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Safety
Issues Hamper Dual PPAR Agonists
Is Partial Antagonism the Solution? *
By
Allan B. Haberman, Ph.D.
Haberman Associates, The Biopharmaceutical Consortium
September 20, 2006
Glitazars
have elicited high hopes and deep disappointment as
potential new drugs. Also known as peroxisome proliferator-activated
receptor (PPAR) alpha/gamma (PPARα/PPARγ) dual
agonists, glitazars offer potential for the treatment of
diabetes as well as components of its precursor--the
metabolic syndrome. Disappointingly, full PPAR agonists
have been plagued by certain adverse side effects. On the
up side, partial PPAR agonists have the potential to retain
the desired efficacy and beneficial effects of full PPAR
agonists while diminishing their unwanted effects.
Glitazars
are designed to treat both insulin resistance (the
inability of tissues such as muscle and fat to utilize
insulin efficiently for the uptake of glucose) and key
aspects of the dyslipidemia that contributes to the high
risk of cardiovascular disease (CVD) in diabetics. The two
lead compounds in this class were muraglitazar
(Bristol-Myers Squibb’s Pargluva) and tesaglitazar (AstraZeneca’s Galida), both of
which were considered promising. However, as discussed
below, both drugs were discontinued in May 2006.
The
economic boon to these drugs’ developers could have been
substantial. At one time, analysts
at Friedman Billings Ramsey estimated that Pargluva would
have 2008 sales of $950 million. In addition, Morgan Stanley’s
peak sales forecast for Pargluva was $1.4 billion.
Diabetes
is on the rise, making the development of safe and
efficacious drugs to treat it all the more critical. The
prevalence of diabetes among Americans is predicted to
more than double by 2050, according to the Centers for
Disease Control and Prevention (CDC). Last year, 5.62% of
Americans had been diagnosed with some form of diabetes. CDC officials warn
that the prevalence of diabetes in 2050—estimated at
12%—could in fact be even higher if the rate of obesity
among Americans continues to rise.
PPAR
Primer
Table
1: Human PPARs as Targets in the Metabolic Syndrome
|
Receptor
|
Functions
|
Conditions
targeted by agonists
|
|
PPARα
|
Controls lipid metabolism.
|
Atherogenic dyslipidemia
(elevated serum triglycerides and low HDL). Target
of fibrate drugs.
|
|
PPARγ
|
Controls glucose metabolism
and adipocyte differentiation.
|
Insulin resistance in type 2
diabetes. Target of thiazolidinediones.
|
|
PPARδ
|
Appears to control multiple
aspects of the metabolic syndrome.
|
Metabolic syndrome, obesity,
atherosclerosis.
|
Source:
Haberman Associates
PPARγ is the target for the thiazolidinedione (TZD)
insulin-sensitizing antidiabetic drugs pioglitazone
(Takeda/Lilly’s Actos) and rosiglitazone
(GlaxoSmithKline’s Avandia), which are agonists of PPARγ.
Pioglitazone and rosiglitazone achieved combined 2004
global sales of US $3.96 billion shared between Takeda and
Eli Lilly (52%) and GlaxoSmithKline (48%), according
to La Merie Business Intelligence. In 2005, Avandia
achieved worldwide sales of $2.45 billion.
PPARα
is the target of the fibrate drugs, which can decrease
serum triglycerides and moderately increase serum HDL in
patients with metabolic syndrome. However, fibrates are
weak agonists of PPARα,
and high doses are required for effective
treatment. Researchers and companies have therefore been
working on developing potent, specific agonists of PPARα
for treatment of atherogenic dyslipidemia (e.g., Ligand/Lilly’s
LY674, in Phase II clinical trials) as well as the
glitazar class of PPARα/PPARγ
agonists.
PPARδ
is also a target for drug discovery and development.
Preclinical studies in rhesus monkeys suggest that
agonists of PPARδ may increase serum HDL while
lowering fasting blood glucose. (Oliver, Shenk, Snaith et
al. 2001). GlaxoSmithKline’s PPARδ agonist GW501516
is in Phase II clinical trials aimed at raising serum HDL
in patients with atherogenic dyslipidemia.
Table
2 lists major PPAR agonists in development that are
discussed in this article.
Table
2: Selected PPAR Agonists in Development
|
Agent
|
Company
|
Target
|
Stage
|
|
Muraglitazar
(Pargluva)
|
Bristol-Myers
Squibb
|
PPARα/PPARγ
(dual agonist)
|
Preregistration, type 2
diabetes; discontinued, May 2006
|
|
Tesaglitazar (Galida)
|
AstraZeneca
|
PPARα/PPARγ
(dual agonist)
|
Phase III, type 2 diabetes;
discontinued, May 2006
|
|
LY674
|
Ligand/Lilly
|
PPARα
|
Phase II, dyslipidemia
|
|
GW501516
|
GlaxoSmithKline
|
PPARδ
|
Phase II, dyslipidemia
|
|
Metaglidisen
|
Metabolex
|
PPARγ
(partial agonist)
|
Phase II/III, type 2
diabetes
|
|
FK614
|
Astellas
|
PPARγ
(partial agonist)
|
Phase II, type 2 diabetes
|
|
PA-082
|
Roche
|
PPARγ
(partial agonist)
|
Preclinical, type 2 diabetes
|
Source:
Haberman Associates
Muraglitazar
& Tesaglitazar—High Hopes Thwarted by Adverse
Cardiovascular Events
Clinical trials with muraglitazar demonstrated
efficacy, coupled with troubling safety problems.
