Page 97 - 51 the significance--29.2_opt

Interleukin-1β receptor antagonists

Interleukin-1β is a proinflammatory cytokine that inhibits the function
and promotes the apoptosis of pancreatic β-cells. β-cells producing
79
this cytokine have been observed in pancreatic sections obtained from
patients with T2DM. Depending on culture conditions, high glucose lev-
els have been shown to increase β-cell production and the release of
interleukin-1β, followed by functional impairment and apoptosis. Using
79
an antagonist to prevent interleukin-1β from binding to its receptor
protects human β-cells from glucose-induced functional impairment
and apoptosis. This therapeutic approach has the potential to block
80
the pathogenic progression of T2DM.
Anakinra, a recombinant human interleukin-1–receptor antagonist, is
currently in Phase 2 development. A recent study has demonstrated
that HbA levels in T2DM patients treated with this compound for 13
1c
weeks were 0.46% lower than in those treated with placebo. In addi-
79
tion, anakinra was associated with improved β-cell secretory function
and reduced markers of systemic inflammation. In terms of safety, no
79
cases of symptomatic hypoglycaemia or serious, drug related adverse
events were observed during this study. Table 8 presents a ‘SWOT’
79
analysis of interleukin-1β receptor antagonists.
Table 8. Interleukin-1β receptor antagonists – Strengths, Weaknesses, Opportunities and
Threats.
Strengths Weaknesses

z Novel mode of action z Still in the early stages of development
z Orally active z Not yet supported by a large body of late phase
clinical data
z Impedes the pathogenic progression of T2DM
z No data on long-term antagonism of interleukin-1β
receptor
z Interleukin-1β receptor antagonists are an unknown
quantity in T2DM management
z Unknown how Interleukin-1β receptor antagonists
could fit in combination therapy

z Interleukin-1β receptor widely expressed in the body
Opportunities Threats
z T2DM management is moving beyond simple z Emergence of other agents with a more familiar
glycaemic parameters mode of action

z The position of many OADs is being eroded by z Doubts over whether this drug target represents a
safety concerns (e.g. SUs, TZDs) viable, long-term treatment strategy
z Patient-centric treatment is increasingly important
z The only therapy that targets the pathogenesis of
T2DM

97