MDCO » Topics » Cangrelor

These excerpts taken from the MDCO 10-K filed Mar 2, 2009.
Cangrelor
 
Overview
 
We are developing cangrelor, a short-acting injectable antiplatelet agent, to prevent platelet activation and aggregation in the clotting process. Cangrelor is designed to bind directly to the P2Y12 receptor, a receptor that has been implicated in platelet activation. We exclusively licensed cangrelor in December 2003 from AstraZeneca. Under the terms of our agreement with AstraZeneca, we have exclusive license rights to develop, market and sell cangrelor worldwide, excluding Japan, China, Korea, Taiwan and Thailand.
 
We are developing cangrelor for potential use as an intravenous antiplatelet agent in the critical care setting of the cardiac catheterization laboratory. Based on input from our hospital customers in the cardiac catheterization laboratory, we believe that the critical care limitations of current oral therapy, such as clopidogrel, the leading oral P2Y12 receptor antiplatelet agent, which include delayed onset, prolonged effect and unpredictable effect, have created a need for an intravenous platelet inhibitor that acts quickly, is cleared from the bloodstream rapidly and enables rapid recovery of platelet function. We believe that pre-clinical studies and clinical studies of cangrelor to date suggest that cangrelor has these attributes. These clinical studies consist of Phase I and Phase II clinical trials of cangrelor conducted by AstraZeneca prior to licensing this product candidate to us, and a 40-subject clinical trial that we conducted in healthy volunteers to identify a dosing strategy for use of cangrelor. Specifically, these studies suggest that cangrelor may have:
 
  •  an immediate inhibitory effect on platelets;
 
  •  an inhibitory effect on platelet activation and aggregation that is proportional to the dose administered;
 
  •  inhibitory effects that are sustainable through the period of infusion;
 
  •  a plasma half-life of less than five minutes; and
 
  •  platelet function recovery in less than an hour.
 
Medical Need
 
In the cardiac catheterization laboratory, the use of antiplatelet agents that block platelet activation is considered important therapy because several studies of oral platelet inhibitors have demonstrated better patient outcomes when these agents are administered before coronary angioplasty.
 
There is currently no intravenous drug that primarily inhibits platelet activation. One of the leading oral platelet inhibitors is clopidogrel, which, like cangrelor, blocks the adenosine diphosphate receptor and is one of the classes of platelet inhibitors referred to as thienopyridines. Clopidogrel is commonly administered at a high dose by giving patients four to eight oral tablets before the angioplasty procedure. This practice is known as pre-loading. Although clopidogrel pre-loading has been shown to improve ischemic outcomes in coronary angioplasty, there are several safety and convenience issues with the use of this agent in critical care practice:
 
  •  Clopidogrel requires liver metabolism to form the active agent; therefore, the pre-loading dose may require up to six hours to achieve its full effect.
 
  •  There does not appear to be a clear relationship between increased dosage and intended effect that is consistent across different patient groups.
 
  •  The inhibition of platelet function is irreversible, meaning the agent remains bound to receptors for the life of the platelet, which is typically ten days. This may impede patient management and treatment flexibility, as well as increase the potential for bleeding, especially if a patient needs cardiac surgery, which is usually delayed for days awaiting the generation and release of new platelets from the bone marrow.


10


Table of Contents

 
  •  Oral agents are difficult to administer in the critical care setting because they need to be swallowed by patients who may have received light anesthesia. This is especially true when there is a need to swallow multiple tablets in a restricted period of time.
 
Based on input from our hospital customers in the cardiac catheterization laboratory, we believe that the combination of the reduction in ischemic events through platelet inhibition and the critical care limitations of current oral therapy have created a need for an injectable platelet inhibitor that acts quickly and is cleared from the bloodstream rapidly.
 
In the operating room, surgeons have not had an approved agent at their disposal to control thrombosis during surgery by inhibiting platelets. The antiplatelet agents currently approved for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral thienopyridines and aspirin, have not demonstrated feasibility in surgery due to bleeding concerns or the necessity of long infusions. We believe that cangrelor has potential for use in surgery due to its rapid effect in inhibiting platelets and the rapid recovery of platelet function following cessation of administration.
 
Clinical Development
 
We are currently evaluating cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI in two separate Phase III clinical trials. The larger trial, which we refer to as the CHAMPION-PCI trial and for which we commenced enrollment in March 2006, is an approximately 9,000-patient trial designed to evaluate whether use of intravenous cangrelor is superior to the use of eight 75 mg clopidogrel tablets (600 mg) in patients undergoing PCI. The primary composite endpoint of the CHAMPION-PCI trial will measure death, MI, or urgent revascularization at 48 hours after the procedure. Patients in this trial may be treated with other intravenous anticoagulants, such as Angiomax, heparin and GP IIb/IIIa inhibitors, at the investigator’s discretion.
 
The second trial, which we refer to as the CHAMPION-PLATFORM trial and for which we commenced enrollment in October 2006, compares cangrelor to the use of eight 75 mg clopidogrel tablets (600 mg) administered at the end of the procedure in patients undergoing PCI. We currently expect to enroll approximately 6,400 patients in this trial. This trial will measure the composite endpoint of death, MI, or urgent revascularization at 48 hours after the procedure. The FDA has recommended that we use an alternative statistical design for this trial. Implementing the FDA’s recommendation, we have developed an alternative statistical design for this trial to allow potential modifications to the study based on accumulated data at 70% enrollment.
 
There were approximately 8,000 patients enrolled in CHAMPION-PCI and approximately 4,100 patients enrolled in CHAMPION-PLATFORM at the end of 2008. We plan to complete patient enrollment in both trials by the end of the third quarter of 2009. If we complete these trials on a timely basis and the results of these trials are favorable, we anticipate making submissions for marketing approvals in the United States in 2009 and in the European Union and selected markets thereafter.
 
Cangrelor
 
Overview
 
We are developing cangrelor, a short-acting injectable antiplatelet agent, to prevent platelet activation and aggregation in the clotting process. Cangrelor is designed to bind directly to the P2Y12 receptor, a receptor that has been implicated in platelet activation. We exclusively licensed cangrelor in December 2003 from AstraZeneca. Under the terms of our agreement with AstraZeneca, we have exclusive license rights to develop, market and sell cangrelor worldwide, excluding Japan, China, Korea, Taiwan and Thailand.
 
We are developing cangrelor for potential use as an intravenous antiplatelet agent in the critical care setting of the cardiac catheterization laboratory. Based on input from our hospital customers in the cardiac catheterization laboratory, we believe that the critical care limitations of current oral therapy, such as clopidogrel, the leading oral P2Y12 receptor antiplatelet agent, which include delayed onset, prolonged effect and unpredictable effect, have created a need for an intravenous platelet inhibitor that acts quickly, is cleared from the bloodstream rapidly and enables rapid recovery of platelet function. We believe that pre-clinical studies and clinical studies of cangrelor to date suggest that cangrelor has these attributes. These clinical studies consist of Phase I and Phase II clinical trials of cangrelor conducted by AstraZeneca prior to licensing this product candidate to us, and a 40-subject clinical trial that we conducted in healthy volunteers to identify a dosing strategy for use of cangrelor. Specifically, these studies suggest that cangrelor may have:
 
  •  an immediate inhibitory effect on platelets;
 
  •  an inhibitory effect on platelet activation and aggregation that is proportional to the dose administered;
 
  •  inhibitory effects that are sustainable through the period of infusion;
 
  •  a plasma half-life of less than five minutes; and
 
  •  platelet function recovery in less than an hour.
 
Medical Need
 
In the cardiac catheterization laboratory, the use of antiplatelet agents that block platelet activation is considered important therapy because several studies of oral platelet inhibitors have demonstrated better patient outcomes when these agents are administered before coronary angioplasty.
 
There is currently no intravenous drug that primarily inhibits platelet activation. One of the leading oral platelet inhibitors is clopidogrel, which, like cangrelor, blocks the adenosine diphosphate receptor and is one of the classes of platelet inhibitors referred to as thienopyridines. Clopidogrel is commonly administered at a high dose by giving patients four to eight oral tablets before the angioplasty procedure. This practice is known as pre-loading. Although clopidogrel pre-loading has been shown to improve ischemic outcomes in coronary angioplasty, there are several safety and convenience issues with the use of this agent in critical care practice:
 
  •  Clopidogrel requires liver metabolism to form the active agent; therefore, the pre-loading dose may require up to six hours to achieve its full effect.
 
