News: Merck's Investigational Rolofylline Associated with Improved …
In a Phase III pilot dose-ranging study of patients hospitalized
with acute heart failure syndrome and renal impairment treatment with
rolofylline, an investigational adenosine A(1) receptor antagonist in
development by Merck & Co., Inc., administered with intravenous (IV)
loop diuretics was associated with improved dyspnea (shortness of
breath) and preserved renal function compared to treatment with
placebo and IV diuretics. In addition, in a post-hoc analysis,
treatment with rolofylline was associated with a trend towards reduced
60-day mortality or hospital readmission for cardiovascular or renal
causes. These results were presented today as a late-breaking abstract
at the Annual Scientific Session of the American College of
Cardiology.
Rolofylline increases renal blood flow and urine production by
blocking adenosine-mediated vasoconstriction of the afferent
arterioles of the kidneys and inhibiting salt and water reabsorption
by the kidney.
“Preserving kidney function is an important goal for improving the
prognosis of patients with acute heart failure,” said lead
investigator Barry M. Massie, M.D., chief of cardiology, VA Hospital,
San Francisco. “Although current practice guidelines call for
treatment with diuretics, it is well-established that diuretics can be
associated with worsening renal function. We now need to assess in
larger clinical trials whether rolofylline can positively affect acute
symptoms of heart failure and help preserve renal function.”
About the pilot study
The pilot study evaluated 301 patients with acute heart failure
syndrome with elevated BNP (B-type natriuretic peptide) and renal
impairment as defined by estimated creatinine clearance of 20-80
ml/min. tetracycline. Patients were randomized to placebo, 10 mg, 20 mg or 30 mg of
rolofylline (four hour infusion, once daily for three days)
administered with IV loop diuretics. Because of the potential for
adenosine A(1) receptor antagonism to reduce the seizure threshold in
patients already at risk for seizures, high risk patients were
excluded from the study and intermediate risk patients were treated
prophylactically with oral lorazepam (1 mg).
The study was designed to identify the dose and, based on post hoc
analyses of the treatment results and the patient population studied,
refine the inclusion criteria and endpoints for the confirmatory Phase
III studies. The results of the pilot study are limited by the study
size and number of treatment groups and require confirmation in a
larger prospective clinical study.
The study evaluated the proportion of patients in the categories
of treatment failure, treatment success, or no change. Treatment
failure was defined as death, hospital readmission or
physician-determined worsening heart failure or persistent renal
impairment (defined by serum creatinine increases >= 0.3 mg/dL at Day
7 confirmed at Day 14). Treatment success was defined as improvement
in patient-reported dyspnea at 24 and 48 hours and not as a treatment
failure. Re-hospitalization and death rates were recorded at 60 days.
Results with rolofylline
Patients treated with rolofylline 30 mg were more likely to
achieve treatment success compared to patients treated with placebo,
53 percent (39/74) and 37 percent (29/78), respectively, and less
likely to experience treatment failure compared to patients treated
with placebo, 16 percent (12/74) and 28 percent (22/78), respectively.
A similar number of patients in each treatment group were classified
as unchanged; 31 percent (23/74) with rolofylline 30 mg versus 35
percent (27/78) on placebo.
Nearly 60 percent of patients treated with rolofylline 30 mg
reported marked or moderately improved dyspnea at day 2 and day 3,
compared to 41 percent of patients on placebo. Fewer patients on
rolofylline 30 mg had persistent renal impairment compared to patients
on placebo, 8 percent and 18 percent, respectively. Treatment with
rolofylline 30 mg was associated with a trend towards reduced 60-day
mortality or hospital readmission for cardiovascular or renal causes.
In this small pilot study, the rates of adverse events seen across
treatment groups were similar.
The confirmatory Phase III studies with rolofylline 30 mg are
underway. PROTECT 1 and PROTECT 2 studies (known as PROTECT) are
currently enrolling patients in the US, Canada, Europe, Israel and
Russia. Additional information is available on www.clinicaltrials.gov.
About acute heart failure
Acute heart failure (AHF) is the abrupt worsening of heart failure
symptoms. It is the leading cause of hospitalization in patients over
age 65, with over a million hospital discharges annually in the US.
Despite current treatment options, AHF is associated with high
mortality rates in Western countries (US and Europe) and frequent
hospitalizations. AHF is associated with significant renal failure and
renal deterioration which contribute to morbidity and mortality.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical
company dedicated to putting patients first. Established in 1891,
Merck currently discovers, develops, manufacturers and markets
vaccines and medicines to address unmet medical needs. The Company
devotes extensive efforts to increase access to medicines through
far-reaching programs that not only donate Merck medicines but help
deliver them to the people who need them. Merck also publishes
unbiased health information as a not-for-profit service. For more
information, visit www.merck.com.
Forward-Looking Statement
This press release contains “forward-looking statements” as that
term is defined in the Private Securities Litigation Reform Act of
1995. These statements are based on management’s current expectations
and involve risks and uncertainties, which may cause results to differ
materially from those set forth in the statements. The forward-looking
statements may include statements regarding product development,
product potential or financial performance. No forward-looking
statement can be guaranteed and actual results may differ materially
from those projected. Merck undertakes no obligation to publicly
update any forward-looking statement, whether as a result of new
information, future events, or otherwise. Forward-looking statements
in this press release should be evaluated together with the many
uncertainties that affect Merck’s business, particularly those
mentioned in the risk factors and cautionary statements in Item 1A of
Merck’s Form 10-K for the year ended Dec. 31, 2007, and in any risk
factors or cautionary statements contained in the Company’s periodic
reports on Form 10-Q or current reports on Form 8-K, which the Company
incorporates by reference.
