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Phosphagenics successfully delivers insulin across the skin in humans
No adverse reactions reported
Key Points:
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TPM-02/Insulin applied as a gel delivered insulin through the skin and into the bloodstream
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TPM-02/Insulin significantly lowered blood glucose levels
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TPM-02/Insulin did not produce any adverse reactions
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TPM-02 carrier platform has now shown the ability to deliver large molecules (e.g. proteins) through the skin in humans
Phosphagenics Limited (“Phosphagenics”) (ASX: POH) announced today the interim results from its Phase I transdermal insulin clinical trial, demonstrating that it had successfully delivered insulin through the skin in a way that could radically alter patient care for many diabetics around the world, especially those with Type 2.
From one topical application of TPM-02/Insulin applied as a gel, insulin was shown to safely penetrate the human skin and then be delivered into the blood stream over a sustained period of time.
Dr William Hsu, co-investigator for this trial and clinician at the Joslin Diabetes Center of the Harvard Medical School, Boston, USA, said the trial results are evidence of the safety and tolerability of TPM-02/Insulin and demonstrate that this technology can deliver large molecules such as proteins through the skin.
“The primary objective was to confirm the safety and tolerability of TPM-02/Insulin, and this was achieved with no adverse reactions," Dr Hsu said.
“The trial also demonstrated the ability of TPM-02/Insulin to deliver insulin into the blood stream at levels high enough to produce significant effects. This is a very impressive result, given that it was administered as a single dose to healthy volunteers.
“This technology could eventually transform and expand the world’s multi-billion dollar insulin market by providing a non-invasive and effective treatment for many of the world’s 194 million diabetics, the majority of which are classified as Type 2,” he said.
In the study, 20 healthy male volunteers, aged between 18 and 45, fasted overnight and then randomly received a single dose of TPM-02/Insulin or a placebo gel, applied directly onto the skin. Volunteers were then monitored for a period of 48 hours to assess the primary endpoint of safety.
Conducted at the Centre for Clinical Studies in Melbourne, Australia, and in accordance with ICH GCP standards and under the guidance and supervision of Professor Leon Bach, blood glucose and insulin levels, and the insulin biomarker C-peptide were all measured as secondary endpoints.
”To see TPM-02/Insulin produce a statistically significant and sustained effect on key markers, such as blood glucose concentration, insulin, and C-peptide is very encouraging and warrants significant future development,” Dr Hsu said.
Dr Esra Ogru , Executive Director of Research and Development at Phosphagenics, said that this was a milestone for Phosphagenics and allows it to now move rapidly into its next stage of development with TPM-02/Insulin.
“With this success we will now start exploring ways to apply this technology to other pharmaceutical products, as well as developing other routes of administration, such as oral and inhalation,” Dr Ogru said.
Phosphagenics Managing Director, Harry Rosen added: “This result supports our recent focus on developing this novel patented technology. We expect this development to enhance international interest in Phosphagenics’ technology as it is a key milestone in the delivery of large molecules effectively and safely through the skin.”
ENDS….
APPENDIX AND NOTES TO EDITORS
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 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.
The International Diabetes Foundation (IDF) estimates that direct and indirect healthcare costs associated with diabetes exceed $US153 billion globally. 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.
About the TPM-02/Insulin Clinical Trial
Objectives
Conducted at the Centre for Clinical Studies (a division of Nucleus Network Limited, Melbourne, Australia) in accordance with ICH GCP standards, the primary objective of this study was to assess the safety and tolerability of this unique technology in delivering insulin through the skin.
Blood glucose, endogenous insulin, exogenous insulin and insulin C-peptide levels were also measured as secondary endpoints.
Study Outline
In a double blind study, 20 healthy male volunteers aged between 18 and 45 were fasted overnight and then randomly assigned to receive either TPM-02/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.
Blood was collected at intervals of between 15 and 30 minutes for up to 9 hours. Plasma samples were analysed for glucose, insulin and C-peptide.
Conducted over one week, subjects were directly monitored for a total of 48 hours after the initial application.
Key Results
i) Blood Glucose Concentration vs Time
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ii) Blood Insulin (Endogenous) levels vs Time
iii) Blood C-peptide vs Time
iv) Blood Insulin (Exogenous i.e. Lispro) Concentration
Exogenous insulin (Lispro) was detected utilising a commercially available kit. Further analysis of this data is currently underway.
Discussion of results
The primary objective of the study was achieved by demonstrating the safety of the application of the gel. The secondary objective, that insulin can be delivered through the skin into the bloodstream without breaking the skin, and can be effective in its role of regulating blood glucose levels, has also been clearly demonstrated.
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. The response to the oral glucose tolerance test by the subjects that received the insulin gel treatment clearly tended to be that of a lowering of blood glucose compared to the subjects that received the placebo gel. This is seen in the first graph when comparison is made of the area under the curve (AUC) for both treatments: the treated group has a significantly smaller curve for both treatments: the treated group has a significantly smaller than the placebo group (p<0.05), indicating that less glucose accumulates in the blood. The lesser amount of glucose 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 at least 6 hours.
The endogenous blood insulin levels that were measured are shown in the second graph, and were obtained by measuring the amounts of endogenous insulin. The area under the curve was significantly decreased in the group of subjects that received the insulin gel (p<0.05). An interpretation from this response is 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 show significantly lower levels present in the treated group compared to placebo (p<0.05). This lower amount of C-peptide also strongly suggests that less endogenous insulin was secreted; again, this indicating that it was a result of the body needing to release less insulin from the pancreas because the gel delivered its insulin into the circulation.
The type of insulin that was used in the gel formulation was a fast-acting type, with a normal time-course of action after injection of only 1.5 - 3 hours. These results strongly suggest that the activity after application is sustained for at least 6 hours, supporting the belief held by Phosphagenics that the gels based on TPM can produce a “reservoir” of drug within the skin, for slow release into the blood.
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 gel TPM-02/Insulin. The study also shows that the exogenous insulin Lispro was delivered systemically through the skin. The implication from this is that the insulin was absorbed and stimulated 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.
The broader implications are that:
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a novel delivery system for insulin that does not injure the skin is real;
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the delivery platform using TPM technology can produce sustained delivery;
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there is likely to be an extensive suite of drugs that were previously not deliverable through the skin, that can now be delivered with the platform; and
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the TPM-02 platform may also be applicable for delivering large molecules via other routes of administration.
A final report that will include a detailed analysis of exogenous insulin concentrations is envisaged by September, 2006.
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