Ex. 99.3
OXiGENE, Inc.
Conference Call Transcript
Prepared by:
The Transcription Center
12110 N. Pecos Street
Westminster, CO 80234-2076
Moderator: Bjorn Nordenvall
August 20, 2001
11:00 a.m. ET
Operator: Ladies and gentlemen, thank you for standing by. Welcome to the
Oxigene conference call. During the presentation, all
participants will be in a listen-only mode. Afterwards you will
be invited to participate in the question-and-answer session.
At that time if you have a question, you will need to press the
one followed by the four on your pushbutton phone. As a
reminder, this conference is being recorded Monday, August
20th, 2001. I would now like to turn the conference over to Ms.
Tammy Bishop. Please go ahead, ma'am.
Tammy Bishop: Thank you. Good morning. This is Tammy Bishop, Director of
Investor Relations and Corporate Communications at Oxigene.
Thank you for participating in this conference call to discuss
Oxigene's collaboration with Bristol-Myers Squibb in the
development of Combretastatin CA4P. You should have received
your copy of our press release by now, however in the event you
haven't, please contact Kristen Wilson of Oxigene at
617-673-7800 and she will forward a release to you immediately.
For today's call we have Dr. Bjorn Nordenvall, Oxigene's
Chairman and Chief Executive Officer; Fred Driscoll, Oxigene's
President and Chief Financial Officer; and Dai Chaplan,
Oxigene's Chief Scientific Officer and Head of Research and
Development. Also joining us on the call today is Hakan
Mellstedt, Professor from the Karolinska Institute and chairman
of Oxigene's clinical trial advisory board.
Following the update from Dr. Nordenvall and Dr. Chaplan, there
will be a question-and-answer session, but before we start I
would like to remind you that this conference call relates to
clinical trials and our current expectations or forecasts of
future events. These and other forward-looking statements
involve risks and uncertainties that may cause the company's
actual results or outcomes to be materially different from
those anticipated and discussed in this conference call.
Factors that may cause such differences include but are not
limited to those risks and uncertainties associated with the
efficacy of our technology and its efficacy at acceptable
dosage level in humans, the regulatory approval of the
company's proprietary drugs, the ability to raise capital when
needed and on reasonable terms and other risks included in the
company's annual report on Form 10K and in the company's other
filings with the SEC during the past 12 months.
That said, at this time I will turn the call over to Dr. Bjorn
Nordenvall. Please go ahead, Dr. Nordenvall.
Bjorn Nordenvall: Thank you, Tammy. Good morning and thank you for
joining us today for the update of our collaboration with
Bristol-Myers Squibb and the development of Combretastatin A4
product. Hopefully you have had a chance to review this
morning's press release. I would like to first point out that
it is our general policy of Oxigene not to respond to each and
every rumor that appears in the financial and in the investment
community. However, it is our policy to convey accurate
information regarding our ongoing research and business
activities and in doing so we also cover questions raised by
certain rumors.
Therefore, Oxigene is conducting this conference call to keep
interested members of the community informed. First, let me say
without question on behalf of Oxigene that the BMS Phase I
trial of Combretastatin has not failed or been suspended by the
FDA. The trial is ongoing, contrary to rumors and we remain
confident that the trial will produce positive results.
Oxigene has entered into licensing and collaboration agreements
with Bristol-Myers Squibb and under that agreement we are
legally prohibited from specifically speaking about various
events and the progress of the trials. That was mandated by BMS
and we understand it's part of their general policy which is
quite understandable for a company of that size. However, we
would like to review our collaboration with Bristol-Myers.
Bristol-Myers has agreed to a level of discussion included in
today's press release. We want to give the information to the
extent we can do so within the legal confines of our agreement.
Before doing so, I want to remind you, that, prior thereto,
Oxigene had conducted its own initial Phase I trials in the
U.S. and in the U.K. We have reported on the U.K. results and
expect our final report on the U.S. result to be released this
year. We have released certain preliminary interim results
regarding our trials to date and we believe this information is
quite encouraging.
In March of this year, 2001, BMS began coordinating a Phase I
safety trial of Combretastatin at sites in the U.S. This trial
is currently open to patients with certain types of solid
tumors. Patients in this Phase I trial are receiving
Combretastatin A4 alone with the aim of obtaining the maximum
amount of data to determine the optimal dose and dosing
schedule that will be used in subsequent clinical trials.
