Focus

Trends in Diabetes Research

Against the increasing diabetes disease burden, the insulin and OAD (Oral-Anti-diabetic) drug segments are bound to see robust growth. Divya Pamnani reviews the current market scenarios for each segment and profiles research trends that are driving the billion dollar diabetes industry

Diabetes is today recognised as a major lifestyle disease in the India, with the country having possibly the largest number of diabetics in the world. It's ageing population, sedentary lifestyles, high stress levels, improper sleep and deteriorating eating habits are factors contributing to India being dubiously hailed as the world's diabetic capital. According to the International Diabetes Federation report of 2006, there are around 41 million diabetics in India, which is expected to rise to 70 million by the year 2025. Having reached such epidemic levels, this emphasises the need for novel agents to surface in the market, in particular the insulin market, which still offers the most widespread and effective blood sugar lowering treatment.

Against this disease burden, the insulin and OAD (oral-antidiabetic) drug segments are bound to see robust growth.

Insulin Market Scenario

According to the Global Insulin Market report, the global insulin market currently estimated at $ 7.5 billion, growing at a compound annual growth rate (CAGR) of 14 per cent is expected to rise to a whopping $ 14.5 billion by 2010. This is directly linked to the growing number of diabetics. This report predicts that approximately 380 million people will suffer from diabetes by 2025. Nearly one-third of total diabetes patients will be from India and China. Presently both have fledgling, but emerging insulin markets. In addition, this report estimates that 60 per cent of the insulin available in the market today is available in injectable form through syringes, pens, and pumps. The market report claims that non-invasive insulin therapy is the current R&D benchmark, for effective management of type 1 and type 2 diabetes. This will subsequently offer patient potential and marketing strength.

Currently insulin is the only the gold standard treatment for type 1 diabetes, and is also increasingly recommended for treatment of type 2 diabetes. However, unmet needs in regards to administration of insulin and its efficacy exist in the market. Insulin injections, currently the most widespread form of administration, have several inherent disadvantages which include local pain, itching, allergy, and insulin lipodystrophy around the injection site. Insulin lipodystrophy results in atrophy of fats at the frequent sites of insulin injection (It can be observed as irregular depressions on the skin). Further clinical trials have shown that even on injectable insulin treatment, a significant percentage of patients fail to attain lasting gylcemic control due to noncompliance. Essentially, administration of insulin needs closer R&D attention.

With regards to efficacy, novel insulin needs to have a similar onset of action profile mimicking the body's own insulin pattern both between meals (prandial) and during night (basal) to control blood glucose levels. A Type 2 diabetic patient cannot produce the first-phase insulin release spike in relation to meals, release glucose from liver and absorb additional glucose from the food, due to poorly functioning beta cells of the pancreas. Therefore an unmet need is to mimic the first-phase insulin release spike closely. In addition to this, the benchmark insulin formulation needs to exhibit 24-hour activity to control blood sugar level in the body, without having a peak in its metabolic effect. According to the Insulin Market report, there is no insulin preparation on the market today that fits the efficacy-convenience-bill entirely.

The insulin industry is focusing on bridging this gap between current therapy and the unmet need by introducing devices with innovative technology aimed at different routes of administration. Recent developments in the administration of insulin include inhalable insulin, topical patches, buccal spray insulin, and nasal/intranasal spray formulations.

Buccal Spray Insulin

Generex Biotechnology, Canada has under its wing, Oral-lyn TM, an oral insulin spray product. The liquid formulation is absorbed into the body by the lining of the inner mouth using the company's proprietary RapidMistTM device. Since it is buccally absorbed, no insulin is deposited in the lungs by the Oral-lyn RapidMist. August 2007 saw the commercial launch of Oral-lyn in the Indian market. Generex Biotechnology entered into Master Product Licensing and Distribution Agreement of Oral-lyn with Shreya Life Sciences, the fourth largest distributor of insulin in India. In April 2008, Generex entered into a similar agreement for the distribution of Oral-lyn in China, Hong Kong, and the following additional countries: Indonesia, South Korea, Malaysia, the Philippines, Singapore, Thailand, and Vietnam. Presently - Generex Oral-lyn is in Phase III clinical trials at several sites around the world - US, Canada and Ukraine.

Oral Insulin

Oral insulin, also hailed as the 'next generation insulin' intends to bridge the present gap, aiming to establish efficacy, while simultaneously providing convenience to diabetic patients. Investment in research is substantial and ongoing, clinical trials are looking promising, oral insulin could be the next breakthrough in decades of insulin research. This means that millions of diabetics world over could soon forego injections.

Biocon Ltd, Bangalore is developing the IN-105 conjugated insulin molecule, administered as a tablet and delivered through the portal vein. In the clinic, this molecule has completed Phase I trials and is expected to enter Phase II in India later this year to illustrate proof of concept. The encouraging results of the Phase Ia and Ib studies represent a pivotal hurdle crossed in the development of IN-105 as a product. IN-105 will enter Phase I trials in Europe towards the end of the year. Transgene Biotek, Andhra Pradesh, unique in its approach, is developing an oral insulin technology using biodegradable novel polymeric nanoparticles loaded with insulin as a new carrier to ferry the insulin across the intestinal epithelial tissues. Nanoparticles are solid spherical particles with a size range of 10 and 1000 nm containing dispersed drugs. Transgene has attempted to improve the intestinal absorption of insulin and other peptides. The technology has been well proven in animal models, and human clinical studies are in progress.

