A phase 2 study of the novel antiplatelet drug SCH 530348 (Schering-Plough),
suggesting it may be able to reduce ischemic events without increasing bleeding
in patients undergoing elective PCI, has now been published in the March 14,
2009, issue of the Lancet [1].

The study was first presented, and reported by heartwire at the time, at the
American College of Cardiology (ACC) meeting in 2007, where it was greeted with
much excitement over the possibility of a drug that might be able to separate
the benefits of platelet inhibition (reduced ischemic events) from the risks
(increased bleeding).

Lead author Dr Richard Becker (Duke University, Durham, NC) told heartwire that
the Lancet paper contains the same data that were presented at ACC 2007, along
with "quite a lot of additional information."

"For example, at the ACC presentation, we focused on the group of patients who
actually underwent PCI, which is the set of primary interest, but in the paper
we also report on the whole population of patients, including those who received
the bolus dose of the drug but who then did not end up undergoing PCI but were
managed medically (381 patients) or underwent CABG (76 patients) and so would
not have received maintenance doses." He described this as a real-world
population that would receive the drug. He added that in the patients managed
medically, the bolus dose of SCH 530348 was associated with a very low rate of
bleeding and no TIMI major bleeding.

SCH 530348 blocks the protease-activated receptor 1 (PAR-1) on platelets to
which thrombin binds, so the drug inhibits thrombin-induced platelet activation.
Becker explained why this is thought to be able to separate the reduction in
ischemia from the increased bleeding risk seen with other antiplatelet agents.
"The theory is that hemostasis is predominantly platelet mediated, whereas
thrombosis in the coronary artery is mediated by both platelets and thrombin
generation. This drug appears to prevent the ischemic effect of thrombin
generation by preventing thrombin from binding to platelets, whereas it still
allows thrombin to cleave fibrinogen and form fibrin--the final step in
coagulation--and it still allows platelets to aggregate for normal hemostasis.
So we are attempting to uncouple the benefit/risk relationship seen with all
previous antithrombotic drugs."

Note of Caution--Too Early to Know for Sure

While there clearly is much enthusiasm over this new drug, some experts are
being cautious about basing too much on a phase 2 trial. Dr Shamir Mehta
(McMaster University, Hamilton, ON) summed such feeling up: "There is no
question that the mechanism of action of the drug is novel and the initial
results are promising. But remember, this is just a phase 2 study, and we need
to wait for phase 3 trials before making definitive statements with regard to
efficacy or safety. Often, drugs may initially appear to be favorable but fail
to live up to expectations when studied in larger numbers of patients," he
commented to heartwire.

A similar view was voiced by Dr Shaun Goodman (St Michael's Hospital, Toronto,
ON). He commented to heartwire: "This agent does indeed look promising, and,
compared with several other 'antithrombin' therapies we have available at
present, its mechanism of action is novel. However, as with all drugs at this
stage (phase 2, dose finding), it is too early to tell whether its potential
will be realized, and the ongoing phase 3 studies will need to inform us further
about both the efficacy 'signal' and safety. Clearly, this phase 2 study was not
powered to definitively address either of these, but it is encouraging that the
absolute number of major and minor bleeding events (albeit quite low in this
population that included patients undergoing non-urgent PCI) was not different
from that seen in the placebo group (including in the subset of patients went on
to bypass surgery). Since the non-TIMI bleeding rates were consistently
numerically higher (although not statistically significant) in the SCH 530348
groups compared with placebo, I suspect there will ultimately be some increased
risk of bleeding when you add another antithrombin therapy to standard therapy
(eg, aspirin with or without clopidogrel) in this patient population."

Neither Mehta nor Goodman is involved with trials of SCH 530348.

Platelet-Function Tests

Becker noted that the Lancet paper also reported detailed results on
platelet-function testing showing that SCH 530348 achieved 90% inhibition of
PAR-1 at the lowest maintenance dose (0.5 mg), and this increased to 100% at the
two higher maintenance doses. "We decided to go with the highest (2.5-mg)
maintenance dose for the phase 3 studies, because the safety results suggested
this was still not associated with an increase in bleeding, and we wanted to
make sure that the drug was not underdosed in high-risk patients. Our feeling
was that if we can induce 100% inhibition of the receptor, we should do it, so
this hypothesis can be tested properly."

