About TPM/Insulin Phase 1b Trial

Objectives

Conducted by CMAX (a division of IDT, Australia) at the Royal Adelaide Hospital in accordance with ICH Good Clinical Practice standards. The primary objective of this study was to assess the pharmacokinetics and pharmacodynamics of TPM/Insulin formulations. Blood glucose, insulin and C-peptide levels were all assessed as primary endpoint markers.

The secondary endpoints were the safety and tolerability of this unique technology in delivering insulin formulations through the skin.

Study Outline

In a double-blind study, healthy male volunteers aged between 18 and 45 were fasted overnight and then randomly assigned to receive either a formulation of TPM/Insulin or a  placebo gel, applied in a single dose directly to the skin.

Two oral glucose tolerance tests (OGTT) were conducted 4 hours apart. The oral glucose tolerance test is designed to assess how well the body utilises glucose after it has been absorbed from the gut into the circulation.

Blood was collected at intervals of between 15 and 30 minutes for up to 24 hours. Plasma samples were analysed for glucose, endogenous insulin and C-peptide levels. Subjects were directly monitored for a total of 48 hours after the initial application.

Key Results

Figure 1- Mean Blood Glucose Concentration vs Time

Figure 2 – Mean Blood Endogenous Insulin Concentration vs Time

 Figure 3 - Mean Blood C-peptide Concentration vs Time

Discussion of results

The primary objective of the study, to assess the pharmacodynamic effect of TPM/Insulin, was achieved demonstrating that insulin was delivered through the skin into the bloodstream, and had effect in regulating blood glucose levels. The secondary objective was also achieved by demonstrating the safety of the application of the TPM/Insulin formulations. No adverse reactions were observed.

The blood glucose concentrations in subjects that received the TPM/Insulin gel were significantly less (p = 0.016) than the blood glucose concentrations in subjects that received the placebo gel (Figure 1). The smaller concentrations of glucose in treated subjects most likely reflects the presence of the extra insulin that was delivered by the gel, relative to the body’s own supply of insulin. The second oral glucose tolerance test also suggests that the effect of the gel treatment was sustained for up to 8 hours. 

The blood endogenous insulin response over time to the oral glucose tolerance test was highly significantly different (p < 0.001) in subjects that received the TPM/Insulin gel compared to subjects that received the placebo gel (Figure 2). This response indicates that the body released less of its own insulin from the pancreas because of the presence of the additional insulin that was received from the gel.

C-peptide is secreted from the pancreas together with, and in equimolar amounts to, insulin (i.e., an equal number of each molecule). The C-peptide and insulin molecules are protein chains that are split from the molecule proinsulin (an inactive precursor to insulin). This makes C-peptide useful as a reliable marker of insulin production and release by the pancreas. Once insulin is injected into the body to increase its level in the blood, this signals the pancreas to release less insulin. Therefore, delivery of insulin into the blood is shown by lowered blood C-peptide levels, and the assay of C-peptide was used as further proof of delivery. 

The profiles for C-peptide were highly significantly different over time (p < 0.001) in subjects that received TPM/Insulin gel when compared to subjects that received the placebo gel (Figure 3). The lower amount of C-peptide strongly suggests that less endogenous insulin was secreted; again as a result of the body needing to release less insulin from the pancreas because the gel delivered its insulin into the circulation.

Summary

The outcomes of the trial show that the glucose, endogenous insulin and C-peptide responses by the body to the oral glucose tolerance test are significantly reduced by the transdermal delivery of insulin in the TPM/Insulin formulation. The clear implication from these results is that the exogenous insulin in the gel was delivered through the skin, absorbed in sufficient quantity to stimulate the uptake of ingested glucose into target organs, such as muscle and liver, and as a consequence, the production of endogenous insulin, in response to high glucose, was reduced. The blood concentrations of C-peptide, a substance secreted by the pancreas simultaneously with insulin, were also lower in the subjects that received the transdermal gel, indicating a decreased need for the body to release its own insulin in these subjects.

About Diabetes

Diabetes is an illness that occurs when the body does not produce or properly use the hormone insulin.

Insulin, which is produced in the pancreas, enables muscles and other tissues to absorb and utilise glucose (a form of sugar) as the body’s energy source.

When individuals have diabetes, either their pancreas does not produce the insulin they need or their body cannot use its own insulin effectively. As a result, people with diabetes do not use enough of the glucose in the food they eat.  This leads to the amount of glucose in the blood increasing, a condition referred to as "high blood sugar" or "hyperglycaemia".  High levels of glucose in the blood can lead to medical complications.

According to the International Diabetes Federation (IDF), in 2007, the world is estimated to spend at least US$ 232 billion to treat and prevent diabetes and its complications. IDF believes that some costs are preventable through disease control and management that decreases the longer term costs of complications, such as blindness and vision impairment, cardiovascular disease and kidney failure. At present there is no cure for diabetes.          

The world pharmaceutical market for diabetes is estimated to be worth more than $US18 billion per annum and growing, it’s forecasted that today’s 194 million diabetics will increase to 380 million by 2025.

About Phosphagenics’ Transdermal Carrier Technology

Phosphagenics’ patented transdermal carrier technology (TPM) utilises natural dermal transport mechanisms to rapidly transport small and large molecules across the skin without disrupting or damaging its surface.

The Company believes that the key advantages of this delivery system includes the fact that it possesses anti-inflammatory and anti-erythema properties, thus minimising skin irritation, and has the ability to provide a sustained systemic delivery of a wide range of drugs ­– ranging from relatively small molecules (e.g. morphine, fentanyl, oxycodone, atropine, estradiol, testosterone) to large molecules (e.g. insulin and PTH) – from a single application. Additionally, the TPM delivery technology can be cost-effectively manufactured in a wide range of presentations (e.g. gel, paste, liquid and powder) adding value to existing pharmaceuticals.           

About Phosphagenics Limited

Phosphagenics is a Melbourne-based, globally driven biotechnology company focused on the discovery of new and cost effective ways to enhance the bioavailability, activity, safety and delivery of proven pharmaceutical and nutraceutical products.

Phosphagenics’ core technology is built around the science and application of phosphorylation, a process where the addition of a phosphate group has been found to enhance the bioavailability, activity and safety of existing pharmaceuticals and nutraceuticals, as well as to assist in the production of drug delivery platforms.

Phosphagenics’ shares are listed on the Australian Stock Exchange (POH) and the London Stock Exchange's Alternative Investment Market (PSG). An ADR – Level 1 program was established in the U.S. with The Bank of New York Mellon (PPGNY) for U.S. investors to trade in Phosphagenics’ stock on the ‘over-the-counter’ market. In July 2007, this was upgraded to the International OTCQX, a new premium market tier in the U.S. for international exchange-listed companies, operated by Pink Sheets, LLC.