Capsulin™ IR (insulin replacement)

• As an alternative to inhaled/injected insulin, Capsulin™ IR will effectively deliver insulin orally to those with Type 1 diabetes and late stage Type 2, where they are dependent on insulin replacement
• Reducing the need for injections and/or inhaler equipment
• Potentially improving glycaemic control through optimal physiological delivery route
• Improving compliance

Study Results

Phase IIa study (Type 1 Diabetes)

The second clinical study of Diabetology's oral insulin product Capsulin™ was completed in the UK in July 2005 to investigate the effect of administering two doses of the product in capsules to patients with Type 1 diabetes by measuring blood glucose and circulating plasma insulin levels. This was a single-centre, open-label, two-way sequential oral dose-finding study using male volunteers with Type 1 diabetes. The two doses investigated were 150iu and 300iu with the volunteers challenged with each dose on one occasion, separated by at least a 120-hour washout period. The primary endpoint was the absolute change in blood glucose after administration of Capsulin™; the secondary endpoints included its effect on plasma insulin levels.

During the course of the study, mean blood glucose levels dropped in the subjects; those receiving the higher dose showed a higher fall and blood glucose levels were continuing to fall even at the end of the 7-hour study period. Insulin levels were detectable above background in the patients’ bloodstream at various times throughout the course of the study. The main conclusions of the study are as follows:

• Capsulin appears to be safe & well tolerated in patients with Type 1 diabetes;
• Capsulin produced consistent increases in blood insulin levels within 30-120 minutes after dosing;
• Capsulin controlled blood glucose levels for an extended time period after dosing;
• Both increases in insulin levels and control of glucose levels were dose-dependent.

The study results also supported the hypothesis made as a result of the Phase II study outcome that oral delivery of insulin can help restore hepatic control of the insulin regulation system.

Phase I study

The first clinical study of Capsulin was completed in the UK in April 2005 in healthy volunteers to investigate and measure the effect of orally administering insulin in the Axcess formulation on blood glucose, c-peptide and circulating insulin levels in healthy subjects. The study was open label and sequential; although there was no blinding in the study, the parameters being examined in the study were derived from blood and subjective bias in the data collected was thus minimised. The main conclusions of the study are as follows:

• Capsulin was well tolerated by the volunteers;
• Capsulin shows evidence of bioavailability and was biologically active in humans (fall in blood glucose levels and suppression of C-peptide levels);
• There was a marked non-linear relationship between plasma insulin levels in the two naso-jejeunal groups suggesting that the 170iu dose may be >90% bound by the liver insulin receptors with minimal overspill of insulin into the circulation, whereas the 340iu dose floods the liver and spills over into plasma (10 times the plasma levels with 170iu).

This graph, from the phase I trial, illustrates the elevation in plasma insulin levels of healthy subjects following administration of 170iu Capsulin™.This allowed us to green light the progression of the development project into phase II.

Strong pre-clinical study results

Diabetology has studied its novel oral insulin formulations in multiple animal model systems including rats, juvenile pigs, primates and diabetic dogs. Results demonstrate:

1. Successful insulin absorption through the intestine;
2. Consistent 6-10% bioequivalence as assessed by impact upon blood glucose concentration relative to injected insulin;
3. No chemical interaction between insulin and the carrier formulation;
4. No unexpected toxicity or safety issues; and
5. Predictable onset of activity.

Background on Diabetes & Insulin

• 171 million people with diabetes in 2000
• 366 million people with diabetes by 2030
• Incidence is set to more than double in the next 25 years
• Global epidemic resulting from the spread of the “western lifestyle”
• Diabetes causes about 5% of all deaths globally each year

The inexorable spread of the western lifestyle across the world is precipitating a diabetes epidemic. Diabetes is the most common human endocrine disease and the term covers a group of metabolic disorders whose central feature is elevated blood glucose, or hyperglycemia. Sustained hyperglycemia results in the deterioration of multiple tissue types, particularly vascular tissues, and may eventually lead to kidney failure, cardiovascular disease, leg ulcers, stroke, neuropathy and retinopathy. In 2002 it was estimated that the direct and indirect cost of diabetes was $132 billion annually in the US alone.

The principal regulator of blood glucose concentration is insulin, a hormone synthesized by the ß islet cells of the pancreas and secreted in response to elevated blood glucose levels. Insulin increases the uptake of glucose by multiple tissues, promotes its utilization as an energy source, reduces the production of new glucose, and slows down the production and release of alternative energy sources such as fatty acids. Its principal target organs are the liver, skeletal muscle and fat tissue. In particular, the liver plays a central role in maintaining blood glucose concentration within normal limits since it is both a major point of glucose uptake when blood levels of the substance rise and the primary source of glucose production to counter low blood glucose levels (hypoglycaemia).

Publications

Poster presented at ADA 2005:

Absorption of Orally Ingested Insulin in Human Type 1 Diabetic Subjects:Proof of Concept Study

Click Here for Details (pdf)

Poster presented at ADA 2004:

Early Evaluation of a Novel Oral Insulin Delivery System in Healthy Volunteers

Click Here for Details (pdf)