  •  There does not appear to be a clear relationship between increased dosage and intended effect that is consistent across different patient groups.
 
  •  The inhibition of platelet function is irreversible, meaning the agent remains bound to receptors for the life of the platelet, which is typically ten days. This may impede patient management and treatment flexibility, as well as increase the potential for bleeding, especially if a patient needs cardiac surgery, which is usually delayed for days awaiting the generation and release of new platelets from the bone marrow.


10


Table of Contents

 
  •  Oral agents are difficult to administer in the critical care setting because they need to be swallowed by patients who may have received light anesthesia. This is especially true when there is a need to swallow multiple tablets in a restricted period of time.
 
Based on input from our hospital customers in the cardiac catheterization laboratory, we believe that the combination of the reduction in ischemic events through platelet inhibition and the critical care limitations of current oral therapy have created a need for an injectable platelet inhibitor that acts quickly and is cleared from the bloodstream rapidly.
 
In the operating room, surgeons have not had an approved agent at their disposal to control thrombosis during surgery by inhibiting platelets. The antiplatelet agents currently approved for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral thienopyridines and aspirin, have not demonstrated feasibility in surgery due to bleeding concerns or the necessity of long infusions. We believe that cangrelor has potential for use in surgery due to its rapid effect in inhibiting platelets and the rapid recovery of platelet function following cessation of administration.
 
Clinical Development
 
We are currently evaluating cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI in two separate Phase III clinical trials. The larger trial, which we refer to as the CHAMPION-PCI trial and for which we commenced enrollment in March 2006, is an approximately 9,000-patient trial designed to evaluate whether use of intravenous cangrelor is superior to the use of eight 75 mg clopidogrel tablets (600 mg) in patients undergoing PCI. The primary composite endpoint of the CHAMPION-PCI trial will measure death, MI, or urgent revascularization at 48 hours after the procedure. Patients in this trial may be treated with other intravenous anticoagulants, such as Angiomax, heparin and GP IIb/IIIa inhibitors, at the investigator’s discretion.
 
The second trial, which we refer to as the CHAMPION-PLATFORM trial and for which we commenced enrollment in October 2006, compares cangrelor to the use of eight 75 mg clopidogrel tablets (600 mg) administered at the end of the procedure in patients undergoing PCI. We currently expect to enroll approximately 6,400 patients in this trial. This trial will measure the composite endpoint of death, MI, or urgent revascularization at 48 hours after the procedure. The FDA has recommended that we use an alternative statistical design for this trial. Implementing the FDA’s recommendation, we have developed an alternative statistical design for this trial to allow potential modifications to the study based on accumulated data at 70% enrollment.
 
There were approximately 8,000 patients enrolled in CHAMPION-PCI and approximately 4,100 patients enrolled in CHAMPION-PLATFORM at the end of 2008. We plan to complete patient enrollment in both trials by the end of the third quarter of 2009. If we complete these trials on a timely basis and the results of these trials are favorable, we anticipate making submissions for marketing approvals in the United States in 2009 and in the European Union and selected markets thereafter.
 
Cangrelor


 




Overview


 



We are developing cangrelor, a short-acting injectable
antiplatelet agent, to prevent platelet activation and
aggregation in the clotting process. Cangrelor is designed to
bind directly to the P2Y12 receptor, a receptor that has been
implicated in platelet activation. We exclusively licensed
cangrelor in December 2003 from AstraZeneca. Under the terms of
our agreement with AstraZeneca, we have exclusive license rights
to develop, market and sell cangrelor worldwide, excluding
Japan, China, Korea, Taiwan and Thailand.


 



We are developing cangrelor for potential use as an intravenous
antiplatelet agent in the critical care setting of the cardiac
catheterization laboratory. Based on input from our hospital
customers in the cardiac catheterization laboratory, we believe
that the critical care limitations of current oral therapy, such
as clopidogrel, the leading oral P2Y12 receptor antiplatelet
agent, which include delayed onset, prolonged effect and
unpredictable effect, have created a need for an intravenous
platelet inhibitor that acts quickly, is cleared from the
bloodstream rapidly and enables rapid recovery of platelet
function. We believe that pre-clinical studies and clinical
studies of cangrelor to date suggest that cangrelor has these
attributes. These clinical studies consist of Phase I and
Phase II clinical trials of cangrelor conducted by
AstraZeneca prior to licensing this product candidate to us, and
a 40-subject clinical trial that we conducted in healthy
volunteers to identify a dosing strategy for use of cangrelor.
Specifically, these studies suggest that cangrelor may have:


 
























































  • 

an immediate inhibitory effect on platelets;
 
  • 

an inhibitory effect on platelet activation and aggregation that
is proportional to the dose administered;
 
  • 

inhibitory effects that are sustainable through the period of
infusion;
 
  • 

a plasma half-life of less than five minutes; and
 
  • 

platelet function recovery in less than an hour.


 




Medical
Need



 



In the cardiac catheterization laboratory, the use of
antiplatelet agents that block platelet activation is considered
important therapy because several studies of oral platelet
inhibitors have demonstrated better patient outcomes when these
agents are administered before coronary angioplasty.


 



There is currently no intravenous drug that primarily inhibits
platelet activation. One of the leading oral platelet inhibitors
is clopidogrel, which, like cangrelor, blocks the adenosine
diphosphate receptor and is one of the classes of platelet
inhibitors referred to as thienopyridines. Clopidogrel is
commonly administered at a high dose by giving patients four to
eight oral tablets before the angioplasty procedure. This
practice is known as pre-loading. Although clopidogrel
pre-loading has been shown to improve ischemic outcomes in
coronary angioplasty, there are several safety and convenience
issues with the use of this agent in critical care practice:


 




































  • 

Clopidogrel requires liver metabolism to form the active agent;
therefore, the pre-loading dose may require up to six hours to
achieve its full effect.
 
  • 

There does not appear to be a clear relationship between
increased dosage and intended effect that is consistent across
different patient groups.
 
  • 

The inhibition of platelet function is irreversible, meaning the
agent remains bound to receptors for the life of the platelet,
which is typically ten days. This may impede patient management
and treatment flexibility, as well as increase the potential for
bleeding, especially if a patient needs cardiac surgery, which
is usually delayed for days awaiting the generation and release
of new platelets from the bone marrow.





10





Table of Contents





 
















  • 

Oral agents are difficult to administer in the critical care
setting because they need to be swallowed by patients who may
have received light anesthesia. This is especially true when
there is a need to swallow multiple tablets in a restricted
period of time.


 



Based on input from our hospital customers in the cardiac
catheterization laboratory, we believe that the combination of
the reduction in ischemic events through platelet inhibition and
the critical care limitations of current oral therapy have
created a need for an injectable platelet inhibitor that acts
quickly and is cleared from the bloodstream rapidly.


 



In the operating room, surgeons have not had an approved agent
at their disposal to control thrombosis during surgery by
inhibiting platelets. The antiplatelet agents currently approved
for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral
thienopyridines and aspirin, have not demonstrated feasibility
in surgery due to bleeding concerns or the necessity of long
infusions. We believe that cangrelor has potential for use in
surgery due to its rapid effect in inhibiting platelets and the
rapid recovery of platelet function following cessation of
administration.


 




Clinical
Development



 



We are currently evaluating cangrelor’s effectiveness and
safety in preventing ischemic events in patients who require PCI
in two separate Phase III clinical trials. The larger
trial, which we refer to as the CHAMPION-PCI trial and for which
we commenced enrollment in March 2006, is an approximately
9,000-patient
trial designed to evaluate whether use of intravenous cangrelor
is superior to the use of eight 75 mg clopidogrel tablets
(600 mg) in patients undergoing PCI. The primary composite
endpoint of the
CHAMPION-PCI
trial will measure death, MI, or urgent revascularization at
48 hours after the procedure. Patients in this trial may be
treated with other intravenous anticoagulants, such as Angiomax,
heparin and GP IIb/IIIa inhibitors, at the
investigator’s discretion.