A
Phase III randomized, controlled clinical trial with 1,159
type 2 diabetics whose blood glucose was inadequately
controlled with metformin compared treatment with
muraglitazar to treatment with pioglitazone, both in
combination with metformin (Kendall, Rubin, Mohideen et
al. 2006). This study showed that muraglitazar plus
metformin gave a significantly greater average improvement
in long-term glycemic control, as measured by reductions
in serum levels of hemoglobin A1c (HbA1c; a
glycosylated form of hemoglobin), than pioglitazone plus
metformin. After 12 weeks of treatment, muraglitazar also
reduced mean plasma triglycerides by 28% as compared to
14% for pioglitazone, and muraglitazar increased mean
plasma HDL by 19% as compared to 14% for pioglitazone. All
these differences were statistically significant.
As
the result of positive clinical trial data for
muraglitazar presented to the US Food and Drug
Administration (FDA) by Bristol-Myers Squibb
(BMS) and Merck (which was BMS’ development partner for
the drug) in support of its New Drug Application, an FDA
Advisory Committee voted 8 to 1 to approve the use of muraglitazar
for controlling blood glucose levels in type 2 diabetics
in September 2005. However, in October of the same year, the FDA issued an
approvable letter for muraglitazar requesting additional
data on the drug’s cardiovascular safety. Two days
later, researchers at the Cleveland Clinic published an
independent analysis of Phase II and Phase III data
(available as publicly disclosed documents on the FDA Web
site), focusing on safety issues, as an advance online
publication in the Journal
of the American Medical Association; it appeared in
print in November 2005. The researchers found that death,
nonfatal myocardial infarction (MI), or stroke occurred in
1.47% of patients treated with muraglitazar as compared to
0.67% of patients in combined control groups (i.e.,
treated with pioglitazone or placebo). With respect
to a more comprehensive composite outcome that included
the incidence of death, nonfatal MI, stroke, congestive
heart failure (CHF), and transient ischemic attack (TIA),
the incidence was 2.11% of muraglitazar-treated patients
as compared to 0.81% for the control groups. These
differences were statistically significant. On the basis
of their analysis, the researchers recommended that
muraglitazar not be approved until a dedicated clinical
trial designed to assess cardiovascular outcomes is
performed (Nissen, Wolski and Topol 2005.)
As
the result of the FDA’s issuance of the approvable
letter, Merck
pulled out of its collaboration with BMS in October 2005.
In May 2006, BMS discontinued muraglitazar, citing that in the amount of time it would take to
complete the trials, better therapies would likely be
available.
Because
of these safety concerns and increased regulatory
scrutiny, AstraZeneca (AZ) in late 2005 delayed its filing
target for its Phase III glitazar, tesaglitazar, until
2007, so that it could conduct additional safety trials.
In May 2006, AZ discontinued development of tesaglitazar.
The company cited higher than expected blood creatinine
levels in patients treated with the drug, which indicates
potential kidney toxicity. Thus, the two glitazars that
were the most advanced in development, muraglitazar and
tesaglitazar, were both discontinued in the same month.
This puts development of other glitazars by such companies
as Lilly, Ligand, Roche, Mitsubishi, and Novartis, as well
as PPAR pan-agonists (i.e., alpha, beta, and gamma
agonists), which are being developed by GlaxoSmithKline and
Plexxicon, under a dark cloud.
Safety
Issues with PPAR Agonists
Throughout
the history of development of PPAR agonists, many of these
agents have been plagued with safety issues. The first TZD
PPARγ agonist for type 2 diabetes to be approved,
troglitazone (Warner-Lambert’s Rezulin), was launched in
the
US
in 1997. It was voluntarily withdrawn in 2000 in response
to reports of serious hepatotoxicity seen in a small number of
patients during the postmarketing period. The currently
approved TZD PPARγ agonists, pioglitazone and
rosiglitazone, do not display this toxicity. Using studies
in cell culture, researchers are attempting to understand
the idiosyncratic hepatotoxicity of troglitazone. For
example, troglitazone was found to cause a greater degree
of perturbation of gene expression in hepatocytes in
several pathways that may be involved in toxicity, as
compared to pioglitazone and rosiglitazone (Vansant,
Pezzoli, Saiz et al. 2006).
However,
treatment with both pioglitazone and rosiglitazone is
associated with peripheral edema in approximately 3–5%
of patients treated with a TZD as a monotherapy, and at a
higher incidence when the TZD is combined with other
antidiabetics (Nesto, Bell, Bonow et al. 2003). CHF is
also seen in approximately 1–2% of patients treated with
both one of the approved TZDs and insulin, but is less
than 1% in patients treated with a TZD as a monotherapy.
