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Diabetes and the pharmaceutical industry
New approaches to insulin therapy
Ever since its first introduction, it has been
necessary to administer insulin by subcutaneous
injection. This is because insulin is a protein and if
it is taken orally, is rapidly broken down and
inactivated in the stomach and intestines.
However, the discomfort of self-injection is believed
to inhibit some patients with type 2 diabetes from
starting insulin treatment when oral medicines are
not providing adequate control of blood glucose.
Much effort has therefore gone into trying to
develop non-invasive methods of delivery.
Furthest advanced is a device and specially
developed rapid-acting inhaled insulin powder
(Pfizer/sanofi-aventis) to enable delivery by
inhalation into the lungs. This inhaled insulin
system was submitted for authorisation in Europe
in 2004, for use in both type 1 and type 2
diabetes.
Preliminary data from Phase 3 studies indicate that
comparable glycaemic control to subcutaneous
NPH insulin could be achieved with pre-meal
inhaled insulin in type 1 diabetes. In type 2
diabetes, inhaled insulin treatment was found to
give a slightly greater decrease in HbA1C levels over two years than an oral regimen. Changes in
lung function were similar between the groups,
suggesting that inhalation was not harmful to the
lung tissue.
Other companies are also developing inhaled
insulin formulations. Eli Lilly and Alkermes have an
inhaled dry powder insulin system that has recently
started Phase 3 trials in type 1 and type 2
diabetes and Novo Nordisk and Aradigm have a
liquid insulin (NN 1998) inhaler system, also in
Phase 3 trials.
Other delivery routes are also being explored.
Generex Biotechnology is working on an insulin
spray, to be delivered as a fine mist to the mouth,
where it is rapidly absorbed. Delivered by this
route, the insulin had a time of onset of action of
about 30 minutes and a shorter duration of action
(ca. 85 minutes) than regular insulin, making it
suitable for mealtime use. The company will be
seeking approval to begin Phase 3 trials in
Europe.
A true oral insulin is being developed by Nobex,
in which the insulin is combined with a polymer
which protects it from digestion in the stomach and
assists uptake in the intestine. This is currently in
Phase 2 trials. Another oral insulin tablet,
formulated using a different delivery technology, is
being developed by Emisphere Technologies. This
has undergone Phase 1 trials and is expected to
start Phase 2 study in patients with type 2 diabetes
in the second half of 2005.
Finally, Altea Therapeutics is developing a
transdermal patch form of insulin (AT1391)
designed to provide basal insulin requirements,
which is currently in Phase 1 trials.
Non-insulin medicines under development for type 1 diabetes
Currently, no oral medications or injectable
medications other than insulin are authorised for
the treatment of type 1 diabetes. Some alternative
approaches to treatment are, however, in the
earlier stages of clinical testing. These mainly rely
on the idea of intervening to prevent the
autoimmune destruction of beta cells early in the
onset of the disease.
Develogen AG is studying DiaPep277, designed
to block the immune destruction of the insulinsecreting
beta cells in type 1 diabetes. A Phase 2
trial in newly-diagnosed disease provided
evidence for a slowing of beta cell destruction following injection of DiaPep277 and the
company is now conducting a Phase 2 trial of
patients with Latent Autoimmune Diabetes of the
Adult (LADA) - a variant of type 1 diabetes with a
slower progression that emerges in mid-life.
LADA is also being studied by Diamyd
Medical, which is conducting a Phase 2/3 study
with its recombinant human glutamic acid
decarboxylase (GAD protein) at 15 diabetes
clinics throughout Sweden. The company also has
an ongoing Phase 2 trial with this therapeutic in
newly-diagnosed type 1 diabetes.
Another compound that seeks to dampen the
destructive autoimmune reaction in type 1 diabetes
is NBI-6024 under development by Neurocrine
Biosciences. This substance, a genetically
engineered variant of a pancreatic antigen, is now
in Phase 2 studies in patients with newly diagnosed
type 1 diabetes.
Placebos
A placebo is a dummy treatment with no
activity against a patient’s illness and which is
administered to a control group in a clinical
trial. It is given to a proportion of the people
taking part, so that comparisons can be made
with the new compound that is being tested for
activity in the disease. The participants do not
know whether they have the placebo or the
real thing. In order to be considered effective,
the experimental treatment must therefore
produce better results than the placebo.
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| HOW MEDICINES ARE AUTHORISED |
| 1. |
Initial research on new compounds is carried out in the laboratory (pre-clinical development),
using a wide variety of techniques. |
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| 2. |
Promising compounds are then studied in animals, subject to strict ethical and legal controls, to
investigate effects that currently cannot be predicted from computer and test tube studies. |
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| 3. |
A sequence of phases of clinical assessment in humans follows, under strict guidelines: |
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Phase 1: a small number of people, either healthy volunteers or patients with the target
disease, is given the compound. These trials are designed to establish dose limits for the drug
and to measure parameters such as its pharmacokinetics (speed of entry into the circulation).
They are generally not intended to demonstrate efficacy. |
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Phase 2: a larger number of patients with the condition are given the medicine to assess both
that it works and that it does not produce unacceptable side effects. In some cases, Phase 1
and Phase 2 trials may be combined. |
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Phase 3: many more patients, perhaps several thousand, take the medicine under appropriate
supervision for an appropriate period. It is tested in comparison with an established
compound and/or a placebo. These studies are used to establish the efficacy of the new
medicine. If the results prove satisfactory in terms of quality, efficacy and safety, the data are
presented to the medicines evaluation authorities. If the evidence satisfies the authorities, i.e.
the benefits versus risks are acceptable, a marketing authorisation (licence) is issued. |
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Phase 4: the newly-authorised medicine is studied in large numbers of patients in general practice to assess its clinical effectiveness or some aspect of its use. |
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| 4. |
SAMM (Safety Assessment of Marketed Medicines) studies are sometimes initiated after the
medicine has been made available for doctors to prescribe and to help identify any
unforeseen side-effects. These may involve many thousands of patients. |
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| 5. |
GP databases are also used to identify medicine safety issues and to explore the potential for
new and better uses of medicines once the product is available for prescription. |
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TolerRx is working on a humanised monoclonal
antibody to block the autoimmune reaction. In a
Phase 2 study, this compound, TRX4, has been
shown to preserve residual beta cell function for at
least 18 months in new onset type 1 diabetes.
These new approaches have demonstrated that it
is possible to slow or block the autoimmune
process that causes beta cell destruction in type 1
diabetes, and this is encouraging news. However,
these compounds are still at an early stage of
development. Best results are likely to be seen
when such agents are given as early as possible in
the disease process, and it is not likely that they
will be useful in long-established diabetes. Despite
these caveats, it is encouraging that new therapies
for type 1 diabetes are being explored and these
may one day reduce the dependence of some of
those with type 1 on intensive insulin therapy.
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