 



The second trial, which we refer to as the CHAMPION-PLATFORM
trial and for which we commenced enrollment in October 2006,
compares cangrelor to the use of eight 75 mg clopidogrel
tablets (600 mg) administered at the end of the procedure
in patients undergoing PCI. We currently expect to enroll
approximately 6,400 patients in this trial. This trial will
measure the composite endpoint of death, MI, or urgent
revascularization at 48 hours after the procedure. The FDA
has recommended that we use an alternative statistical design
for this trial. Implementing the FDA’s recommendation, we
have developed an alternative statistical design for this trial
to allow potential modifications to the study based on
accumulated data at 70% enrollment.


 



There were approximately 8,000 patients enrolled in
CHAMPION-PCI and approximately 4,100 patients enrolled in
CHAMPION-PLATFORM at the end of 2008. We plan to complete
patient enrollment in both trials by the end of the third
quarter of 2009. If we complete these trials on a timely basis
and the results of these trials are favorable, we anticipate
making submissions for marketing approvals in the United States
in 2009 and in the European Union and selected markets
thereafter.


 




Cangrelor


 




Overview


 



We are developing cangrelor, a short-acting injectable
antiplatelet agent, to prevent platelet activation and
aggregation in the clotting process. Cangrelor is designed to
bind directly to the P2Y12 receptor, a receptor that has been
implicated in platelet activation. We exclusively licensed
cangrelor in December 2003 from AstraZeneca. Under the terms of
our agreement with AstraZeneca, we have exclusive license rights
to develop, market and sell cangrelor worldwide, excluding
Japan, China, Korea, Taiwan and Thailand.


 



We are developing cangrelor for potential use as an intravenous
antiplatelet agent in the critical care setting of the cardiac
catheterization laboratory. Based on input from our hospital
customers in the cardiac catheterization laboratory, we believe
that the critical care limitations of current oral therapy, such
as clopidogrel, the leading oral P2Y12 receptor antiplatelet
agent, which include delayed onset, prolonged effect and
unpredictable effect, have created a need for an intravenous
platelet inhibitor that acts quickly, is cleared from the
bloodstream rapidly and enables rapid recovery of platelet
function. We believe that pre-clinical studies and clinical
studies of cangrelor to date suggest that cangrelor has these
attributes. These clinical studies consist of Phase I and
Phase II clinical trials of cangrelor conducted by
AstraZeneca prior to licensing this product candidate to us, and
a 40-subject clinical trial that we conducted in healthy
volunteers to identify a dosing strategy for use of cangrelor.
Specifically, these studies suggest that cangrelor may have:


 
























































  • 

an immediate inhibitory effect on platelets;
 
  • 

an inhibitory effect on platelet activation and aggregation that
is proportional to the dose administered;
 
  • 

inhibitory effects that are sustainable through the period of
infusion;
 
  • 

a plasma half-life of less than five minutes; and
 
  • 

platelet function recovery in less than an hour.


 




Medical
Need



 



In the cardiac catheterization laboratory, the use of
antiplatelet agents that block platelet activation is considered
important therapy because several studies of oral platelet
inhibitors have demonstrated better patient outcomes when these
agents are administered before coronary angioplasty.


 



There is currently no intravenous drug that primarily inhibits
platelet activation. One of the leading oral platelet inhibitors
is clopidogrel, which, like cangrelor, blocks the adenosine
diphosphate receptor and is one of the classes of platelet
inhibitors referred to as thienopyridines. Clopidogrel is
commonly administered at a high dose by giving patients four to
eight oral tablets before the angioplasty procedure. This
practice is known as pre-loading. Although clopidogrel
pre-loading has been shown to improve ischemic outcomes in
coronary angioplasty, there are several safety and convenience
issues with the use of this agent in critical care practice:


 




































  • 

Clopidogrel requires liver metabolism to form the active agent;
therefore, the pre-loading dose may require up to six hours to
achieve its full effect.
 
  • 

There does not appear to be a clear relationship between
increased dosage and intended effect that is consistent across
different patient groups.
 
  • 

The inhibition of platelet function is irreversible, meaning the
agent remains bound to receptors for the life of the platelet,
which is typically ten days. This may impede patient management
and treatment flexibility, as well as increase the potential for
bleeding, especially if a patient needs cardiac surgery, which
is usually delayed for days awaiting the generation and release
of new platelets from the bone marrow.





10





Table of Contents





 
















  • 

Oral agents are difficult to administer in the critical care
setting because they need to be swallowed by patients who may
have received light anesthesia. This is especially true when
there is a need to swallow multiple tablets in a restricted
period of time.


 



Based on input from our hospital customers in the cardiac
catheterization laboratory, we believe that the combination of
the reduction in ischemic events through platelet inhibition and
the critical care limitations of current oral therapy have
created a need for an injectable platelet inhibitor that acts
quickly and is cleared from the bloodstream rapidly.


 



In the operating room, surgeons have not had an approved agent
at their disposal to control thrombosis during surgery by
inhibiting platelets. The antiplatelet agents currently approved
for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral
thienopyridines and aspirin, have not demonstrated feasibility
in surgery due to bleeding concerns or the necessity of long
infusions. We believe that cangrelor has potential for use in
surgery due to its rapid effect in inhibiting platelets and the
rapid recovery of platelet function following cessation of
administration.


 




Clinical
Development



 



We are currently evaluating cangrelor’s effectiveness and
safety in preventing ischemic events in patients who require PCI
in two separate Phase III clinical trials. The larger
trial, which we refer to as the CHAMPION-PCI trial and for which
we commenced enrollment in March 2006, is an approximately
9,000-patient
trial designed to evaluate whether use of intravenous cangrelor
is superior to the use of eight 75 mg clopidogrel tablets
(600 mg) in patients undergoing PCI. The primary composite
endpoint of the
CHAMPION-PCI
trial will measure death, MI, or urgent revascularization at
48 hours after the procedure. Patients in this trial may be
treated with other intravenous anticoagulants, such as Angiomax,
heparin and GP IIb/IIIa inhibitors, at the
investigator’s discretion.


 



The second trial, which we refer to as the CHAMPION-PLATFORM
trial and for which we commenced enrollment in October 2006,
compares cangrelor to the use of eight 75 mg clopidogrel
tablets (600 mg) administered at the end of the procedure
in patients undergoing PCI. We currently expect to enroll
approximately 6,400 patients in this trial. This trial will
measure the composite endpoint of death, MI, or urgent
revascularization at 48 hours after the procedure. The FDA
has recommended that we use an alternative statistical design
for this trial. Implementing the FDA’s recommendation, we
have developed an alternative statistical design for this trial
to allow potential modifications to the study based on
accumulated data at 70% enrollment.


 



There were approximately 8,000 patients enrolled in
CHAMPION-PCI and approximately 4,100 patients enrolled in
CHAMPION-PLATFORM at the end of 2008. We plan to complete
patient enrollment in both trials by the end of the third
quarter of 2009. If we complete these trials on a timely basis
and the results of these trials are favorable, we anticipate
making submissions for marketing approvals in the United States
in 2009 and in the European Union and selected markets
thereafter.


 




Cangrelor


 




Overview


 



We are developing cangrelor, a short-acting injectable
antiplatelet agent, to prevent platelet activation and
aggregation in the clotting process. Cangrelor is designed to
bind directly to the P2Y12 receptor, a receptor that has been
implicated in platelet activation. We exclusively licensed
cangrelor in December 2003 from AstraZeneca. Under the terms of
our agreement with AstraZeneca, we have exclusive license rights
to develop, market and sell cangrelor worldwide, excluding
Japan, China, Korea, Taiwan and Thailand.


 



We are developing cangrelor for potential use as an intravenous
antiplatelet agent in the critical care setting of the cardiac
catheterization laboratory. Based on input from our hospital
customers in the cardiac catheterization laboratory, we believe
that the critical care limitations of current oral therapy, such
as clopidogrel, the leading oral P2Y12 receptor antiplatelet
agent, which include delayed onset, prolonged effect and
unpredictable effect, have created a need for an intravenous
platelet inhibitor that acts quickly, is cleared from the
bloodstream rapidly and enables rapid recovery of platelet
function. We believe that pre-clinical studies and clinical
studies of cangrelor to date suggest that cangrelor has these
attributes. These clinical studies consist of Phase I and
Phase II clinical trials of cangrelor conducted by
AstraZeneca prior to licensing this product candidate to us, and
a 40-subject clinical trial that we conducted in healthy
volunteers to identify a dosing strategy for use of cangrelor.
Specifically, these studies suggest that cangrelor may have:


 
























































  • 

an immediate inhibitory effect on platelets;
 
  • 

an inhibitory effect on platelet activation and aggregation that
is proportional to the dose administered;
 
  • 

inhibitory effects that are sustainable through the period of
infusion;
 
  • 

a plasma half-life of less than five minutes; and
 
  • 

platelet function recovery in less than an hour.


