Under development by Canadian company Generex Biotechnology, Oral-Lyn is an oral spray formulation of human insulin indicated for the treatment of type 1 and 2 diabetes.

Having secured regulatory approval in 2005 for clinical use of Oral-Lyn in type 2 diabetics in Ecuador, the company is keen to progress phase III trials in the major North American and European markets, where it hopes eventually to achieve comparable success.

The announcement to start Phase III for Oral-Lyn in North America was made on 7 April 2008, beginning with patient screening. The first screening was carried out in Texas in late March 2008. Other clinical sites taking part in the study are located in Maryland, Minnesota, California and in the province of Alberta in Canada.

Non-injectable insulins may improve compliance

At present diabetics who require insulin to keep their blood sugar levels under tight control (target HbA1c levels of <7%) have to administer it by injection. The need for regular daily injections is a major drawback for diabetic patients and can reduce compliance with treatment.

Considerable research effort has been devoted to the development of alternative modes of insulin delivery which can deliver insulin safely and effectively without the need for injection. Various alternatives to injectable insulin have been investigated including:

• Insulin patches
• Insulin pumps
• Inhaled insulin
• Oral formulations designed to resist insulin digestion in the gastrointestinal tract
• Oral formulations for buccal delivery

Generex's Oral-Lyn is a liquid formulation of human insulin that is sprayed into the mouth using its proprietary RapidMist device. In the mouth the insulin is absorbed via the buccal mucosa, an area with a rich vasculature. Generex believes that Oral-Lyn will provide an effective alternative to prandial insulin injections and improve patient compliance with insulin therapy.

Evidence of efficacy in diabetic patients

Approval of Oral-Lyn by the Ecuadorian Ministry of Public Health was based on data from clinical trials conducted in Ecuador which involved more than 250 patients with type 2 diabetes. These showed that Oral-Lyn had comparable efficacy to prandial insulin injections in this patient population.

The company is also hoping to extend use of Oral-Lyn in Ecuador to type 1 diabetic patients and has already initiated a six-month study of its safety and efficacy in adolescent and young adult patients with type1 diabetes.

An earlier short-term study, in which Oral-Lyn was compared with short-acting subcutaneously injected pre-prandial insulin (Humulin), was considered successful. In this study Oral-Lyn was taken both before and after each meal.

The real test of the product's viability, however, will come from large-scale trials involving several thousand patients that will be required by regulatory authorities in North America and Europe. On 6 August 2008, Generex recieved approval to conduct an Oral-Lyn trial on patients diagnosed with or prone to developing impaired glucose tolerance. The approval was recieved from the Ethics Committe at University Campuse Bio Medico, Rome. The study was to help determine whether the glucose levels of patients drop when they are using Oral-Lyn.

Plans are underway for Phase III trials in Canada and Europe to be followed by similar large-scale studies in the US. On 11 March 2008 Generex announced that the labelling and packaging of cannisters for Oral-Lyn had been completed. The cannisters will be used for Phase III clinical trials in the US, Canada and Ukraine.

Diabetes represents a rapidly growing problem

Estimates from the World Health Organisation suggest that 150 million or more people have diabetes, of which type 2 accounts for the vast majority of cases. Worldwide, the costs associated with the treatment of diabetes and its complications are estimated to exceed $200 billion annually.

Adverse lifestyle changes which have seen an explosion in the incidence of obesity, an important risk factor for type 2 diabetes, are contributing to the continual rise in the number of new cases that occur each year. By 2025, prevalence of diabetes is expected to have more than doubled from today's figures.

Left untreated or poorly controlled, diabetes can lead to serious complications such as retinopathy, cardiovascular disease, nephropathy, neuropathy and peripheral vascular disease as well as premature death.

Insulin injections revolutionised the treatment of diabetes when first introduced into clinical practice in the 1920s. The advent of non-injectable insulins, such as Oral-Lyn, have the potential to be just as revolutionary and to make regular insulin therapy much more acceptable to diabetic patients.

Marketing commentary

In addition to all type 1 diabetic patients, for whom insulin is essential therapy, there are about 40-50 million type 2 diabetic patients who also need insulin to control their blood sugar levels effectively. However, the thought of having to self-inject several times a day leads many patients to fail to take their insulin treatment regularly, exposing them to the risk of diabetes-related complications.

Insulin therapies have evolved over recent years to include rapid-acting insulin analogues, analogue mixtures and long-acting insulin analogues. Non-injectable insulins are now poised to enter the market, with analysts predicting that these new insulin formulations could achieve sales in excess of $5bn by the end of the decade.

Generex has recieved approval for commercial sale of Oral-Lyn in several countries. In India, approval was obtained in November 2007. The first commercial order was made by Generex's Indian distributor Shreya Life Sciences in March 2008 for 210,000 cannisters of Oral-Lyn.

On 1 April 2008, Generex signed a licence and distribution agreement with SciGen. Under this agreement, SciGen will acquire approvals for importing, marketing, distributing and selling Oral-Lyn in China, Hong Kong, Indonesia, South Korea, Malaysia, the Philippines, Singapore, Thailand and Vietnam. SciGen will use its own recomnibant human insulin product for the sale of Oral-Lyn in these countries.

On 14 May 2009, Oral-Lyn was launched in Lebanon by Benta SAL. It is available on the market as a box containing one canister and one actuator. The cannister contains 400IU of recombinant human insulin, while an actuator is a device that is used for managing the drug.