Enthusiasm for the
host of clinical data released at the ongoing American Diabetes Association (ADA, June 5-9)
meeting has simmered down as the FDA’s long-term safety concerns will weigh
heavily on whether these drugs will actually make it to market. New data on
weekly versions of GLP-1’s, Phase II data from Roche’s aleglitazar, and data
for a novel class of drugs that aim to treat diabetes by blocking IL-1β were
all important developments in the fight against diabetes, but they are unlikely
to boost the shares of the companies developing them in the near term.
New weekly GLP-1 data.
Will the FDA change its stance on this class?
GlaxoSmithkline, NovoNordisk and Lilly unveiled new data on their respective
GLP-1 analogues: Syncria (albiglutide), Victoza (liraglutide) and Byetta LAR (exenatide).
While the new data was not especially different from data previously released,
it adds evidence of the strong benefits that this class can offer: weight
reduction, compliance benefit, and balanced glycemic control. The key benefits
of this class should be supported by longer clinical studies in a large
population, which could compel the FDA to re-evaluate its view on the
risk-reward profile of GLP-1s. Despite no evidence of thyroid cancer in the
clinical trials, the FDA remains concerned about the association of thyroid
cancer with GLP-1’s given the strong evidence seen in trials in rats, and the
fact that medullar thyroid cancers are slow progressing. Longer clinical trials
are required to prove either way.
into PhIII is a risky bet
Phase II data on
Roche’s aleglitazar is in line with
the data of other PPAR agonists (strong efficacy but safety concerns), which
have been discontinued in the past. It demonstrated a dose-related increase in
serum creatinine levels; thus it seems to be a risky bet to push this compound into
Phase III. Aleglitazar faces concerns similar to AstraZeneca’s dual PPAR
agonist, Galida, which was
discontinued in 2006 because of a larger than acceptable rise in creatinine
levels. The rise in creatinine levels associated with aleglitazar is smaller
than those seen with Galida, but still might not be acceptable, as the increase
is dose-dependent and we could see a continuing rise over time.
Promising data for
XOMA 052 (novel IL-1β blocker, PhI)
Xoma 052 (anakinra), an IL-1β
blocker, will be discussed at ADA as a potential disease modifying therapy for
Type 2 Diabetes Mellitus. Rather than focusing on insulin, this novel approach
to diabetes treatment aims to block the master inflammatory cytokine, IL-1β,
which when elevated can lead to impaired insulin secretion, decreased cell
proliferation, and apoptosis. Progress with this mechanism raises hopes for
Novartis’ IL-1β blocker for Type 2 Diabetes Mellitus, ACZ-885 (PhII)
- Strong efficacy data: Single dose of Xoma 052 reduced HbA1c by
a median of 1.1% with a maximum of 2.2% in three months. In contrast, the
placebo treated subjects showed an increase of 0.1%. The treatment arm also
showed a continuous increase in insulin production at one and three months
compared to baseline as measured by the i.v. stimulation test, while placebo
treated subjects showed no improvement.
- Safety may be a concern: The adverse effect profile will be an
area to watch out for, as IL-1β is an important signal for the inflammatory
response of the body against infection. Thus, blocking IL-1β may increase the
susceptibility of infections. The role of IL-1β is also established in
hematopoesis, so IL-1β blockers can possibly reduce the production of natural
erythropoietin, which can lead to anemia. However, clinical data from Phase I published
in New England Journal of Medicine suggests a clean safety profile.