 




Medical
Need



 



In the cardiac catheterization laboratory, the use of
antiplatelet agents that block platelet activation is considered
important therapy because several studies of oral platelet
inhibitors have demonstrated better patient outcomes when these
agents are administered before coronary angioplasty.


 



There is currently no intravenous drug that primarily inhibits
platelet activation. One of the leading oral platelet inhibitors
is clopidogrel, which, like cangrelor, blocks the adenosine
diphosphate receptor and is one of the classes of platelet
inhibitors referred to as thienopyridines. Clopidogrel is
commonly administered at a high dose by giving patients four to
eight oral tablets before the angioplasty procedure. This
practice is known as pre-loading. Although clopidogrel
pre-loading has been shown to improve ischemic outcomes in
coronary angioplasty, there are several safety and convenience
issues with the use of this agent in critical care practice:


 




































  • 

Clopidogrel requires liver metabolism to form the active agent;
therefore, the pre-loading dose may require up to six hours to
achieve its full effect.
 
  • 

There does not appear to be a clear relationship between
increased dosage and intended effect that is consistent across
different patient groups.
 
  • 

The inhibition of platelet function is irreversible, meaning the
agent remains bound to receptors for the life of the platelet,
which is typically ten days. This may impede patient management
and treatment flexibility, as well as increase the potential for
bleeding, especially if a patient needs cardiac surgery, which
is usually delayed for days awaiting the generation and release
of new platelets from the bone marrow.





10





Table of Contents





 
















  • 

Oral agents are difficult to administer in the critical care
setting because they need to be swallowed by patients who may
have received light anesthesia. This is especially true when
there is a need to swallow multiple tablets in a restricted
period of time.


 



Based on input from our hospital customers in the cardiac
catheterization laboratory, we believe that the combination of
the reduction in ischemic events through platelet inhibition and
the critical care limitations of current oral therapy have
created a need for an injectable platelet inhibitor that acts
quickly and is cleared from the bloodstream rapidly.


 



In the operating room, surgeons have not had an approved agent
at their disposal to control thrombosis during surgery by
inhibiting platelets. The antiplatelet agents currently approved
for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral
thienopyridines and aspirin, have not demonstrated feasibility
in surgery due to bleeding concerns or the necessity of long
infusions. We believe that cangrelor has potential for use in
surgery due to its rapid effect in inhibiting platelets and the
rapid recovery of platelet function following cessation of
administration.


 




Clinical
Development



 



We are currently evaluating cangrelor’s effectiveness and
safety in preventing ischemic events in patients who require PCI
in two separate Phase III clinical trials. The larger
trial, which we refer to as the CHAMPION-PCI trial and for which
we commenced enrollment in March 2006, is an approximately
9,000-patient
trial designed to evaluate whether use of intravenous cangrelor
is superior to the use of eight 75 mg clopidogrel tablets
(600 mg) in patients undergoing PCI. The primary composite
endpoint of the
CHAMPION-PCI
trial will measure death, MI, or urgent revascularization at
48 hours after the procedure. Patients in this trial may be
treated with other intravenous anticoagulants, such as Angiomax,
heparin and GP IIb/IIIa inhibitors, at the
investigator’s discretion.


 



The second trial, which we refer to as the CHAMPION-PLATFORM
trial and for which we commenced enrollment in October 2006,
compares cangrelor to the use of eight 75 mg clopidogrel
tablets (600 mg) administered at the end of the procedure
in patients undergoing PCI. We currently expect to enroll
approximately 6,400 patients in this trial. This trial will
measure the composite endpoint of death, MI, or urgent
revascularization at 48 hours after the procedure. The FDA
has recommended that we use an alternative statistical design
for this trial. Implementing the FDA’s recommendation, we
have developed an alternative statistical design for this trial
to allow potential modifications to the study based on
accumulated data at 70% enrollment.


 



There were approximately 8,000 patients enrolled in
CHAMPION-PCI and approximately 4,100 patients enrolled in
CHAMPION-PLATFORM at the end of 2008. We plan to complete
patient enrollment in both trials by the end of the third
quarter of 2009. If we complete these trials on a timely basis
and the results of these trials are favorable, we anticipate
making submissions for marketing approvals in the United States
in 2009 and in the European Union and selected markets
thereafter.


 




Cangrelor


 




Overview


 



We are developing cangrelor, a short-acting injectable
antiplatelet agent, to prevent platelet activation and
aggregation in the clotting process. Cangrelor is designed to
bind directly to the P2Y12 receptor, a receptor that has been
implicated in platelet activation. We exclusively licensed
cangrelor in December 2003 from AstraZeneca. Under the terms of
our agreement with AstraZeneca, we have exclusive license rights
to develop, market and sell cangrelor worldwide, excluding
Japan, China, Korea, Taiwan and Thailand.


 



We are developing cangrelor for potential use as an intravenous
antiplatelet agent in the critical care setting of the cardiac
catheterization laboratory. Based on input from our hospital
customers in the cardiac catheterization laboratory, we believe
that the critical care limitations of current oral therapy, such
as clopidogrel, the leading oral P2Y12 receptor antiplatelet
agent, which include delayed onset, prolonged effect and
unpredictable effect, have created a need for an intravenous
platelet inhibitor that acts quickly, is cleared from the
bloodstream rapidly and enables rapid recovery of platelet
function. We believe that pre-clinical studies and clinical
studies of cangrelor to date suggest that cangrelor has these
attributes. These clinical studies consist of Phase I and
Phase II clinical trials of cangrelor conducted by
AstraZeneca prior to licensing this product candidate to us, and
a 40-subject clinical trial that we conducted in healthy
volunteers to identify a dosing strategy for use of cangrelor.
Specifically, these studies suggest that cangrelor may have:


 
























































  • 

an immediate inhibitory effect on platelets;
 
  • 

an inhibitory effect on platelet activation and aggregation that
is proportional to the dose administered;
 
  • 

inhibitory effects that are sustainable through the period of
infusion;
 
  • 

a plasma half-life of less than five minutes; and
 
  • 

platelet function recovery in less than an hour.


 




Medical
Need



 



In the cardiac catheterization laboratory, the use of
antiplatelet agents that block platelet activation is considered
important therapy because several studies of oral platelet
inhibitors have demonstrated better patient outcomes when these
agents are administered before coronary angioplasty.


 



There is currently no intravenous drug that primarily inhibits
platelet activation. One of the leading oral platelet inhibitors
is clopidogrel, which, like cangrelor, blocks the adenosine
diphosphate receptor and is one of the classes of platelet
inhibitors referred to as thienopyridines. Clopidogrel is
commonly administered at a high dose by giving patients four to
eight oral tablets before the angioplasty procedure. This
practice is known as pre-loading. Although clopidogrel
pre-loading has been shown to improve ischemic outcomes in
coronary angioplasty, there are several safety and convenience
issues with the use of this agent in critical care practice:


 




































  • 

Clopidogrel requires liver metabolism to form the active agent;
therefore, the pre-loading dose may require up to six hours to
achieve its full effect.
 
  • 

There does not appear to be a clear relationship between
increased dosage and intended effect that is consistent across
different patient groups.
 
  • 

The inhibition of platelet function is irreversible, meaning the
agent remains bound to receptors for the life of the platelet,
which is typically ten days. This may impede patient management
and treatment flexibility, as well as increase the potential for
bleeding, especially if a patient needs cardiac surgery, which
is usually delayed for days awaiting the generation and release
of new platelets from the bone marrow.





10





Table of Contents





 
















  • 

Oral agents are difficult to administer in the critical care
setting because they need to be swallowed by patients who may
have received light anesthesia. This is especially true when
there is a need to swallow multiple tablets in a restricted
period of time.


 



Based on input from our hospital customers in the cardiac
catheterization laboratory, we believe that the combination of
the reduction in ischemic events through platelet inhibition and
the critical care limitations of current oral therapy have
created a need for an injectable platelet inhibitor that acts
quickly and is cleared from the bloodstream rapidly.


