Myogen Reports Results for the Integrated Analysis of ARIES-1 and ARIES-2 Pivotal Trials of Ambrisentan in Pulmonary Arterial H
04 May 2006 - 6:00AM
Business Wire
Myogen, Inc. (Nasdaq: MYOG) today announced results for the
integrated analysis of ARIES-1 and ARIES-2, the pivotal Phase 3
trials evaluating ambrisentan, an oral endothelin receptor
antagonist (ERA), in pulmonary arterial hypertension (PAH). The
integrated analysis was prospectively defined as a supportive
analysis of the ARIES trials' results and was detailed in a data
analysis plan submitted to the U.S. Food and Drug Administration
prior to unblinding the data for either ARIES trial. The primary
efficacy endpoint, placebo-corrected mean change in six-minute walk
distance at week 12 compared to baseline, demonstrated a robust,
dose-dependent increase in exercise capacity with statistical
significance for the combined data for all doses (p less than
0.0001, linear regression model) and for each individual
ambrisentan dose. -0- *T Dose Group Change in 6MWD Nominal p-value
----------------------------------------------------------------------
2.5 mg (n=64) 32.3 meters 0.0219 5 mg (n=130) 44.6 meters less than
0.0001 10 mg (n=67) 51.4 meters 0.0001 *T Improvement in time to
clinical worsening, a key secondary endpoint and measure of disease
progression, was significant for the combined dose analysis (p =
0.0003) and for each of the three individual ambrisentan dose
groups (p less than 0.05 for each group). All other prespecified
secondary efficacy endpoints, including WHO functional class,
SF-36(R) Health Survey and Borg dyspnea index, demonstrated
statistically significant improvements for the combined data for
all dose groups and for the 5 mg and 10 mg doses (p less than 0.05
for each group). Preliminary analysis of the top line safety
results demonstrated that ambrisentan was well tolerated. The most
frequent adverse event was peripheral edema, which was primarily
mild to moderate in severity. No patients treated with ambrisentan
developed serum aminotransferase concentrations greater than
three-times the upper limit of the normal range (3xULN) at any time
during the 12-week treatment period, compared to three patients in
the placebo groups (2.3%). "Since both ARIES trials achieved their
primary efficacy endpoint for all three ambrisentan doses, we
conducted the prespecified analysis of the integrated data
generated by ARIES-1 and ARIES-2 to better understand the dose
response for both the primary and secondary endpoints in these
trials and to generate a more robust measure of the treatment
effect of the 5 mg dose, the common dose in the two trials," said
Dr. J. William Freytag, President and CEO. "The integrated analysis
also enables us to gain a better understanding of the dose-related
incidence of adverse events. This analysis further reinforces our
confidence that ambrisentan has the potential to be a significant
therapeutic advance in the treatment of PAH." The ARIES trials were
randomized, double-blind, placebo-controlled trials of identical
design except for the doses of ambrisentan studied and the
geographic locations of the investigative sites. The trials were
conducted under protocols with identical inclusion and exclusion
criteria. Both trials were designed to enroll 186 patients (62
patients per dose group). ARIES-1 evaluated once-daily doses of 5
mg and 10 mg of ambrisentan. ARIES-2 evaluated once-daily doses of
2.5 mg and 5 mg of ambrisentan. ARIES-1 enrolled 202 patients
primarily in the United States while ARIES-2 enrolled 192 patients
primarily in Europe. Approximately 400 patients are continuing
ambrisentan treatment in long-term trials with maximum exposure of
more than three years. To date, the results of clinical studies
have indicated that ambrisentan may provide some or all of the
following benefits to PAH patients: -- Improvement in exercise
capacity that is significant, early in onset and durable --
Significant improvement in time to clinical worsening -- Low
incidence and severity of liver function test abnormalities at all
doses tested -- Comparable benefit in exercise capacity in patients
with WHO functional class II and class III symptoms -- An apparent
survival benefit when compared with predicted survival based on the
National Institutes of Health Registry formula -- Effectiveness
with once-daily dosing and the potential for dose flexibility --
Potential utility in resuming ERA treatment in patients who have
discontinued treatment with the alternative ERAs, bosentan or
sitaxsentan, or both, due to liver function abnormalities -- No
clinically relevant drug-drug interactions with warfarin-type
anticoagulants or sildenafil, a PDE-5 inhibitor About Pulmonary
Arterial Hypertension PAH is a highly debilitating disease
characterized by severe constriction of the blood vessels in the
lungs leading to very high pulmonary arterial pressures. These high
pressures make it difficult for the heart to pump blood through the
lungs to be oxygenated. Patients with PAH suffer from extreme
shortness of breath as the heart struggles to pump against these
high pressures causing such patients to ultimately die of heart
failure. PAH can occur with no known underlying cause, or it can
occur secondary to diseases such as connective tissue disease,
congenital heart defects, cirrhosis of the liver and HIV infection.
PAH afflicts approximately 200,000 patients worldwide. About
Ambrisentan Ambrisentan is an investigational drug being developed
as a once-daily oral therapy for patients with PAH and has been
granted orphan drug designation for the treatment of PAH in both
the United States and European Union. GlaxoSmithKline licensed
commercial rights for ambrisentan outside of the United States.