We anticipate that enrollment will be complete early next year
and we hope that Phase II trials will commence in the first
half of next year. Because of our agreement with the
Bristol-Myers I cannot comment further regarding specifics of
their Phase I safety trial. I think it may be helpful for us to
remind interested parties that the purpose of Phase I trials
within the drug development industry includes study and
determination of the maximum tolerated dose and the proper
dosing schedule that often adjustments to such dosages are made
within ongoing Phase I safety trials. Dosing is a critical part
of a Phase I trial. You want to make certain that the dose and
dosing schedule you select for your Phase II trial will not be
too high and result in toxicity or too low and result in no
efficacy. This is especially important in a class of new drugs
such as Combretastatin where no previous dosing data exists.
Finally, the Combretastatin trials conducted by Bristol-Myers
have not been halted by the FDA nor have there been any drug
related fatalities. The program is ongoing and both Oxigene and
Bristol-Myers remain fully committed to the development of our
vascular targeting technology. Let me repeat-- prior to
outlicensing the drug to Bristol-Myers Oxigene conducted its
own Phase I studies in Europe and the U.S. involving
approximately 100 patients, the result of which we found to be
highly favorable.
At this time I would like to turn the call over to Dr. Dai
Chaplan, our Head of Research and Development and Chief
Scientific Officer to discuss Oxigene's Phase I results with
you.
Dai Chaplan: Thank you Bjorn. I would like to take a few minutes to explain
vascular targeting. Vascular targeting represents a new
strategy for the treatment of solid tumors. It works by
targeting existing tumor blood vessels that supply critical
nutrients and oxygen to tumor cells with the aim of causing a
rapid and extensive blood flow shutdown of the established
tumor vasculature. A supply of blood is critical to the
development and the continued growth of the tumor cells. If you
cut off the blood supply to the tumor then the effective cells
are compromised and then die. We believe this new type of
approach represents a novel paradigm for the treatment of solid
tumors.
Tubulin binding agents have been used for many years and have
exhibited unique properties. Toxicity can be expected from any
anti-cancer drug and for this reason BMS is conducting a Phase
I safety trial to determine the right dose and the right dosing
schedule for the next phase of clinical development.
Since the biological activity of Combretastatin A4 phosphate
can be monitored by measuring tumor blood flow, much more
information can be gained from Phase I studies about activity
versus toxicity. We believe that comprehensive Phase I
information could improve the design and accelerate the
completion of subsequent trials. At Oxigene we have conducted
three Phase I trials with approximately 100 patients. In one
study, two cardiac events were observed at doses at or above
the maximum tolerated dose. No serious cardiac events were
observed in our other two trials. In all our Phase I trials we
have shown we can demonstrate a reduction of blood flow to
cancerous tumors at doses that were well tolerated with limited
side effects.
In other words, if cardiac events would determine the maximum
tolerated dose, we want to make it clear that CA4P exhibits
tumor blood flow reduction at levels below the dosage at which
any serious cardiac events were observed. And indeed, at those
lower doses there were only limited, very tolerable side
effects.
I will now turn the call back over to Dr. Nordenvall.
B. Nordenvall: Thank you, Dr. Chaplin. In closing, I would like to add that
Oxigene remains at the forefront of this new and exciting
technology and we believe we are several years ahead of other
competitors in this new field. Both Astra Zeneca and Aventis
have announced the initiation of vascular targeting programs
and we view this as a clear confirmation and validation of the
importance and potential of vascular targeting agents. Three of
the leading pharmaceutical companies in the cardio sector are
now actively pursuing vascular targeting. However we believe
Oxigene and Bristol-Myers Squibb are in the lead position with
Combretastatin and we believe this validates vascular targeting
will be an important new approach for the treatment of cancer.
I will now turn the call over to the operator who will open the
call for questions.
Operator: Thank you. Ladies and gentlemen, if you want to register a
question for today's question-and-answer session you will need
to press the one followed by the four on your pushbutton phone.
You will hear a three-tone prompt acknowledging your request.