 



In the operating room, surgeons have not had an approved agent
at their disposal to control thrombosis during surgery by
inhibiting platelets. The antiplatelet agents currently approved
for use in coronary angioplasty, GP IIb/IIIa inhibitors, oral
thienopyridines and aspirin, have not demonstrated feasibility
in surgery due to bleeding concerns or the necessity of long
infusions. We believe that cangrelor has potential for use in
surgery due to its rapid effect in inhibiting platelets and the
rapid recovery of platelet function following cessation of
administration.


 




Clinical
Development



 



We are currently evaluating cangrelor’s effectiveness and
safety in preventing ischemic events in patients who require PCI
in two separate Phase III clinical trials. The larger
trial, which we refer to as the CHAMPION-PCI trial and for which
we commenced enrollment in March 2006, is an approximately
9,000-patient
trial designed to evaluate whether use of intravenous cangrelor
is superior to the use of eight 75 mg clopidogrel tablets
(600 mg) in patients undergoing PCI. The primary composite
endpoint of the
CHAMPION-PCI
trial will measure death, MI, or urgent revascularization at
48 hours after the procedure. Patients in this trial may be
treated with other intravenous anticoagulants, such as Angiomax,
heparin and GP IIb/IIIa inhibitors, at the
investigator’s discretion.


 



The second trial, which we refer to as the CHAMPION-PLATFORM
trial and for which we commenced enrollment in October 2006,
compares cangrelor to the use of eight 75 mg clopidogrel
tablets (600 mg) administered at the end of the procedure
in patients undergoing PCI. We currently expect to enroll
approximately 6,400 patients in this trial. This trial will
measure the composite endpoint of death, MI, or urgent
revascularization at 48 hours after the procedure. The FDA
has recommended that we use an alternative statistical design
for this trial. Implementing the FDA’s recommendation, we
have developed an alternative statistical design for this trial
to allow potential modifications to the study based on
accumulated data at 70% enrollment.


 



There were approximately 8,000 patients enrolled in
CHAMPION-PCI and approximately 4,100 patients enrolled in
CHAMPION-PLATFORM at the end of 2008. We plan to complete
patient enrollment in both trials by the end of the third
quarter of 2009. If we complete these trials on a timely basis
and the results of these trials are favorable, we anticipate
making submissions for marketing approvals in the United States
in 2009 and in the European Union and selected markets
thereafter.


 




Cangrelor
 
Prior to our acquisition of cangrelor, AstraZeneca manufactured all cangrelor bulk drug substance. Following our acquisition of cangrelor, we transferred the manufacturing process for bulk drug to Johnson Matthey Pharma Services for scale-up and manufacture for Phase III clinical trial supply. We are currently in the final development stages of the manufacturing process, including performing engineering lots and preparing for GMP validation.


14


Table of Contents

In October 2004, we also entered into an agreement with Baxter Pharmaceutical Solutions LLC, a division of Baxter Healthcare Corporation, and have entered into purchase order arrangements with Ben Venue, pursuant to which Baxter and Ben Venue manufacture all cangrelor finished drug product for all Phase III clinical trials and carry out release testing. We have not entered into an agreement for commercial supply of cangrelor finished drug product, although we believe our contract manufacturers have the capability to manufacture and package cangrelor on a commercial scale appropriate for launch of the drug when and if cangrelor is approved for sale.
 
Cangrelor
 
Prior to our acquisition of cangrelor, AstraZeneca manufactured all cangrelor bulk drug substance. Following our acquisition of cangrelor, we transferred the manufacturing process for bulk drug to Johnson Matthey Pharma Services for scale-up and manufacture for Phase III clinical trial supply. We are currently in the final development stages of the manufacturing process, including performing engineering lots and preparing for GMP validation.


14


Table of Contents

In October 2004, we also entered into an agreement with Baxter Pharmaceutical Solutions LLC, a division of Baxter Healthcare Corporation, and have entered into purchase order arrangements with Ben Venue, pursuant to which Baxter and Ben Venue manufacture all cangrelor finished drug product for all Phase III clinical trials and carry out release testing. We have not entered into an agreement for commercial supply of cangrelor finished drug product, although we believe our contract manufacturers have the capability to manufacture and package cangrelor on a commercial scale appropriate for launch of the drug when and if cangrelor is approved for sale.
 
Cangrelor


 



Prior to our acquisition of cangrelor, AstraZeneca manufactured
all cangrelor bulk drug substance. Following our acquisition of
cangrelor, we transferred the manufacturing process for bulk
drug to Johnson Matthey Pharma Services for
scale-up and
manufacture for Phase III clinical trial supply. We are
currently in the final development stages of the manufacturing
process, including performing engineering lots and preparing for
GMP validation.





14





Table of Contents






In October 2004, we also entered into an agreement with Baxter
Pharmaceutical Solutions LLC, a division of Baxter Healthcare
Corporation, and have entered into purchase order arrangements
with Ben Venue, pursuant to which Baxter and Ben Venue
manufacture all cangrelor finished drug product for all
Phase III clinical trials and carry out release testing. We
have not entered into an agreement for commercial supply of
cangrelor finished drug product, although we believe our
contract manufacturers have the capability to manufacture and
package cangrelor on a commercial scale appropriate for launch
of the drug when and if cangrelor is approved for sale.


 




Cangrelor


 



Prior to our acquisition of cangrelor, AstraZeneca manufactured
all cangrelor bulk drug substance. Following our acquisition of
cangrelor, we transferred the manufacturing process for bulk
drug to Johnson Matthey Pharma Services for
scale-up and
manufacture for Phase III clinical trial supply. We are
currently in the final development stages of the manufacturing
process, including performing engineering lots and preparing for
GMP validation.





14





Table of Contents






In October 2004, we also entered into an agreement with Baxter
Pharmaceutical Solutions LLC, a division of Baxter Healthcare
Corporation, and have entered into purchase order arrangements
with Ben Venue, pursuant to which Baxter and Ben Venue
manufacture all cangrelor finished drug product for all
Phase III clinical trials and carry out release testing. We
have not entered into an agreement for commercial supply of
cangrelor finished drug product, although we believe our
contract manufacturers have the capability to manufacture and
package cangrelor on a commercial scale appropriate for launch
of the drug when and if cangrelor is approved for sale.


 




Cangrelor


 



Prior to our acquisition of cangrelor, AstraZeneca manufactured
all cangrelor bulk drug substance. Following our acquisition of
cangrelor, we transferred the manufacturing process for bulk
drug to Johnson Matthey Pharma Services for
scale-up and
manufacture for Phase III clinical trial supply. We are
currently in the final development stages of the manufacturing
process, including performing engineering lots and preparing for
GMP validation.





14





Table of Contents






In October 2004, we also entered into an agreement with Baxter
Pharmaceutical Solutions LLC, a division of Baxter Healthcare
Corporation, and have entered into purchase order arrangements
with Ben Venue, pursuant to which Baxter and Ben Venue
manufacture all cangrelor finished drug product for all
Phase III clinical trials and carry out release testing. We
have not entered into an agreement for commercial supply of
cangrelor finished drug product, although we believe our
contract manufacturers have the capability to manufacture and
package cangrelor on a commercial scale appropriate for launch
of the drug when and if cangrelor is approved for sale.


 




Cangrelor


 



Prior to our acquisition of cangrelor, AstraZeneca manufactured
all cangrelor bulk drug substance. Following our acquisition of
cangrelor, we transferred the manufacturing process for bulk
drug to Johnson Matthey Pharma Services for
scale-up and
manufacture for Phase III clinical trial supply. We are
currently in the final development stages of the manufacturing
process, including performing engineering lots and preparing for
GMP validation.





14





Table of Contents






In October 2004, we also entered into an agreement with Baxter
Pharmaceutical Solutions LLC, a division of Baxter Healthcare
Corporation, and have entered into purchase order arrangements
with Ben Venue, pursuant to which Baxter and Ben Venue
manufacture all cangrelor finished drug product for all
Phase III clinical trials and carry out release testing. We
have not entered into an agreement for commercial supply of
cangrelor finished drug product, although we believe our
contract manufacturers have the capability to manufacture and
package cangrelor on a commercial scale appropriate for launch
of the drug when and if cangrelor is approved for sale.