Edema and CHF were seen as adverse effects of muraglitazar
treatment as well. High-dose muraglitazar treatment
resulted in large percentages of patients exhibiting
peripheral edema (24.9% and 40.1% for 10- and 20- milligram
doses, respectively); as a result, FDA approval was sought
only for lower doses of the drug (Nissen,
Wolski, and Topol 2005). The pathogenesis of edema
in TZD- or glitazar-treated patients is unknown.
Another
more common adverse effect of pioglitazone and
rosiglitazone is weight gain, which was also seen with the
dual agonist muraglitazar. This weight gain is
dose-dependent, and is more severe with combination
therapy of insulin and a TZD (Nesto, Bell, Bonow et al. 2003). The major cause of this weight gain
is that PPARγ is a transcription factor that is
involved in adipocyte differentiation and enlargement,
including triglyceride loading in adipocytes. The
beneficial insulin-sensitizing effects of PPARγ
agonists are independent of fat storage, however, because
the two activities are controlled by different sets of
coactivators.
Metabolex’s
lead candidate metaglidasen has a different chemical
structure and mechanism of action than the insulin
sensitizers currently on the market. Unlike pioglitazone
and rosiglitazone, metaglidasen
is not a TZD. Whereas drugs from the TZD class are full
agonists of the PPAR-γ receptor, metaglidasen, in
contrast, is a partial agonist of the PPAR-γ receptor
and selectively modifies gene expression needed for
insulin sensitization without activating the genes
responsible for weight gain and edema.
At
the Keystone Symposia Scientific Conference in
Hayward
,
CA
in January 2006, Metabolex announced the results of a
preclinical study of metaglidasen, which indicated that it
is a partial agonist of PPARγ. As with other partial
agonists of nuclear receptors, it recruits coactivators in
a different manner than the full PPARγ
agonist rosiglitazone. This may explain the
observed different pattern of gene expression seen with
metaglidasen as opposed to rosiglitazone. Specifically,
metaglidasen appears to be less active in activating
pathways that result in adipocyte differentiation and
enlargement. In animal models, metaglidasen improved
glycemic control in an equivalent manner to rosiglitazone,
but with less weight gain and less cardiac hypertrophy.
Preclinical studies also indicate that metaglidasen
treatment preserves the function of insulin-producing
pancreatic beta cells. Because beta-cell function is often
lost over time in type 2 diabetics, resulting in the need
for insulin treatment, this is a potential advantage of
metaglidasen if this finding is confirmed in human
clinical trials.
In
vitro studies by researchers from Astellas and Roche also
indicate that their PPARγ partial agonists (FK614 and
PA-082, respectively) activate pathways that ameliorate
insulin resistance without stimulating fat accumulation in
adipocytes (Fujimura, Kimura, Oe et al. 2006;
Burgermeister, Schnoebelen, Flament et al. 2006).
Intriguingly,
in vitro and animal studies indicate that two angiotensin
II receptor blockers (ARBs) approved for the treatment of
hypertension, telmisartan (Abbott/Boehringer Ingelheim’s
Micardis) and irbesartan
(Sanofi-Aventis/BMS’ Avapro) are also partial agonists
of PPARγ (Schupp, Clemenz, Gineste et al. 2005). This
is not a class effect of all ARBs (and is independent of
angiotensin II blocking activity), and telmisartan in
particular appears to function as a PPARγ partial
agonist at pharmacologically relevant concentrations. Both
of these agents have established safety profiles. Because
the metabolic syndrome includes hypertension as well as
insulin resistance, these findings with telmisartan and
irbesartan suggest the potential of developing safe and
effective drugs that treat both aspects of the syndrome.
Studies
with partial agonists of PPARγ suggest that a focus
on partial PPAR agonists may be a way of developing agents
that have the desired efficacy of PPAR agonists without at
least some of their potential adverse effects. However,
development of PPAR agonists remains a challenging
endeavor.
Allan
B. Haberman, Ph.D. is Principal of Haberman
Associates, Wayland,
Massachusetts
.
* This article is based in part on Dr. Haberman’s CHA
Advances report “Emerging
Targets in Diseases with High Unmet Need: Alzheimer’s
Disease, Lung Cancer, Dyslipidemia, Type 2 Diabetes, and
COPD,” published in June 2006 by Cambridge
Healthtech Associates. For more information, contact
Beverly Stone at 781-547-0087.
References
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of glycemic control, triglycerides, and HDL cholesterol
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proliferator-activated receptor activator, in patients
with type 2 diabetes inadequately controlled with
metformin monotherapy: a double-blind, randomized,
pioglitazone-comparative study.” Diabetes Care 29: 1016–1023, 2006.
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Nesto, D Bell, RO Bonow et al. “Thiazolidinedione use,
fluid retention, and congestive heart failure: a consensus
statement from the American Heart Association and the
American Diabetes Association.” Circulation
108: 2941–2948, 2003.
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Nissen, K Wolski, and EJ Topol. “Effect of muraglitazar
on death and major adverse cardiovascular events in
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Copyright
2006, All Rights Reserved. Cambridge Healthtech Institute.
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