Ambrisentan is a non-sulfonamide, propanoic acid-class, type-A
selective endothelin receptor antagonist. Endothelin is a small
peptide hormone that plays a critical role in the control of blood
flow and cell growth. Elevated endothelin blood levels are
associated with several cardiovascular disease conditions,
including pulmonary arterial hypertension, chronic renal disease,
coronary artery disease, hypertension and chronic heart failure.
Myogen believes that agents that block the detrimental effects of
endothelin may provide significant benefits in the treatment of
these conditions. About Myogen Myogen is a biopharmaceutical
company focused on the discovery, development and commercialization
of small molecule therapeutics for the treatment of cardiovascular
disorders. Myogen currently has two product candidates in
late-stage clinical development: ambrisentan for the treatment of
patients with pulmonary arterial hypertension and darusentan for
the treatment of patients with resistant hypertension. Myogen and
GlaxoSmithKline have entered into a global PAH collaboration in
which Myogen has distribution and marketing rights to
GlaxoSmithKline's Flolan (epoprostenol sodium) in the United States
for the treatment of PAH and GlaxoSmithKline has licensed
ambrisentan from Myogen for all territories outside of the United
States, where Myogen retains exclusive rights. Myogen also conducts
a target and drug discovery research program focused on the
development of disease-modifying drugs for the treatment of chronic
heart failure and related cardiovascular disorders. Please visit
Myogen's website at www.myogen.com. About Flolan (epoprostenol
sodium) Flolan was approved by the FDA in 1995 and is indicated for
the long-term intravenous treatment of primary pulmonary
hypertension and pulmonary hypertension associated with the
scleroderma spectrum of disease in NYHA Class III and Class IV
patients who do not respond adequately to conventional therapy. Use
of Flolan is contraindicated in patients with congestive heart
failure due to severe left ventricular systolic dysfunction. Flolan
should not be used in patients who develop pulmonary edema during
dose initiation. Flolan is also contraindicated in patients with
known hypersensitivity to the drug or structurally related
compounds. Flolan should be used only by clinicians experienced in
the diagnosis and treatment of pulmonary hypertension. The
diagnosis of PPH or PH/SSD should be carefully established. Please
consult complete prescribing information for Flolan at www.gsk.com.
Safe Harbor Statement This press release contains forward-looking
statements that involve significant risks and uncertainties,
including summary statements relating to the combined analysis of
the Company's ARIES clinical trials, summary statements relating to
the results of the Company's prior clinical trials of ambrisentan
in patients with PAH and the related extension trials, and summary
statements relating to the potential efficacy and safety profile of
ambrisentan. Actual results could differ materially from those
projected and the Company cautions investors not to place undue
reliance on the forward-looking statements contained in this
release. Top line results may not be confirmed upon full analysis
of the detailed results of a trial and additional information
relating to the safety, efficacy or tolerability of the Company's
product candidates, including ambrisentan, may be discovered upon
further analysis of trial data and upon review and analysis of
additional trial data, including data from the Company's ongoing
extension trials of ambrisentan in patients with PAH. Even though
prospectively defined, analyses that combine the results of
separate trials, including this analysis, may not be accepted by
regulatory agencies. Even though ambrisentan met the defined safety
and efficacy endpoints, regulatory authorities may not approve it
for marketing. If ambrisentan is approved, the Company may not be
able to successfully market it, or the Company may face
post-approval problems that require its withdrawal from the market.
There can be no assurance that Myogen's product candidates,
including ambrisentan, will be proven safe and effective for use in
humans. Abnormal elevations of liver function test results,
including elevated serum aminotransferase concentrations, have been
reported in a Phase 2 trial of ambrisentan and in trials of other
endothelin receptor antagonists. If ambrisentan is approved for
marketing, the market size for PAH and the market acceptance of
ambrisentan to treat PAH is uncertain, and ambrisentan may never be
a profitable product. The Company's results may be affected by its
effectiveness at managing its financial resources, its ability to
successfully develop and market its product candidates, competition
from other biotechnology and pharmaceutical companies, difficulties
or delays in manufacturing its products, and regulatory
developments involving current and future products. Delays in
regulatory approvals or in initiating or conducting clinical
trials, whether caused by regulatory issues, competition, adverse
events, patient enrollment rates or other factors, could adversely
affect the Company's financial position and prospects. If the
Company is unable to raise additional capital when required or on
acceptable terms, it may have to significantly delay, scale back or
discontinue one or more of its drug development or discovery
research programs. Myogen may not ever have any products that
generate significant revenue. Additional risks and uncertainties
relating to the Company and its business can be found in the "Risk
Factors" section of Myogen's Form 10-K for the year ended December
31, 2005, and Myogen's reports on Form 10-Q and Form 8-K. It is
Myogen's policy to only update or reconfirm its public guidance by
issuing a press release or filing a periodic or current report with
the Securities and Exchange Commission. The Company generally plans
to provide guidance as part of its annual and quarterly earnings
releases but reserves the right to provide guidance at different
intervals or to revise its practice in future periods. All
information in this press release is as of May 3, 2006. Myogen
undertakes no duty or obligation to update any forward-looking
statements contained in this release as a result of new
information, future events or changes in the Company's
expectations. The Company also disclaims any duty to comment upon
or correct information that may be contained in reports published
by the investment community.
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