 




Cangrelor
 
We expect that cangrelor will compete with oral platelet inhibitors that are used in critical care settings, if approved, such as clopidogrel from Bristol Meyers Squibb/Sanofi Pharmaceuticals Partnership, as well as prasugrel, an anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and elinogrel, an anti-clotting agent, currently being developed by Novartis and Portola.
 
Cangrelor
 
We expect that cangrelor will compete with oral platelet inhibitors that are used in critical care settings, if approved, such as clopidogrel from Bristol Meyers Squibb/Sanofi Pharmaceuticals Partnership, as well as prasugrel, an anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and elinogrel, an anti-clotting agent, currently being developed by Novartis and Portola.
 
Cangrelor


 



We expect that cangrelor will compete with oral platelet
inhibitors that are used in critical care settings, if approved,
such as clopidogrel from Bristol Meyers Squibb/Sanofi
Pharmaceuticals Partnership, as well as prasugrel, an
anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and
elinogrel, an anti-clotting agent, currently being developed by
Novartis and Portola.


 




Cangrelor


 



We expect that cangrelor will compete with oral platelet
inhibitors that are used in critical care settings, if approved,
such as clopidogrel from Bristol Meyers Squibb/Sanofi
Pharmaceuticals Partnership, as well as prasugrel, an
anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and
elinogrel, an anti-clotting agent, currently being developed by
Novartis and Portola.


 




Cangrelor


 



We expect that cangrelor will compete with oral platelet
inhibitors that are used in critical care settings, if approved,
such as clopidogrel from Bristol Meyers Squibb/Sanofi
Pharmaceuticals Partnership, as well as prasugrel, an
anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and
elinogrel, an anti-clotting agent, currently being developed by
Novartis and Portola.


 




Cangrelor


 



We expect that cangrelor will compete with oral platelet
inhibitors that are used in critical care settings, if approved,
such as clopidogrel from Bristol Meyers Squibb/Sanofi
Pharmaceuticals Partnership, as well as prasugrel, an
anti-platelet agent from Eli Lilly and Sankyo Co., Ltd. and
elinogrel, an anti-clotting agent, currently being developed by
Novartis and Portola.


 




Cangrelor
 
Research and development expenditures related to cangrelor increased by approximately $6.1 million in 2008 compared to 2007 as enrollment continued in the two pivotal Phase III clinical trials that we continue to conduct for the evaluation of cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI. Research and development spending associated with our CHAMPION-PCI and CHAMPTION-PLATFORM trials increased during 2008 primarily due to an increase in the number of countries in which we are recruiting patients through contract research organizations for these trials. In March 2006, we commenced enrollment of our CHAMPION-PCI trial, which we designed to evaluate whether use of intravenous cangrelor is superior to use of clopidrogrel tablets in patients undergoing PCI. We commenced enrollment in October 2006 of a second trial, called CHAMPION-PLATFORM, which compares cangrelor plus usual care to placebo plus usual care in patients who require PCI. We currently expect to enroll approximately 9,000 patients in the CHAMPION-PCI trial and 6,400 patients in the CHAMPION-PLATFORM trial.
 
As of December 31, 2008, we had enrolled approximately 8,000 patients in our CHAMPION-PCI trial and approximately 4,100 patients in our CHAMPION-PLATFORM trial. We expect to complete patient enrollment in both trials by the end of the third quarter of 2009.
 
If we complete these trials on a timely basis and the results of these trials are favorable, we anticipate making submissions for marketing approvals in the United States in 2009 and in the European Union and selected markets thereafter.
 
Cangrelor
 
Research and development expenditures related to cangrelor increased by approximately $6.1 million in 2008 compared to 2007 as enrollment continued in the two pivotal Phase III clinical trials that we continue to conduct for the evaluation of cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI. Research and development spending associated with our CHAMPION-PCI and CHAMPTION-PLATFORM trials increased during 2008 primarily due to an increase in the number of countries in which we are recruiting patients through contract research organizations for these trials. In March 2006, we commenced enrollment of our CHAMPION-PCI trial, which we designed to evaluate whether use of intravenous cangrelor is superior to use of clopidrogrel tablets in patients undergoing PCI. We commenced enrollment in October 2006 of a second trial, called CHAMPION-PLATFORM, which compares cangrelor plus usual care to placebo plus usual care in patients who require PCI. We currently expect to enroll approximately 9,000 patients in the CHAMPION-PCI trial and 6,400 patients in the CHAMPION-PLATFORM trial.
 
As of December 31, 2008, we had enrolled approximately 8,000 patients in our CHAMPION-PCI trial and approximately 4,100 patients in our CHAMPION-PLATFORM trial. We expect to complete patient enrollment in both trials by the end of the third quarter of 2009.
 
If we complete these trials on a timely basis and the results of these trials are favorable, we anticipate making submissions for marketing approvals in the United States in 2009 and in the European Union and selected markets thereafter.
 
Cangrelor


 



Research and development expenditures related to cangrelor
increased by approximately $6.1 million in 2008 compared to
2007 as enrollment continued in the two pivotal Phase III
clinical trials that we continue to conduct for the evaluation
of cangrelor’s effectiveness and safety in preventing
ischemic events in patients who require PCI. Research and
development spending associated with our CHAMPION-PCI and
CHAMPTION-PLATFORM trials increased during 2008 primarily due to
an increase in the number of countries in which we are
recruiting patients through contract research organizations for
these trials. In March 2006, we commenced enrollment of our
CHAMPION-PCI trial, which we designed to evaluate whether use of
intravenous cangrelor is superior to use of clopidrogrel tablets
in patients undergoing PCI. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM, which compares
cangrelor plus usual care to placebo plus usual care in patients
who require PCI. We currently expect to enroll approximately
9,000 patients in the CHAMPION-PCI trial and
6,400 patients in the CHAMPION-PLATFORM trial.


 



As of December 31, 2008, we had enrolled approximately
8,000 patients in our CHAMPION-PCI trial and approximately
4,100 patients in our CHAMPION-PLATFORM trial. We expect to
complete patient enrollment in both trials by the end of the
third quarter of 2009.


 



If we complete these trials on a timely basis and the results of
these trials are favorable, we anticipate making submissions for
marketing approvals in the United States in 2009 and in the
European Union and selected markets thereafter.


 




Cangrelor


 



Research and development expenditures related to cangrelor
increased by approximately $6.1 million in 2008 compared to
2007 as enrollment continued in the two pivotal Phase III
clinical trials that we continue to conduct for the evaluation
of cangrelor’s effectiveness and safety in preventing
ischemic events in patients who require PCI. Research and
development spending associated with our CHAMPION-PCI and
CHAMPTION-PLATFORM trials increased during 2008 primarily due to
an increase in the number of countries in which we are
recruiting patients through contract research organizations for
these trials. In March 2006, we commenced enrollment of our
CHAMPION-PCI trial, which we designed to evaluate whether use of
intravenous cangrelor is superior to use of clopidrogrel tablets
in patients undergoing PCI. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM, which compares
cangrelor plus usual care to placebo plus usual care in patients
who require PCI. We currently expect to enroll approximately
9,000 patients in the CHAMPION-PCI trial and
6,400 patients in the CHAMPION-PLATFORM trial.


 



As of December 31, 2008, we had enrolled approximately
8,000 patients in our CHAMPION-PCI trial and approximately
4,100 patients in our CHAMPION-PLATFORM trial. We expect to
complete patient enrollment in both trials by the end of the
third quarter of 2009.


 



If we complete these trials on a timely basis and the results of
these trials are favorable, we anticipate making submissions for
marketing approvals in the United States in 2009 and in the
European Union and selected markets thereafter.


 




Cangrelor


 



Research and development expenditures related to cangrelor
increased by approximately $6.1 million in 2008 compared to
2007 as enrollment continued in the two pivotal Phase III
clinical trials that we continue to conduct for the evaluation
of cangrelor’s effectiveness and safety in preventing
ischemic events in patients who require PCI. Research and
development spending associated with our CHAMPION-PCI and
CHAMPTION-PLATFORM trials increased during 2008 primarily due to
an increase in the number of countries in which we are
recruiting patients through contract research organizations for
these trials. In March 2006, we commenced enrollment of our
CHAMPION-PCI trial, which we designed to evaluate whether use of
intravenous cangrelor is superior to use of clopidrogrel tablets
in patients undergoing PCI. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM, which compares
cangrelor plus usual care to placebo plus usual care in patients
who require PCI. We currently expect to enroll approximately
9,000 patients in the CHAMPION-PCI trial and
6,400 patients in the CHAMPION-PLATFORM trial.