If your question has been answered or you would like to
withdraw your polling request, you may do so by pressing the
one followed by the three. And if you are using a speakerphone,
please pick up your handset before entering your request. One
moment please for the first question.
[Questioner #1] please go ahead with your questions.
[Questioner #1]: Gentlemen, thanks for clarifying some of these issues. I
wish this conversation had taken place maybe-- at least six
months ago. However this is a good start. If I understand your
interpretation then, Bristol-Myers -- and I'm saying this as a
layman-- Bristol-Myers looked at your Phase I data and decided
that the issue of toxicity maybe hadn't been dealt with quite
in the way they would have liked. So they are doing their own
Phase I trial with a focus on toxicity because as you say, this
is a new type of drug and there's no road map to go by.
My first question is-- would that be a correct summary?
B. Nordenvall: So the first question is why is Bristol-Myers doing their Phase
I trial now since we also have done Phase I trials. I would
like-- Dai, could you answer this?
D. Chaplan: Yes. I mean I think the points you've made-- it's true. I mean
this is vascular targeting and Bjorn made the point, the fact
that this area is now a major focus of the number one, number
two and number three in oncology. Ourselves with BMS, Astra
Zeneca and Aventis. In a new area clearly you want to
understand what the toxicities are.
The other interesting point about this area is the fact that we
can, unlike many other treatments, monitor the effectiveness of
the therapy in Phase I in terms of its biological effectiveness
in terms of shutting down tumor blood flow. So one can actually
achieve a lot of information, both on activity and toxicity, in
a Phase I study without going to a Phase II study.
So you cannot only learn about the toxicities of a new class of
agent, you can also look at the biological effectiveness in the
Phase I. With other agents where you can't measure biological
effectiveness you have to move more rapidly to a Phase II study
which may take more time. We believe that understanding the
activity, toxicity of these drugs in the Phase I as it is going
on will enable us to design and speed up the development in
subsequent clinical trials.
Hakan Mellstedt is also on the line. He may want to comment as
well.
Hakan Mellstedt: Yes, I want, yes, to comment with regard to these
new types of agents. I mean look at traditional-- we have
chemo-therapeutics agents which have required a different mode
of action and the way you monitor toxicity is different from
the way we have to monitor toxicity. These new agents,
especially vascular targeting drug. And therefore Bristol-Myers
Squibb wanted to enlarge the battery of techniques applied to
study cardiac toxicity which has not previously been so in
detail and they followed mostly what was applied for chemo-
therapeutic drugs.
So we get much information by applying a large battery of tests
as well as-- I mean here is a unique situation where we can
apply biological effect which normally you can't do in
chemotherapy. You have to just look for tumor shrinkage and
that is not used as a measurement in Phase II. But here we-- in
Phase II, only in Phase II study with chemo-therapeutic. So I
think here it's a much better situation. But it takes a much
longer time to go forward monitoring all these kinds of effects
because their treatment rate cannot be so fast as
chemo-therapeutic agents and you have to evaluate patient by
patient more carefully. And maybe also you have to be more
careful in selecting the patients which you recruit to these
types of studies.
[Questioner #1]: OK. Thank you, gentlemen. May I ask a related follow on
question?
B. Nordenvall: Yes.
[Questioner #1]: The other frustration frankly has been the delay because
your agreement with Bristol-Myers dates to December of 1999 and
we now learn finally that Bristol-Myers is recruiting patients
beginning in March of this year. So some 15 months it seems to
me has been lost. And you state that you still think you are
the leader-- you have the lead in the clinical research on
these vascular targeting agents but I guess my question is what
on earth was going on during this 15-month delay which as you
well know from previous conversations we've had was enormously
frustrating to all Oxigene shareholders.
B. Nordenvall: OK. I could sort out the question. And when we did the
licensing deal with Bristol-Myers in December of `99 we were in
the midst of our own Phase I trials. And the reason why we were
able to get such a good deal with Bristol-Myers and the
excitement from the industry, also other oncology companies,
was the fact that we now could demonstrate that we could shut
down the blood flow with Combretastatin in doses that were
tolerable for the patients.
