New Data Shows Lantus® Activation of Insulin Receptor Comparable to Human Insulin

Paris (ots/PRNewswire) -

- Human and in vivo Studies Indicate Lantus(R) Metabolites do not
ConferCarcinogenic Potential via IGF-1 Receptor Activation

Sanofi announced at the 71st American Diabetes Association
Scientific Sessions 2011 the results of four studies[1,2,3,4]
indicating that the effect of Lantus(R) (insulin glargine)
metabolites on the IGF-1 receptor is distinctly different from
AspB10, the only insulin analog shown to have a carcinogenic effect.

Insulin receptor signalling pattern of AspB10 distinctly
different from glargine

The goal of the first study[1] by Tennagels et al was to
investigate the metabolic and mitogenic signalling of [AspB10]
insulin (AspB10 or also called X10) and insulin glargine in vitro and
in vivo. AspB10 is the only insulin analog shown so far to have a
tumorogenic effect (breast cancer in rats).The study showed that
following subcutaneous injection of 1.0 or 12.5 U/kg in rats, neither
human insulin nor insulin glargine nor AspB10 induced IGF-1 receptor
activation in responsive tissues, whereas IGF-1 injection produced a
robust activation.

In the study, AspB10 induced an increased and prolonged
activation of insulin receptor (IR) signalling molecules in several
tissues. The IR signalling pattern found for AspB10 is distinctly
different from that of human insulin and insulin glargine, confirming
earlier in vitro findings.

In vitro, AspB10 displays a higher affinity toward both IR and
IGF-1 receptors, a prolonged occupancy time at the IR and a higher
proliferation rate in mammalian cell lines. This is the basis for the
contention that insulin analogs with increased IGF-1 receptor
affinity in vitro also have increased growth promoting activity in
vivo. The study shows, however, that the IGF-1 receptor is not
involved in the mode of action of AspB10, the only insulin analog
shown to have a carcinogenic effect.

Furthermore, the study underlines the distinct differences
between insulin receptor signalling patterns of AspB10 is distinctly
different from human insulin and insulin glargine, suggesting that
insulin glargine does not confer carcinogenic potential through IGF-1
receptor activation.

The goal of the second study[2] by Tennagels et al was to further
elucidate the characteristics of insulin glargine signalling in rats.
It investigated the time action profile of insulin glargine in
different rat tissues with respect to pharmacological and signalling
parameters and compared it to human insulin, insulin detemir and
AspB10.

Male Wistar rats were injected subcutaneously with 1 U/kg of
either human insulin or each of the insulin analogs, and the effects
on blood glucose and activation status of IR, IGF-1 receptor and
additional pathways in tissue samples derived from muscle, fat,
liver, heart and kidney investigated over time. The time course of IR
signalling by human insulin and insulin glargine clearly correlated
with the time course of their pharmacodynamic effects, whereas the
time course of IR signalling by insulin glargine was found to be
distinctively different from that of AspB10.

Insulin glargine treatment resulted in activation levels of IR
that were comparable to human insulin although delayed in some
tissues. In contrast, AspB10 treatment resulted in at least two- to
threefold higher activation and significantly longer duration in most
tissues ex vivo, confirming the in vitro observations of increased
affinity and occupancy time of the IR.

Importantly, neither human insulin nor insulin glargine nor
AspB10 treatment resulted in any detectable IGF-1 receptor activation
in muscle and heart tissue, whereas injection of IGF-1 increased
activation of this receptor.

Glargine metabolized to products with lower affinity for IGF-1 vs
human insulin

The goal of the third study[3], involving 12 patients with type 1
diabetes, was to investigate the plasma exposure to insulin glargine
and its metabolites. The study showed following subcutaneous
injection, insulin glargine was almost completely transformed into
two metabolites (M1 and M2), with M1 accounting almost totally for
the pharmacodynamic effect of injected glargine.

Insulin glargine and M2 were only detectable in approximately
one-third of patients and at a few time points only. When detectable,
insulin glargine and M2 exposure did not increase with increasing
dose, and concentrations were far below endogenous interprandial
plasma insulin concentrations of people without diabetes.