 



As of December 31, 2008, we had enrolled approximately
8,000 patients in our CHAMPION-PCI trial and approximately
4,100 patients in our CHAMPION-PLATFORM trial. We expect to
complete patient enrollment in both trials by the end of the
third quarter of 2009.


 



If we complete these trials on a timely basis and the results of
these trials are favorable, we anticipate making submissions for
marketing approvals in the United States in 2009 and in the
European Union and selected markets thereafter.


 




Cangrelor


 



Research and development expenditures related to cangrelor
increased by approximately $6.1 million in 2008 compared to
2007 as enrollment continued in the two pivotal Phase III
clinical trials that we continue to conduct for the evaluation
of cangrelor’s effectiveness and safety in preventing
ischemic events in patients who require PCI. Research and
development spending associated with our CHAMPION-PCI and
CHAMPTION-PLATFORM trials increased during 2008 primarily due to
an increase in the number of countries in which we are
recruiting patients through contract research organizations for
these trials. In March 2006, we commenced enrollment of our
CHAMPION-PCI trial, which we designed to evaluate whether use of
intravenous cangrelor is superior to use of clopidrogrel tablets
in patients undergoing PCI. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM, which compares
cangrelor plus usual care to placebo plus usual care in patients
who require PCI. We currently expect to enroll approximately
9,000 patients in the CHAMPION-PCI trial and
6,400 patients in the CHAMPION-PLATFORM trial.


 



As of December 31, 2008, we had enrolled approximately
8,000 patients in our CHAMPION-PCI trial and approximately
4,100 patients in our CHAMPION-PLATFORM trial. We expect to
complete patient enrollment in both trials by the end of the
third quarter of 2009.


 



If we complete these trials on a timely basis and the results of
these trials are favorable, we anticipate making submissions for
marketing approvals in the United States in 2009 and in the
European Union and selected markets thereafter.


 




Cangrelor
 
We are developing cangrelor for potential use as an antiplatelet agent in the critical care settings of the cardiac catheterization laboratory, the operating room and/or the emergency department. Research and development expenditures related to cangrelor increased in 2007 compared to 2006 as a result of the two pivotal Phase III clinical trials that we continue to conduct for the evaluation of cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI. In March 2006, we commenced enrollment of our CHAMPION-PCI trial. We commenced enrollment in October 2006 of a second trial, called CHAMPION-PLATFORM.
 
We enrolled approximately 3,000 and 2,000 patients in our CHAMPION-PCI trial during 2007 and 2006, respectively. We enrolled approximately 1,650 and 150 patients in our CHAMPION-PLATFORM trial during 2007 and 2006, respectively.
 
Cangrelor
 
We are developing cangrelor for potential use as an antiplatelet agent in the critical care settings of the cardiac catheterization laboratory, the operating room and/or the emergency department. Research and development expenditures related to cangrelor increased in 2007 compared to 2006 as a result of the two pivotal Phase III clinical trials that we continue to conduct for the evaluation of cangrelor’s effectiveness and safety in preventing ischemic events in patients who require PCI. In March 2006, we commenced enrollment of our CHAMPION-PCI trial. We commenced enrollment in October 2006 of a second trial, called CHAMPION-PLATFORM.
 
We enrolled approximately 3,000 and 2,000 patients in our CHAMPION-PCI trial during 2007 and 2006, respectively. We enrolled approximately 1,650 and 150 patients in our CHAMPION-PLATFORM trial during 2007 and 2006, respectively.
 
Cangrelor


 



We are developing cangrelor for potential use as an antiplatelet
agent in the critical care settings of the cardiac
catheterization laboratory, the operating room
and/or the
emergency department. Research and development expenditures
related to cangrelor increased in 2007 compared to 2006 as a
result of the two pivotal Phase III clinical trials that we
continue to conduct for the evaluation of cangrelor’s
effectiveness and safety in preventing ischemic events in
patients who require PCI. In March 2006, we commenced enrollment
of our CHAMPION-PCI trial. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM.


 



We enrolled approximately 3,000 and 2,000 patients in our
CHAMPION-PCI trial during 2007 and 2006, respectively. We
enrolled approximately 1,650 and 150 patients in our
CHAMPION-PLATFORM trial during 2007 and 2006, respectively.


 




Cangrelor


 



We are developing cangrelor for potential use as an antiplatelet
agent in the critical care settings of the cardiac
catheterization laboratory, the operating room
and/or the
emergency department. Research and development expenditures
related to cangrelor increased in 2007 compared to 2006 as a
result of the two pivotal Phase III clinical trials that we
continue to conduct for the evaluation of cangrelor’s
effectiveness and safety in preventing ischemic events in
patients who require PCI. In March 2006, we commenced enrollment
of our CHAMPION-PCI trial. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM.


 



We enrolled approximately 3,000 and 2,000 patients in our
CHAMPION-PCI trial during 2007 and 2006, respectively. We
enrolled approximately 1,650 and 150 patients in our
CHAMPION-PLATFORM trial during 2007 and 2006, respectively.


 




Cangrelor


 



We are developing cangrelor for potential use as an antiplatelet
agent in the critical care settings of the cardiac
catheterization laboratory, the operating room
and/or the
emergency department. Research and development expenditures
related to cangrelor increased in 2007 compared to 2006 as a
result of the two pivotal Phase III clinical trials that we
continue to conduct for the evaluation of cangrelor’s
effectiveness and safety in preventing ischemic events in
patients who require PCI. In March 2006, we commenced enrollment
of our CHAMPION-PCI trial. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM.


 



We enrolled approximately 3,000 and 2,000 patients in our
CHAMPION-PCI trial during 2007 and 2006, respectively. We
enrolled approximately 1,650 and 150 patients in our
CHAMPION-PLATFORM trial during 2007 and 2006, respectively.


 




Cangrelor


 



We are developing cangrelor for potential use as an antiplatelet
agent in the critical care settings of the cardiac
catheterization laboratory, the operating room
and/or the
emergency department. Research and development expenditures
related to cangrelor increased in 2007 compared to 2006 as a
result of the two pivotal Phase III clinical trials that we
continue to conduct for the evaluation of cangrelor’s
effectiveness and safety in preventing ischemic events in
patients who require PCI. In March 2006, we commenced enrollment
of our CHAMPION-PCI trial. We commenced enrollment in October
2006 of a second trial, called CHAMPION-PLATFORM.


 



We enrolled approximately 3,000 and 2,000 patients in our
CHAMPION-PCI trial during 2007 and 2006, respectively. We
enrolled approximately 1,650 and 150 patients in our
CHAMPION-PLATFORM trial during 2007 and 2006, respectively.


 




Cangrelor
 
In December 2003, the Company acquired from AstraZeneca AB exclusive license rights to cangrelor for all countries other than Japan, China, Korea, Taiwan and Thailand. Under the terms of the agreement, the Company has the rights to the patents, trademarks, inventories and know-how related to cangrelor. In exchange for the license, in January 2004, the Company paid an upfront payment upon entering into the license and agreed to make additional payments upon reaching certain regulatory milestones. Under the terms of the license agreement, the Company will be obligated to pay royalties on a country-by-country basis on future annual sales of cangrelor, and on any sublicense royalties earned, until the later of (1) the duration of the licensed patent rights which are necessary to manufacture, use or sell cangrelor in a country or (2) ten years from the Company’s first commercial sale of cangrelor in such country. The licenses and rights under the agreement remain in force on a country-by-country basis until the Company ceases selling cangrelor in such country or the agreement is otherwise terminated. The Company may terminate the agreement upon 30 days


F-36


Table of Contents

 
THE MEDICINES COMPANY
 
NOTES TO CONSOLIDATED FINANCIAL STATEMENTS — (Continued)
 
written notice, unless AstraZeneca, within 20 days of having received the Company’s notice, requests that the Company enter into good faith discussions to redress its concerns. If the Company cannot reach a mutually agreeable solution with AstraZeneca within three months of the commencement of such discussions, the Company may then terminate the agreement upon 90 days written notice. Either party may terminate the agreement for material breach upon 60 days prior written notice, if the breach is not cured within such 60 days.
 