Since then we have completed our Phase I trials and we have
recently completed them in the U.K., reported those results at
ASCO and now also in the U.S. And of course Bristol-Myers has
worked with us closely to complete our own Phase I trials since
December of `99. Now they announced end of last year that they
will now start their program which has now started with the
first patients recruited here in March this year. So they have
been with us since December of `99 and I think that both Dai
and also Hakan Mellstedt are trying to explain why
Bristol-Myers is doing it the way they are doing it and we can
only say that we are happy with the collaboration and we have
worked closely with Bristol-Myers since December of `99.
Dai, will you further comment a little bit about additional
information regarding this issue and also we have been
claiming-- we are claiming today too that we are a world leader
in vascular targeting and can you comment here about the
situation with us versus our two competitors, Astra Zeneca and
Aventis, where we are and where they are, and where we are
together with Bristol-Myers ?
D. Chaplan: I think I can. I think that-- I'd like to make the point first
of all that vascular targeting is becoming a very hot
scientific topic in terms of drug development and I can't think
of another drug development at the moment, one specific area,
where we have all the major competitors working on this area.
And clearly we've been in the area as you say a long time. When
you develop a new drug for a new area there's lots of things to
learn, there's lots of ways as Hakan Mellstedt said about doing
and how you monitor patients, how you understand the toxicity
versus activity profile. We know a lot about that information.
Our competitors are starting to get onto that ladder and learn
about these drugs.
Clearly earlier this year Astra Zeneca announced they were
going into Phase I clinical study with their tubulin binding
vascular targeting drug and their Phase I study started in the
first half of this year. Approximately three weeks ago Aventis
announced that they were putting their vascular targeting
tubulin binding agent into clinical trials before the end of
this year. So clearly we are ahead of the game. We have a
knowledge base on how these drugs work, how to monitor the
drugs and are building up how to take them into subsequent
trials. So clearly we are ahead of the game. We have
competitors. Clearly we've moved into the field but we're still
ahead of the game and we have a very large database now in the
clinic of how these drugs work and how they can best be used in
subsequent trials.
[Questioner #1]: Good. Thank you.
Operator: [Questioner #2], please go ahead with your questions.
[Questioner #2]: Thanks for clarifying a couple of issues. Just a few more
questions. You used quite specific language and said the trial
is not suspended pending FDA review but there are other reasons
for trials to stop recruitment. Is the trial actually accepting
new patients right now?
B. Nordenvall: Would you answer?
Fred Driscoll: Yes. [Questioner #2], this is Fred. We have been in contact
with as Bjorn stated in the conference call that BMS has
supported what we've said in our press release and we are
actively from what we have been told by them-- they are
recruiting patients into their multiple sites in the U.S.
[Questioner #2]: Can you comment-- I mean obviously the rumors that have
triggered this call-- I think we all know what they are. I
think the one allegation was that the trial of the
Massachusetts General Hospital had stopped due to a minor
cardiac infarction or event of some sort. Can you comment
specifically on the trial of that center?
F. Driscoll: Unfortunately, based upon our agreement with BMS we just can't
provide that information to you. Let me say this-- you know,
when you speak with people outside of the company you may be
getting less than complete and accurate information thereby,
people forming their own conclusions. However, as I said
earlier, we would stress that Oxigene and BMS have publicly
stated in the press release from this morning that these trials
are open to patients and ongoing in these multiple centers.
[Questioner #2]: OK. And then you had talked about, you know, that it's
normal in a Phase I for dosing, for the dose to be readjusted,
especially when you're starting with a new mechanism of action
that hasn't been studied before. That leads to a sort of
inference that there may be some readjustments due to some sort
of adverse affect. Is that a fair inference?
F. Driscoll: No. I mean if what you're suggesting is why is BMS doing what
they're doing, again, we can't and won't comment on the conduct
of their clinical trials. These are their clinical trials and I
don't think we can really make reference to what they're doing
with respect to the dosing other than what we've already said
and what Dai and Hakan have said in this conference call.
D. Chaplin: Maybe I can add to that, Fred. I think that what we've stated
in our Phase I trials, that we've seen two cardiac events in
the treatment of nearly 100 patients. Some of those patients
have received many doses of Combretastatin so clearly when you
look at the instance of cardiac effects per dose it's a lot
less than even the 2 percent that we've reported in our trials
from our studies. But we also note that we've the reported the
U.K. study earlier this year at the ASCO meeting. There were no
cardiac events. The dose limiting toxicities were ataxia and
tumor pain. The cardiac events have been seen in one site, one
study, one dosing schedule and those will be reported at the
NCI URTC meeting in Miami at the end of October.
