standard,” noted Gerard Soula, CEO of Adocia. “This combination could therefore extend glargine’s market potential towards the premix market. This combo based on insulin glargine, an insulin off-patent in 2015, has been internationally patented in 2012.”

Adocia specializes in the development of ‘best-in-class’ medicines from already-approved therapeutic proteins. The company’s BioChaperone technology makes insulin glargine compatible with fast-acting insulin analogs. Through the BioChaperone state-of-the-art technological platform, Adocia aims to enhance the effectiveness and safety of therapeutic proteins and their ease of use for patients, with the aim of making these medicines accessible to the broadest public.

“Adocia’s BioChaperone proprietary technology allows for a clear and stable solution of insulin glargine and a fast-acting analog insulin, two products that are not compatible under natural conditions,” commented Olivier Soula, deputy general director and R&D director at Adocia. “In this clinical trial, we are testing one of the potential combinations but alternative combinations, namely with insulin glulisine (Apidra, Sanofi) and insulin Aspart (NovoLog, Novo Nordisk) have also been validated in preclinics.”

Results from this clinical trial are expected during the first quarter of 2014. Adocia additionally is developing a unique combination of fast-acting insulin and slow-acting insulin, for an optimal insulin therapy with one single product.

Technological advances
Scientists are developing an instrument that would allow diabetics to measure their blood-sugar level without pricking their fingers several times daily via home blood-glucose monitoring. Researchers from the Technische Universität Dresden (Germany) and Fraunhofer Electron Beam and Plasma Technology FEP are working on a spectrometer so small that in can fit into a mobile phone.

Standard spectrometers traditionally have not been built smaller because of an inherent restriction in their functional principle, so the aforementioned scientists have chosen another method. The researchers use metallic nano-antennas for harvesting, filtering and amplifying of incoming photons. They reportedly have developed a laboratory-scaled process to electrochemically grow such gold or silver nano-rod arrays into pores of an anodized aluminum-oxide matrix, and have proven its variability and functionality. The scientists plan to upscale the manufacturing process to make it feasible for mass production.
In other groundbreaking research, breathalyzer technology is being developed to detect acetone levels to monitor blood glucose in diabetics. The novel hand-held, noninvasive monitoring device that uses multilayer nanotechnology to detect acetone has been demonstrated to correlate with blood-glucose levels in the breath of diabetes patients.

Existing technology such as a blood-glucose meter is invasive and leads to patient discomfort, often causing low compliance. That in turn can result in poor health outcomes. Other common problems with existing attempted breathalyzer technology include inconstant results due to the natural humidity of one’s breath, high temperature requirements, and lack of selectivity.

Ronny Priefer, Ph.D., of Western New England University created the multilayer technology using nanometer-thick films composed of two polymers that interact with acetone. This crosslinks the polymers and changes the physicochemical nature of the film, which provides a quantification of the acetone and thus the blood-glucose levels. This technology is different because it only accounts for acetone and does not react with other components in the breath.

The current breathalyzer is about the size of a book. Priefer’s team is reportedly developing one that is smaller and more similar to the size of a breathalyzer typically used to detect blood alcohol content levels.

Western New England University clinics are anticipating performing controlled testing with patients in late 2014 or early 2015. This testing would analyze readings from the breathalyzer, finger pricking, and actual glucose levels from drawn blood. Patients are expected to use the breathalyzers in an uncontrolled setting for about two years, keep a record of their readings and report back.

Posted: December 2013

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