Diabetology has developed a
novel oral formulation of insulin using its
in-licensed Axcess™ drug delivery technology.
This delivery technology uses no NCE’s
and has been shown to be effective as an oral
delivery system for peptides in multiple animal
models using not only insulin but also calcitonin
and parathyroid hormone (PTH). It is reasonable
to project that this product, trade-marked
as Capsulin™, could replace a significant
proportion of the sales of injected and infused
insulin.
Oral insulin has many potential advantages
over other forms of Insulin dellivery, as
it most closely mimics the natural insulin
secretion pathway from the pancreas to the
liver. By delivering Insulin to the liver
as the oral route does, the main organ of
glucose regulation is solicited, and insulin
side-effects in the peripheral circulation
(from other routes of administration) may
be avoided.
Target:
Insulin replacement for
diabetics
Stage:
Successfully completed phase 2a
Background on Diabetes
& Insulin
The inexorable spread of the
western lifestyle across the world is precipitating
a diabetes epidemic. Current worldwide prevalence
is estimated at 2.3% (or 150 million people)
and the number of diabetics is increasing
by 4-5% p.a., implying that there could be
over 220 million diabetics in the world by
2020. 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. It is
estimated that the direct medical costs of
diabetes amount to nearly $92 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).
Frequent Q&A on Capsulin™
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Study Results
Phase
2a study (Type 1 Diabetics):
The second clinical study of
Diabetology Ltd.'s oral insulin product Capsulin™
was undertaken in the UK in 2004 to investigate
the effect of administering two doses of the
product in capsules to Type 1 diabetics 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 Type 1 diabetic volunteers.
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 Type 1 diabetics;
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 1 study outcome
that oral delivery of insulin can help restore
hepatic control of the insulin regulation
system.
Phase 1 study:
The first clinical study of
Capsulin was undertaken in the UK in 2003
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
1 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
2.
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:
successful insulin absorption through
the intestine;
consistent 6-10% bioequivalence as assessed
by impact upon blood glucose concentration
relative to injected insulin;
no chemical interaction between insulin
and the carrier formulation;
no unexpected toxicity or safety issues;
and
predictable onset of activity.
Poster presented at ADA 2005:
Absorption of Orally Ingested
Insulin in Human Type 1 Diabetic Subjects:Proof
of Concept Study