So I think that one has to take this in the context that many
drugs, many emerging drugs and many drugs already in the
marketplace, do have some cardiac effects. One can indicate
some anti-cancer drugs like 5FU and one could indicate
biological agents like the interleukins which have higher
cardiac incidence effects.
So I think one has to look at it in the sense that this is
something which is not surprising in any drug development.
Every drug has a toxicity profile and we're learning about
vascular targeting agents and what profile they have and the
importance of not only dose but dose scheduling.
H. Mellstedt: Yes. I can just also add that I have been developing drugs in
cancer therapy now since the beginning of `70s and we always
see cardiac side effects in various kind of drugs. So for me
it's not amazing at all. I remember that we had a lot of
cardiac toxic effects of interferon when we started to develop
that at the end of the `70s and we learned how to handle them
and we learned which patients should not be included in that
kind of treatment schedule. And now-- I mean interferon is
widely used and nobody thinks about it as a cardiotoxic drug.
We know the limitations.
[Questioner #2]: OK. Well, let me ask this. Has Bristol-Myers in any way had to
radically change it's dosing or its approach to dosing during
its Phase I since it started in March in response to any event,
serious or mild or whatever it may be?
B. Nordenvall: Well, as we have said now, we cannot specifically comment on
results from Bristol-Myers' ongoing trial, either positive or
negative. And what we are allowed to say, and that is exactly
what we are doing today, also in the press release, confirmed
by Bristol-Myers , is that this trial is ongoing. It is
expected to be completed here at the beginning of next year.
And the reason for them to conduct this trial I think has been
very well explained by both Dai Chaplan and Hakan Mellstedt and
also shows that Bristol-Myers understands this technology and
they have worked with us now since December of `99. They also
understand Combretastatin. And for us I think it's positive to
have a partner who understands the technology and the drug and
to-- and they are doing this development according to the
industry standards and carefully trying now to determine the
right dose. And this is exactly what they have been doing now
since March of this year.
[Questioner #2]: I guess the key thing is for you to say for the record that
there have been no adverse events reported to the FDA?
B. Nordenvall: Fred?
F. Driscoll: Again, I'm not going to go there, [Questioner #2]. I can't make
comment on what BMS has done. We have-- I can tell you this--
we have not received from Bristol-Myers any form of a halt
notice or any form of a stopping of the trials. That would have
been obviously a serious material adverse affect which under
Reg FD we would have been forced to disclose. We did not
disclose that. I think that's the position on that.
[Questioner #2]: Ok [inaudible] that BMS has not informed you.
F. Driscoll: I think, [Questioner #2], I've answered the question.
[Questioner #2]: Lastly BMS in terms of recruitment BMS started enrolling
in March. Is 9-10 months reasonable time for enrollment in a
Phase I trial [inaudible] 100 patients. Would you say that's
reasonable for a Phase I trial that number of patients?
B. Nordenvall: Could you repeat the question?
[Questioner #2]: [inaudible] Is that reasonable for a Phase I trial? [inaudible]
D. Chaplin: It depends-- you know, it clearly depends on how a Phase I
trial is constructed and as Hakan Mellstedt said, clearly if
you go into more complex measurements of biological effect in a
Phase I versus other kinds of toxicity monitoring, then clearly
recruitment is somewhat slower than you would anticipate in a
normal Phase I trial because you're accruing a lot more
information which can then be subsequently used in the design
of subsequent studies. So it's not unreasonable. I think that
we anticipate this trial will be completed in the early part of
next year. [crosstalk]
H. Mellstedt: I think that this time is reasonable because this type of Phase
I study which is not as other Phase I studies in cancer drug
development. So this should take longer time and what is an
advantage of this may be-- I don't know-- they are testing a
different lot of doses during these Phase I studies as they
also can measure the biological effect and in this combining
side effect measurements as well as biological effect you can
during this time period get a very good estimation of an
optimal dose to be dosed in further Phase II studies. So I
think it's fair to use about nearly a year. And I have seen
these kinds of Phase I studies to take for one year so I don't
think it's unusual.