Two phase 3 studies with the drug are now ongoing. These are TRA-CER in ACS
patients, which is being coordinated at Duke and in which SCH 530348 is being
given at the 40-mg bolus dose plus a 2.5-mg maintenance dose, and the
TRA-2P-TIMI-50 study, which is testing just the 2.5-mg maintenance dose in
secondary prevention in patients with prior MI, stroke, or peripheral vascular
disease. These two studies are still recruiting, and results are not expected
for several years.

Becker explained that he envisages that SCH 530348 would need to be given in
addition to aspirin and clopidogrel in patients undergoing PCI and receiving a
new stent, especially for the first few weeks, but in secondary-prevention
patients aspirin plus SCH 530348 may be all that is needed, because there is
less propensity for thrombosis in these patients.

Possible Other Indications

He also pointed out that PAR-1 also occurs on smooth-muscle cells and
inflammatory cells, and it is possible that drugs that inhibit this receptor may
have other benefits, such as stabilizing plaques and reducing in-stent
restenosis. The phase 3 studies under way will include substudies to investigate
these effects--by looking at what the drug is doing to other cell types as well
as platelets. There are several other PAR-1 blockers in development, and they
are being investigated in other areas as well as cardiology. One of these is
oncology, because there is some evidence that PAR-1 may be involved in tumor
growth and metastases.

The current phase 2 study randomized 1030 patients undergoing coronary
angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20
mg, or 40 mg) or matching placebo in a 3:1 ratio. Those in the SCH 530348 group
who subsequently underwent PCI were randomly assigned again to one of three
maintenance doses (0.5 mg, 1.0 mg, or 2.5 mg per day) for 60 days. The patients
assigned to a placebo loading dose remained on placebo during the maintenance
phase. Study drug was given on top of all normal drugs (aspirin, clopidogrel,
and heparin or bivalirudin). The primary end point was the incidence of
clinically significant major or minor bleeding according to the TIMI scale.

Patients who underwent PCI were the primary evaluable cohort. In this group,
there was no significant difference in bleeding rates between any of the SCH
530348 doses and placebo. The authors say: "Although the bleeding rates were low
overall, we cannot exclude a small to moderate increase in bleeding with SCH
530348."

The trial was not powered to specifically test clinical efficacy, but results
showed a trend toward fewer ischemic events in SCH-530348¡Vtreated patients. The
authors add: "The biology around inhibition of thrombin-induced platelet
activation provides a mechanistic basis for differences that might be of
clinical relevance."

They conclude: "Our study provides preliminary evidence for the feasibility and
safety of thrombin-receptor inhibition among patients with coronary artery
disease undergoing PCI."

In an accompanying editorial [2], Drs Alessandro Colombo and Piera Merlini
(Luigi Sacco Hospital and Niguarda Hospital, Milano, Italy) say that the current
study suggests that SCH 530348 is safe, a conclusion strengthened by its being
used with two other antiplatelet agents. They add: "This clinical report of a
new antithrombotic drug developed on the basis of new knowledge about the
coagulation cascade suggests that the drug works. Is the dream of an effective
antithrombotic drug with a low bleeding risk becoming reality? Will this
approach be effective in the acute setting (eg, primary percutaneous coronary
intervention) and even in secondary prevention? Phase 3 trials will determine
whether we are entering a new antithrombotic era."

Becker receives research funding from Schering-Plough. Other coauthors have
received honoraria, research funding, and consulting fees from Schering-Plough
or are employees of Schering-Plough. One author owns stock and stock options in
Schering-Plough.


Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH
530348 in patients undergoing non-urgent percutaneous coronary intervention: a
randomized, double-blind, placebo-controlled phase II study. Lancet 2009;
373:919¡V928.
Colombo A and Merlini P. The ischaemia/bleeding balance in PCI. Lancet 2009;
373:872-873.