15.   Strategic Alliances
 
Cangrelor
 
In December 2003, the Company acquired from AstraZeneca AB exclusive license rights to cangrelor for all countries other than Japan, China, Korea, Taiwan and Thailand. Under the terms of the agreement, the Company has the rights to the patents, trademarks, inventories and know-how related to cangrelor. In exchange for the license, in January 2004, the Company paid an upfront payment upon entering into the license and agreed to make additional payments upon reaching certain regulatory milestones. Under the terms of the license agreement, the Company will be obligated to pay royalties on a country-by-country basis on future annual sales of cangrelor, and on any sublicense royalties earned, until the later of (1) the duration of the licensed patent rights which are necessary to manufacture, use or sell cangrelor in a country or (2) ten years from the Company’s first commercial sale of cangrelor in such country. The licenses and rights under the agreement remain in force on a country-by-country basis until the Company ceases selling cangrelor in such country or the agreement is otherwise terminated. The Company may terminate the agreement upon 30 days


F-36


Table of Contents

 
THE MEDICINES COMPANY
 
NOTES TO CONSOLIDATED FINANCIAL STATEMENTS — (Continued)
 
written notice, unless AstraZeneca, within 20 days of having received the Company’s notice, requests that the Company enter into good faith discussions to redress its concerns. If the Company cannot reach a mutually agreeable solution with AstraZeneca within three months of the commencement of such discussions, the Company may then terminate the agreement upon 90 days written notice. Either party may terminate the agreement for material breach upon 60 days prior written notice, if the breach is not cured within such 60 days.
 
15.   Strategic Alliances
 
Cangrelor


 



In December 2003, the Company acquired from AstraZeneca AB
exclusive license rights to cangrelor for all countries other
than Japan, China, Korea, Taiwan and Thailand. Under the terms
of the agreement, the Company has the rights to the patents,
trademarks, inventories and know-how related to cangrelor. In
exchange for the license, in January 2004, the Company paid an
upfront payment upon entering into the license and agreed to
make additional payments upon reaching certain regulatory
milestones. Under the terms of the license agreement, the
Company will be obligated to pay royalties on a
country-by-country
basis on future annual sales of cangrelor, and on any sublicense
royalties earned, until the later of (1) the duration of
the licensed patent rights which are necessary to manufacture,
use or sell cangrelor in a country or (2) ten years from
the Company’s first commercial sale of cangrelor in such
country. The licenses and rights under the agreement remain in
force on a
country-by-country
basis until the Company ceases selling cangrelor in such country
or the agreement is otherwise terminated. The Company may
terminate the agreement upon 30 days





F-36





Table of Contents





 




THE
MEDICINES COMPANY




 




NOTES TO
CONSOLIDATED FINANCIAL
STATEMENTS — (Continued)


 



written notice, unless AstraZeneca, within 20 days of
having received the Company’s notice, requests that the
Company enter into good faith discussions to redress its
concerns. If the Company cannot reach a mutually agreeable
solution with AstraZeneca within three months of the
commencement of such discussions, the Company may then terminate
the agreement upon 90 days written notice. Either party may
terminate the agreement for material breach upon 60 days
prior written notice, if the breach is not cured within such
60 days.


 















15.  

Strategic
Alliances



 




Cangrelor


 



In December 2003, the Company acquired from AstraZeneca AB
exclusive license rights to cangrelor for all countries other
than Japan, China, Korea, Taiwan and Thailand. Under the terms
of the agreement, the Company has the rights to the patents,
trademarks, inventories and know-how related to cangrelor. In
exchange for the license, in January 2004, the Company paid an
upfront payment upon entering into the license and agreed to
make additional payments upon reaching certain regulatory
milestones. Under the terms of the license agreement, the
Company will be obligated to pay royalties on a
country-by-country
basis on future annual sales of cangrelor, and on any sublicense
royalties earned, until the later of (1) the duration of
the licensed patent rights which are necessary to manufacture,
use or sell cangrelor in a country or (2) ten years from
the Company’s first commercial sale of cangrelor in such
country. The licenses and rights under the agreement remain in
force on a
country-by-country
basis until the Company ceases selling cangrelor in such country
or the agreement is otherwise terminated. The Company may
terminate the agreement upon 30 days





F-36





Table of Contents





 




THE
MEDICINES COMPANY




 




NOTES TO
CONSOLIDATED FINANCIAL
STATEMENTS — (Continued)


 



written notice, unless AstraZeneca, within 20 days of
having received the Company’s notice, requests that the
Company enter into good faith discussions to redress its
concerns. If the Company cannot reach a mutually agreeable
solution with AstraZeneca within three months of the
commencement of such discussions, the Company may then terminate
the agreement upon 90 days written notice. Either party may
terminate the agreement for material breach upon 60 days
prior written notice, if the breach is not cured within such
60 days.


 















15.  

Strategic
Alliances



 




Cangrelor


 



In December 2003, the Company acquired from AstraZeneca AB
exclusive license rights to cangrelor for all countries other
than Japan, China, Korea, Taiwan and Thailand. Under the terms
of the agreement, the Company has the rights to the patents,
trademarks, inventories and know-how related to cangrelor. In
exchange for the license, in January 2004, the Company paid an
upfront payment upon entering into the license and agreed to
make additional payments upon reaching certain regulatory
milestones. Under the terms of the license agreement, the
Company will be obligated to pay royalties on a
country-by-country
basis on future annual sales of cangrelor, and on any sublicense
royalties earned, until the later of (1) the duration of
the licensed patent rights which are necessary to manufacture,
use or sell cangrelor in a country or (2) ten years from
the Company’s first commercial sale of cangrelor in such
country. The licenses and rights under the agreement remain in
force on a
country-by-country
basis until the Company ceases selling cangrelor in such country
or the agreement is otherwise terminated. The Company may
terminate the agreement upon 30 days





F-36





Table of Contents





 




THE
MEDICINES COMPANY




 




NOTES TO
CONSOLIDATED FINANCIAL
STATEMENTS — (Continued)


 



written notice, unless AstraZeneca, within 20 days of
having received the Company’s notice, requests that the
Company enter into good faith discussions to redress its
concerns. If the Company cannot reach a mutually agreeable
solution with AstraZeneca within three months of the
commencement of such discussions, the Company may then terminate
the agreement upon 90 days written notice. Either party may
terminate the agreement for material breach upon 60 days
prior written notice, if the breach is not cured within such
60 days.


 















15.  

Strategic
Alliances



 




Cangrelor


 



In December 2003, the Company acquired from AstraZeneca AB
exclusive license rights to cangrelor for all countries other
than Japan, China, Korea, Taiwan and Thailand. Under the terms
of the agreement, the Company has the rights to the patents,
trademarks, inventories and know-how related to cangrelor. In
exchange for the license, in January 2004, the Company paid an
upfront payment upon entering into the license and agreed to
make additional payments upon reaching certain regulatory
milestones. Under the terms of the license agreement, the
Company will be obligated to pay royalties on a
country-by-country
basis on future annual sales of cangrelor, and on any sublicense
royalties earned, until the later of (1) the duration of
the licensed patent rights which are necessary to manufacture,
use or sell cangrelor in a country or (2) ten years from
the Company’s first commercial sale of cangrelor in such
country. The licenses and rights under the agreement remain in
force on a
country-by-country
basis until the Company ceases selling cangrelor in such country
or the agreement is otherwise terminated. The Company may
terminate the agreement upon 30 days





F-36





Table of Contents





 




THE
MEDICINES COMPANY




 




NOTES TO
CONSOLIDATED FINANCIAL
STATEMENTS — (Continued)


 



written notice, unless AstraZeneca, within 20 days of
having received the Company’s notice, requests that the
Company enter into good faith discussions to redress its
concerns. If the Company cannot reach a mutually agreeable
solution with AstraZeneca within three months of the
commencement of such discussions, the Company may then terminate
the agreement upon 90 days written notice. Either party may
terminate the agreement for material breach upon 60 days
prior written notice, if the breach is not cured within such
60 days.


 















15.  

Strategic
Alliances



 




EXCERPTS ON THIS PAGE:

10-K (36 sections)
Mar 2, 2009
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