B. Nordenvall: What we can say here is that we have done our Phase I in nearly
100 patients and of course Bristol-Myers have all the data from
these trials and they are using those data carefully now to
help them also in the further development of Combretastatin and
what they are doing now is trying to get some extra information
to be sure that they will dose with the right dose in the next
phase of clinical development. Not too high and not too low.
And the way they are conducting these trials is very very
complicated with respect to the fact that the equipment is very
sophisticated and the selection criteria is also very critical
here and it's also very critical to have the right patients
here for getting the right answers. Remember, this is still
early in development and the next big step for this development
will start when Bristol-Myers has completed what they have just
now announced together with us that they are doing right now,
meaning this trial that started in March. And it's expected to
be completed here early next year.
[Questioner #2]: OK. Thanks for clearing up some things.
Operator: [Questioner #3], private investor, please go ahead with your
questions.
[Questioner #3]: Hi. I have a question for Dai Chaplan. Looking ahead-- we've
heard about the next generation of VTAs or vascular targeting
agents. Do you have any comments on this?
D. Chaplan: Well, our program for developmening the next generation of
vascular targeting agents has been very active with both our
own program with Baylor and with BMS. I think I can say that
these programs are looking very promising and we hope to come
out with more information later this year. We anticipate our
first presentation on our second generation compounds will take
place at the NCI URTC meeting at the end of October.
[Questioner #3]: I have one follow up question. This might be repetitive but if
BMS has full responsibility for CA4P, what is Oxigene currently
working on?
B. Nordenvall: OK. What are we working on. Dai, will you take that as our head
of research and development? What are we doing?
D. Chaplan: I think that we're aware that we've retained the rights to use
CA4P for local administration. We're actively pursuing the use
of Combretastatin A4 phosphate in ocular diseases. One of those
is diabetic retinopathy. We're also in discussions with a
European stent firm for the use of Combretastatin A4 on stents
in restinosis and basically as I've just mentioned we've also
got our own BTA program developing other small molecules and
also the antibody vascular targeting approach with Peregrine in
Arcus. All of these programs, I think we can say quite
confidently, are on track and look very promising. We'll report
more data later this year.
B. Nordenvall: OK. Thank you, Dai. Any more questions?
Operator: Yes, [Questioner #4], a private investor, please go ahead with
your questions.
[Questioner #4]: Thank you very much. First I want to thank you for having
a conference call, not just issuing a press release. It's very
helpful as a private investor. I'd also like to thank
[Questioner #2] for his specific questions. My question is in
your discussions with BMS have they indicated any interest or
willingness to issue any releases or any follow ups? And the
second question is do you know when they expect to report their
results from Phase I and in what form will they be reporting
it?
F. Driscoll: Thanks for the question. It's Fred. As I think we said a little
bit earlier, BMS is-- let me first say, has been involved in
this press release and has given us their approval to go
forward with it. However, as a big pharmaceutical firm I think
it's their general policy as well as other large companies like
them not to directly participate in calls like these. So I hope
that answers your question on that one-- the first part of your
question.
Could you repeat the second part of it?
[Questioner #4]: Yes, sure. Thanks very much. The second question was do
you know when they expect to report the results of Phase I and
in what form they would be doing that? I know it's to be
completed in January but do you know when they might be
reporting any results in an appropriate professional forum from
the Phase I?
B. Nordenvall: Dai, would you comment on this?
D. Chaplan: Yeah. I mean that will be at their discretion, when to report
the Phase I. And clearly the only thing that will be apparent
from our point of view unless BMS go and report it is the
appearance of milestones as the drug passes through a variety
of clinical steps. I would anticipate that once a study is
completed they would present the data later, the middle to the
end of next year. But that again is not under our control.
That's up to just general policy within a large pharmaceutical
company. But I imagine, particularly if you have a study which
is unique with an agent which is, if you like, pushing forward
in a whole new approach to cancer therapy, they would be
eventually as keen as us to get their science out and presented
next year. But again, we have no control over that's. That's up
to Bristol-Myers Squibb.
[Questioner #4]: Thank you. And once again, I want to thank you for having
a conference call to forthrightly address these concerns and
rumors.
D. Chaplan: You're welcome. Thank you.
B. Nordenvall: Any more questions?
Operator: Yes. [Questioner #5], please go ahead with your questions.
