Myogen Reports Positive Top Line Results for Second Ambrisentan Pivotal Phase 3 Trial in Pulmonary Arterial Hypertension; ARIES
April 10 2006 - 7:00AM
Business Wire
Myogen, Inc. (Nasdaq: MYOG) today announced positive top line
results of the ARIES-1 trial, the second pivotal Phase 3 trial
evaluating ambrisentan, an oral endothelin receptor antagonist
(ERA), in pulmonary arterial hypertension (PAH). The trial met the
primary efficacy endpoint of improved exercise capacity for both
ambrisentan dose groups, with an excellent safety profile and no
observed liver function abnormalities in the ambrisentan treatment
groups. On the basis of the results of ARIES-1 & -2, Myogen
expects to submit the ambrisentan New Drug Application to the U.S.
Food and Drug Administration (FDA) in the fourth quarter of 2006.
The primary efficacy endpoint of the ARIES-1 trial was the
placebo-corrected mean change in six-minute walk distance (6MWD) at
week 12 compared to baseline. Results of the trial demonstrated
that with once-daily dosing, 10 mg of ambrisentan improved the
placebo-corrected mean 6MWD by 51.4 meters (p=0.0001) and 5 mg of
ambrisentan improved the placebo-corrected mean 6MWD by 30.6 meters
(p=0.0084), indicating improved exercise capacity. For the placebo
group, the mean 6MWD at week 12 decreased from baseline by 7.8
meters. Time to clinical worsening did not reach statistical
significance likely due to the relatively low incidence of clinical
worsening events observed in the trial. Other secondary endpoints
had clinically relevant improvements that achieved p values of less
than 0.05 but were not considered statistically significant due to
the pre-specified approach for multiple comparisons. The trial
safety results demonstrated ambrisentan was generally well
tolerated. The most frequent adverse event was peripheral edema. No
patients treated with ambrisentan developed serum aminotransferase
concentrations greater than three times the upper limit of the
normal range at any time during the 12 week treatment period,
compared to two patients in the placebo group, only one of which
was confirmed upon re-test. Ambrisentan had no apparent effect on
the activity or dosing of warfarin-type anticoagulants commonly
co-administered to patients with PAH. The delivery of the ARIES-1
trial results triggers a $5.25 million milestone payment under
Myogen's ambrisentan sublicense agreement with GlaxoSmithKline.
"With two positive, well-controlled studies demonstrating robust
efficacy and a safety database of more than 400 patients on
long-term treatment, we have the foundation for high quality
regulatory submissions worldwide," said Dr. Michael Gerber, Senior
Vice President of Clinical Development and Regulatory Affairs for
Myogen. "Based on the properties of ambrisentan and the clinical
results obtained to date, we believe that, if approved, ambrisentan
has the potential to offer significant advantages over other
endothelin receptor antagonists for the treatment of PAH." In
January 2004, Myogen announced the initiation of two pivotal Phase
3 clinical trials, ARIES-1 and ARIES-2, evaluating the safety and
efficacy of ambrisentan in patients with 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. 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. The primary efficacy endpoint was exercise
capacity, measured as the mean change from baseline at 12 weeks in
the 6MWD compared to placebo. Secondary endpoints include time to
clinical worsening, World Health Organization (WHO) functional
class, SF-36(TM) Health Survey, and Borg dyspnea index. ARIES-1
enrolled 202 patients primarily from the United States while
ARIES-2 enrolled 192 patients primarily from Europe. In addition,
approximately 400 patients continue 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 treated --
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 endothelin receptor antagonist (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 sublicensed 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. The Company believes that
agents that block the detrimental effects of endothelin may provide
significant benefits in the treatment of these conditions.
Conference Call J. William Freytag, President and CEO, and other
members of Myogen's senior management will discuss the ARIES-1 top
line results via webcast and conference call on Monday, April 10,
2006 at 8:30 am Eastern. To access the live webcast, please log on
to the Company's website at www.myogen.com and go to the Investor
Relations section. Alternatively, callers may participate in the
conference call by dialing 800-219-6110 (domestic) or
011-1-303-262-2194 (international). Webcast and telephone replays
of the conference call will be available approximately two hours
after the completion of the call through Friday, April 28, 2006.
Callers can access the replay by dialing 800-405-2236 (domestic) or
011-1-303-590-3000 (international). The passcode is 11058293#.
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 partnership 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 sublicensed ambrisentan from Myogen for all
territories outside of the United States. 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 top line results of
the Company's ARIES-1 clinical trial, summary statements relating
to the results of the Company's Phase 2 trial of ambrisentan in
patients with PAH and the related extension trial, 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. If the
Company's product candidates do not meet safety or efficacy
endpoints in clinical evaluations, they will not receive regulatory
approval and the Company will not be able to market them. Even if
the Company's product candidates meet safety and efficacy
endpoints, regulatory authorities may not approve them, the Company
may not be able to successfully market them, or the Company may
face post-approval problems that require the withdrawal of its
product 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.
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 April 10, 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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