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SCHERING-PLOUGH PRESENTS CLINICAL DATA ON CCR5 RECEPTOR ANTAGONIST
AT 9TH CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS
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Following yesterday's oral presentation by a researcher from Schering Plough,
Mark Laughlin, about their entry inhibitor for HIV, Schering issued this
statement which I feel you'd like to read.
Schering-Plough Research Institute today presented preliminary clinical data
on its CCR5 receptor antagonist, a novel therapeutic approach in the
treatment of HIV infection, at the 9th Conference on Retroviruses and
Opportunistic Infections in Seattle. In an oral presentation at the
conference's opening session on new antiretroviral agents, Mark M. Laughlin,
M.D., director, clinical pharmacology, Schering-Plough Research Institute,
presented clinical results showing a direct antiviral effect in patients in
fected with the HIV-1 virus. Schering-Plough Research Institute is the
pharmaceutical research and development arm of Schering-Plough Corporation of
Kenilworth, N.J.
Background on SCH-C
Schering-Plough Research Institute has identified small molecule antagonists
to the CCR5 chemokine receptor. Several classes of molecules have emerged
from high throughput screening efforts and medicinal chemistry optimization
has led to a lead clinical candidate known as SCH-C. This orally available
compound efficiently blocks cell entry of a wide range of primary HIV-1
isolates that use the CCR5 receptor for infection (R5 viruses). An animal
model for HIV infection (SCID-hu Thy/Liv mice) showed a dose-related
reduction in HIV viral load. In an Early Phase single-dose study in healthy
volunteers, SCH-C administered orally at doses ranging from 25 mg to 600 mg
was shown to be well tolerated at all doses. The compound does not inhibit
HIV isolates that gain entry into cells via the CXCR4 receptor (X4 viruses).
Tissue culture studies in vitro and testing in an animal model (HIV-infected
SCID-hu Thy/Liv mice) indicate that there is no apparent viral switch from R5
to X4. The compound demonstrates a favorable drug metabolism and
pharmacokinetic profile, and is synergistic with other antiretrovirals in
vitro.
An ongoing Phase 1b clinical study of SCH-C in HIV-infected patients is
designed to evaluate the compound's safety and tolerability, and to determine
its pharmacokinetic profile. The study also investigates the compound's
potential for antiviral effects.
Results of Ongoing SCH-C Phase-Ib Study Presented at Retrovirus
In the first cohort of the ongoing SCH-C Phase Ib study, 12 adults
chronically infected with HIV-1 currently on no antiretroviral agents and
with CD4+ cell counts above 250/mm3 were administered
25 mg SCH-C as monotherapy orally every 12 hours for 10 days. Results
demonstrated that SCH-C was safe and well tolerated in these patients.
Preliminary analysis of the pharmacokinetic profile of SCH-C was similar to
that seen in an Early Phase study in healthy volunteers, with mean Cmax and
Cmin levels at steady state of approximately 140nM and 90nM, respectively.
Analysis of SCH-C over the 10 days of dosing and during washout show that
there is a short lag time in antiviral effect as well as a prolonged
antiviral effect following cessation of dosing (see figure below). Ten of 12
patients had at least a 0.5 log10 reduction in viral load from baseline
during dosing, with four subjects achieving a 1.0 log10 or greater reduction
in viral load.
Safety and Tolerability
In the first cohort of this study, SCH-C was shown to be safe and well
tolerated. There were no discontinuations of SCH-C due to adverse events,
although 7 of 12 patients reported at least one adverse event. The most
frequently reported adverse event was headache (3/12), which were considered
mild, possibly related to SCH-C and of short duration. Another reported
adverse event was bad taste (2/12), which was considered mild, possibly
related to SCH-C and of long duration. There was one reported severe adverse
event (vasovagal syncope), which was unlikely related to SCH-C. In one
patient, there was one isolated triplet (three premature heart beats)
observed during 10 days of continuous cardiac telemetry monitoring. This
occurred on day 7 of 10 days of dosing, and was possibly related to SCH-C.
Study Design/Patient Demographics
The ongoing SCH-C Phase Ib study in HIV-infected patients is a sequential
rising-dose trial
(12 patients receiving SCH-C per cohort) of SCH-C as monotherapy with daily
doses of 50 mg,
100 mg and 200 mg administered orally every 12 hours for 10 days. Clinical
endpoints of this study are viral kinetics, onset and rebound, safety and
tolerability, and pharmacokinetics.
In this study, HIV-1 RNA levels are determined every 6 hours for 72 hours and
then every 24 hours for the remaining 10 days of dosing. In addition,
periodic HIV-1 RNA levels are determined during follow up. Patients undergo
viral phenotyping prior to dosing, at the end of dosing and at follow up.
Patients with an SI phenotype (syncytium-inducing virus, associated with more
advanced disease) at baseline are excluded from participation.
All patients participating in this study receive SCH-C therapy on an
in-patient basis and undergo
24 hr/day cardiac telemetry to monitor for unexpected or unanticipated
cardiologic effects.
Patient demographics for the first cohort are (mean/range): age 33/25-47;
gender 4 female/8 male;
race 4B/1H/7C; baseline CD4+ count 377/228-586; baseline viral load 38,372
(9,370-157,000); and time from infection 5.3 yrs./2-10 yrs.
Status of Ongoing SCH-C Phase Ib Study
Preliminary clinical results with SCH-C support the CCR5 receptor as a viable
target for antiretroviral therapy. This study is currently enrolling
patients into the second cohort (SCH-C 50 mg BID, n=12). Under the study
protocol, the third cohort (100 mg BID) of this study will not initiate until
after results from the second cohort are analyzed.
SCH-D
Schering-Plough Research Institute has reported that a follow-up CCR5
receptor antagonist known as SCH-D is in preclinical development. This oral
agent has been shown to be more potent than SCH-C against HIV infection in
vitro and has a comparable pharmacokinetic profile. A preclinical toxicology
program with this compound is ongoing. It is anticipated that Phase I
testing of SCH-D in healthy volunteers will be initiated this year.
Background on CCR5 Antagonists
Chemokine receptors expressed on the surface of immune cells are known to
play a critical role in virus infection and transmission. One such chemokine
receptor, CCR5, acts in tandem with another receptor (CD4) to facilitate
entry of HIV into cells. Targeting CCR5 as anti-HIV therapy was initially
suggested by a finding that individuals who lack a functional CCR5 receptor
(i.e., those who have a 32 bp CCR5 mutation) are largely resistant to HIV
infection. Preclinical studies showing that natural ligands and antibodies
to CCR5 can inhibit HIV-1 infection have provided proof-of-principle
validation of the development of CCR5 antagonists as novel antiviral agents.
CCR5 antagonists belong to a new, investigational class of antiretrovirals
known as HIV entry inhibitors. This new class includes various experimental
compounds designed to block cell surface receptors, such as CCR5 or CXCR4, as
well as other novel compounds that block HIV fusion with the cell surface.
Unlike existing HIV drugs that work inside the cell and target viral enzymes
involved in the replication of the virus, entry inhibitors work by blocking
HIV before the virus enters the cell and begins its replication process.
February 25, 2002
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