Still Betting on Inhalable Insulin—MannKind Corp Undeterred

Excubera, the first version of inhaled insulin, approved by the Food and Drug Administration (FDA) in 2006, was dropped by Pfizer in less than a year of poor sales, simply because it failed to gain acceptance by patients and physicians. Exubera cost Pfizer a hefty $ 2.8 billion in pre-tax charges, while revenues were under $ 12 million. Exubera (recombinant human insulin with particle diameters between 1 and 5 mm) was a massive technical achievement, involving the stabilisation of the insulin molecule to make it bioavailable in the dry powder form. It was the first insulin product that did not need to be injected, so when it was approved in January 2006, after being in development for 11 years, there were high expectations. With several advances in devices to inject insulin, the Exubera inhaler, the size of a can of tennis balls, was not appreciated by patients. Not only was the inhaler too large, but dosing was difficult as well. Pen-like injectors seemed like a safer option, with pre-measured doses. Moreover, the complexities of the inhaler device with dosing required healthcare professionals to be trained. Besides the disadvantages of size, dosing and training, Excubera had a known side effect - it reduced lung function and capacity. The worst and last hit that Excubera took was lung cancer. In the Pfizer trial, six of the 4,740 patients treated with Exubera developed lung cancer

After Pfizer exited the market for inhaled insulin, other Big Pharma players like Eli Lilly and Novo Nordisk also walked away from their products AIR Insulin and AERx iDMS respectively, on accounts of commercial and clinical unviability of these products. The ripples of Exubera's failure spread to other drug firms as well, who found it increasingly hard to create a market for their products.

However, California based MannKind Corp., a small biopharmaceutical company, is holding its ground. They are relentlessly optimistic about Technosphere, in the face of this inhaled insulin debacle, which is easily the biggest flop in modern pharmaceutical history. MannKind continues to resist comparisons to Pfizer's Excubera, and continues to fight struggles of flailing company share prices and increased uncertainties in the regulatory environment. There is a lot at stake for Alfred Mann, the billionaire philanthropist behind MannKind, who has bet nearly half of his estimated $ 2.2 billion fortune in the hopes of a blockbuster innovation, believing that Technosphere's day will come. Once clinical benefit of the product is proved, coupled with patient inhalation convenience, Technosphere might receive a reimbursement approval from the healthcare payors across the major country markets after its expected launch in 2010.

Oral Anti-diabetics (OADS) Segment

Oral anti-diabetic drugs, also called oral hypoglycemic drugs, are used to treat mostly type 2 diabetics (non-insulin dependent diabetics). Treatment, relative to severity of the disease involves monotherapy (an oral drug), combination therapy (two or more oral drugs) or combination therapy involving an oral drug with insulin.

There are five main classes of oral agents used in the management of type 2 diabetes which work in different ways to maintain blood glucose control.

Sulfonylureas, Meglitinides, Biguanides, Thiazolidinedione derivatives (also glitazones), Alpha-glucosidase inhibitors, and Fixed combination pills

New Classes of OADs

DPP-IV (dipeptidyl peptidase-4) inhibitors: are a new therapeutic class of drugs, which enhance glucagon-like peptide-1 and gastric inhibitory polypeptide secretion, leading to increased secretion of insulin and inhibition of glucagon secretion. This class of OADs include Januvia (sitagliptin), Galvus (Vildagliptin)

Incretin mimetics: are a distinct class of agents that work to mimic the anti-diabetic or glucose-lowering actions of the naturally occurring human incretin hormone glucagon-like peptide-1 (GLP-1). Mechanism of actions include stimulating the body's ability to produce insulin in response to elevated levels of blood sugar, inhibiting the release of a hormone called glucagon following meals, slowing the rate at which nutrients are absorbed into the bloodstream and reducing food intake. This class includes Byetta (exenatide)Proliferator-Activated Receptor (PPAR) agonist: their mechanism of action include activating nuclear transcription factors— PPAR-alpha and PPAR-gamma receptors, they simultaneously reduce atherogenic triglycerides, raise cardioprotective HDl levels and improve insulin resistance. Galida (tesaglitazar) is a PPAR agonist.

The OADs Market Scenario

According to the Diabetes outlook report, in the year 2000, global retail sales of diabetes drugs was $ 8.1 billion - the market has tripled in six years, currently worth roughly $ 24 billion. According to this report the new blockbusters Januvia, Galvus, Byetta and Actos are existing leading products for oral anti-diabetic drugs in major country markets.

The Diabetes outlook report claims that a key unmet need that is not addressed by old anti-diabetic agents is the relentlessly progressive nature of type 2 diabetes. Because of this progression, even patients who initially succeed in reaching glycemic goals with only diet and exercise will eventually need multidrug treatment, including insulin. Even when intensive monotherapy with metformin, insulin, or a sulfonylurea is successful in lowering fasting blood glucose and HbA1c over the short term, these measurements steadily increase with time due to disease progression.

Reducing weight in obese diabetics undergoing drug treatment is another major unmet need. Of the established drugs for treating type 2 diabetes, insulin, sulfonylureas, and thiazolidinediones (TZDs) cause weight gain. Only metformin is weight neutral and is sometimes associated with modest weight loss. Essentially, the benchmark for new anti-diabetic drugs is that it should target diabetes and obesity. With obesity also on the rise as an epidemic, research targeting both diseases is likely to be a breakthrough.

Email: pamnani.divya@gmail.com