After injection of a therapeutic dose, glargine is minimally
detectable in blood

Finally, the goal of the fourth study[4] was to examine the
metabolism of insulin glargine in patients with type 2 diabetes. This
study confirmed that, after injection of a therapeutic dose in
patients with type 2 diabetes, insulin glargine is minimally
detectable in blood. Its metabolite M1 accounts for most (~90%) of
the plasma insulin concentration.

Notes to editors

About the studies

Study 1[1] and study 2[2]: Animal studies.

Study 3[3]: Plasma concentrations for insulin glargine, M1 and M2
were determined from samples taken in a single-center, randomized,
euglycemic glucose clamp study, where the 12 male persons (BMI 25
kg/m2; A1C < 8.0%) per group received single doses of 0.3, 0.6, or
1.2 U/kg insulin glargine.

Study 4[4]: Insulin glargine, M1, and M2 plasma concentrations
were determined from samples obtained from a single-center, 32 hour
euglycemic glucose clamp study, where 18 type 2 diabetes patients
received a single dose of 0.4 U/kg insulin glargine after one week of
daily administration. Data from 9 subjects and 31 hour glucose clamp
are here.

About Lantus[(R)]

Lantus(R) (insulin glargine) is the first 24-hour once-daily
basal insulin analogue. Lantus(R) is as effective as NPH insulin with
similar reductions in HbA1c, but is associated with lower fasting
blood glucose concentrations. People with type 2 diabetes experience
a consistent and significant reduction in the incidence of nocturnal
hypoglycemia with Lantus(R).[5]

Lantus(R) is one of the most widely-studied insulins for the
treatment of type 1 and type 2 diabetes. It has been tested in over
100 clinical studies, many of which are completed and published.
These studies include detailed safety evaluations and constitute
in-depth evidence for the absence of effects related to growth
promoting or tumor promoting activity.

With the estimated experience of nearly 34 million patient-years
worldwide, Lantus(R) has been used safely and effectively by adults
and children (6 years and older) in the treatment of type 1 diabetes
and in adult patients with type 2 diabetes since it received
marketing authorization in 2000.

About the Sanofi Diabetes Division

Sanofi strives to help people manage the complex challenges of
diabetes by delivering innovative, integrated and personalized
solutions. Driven by valuable insight that comes from listening to
and engaging with people living with diabetes, the Company is forming
partnerships to offer diagnostics, therapies, services, and devices.
Sanofi markets both injectable and oral medications for people with
type 1 or type 2 diabetes. Investigational compounds in the pipeline
include an injectable GLP-1 agonist being studied as a single agent,
in combination with basal insulins, and/or in combination with oral
antidiabetic agents.

About Sanofi

Sanofi, a global and diversified healthcare leader, discovers,
develops and distributes therapeutic solutions focused on patients'
needs. Sanofi has core strengths in the field of healthcare with
seven growth platforms: diabetes solutions, human vaccines,
innovative drugs, rare diseases, consumer healthcare, emerging
markets and animal health. Sanofi is listed in Paris and in New York
.

References

1. Tennagels N., Sommerfeld M., Müller G., Tschank G., Habermann
P., Seipke G., et al. Metabolic and mitogenic signaling of AspB10 and
insulin Glargine in vitro and in vivo (0076-OR) ADA 2011

2. Tennagels N., Welte S., Jordan H., Hoffmann M., Werner U.
Characteristics of insulin glargine signalling in rats (1562-P) ADA
2011

3. Bolli G.B., Frick A., Schmidt R., Eisenblaetter T., Becker R.
Plasma exposure to insulin glargine and its metabolites in patients
with type 1 diabetes (0071-OR) ADA 2011

4. Lucidi P., Porcellati F., Rossetti P., Candeloro P., Marinelli
Andreoli A., Frick A., et al. Metabolism of insulin glargine after SC
injection of therapeutic dose in type 2 diabetes mellitus (1092-P)
ADA 2011

5. Wang F
[http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wang%20F%22%5BAuthor%5D
]. et al. Insulin glargine: a systematic review of a long-acting
insulin analogue. Clin. Ther. 2003 25:1541-77

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ots Originaltext: sanofi-aventis Group
Im Internet recherchierbar: http://www.presseportal.de

Contact:
Contacts: Global Diabetes Division Communications, Yanyan Chang,Tel.:
+49-173-689-6295, E-mail: yanyan.chang@sanofi.com