Subject:
ALLIANCE'S CLINICAL DEVELOPMENT PLAN FOR Oxygent
Date:
Wed, 27 May 1998 17:12:33 -0700
From:
Gwen Rosenberg <owner-owner@allp.com>
Reply-To:
Gwen Rosenberg <GHR@allp.com>
Dear Alliance NetFriend:
ALLIANCE PHARMACEUTICAL CORP.'S CLINICAL DEVELOPMENT PLAN FOR Oxygent
On May 14th, Alliance announced that our agreement with Johnson
& Johnson had been restructured so that Alliance regained control of
the clinical development program for Oxygent (perflubron emulsion),
with Johnson & Johnson retaining an exclusive "first offer" for future
marketing rights. Oxygent is an intravascular oxygen carrier ("blood
substitute") designed to temporarily augment oxygen delivery in
patients at risk of acute tissue oxygen deficit due to either
transient anemia, blood loss, or ischemia (inadequate oxygenation
resulting from blood flow abnormalities). Oxygent is compatible with
all blood types, has a shelf-life of approximately two years, is
sterilized, and is produced in Alliance's commercial-scale
manufacturing facility using a well-defined, efficient, proprietary
process.
The following is a summary of the clinical development status
for Oxygent, including the safety profile and drug activity
demonstrated in several Phase I and Phase II studies involving
approximately 540 subjects, 340 of whom received Oxygent.
CLINICAL SAFETY STUDIES PERFORMED TO DATE
Alliance completed two extensive Phase I clinical (human) safety
studies with the current formulation of Oxygent in 1995. These
studies demonstrated clearly that Oxygent is safe at clinically
relevant doses. As expected, Oxygent had no adverse effects on
hemostasis; platelet function, bleeding times, and coagulation
parameters were all normal. There was no suppression of immune
function; no evidence of any complement activation or immunogenic
reactions; and no abnormal changes in liver, pulmonary, or kidney
function. In addition, there were no clinically meaningful effects on
blood chemistry, and no evidence of the systemic hemodynamic effects
or vasoconstriction that have been reported for various
hemoglobin-based oxygen carriers. Finally, data from these safety
studies were submitted to the FDA prior to initiating Phase II
studies, and were first made public at the IBC Fifth Annual Conference
on Blood Substitutes in October 1995.
CLINICAL EFFICACY STUDIES PERFORMED TO DATE
Two large, multicenter, randomized, controlled, single-blind
studies have been conducted by Alliance and Johnson & Johnson to
determine the -drug activity- of Oxygent (the ability of Oxygent to
transport oxygen and deliver it to the tissues) in well-monitored
surgical patients. These trials, completed in 1997, enrolled a total
of 246 general surgery patients (147 orthopedic patients in the
European study, and 109 urological and gynecological patients in the
U.S. study).
The principal objective was to evaluate the efficacy of Oxygent
as a temporary oxygen carrier compared to a unit of autologous blood
(the patient's own blood, collected just prior to the onset of
surgery) by assessing reversal of -transfusion triggers.- Transfusion
triggers are physiological indicators commonly used by physicians to
determine the need for a blood transfusion. The transfusion triggers
employed in these studies included increases in either heart rate
(tachycardia) or cardiac output, decreases in either mean arterial
pressure (hypotension) or mixed venous PO2 (an index of systemic
oxygenation status), ECG changes indicative of myocardial ischemia,
and a minimum hemoglobin level.
With respect to efficacy, the primary endpoints were achieved in
both studies with statistical significance. Oxygent was found to be
more effective than a unit of fresh autologous blood at reversing
transfusion triggers and at delaying the need for a subsequent blood
transfusion. In the U.S. study, 69% of the triggers were reversed
with Oxygent, versus only 37% with blood (p < 0.01); in the European
study, Oxygent reversed 97% of the triggers, compared to 60% for the
blood-transfused controls (p < 0.01). (The values for the two studies
were different mainly because the studies involved different types of
surgical procedures.) The duration of the Oxygent effect (time to
the next transfusion) was approximately 50% longer than blood in both
studies. Oxygent is the only "blood substitute" that has been shown
to improve indicators of systemic oxygenation using invasive
monitoring in patients.
With respect to safety, the product was well-tolerated by the
patients, and there were no clinically significant effects on
hemodynamic parameters, hematology, or blood chemistry. These
results, presented recently at major U.S. and European Anesthesiology
Society meetings, are now being prepared for full publication.
Alliance and Johnson & Johnson also conducted three Phase IIa
studies with cardiopulmonary bypass patients. These preliminary
studies were designed to assess the use of Oxygent during bypass
procedures regarding reversal of transfusion triggers, avoidance of
allogeneic blood, pharmacokinetics, and long-term neurobehavorial
outcome. As reported at a recent meeting of the American Society of
Cardiovascular Anesthesiologists, data from 35 patients demonstrated
that Oxygent provided a significant overall effect of increased
cerebral blood flow during bypass, which resulted in increased oxygen
delivery to the brain. It was hypothesized by the study investigators
that Oxygent may have a local vasodilatory effect on cerebral
vasculature (may enhance perfusion of the brain). Additional results
from these studies will be presented at future scientific meetings.
DECISION TO PROCEED TO PHASE III
There are numerous potential clinical applications for a
temporary oxygen carrier such as Oxygent, including use during surgery
to reduce the patient's exposure to allogeneic blood (a -transfusion
avoidance- indication), use during bypass surgery to prevent
myocardial ischemia or as a neuroprotectant (to reduce the incidence
of neurological dysfunction associated with the procedure), use as a
therapeutic agent for stroke patients, and use during chemotherapy or
radiation therapy to oxygenate tumors and thereby enhance the
effectiveness of these treatments. Based upon extensive preclinical
studies and the recent Phase II clinical experience, Alliance believes
that transfusion avoidance during surgery is the most appropriate
initial clinical application for Oxygent.