[Questioner #5]: Thank you. I guess this question is for Dr. Chaplan. You
mentioned two cardiac events that had been observed and I sort
of missed the part that came after that. Were the events
associated with a higher than normal dosage of CA4P?
D. Chaplan: They were seen in one of the sites with one of the dosing
schedules-- they were seen at or above where we anticipate the
maximum tolerated dose based on other side effects. The U.K.
study was reported at the ASCO meeting with no cardiac events
reported. Dose limiting toxicities were reported as ataxia and
neurological effects and also tumor pain. The other study
that's taken place in Philadelphia has reported no cardiac
events. The full details of those cardiac events will be
reported at the meeting, the NCI URTC meeting in October. But
again, they were seen at high doses. Yes, you were right in
that.
[Questioner #5]: Thank you.
Operator: [Questioner #6] please go ahead with your questions.
[Questioner #6]: I wonder and I've wondered for quite some time-- what is
so different with Combretastatin as compared to other tubulin
targeting agents? I mean first of all you target tubulin and
not vasculature. So the first experiments on Combretastatin
were actually done on tumor sets and not endothelial cells. So
you target tubulin and mitosis and not vasculature. So why do
you introduce a new name into something that already has a
name? Mitosis inhibiting agents or tubulin inhibiting agents.
The Combretastatin targets tubulin and mitosis, not
vasculature. Or could you provide any other explanation?
B. Nordenvall: [Question #6] I think we have the best person on the call to
answer that question and that is the man behind the technology,
Dai Chaplan.
D. Chaplan: I will try not to go into-- I mean I hopefully will answer your
question in a fairly straightforward way. I think your point is
well made. Tubulin binding agents are well known compounds
inhibiting cell division. The reason Combretastatin affects
vasculature and doesn't have the side effects associated with
inhibiting the division of rapidly proliferating tissues, and
we've not seen any of those toxicities in terms of
gastrointestinal affects on the proliferation of white blood
cells, et cetera, is the reason that Combretastatin is a
reversible binder into tubulin. That is, it gets onto tubulin,
[unintelligible] it for a short period of time.
That means it doesn't affect the long term processes of cell
division. But what it does do and what we know from our own
work is that tubulin, as well as being important in cell
division is important in maintaining the shape of the cells
which line blood vessels. And if you-- endothelial cells, the
cells which line blood vessels when they're very new-- tubulin
is critically important in keeping them flat. If you disrupted
the cells round up you can get coagulation, you can get
blockage of vessels.
Now, the fact that it's reversible means that it goes on,
causes its effects on the vasculature but doesn't cause the
long term effects on cell division. The effects on their
vasculature are essentially irreversible so even though the
drug comes off, you've [unintelligible] catastrophic effects on
the tumor, newly formed tumor vasculature. Also, the drug has a
very short plasma half life which means it doesn't have the
cytotoxic profile of other tubulin binding agents.
That is why we believe, not only we-- now the top three big
pharmaceutical companies in the world are working on tubulin
binding vascular damaging agents and it's been a very big
convincing program because everybody wants to work on new
molecular targets. But now all big three, big pharmaceutical
companies, are convinced-- we've convinced them
[unintelligible] with our work that tubulin binding agent, if
you develop reversible ones with certain other parameters have
primarily affects on vasculature and are not cytotoxic
molecules.
That's the reason that there's so much interest and you've got
Astra Zeneca, Bristol-Myers Squibb and Aventis all working on
tubulin binding agents. They did all this work on cytotoxic
compounds 30 years ago. Now, they've realized if you develop
the right molecules like we've done you really can get
compounds which selectively damage newly formed vasculature in
the tumor. Hopefully that's addressed some of your questions. I
could take an hour going over that but I don't think it would
be good use of the conference call.
B. Nordenvall: Thank you, Dai. Are there additional questions?
Operator: I am showing no further questions at this time.
B. Nordenvall: OK. Then I would like to take the opportunity to thank you all
for joining this conference call and look forward to continue
to discuss these important development programs with you in the
near future. Thank you very much and bye bye.
Operator: Ladies and gentlemen, that does conclude your conference call
for today. You may all disconnect and thank you for
participating.