While Alliance appreciates the merit of exploring a variety of
applications for the product in the future, we are firm in our
commitment to start a Phase III trial without undue delay. The use of
Oxygent during surgeries would address a significant medical need -
there are approximately 3.5 million surgical procedures performed
annually in the U.S., and more than seven million worldwide, wherein
one to four units of allogeneic blood are anticipated to be transfused
into the patient.
INITIAL PHASE III TRIAL WITH Oxygent
Alliance's planned Phase III transfusion avoidance trial will
incorporate -acute normovolemic hemodilution- (ANH), the blood
conservation technique that was used in the Phase II studies. ANH
involves removing a portion of the patient's blood immediately before
surgery and replacing the extracted volume with a plasma expander.
The remaining blood is therefore diluted, so that fewer red blood
cells are lost during surgical bleeding. The removed blood is
reinfused as needed throughout the surgery.
Although ANH has been recommended for many years as a simple
method to lessen the need for allogeneic blood, the effectiveness of
this technique is limited unless aggressive hemodilution (collection
of three or more units) is performed. Many physicians are reluctant
to conduct aggressive hemodilution due to concerns that the rapid
removal of several units of blood would reduce the amount of oxygen
available to the tissues, potentially compromising the safety of the
patient. Alliance believes that our patented method for Augmented ANH
(A-ANH), which combines ANH with the use of oxygen-carrying drugs such
as Oxygent, will permit these levels of hemodilution to occur safely.
A-ANH would thereby increase the utility of the hemodilution procedure
as an effective means to reduce, and potentially avoid, allogeneic
blood transfusion in many surgical patients.
THE USE OF Oxygent FOR "SAFER, MORE WIDELY AVAILABLE, MORE
COST-EFFECTIVE" AUTOLOGOUS BLOOD CONSERVATION
Alliance believes that the safest blood for patients is
typically their own blood. Autologous blood conservation strategies
have been gaining in popularity as patients and physicians attempt to
avoid the use of allogeneic blood. Approximately ten states,
including California, have passed laws in recent years mandating that
patients be informed about autologous blood methods prior to their
surgeries. Concerns about the risks of allogeneic blood have led to
the use of pre-operative autologous donation and/or autologous blood
salvage techniques in approximately one million surgeries performed in
the U.S. each year, despite the limitations of these methods.
Pre-operative autologous donation (PAD) requires that patients
predonate a few units of their own blood during the four to six weeks
prior to surgery. While PAD is accepted as a standard-of-care for
some surgeries, the amount of blood that can be predonated is often
inadequate to avoid allogeneic transfusions, it is not applicable for
use in urgent surgical situations, it does not eliminate the risk of
clerical error (labeling mistakes, transfusing the wrong unit to the
wrong patient, etc.), it does not eliminate the potential for
bacterial contamination, and, like allogeneic blood, its oxygen
delivery efficiency decreases significantly during storage.
Autologous blood salvage, the recovery of blood lost during
surgery by means of a cell salvage device, is generally not
cost-effective unless at least three units of red blood cells can be
collected and re-transfused. The technique provides salvage of red
cells, but not platelets, white cells, or clotting factors, all of
which are preserved with the A-ANH technique.
Alliance's new A-ANH technology could potentially represent a
safer, more widely available, and more cost-effective autologous blood
conservation strategy than PAD and autologous blood salvage. If our
Phase III trial validates the safety and drug activity demonstrated in
previous studies, A-ANH with Oxygent could become an easily performed,
broadly utilized technique that allows conservation of the patient's
fresh, whole blood while maintaining adequate tissue oxygenation
during the surgical procedure. It is in the patient's best interest
to use as many blood preservation strategies as possible, and Alliance
believes that A-ANH could provide an important new strategy to limit
the patient's exposure to allogeneic blood. If widely utilized, it
could have an additional societal benefit of alleviating the
allogeneic blood shortages that have become commonplace in the U.S.
and other areas of the world.
ALLIANCE'S PLANS FOR PHASE III STUDIES WITH Oxygent
Alliance intends to pursue a Phase III surgical study
incorporating A-ANH in the immediate future. The protocol for this
study is being finalized and is expected to be submitted to the FDA
within the next 60 days. We anticipate that a formal End-of-Phase II
meeting will be held with the FDA shortly thereafter, and, assuming
agreement is reached on the protocol design, a pivotal clinical study
could start this fall.
In addition to the surgical indication, Alliance plans to
continue to investigate the use of Oxygent as a therapeutic drug to
prevent or reduce neurological damage during cardiopulmonary bypass
procedures. Other potential applications for Oxygent are also being
explored.
We will continue to keep you informed about Alliance's progress
with Oxygent and our other products. If you have any questions,
please contact me via telephone at (619) 558-4375, or via fax at (619)
678-4133. If you would like to receive Alliance updates through the
Internet, please send your name and e-mail address to corpcom@allp.com
and indicate if you prefer electronic updates in place of, or in
addition to, the hard copy versions.
Sincerely,
Gwen Rosenberg
Vice President, Corporate Communications
Except for historical information, the matters set forth in this
letter are forward-looking statements that are subject to risks and
uncertainties that could cause actual results to differ materially
from those set forth herein, including the uncertainties associated
with the conduct of preclinical or clinical studies and the timing or
ability to investigate scientific data. Alliance refers you to
cautionary information contained in documents the Company files with
the Securities and Exchange Commission from time to time, including
the last Form 10-K and Form 10-Q, and those risk factors set forth in
the recent registration statement on Form S-3 (Registration Number
333-15905). |
