Gone for good.
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From the 2012 Annual report. Maybe another reason to partner with Genentech (Roche)?
https://materials.proxyvote.com/Approved/713661/20120822/AR_140648/
In-Licensing Collaborations
The following discussions cover our collaborations and in-licensing obligations related to our
products in clinical trials:
PS-Targeting Program
During fiscal year 2011, we expensed $114,000 associated with milestone obligations under inlicensing
agreements covering our PS-targeting program, which is included in research and development
expense in the accompanying consolidated statements of operations. We did not incur any milestone related
expenses during fiscal years 2012 and 2010. In addition, no product revenues have been generated from the
PS-targeting program to date. The following represents a summary of our current potential milestone
obligations under our various agreements covering our bavituximab and PGN650 programs:
Bavituximab
In August 2001 and August 2005, we exclusively in-licensed the worldwide rights to the PS-targeting
technology platform from the UT Southwestern Medical Center at Dallas (“UTSWMC”), including
bavituximab. During November 2003, we entered into a non-exclusive license agreement with Genentech,
Inc., to license certain intellectual property rights covering methods and processes for producing antibodies
used in connection with the development of our PS-targeting program. During December 2003, we entered
into an exclusive commercial license agreement with Avanir Pharmaceuticals, Inc., (“Avanir”) covering the
generation of a chimeric monoclonal antibody. In March 2005, we entered into a worldwide non-exclusive
license agreement with Lonza Biologics (“Lonza”) for intellectual property and materials relating to the
expression of recombinant monoclonal antibodies for use in the manufacture of bavituximab.
Under our in-licensing agreements relating to bavituximab, we typically pay an up-front license fee,
annual maintenance fees, and are obligated to pay future milestone payments based on potential clinical
development and regulatory milestones, plus a royalty on net sales and/or a percentage of sublicense income.
The applicable royalty rate under each of the foregoing in-licensing agreements is in the low single digits.
The following table provides certain information with respect to each of our in-licensing agreements relating to our bavituximab program.
(1) Potential future milestone obligations are generally tied to regulatory progress to gain product approval, which approval significantly
depends on positive clinical trials results. In addition, potential future milestone obligations vary by license agreement (as defined in each
license agreement) and depend on valid claims under each of these underlying agreements at the time the potential milestone is achieved,
however, the following clinical development and regulatory milestones are typical of such potential future milestone events: upon dosing
of first patient in a Phase I, Phase II, and/or Phase III clinical trial; completion of patient enrollment in a phase II trial; submission of a
biologics license application in the U.S.; and upon FDA approval.
(2) Expiration date of the license agreement occurs upon expiry of underlying patents. These patents, and certain related patent applications
that may issue as patents, are currently set to expire between 2019 and 2021.
(3) Expiration date of the license agreement occurs upon expiry of underlying patents. These patents, and certain related patent applications
that may issue as patents, are currently set to expire between 2023 and 2025.
(4) Expiration date of the license agreement is 15 years from first commercial sale or upon expiry of underlying patents, whichever occurs last.
The last patent covered under this license agreement expires in November 2016.
(5) In fiscal year 2011, we incurred a milestone fee of 37,500 pounds sterling ($64,000 U.S.) upon commencement of patient enrollment in our
first randomized phase II clinical trial using bavituximab, which amount would continue as an annual license fee thereafter until completion
of patient enrollment, at which time the annual license fee would increase to 75,000 pounds sterling per annum. During fiscal year 2012,
we completed patient enrollment of the aforementioned phase II clinical trial, which triggered the annual license fee to increase to 75,000
pounds sterling per annum (or approximately $122,000 U.S. based on the exchange rate at April 30, 2012). In addition, in the event we
utilize an outside contract manufacturer other than Lonza to manufacture bavituximab for commercial purposes, we would owe Lonza
300,000 pounds sterling per year (or approximately $488,000 U.S. based on the exchange rate at April 30, 2012).
(6) Expiration date of license agreement is 10 years from first commercial sale in each respective country.
Of the total potential future milestone obligation of $6,800,000, we anticipate milestone obligations not
to exceed $200,000 during fiscal year 2013. In addition, of the total potential future milestone obligations of
$6,800,000, up to $6,400,000 would be due upon the first commercial approval of a drug candidate developed
under our PS-targeting program, including bavituximab, with the technologies licensed pursuant to such license
agreements. However, given the uncertainty of the drug development and the regulatory approval process, we
are unable to predict with any certainty when any of these milestones will occur, if at all.
PGN650
In October 1998, we exclusively in-licensed worldwide rights from UTSWMC, to certain patent
families, which was amended in January 2000 to license patents related to aminophospholipid targeting
conjugates, such as PGN650. Under the October 1998 license agreement, as amended, we are obligated to
pay UTSWMC future milestone payments of up to $300,000 for PGN650 based on the achievement of certain
potential clinical development and commercial milestones, plus a low single digit royalty on net sales. Under
this agreement, we do not anticipate any milestone obligations during fiscal year 2013.
In addition, during fiscal year 2007, we entered into a research collaboration agreement and a
development and commercialization agreement with Affitech A/S regarding the generation and
commercialization of a certain number of fully human monoclonal antibodies under our platform technologies
to be used as possible future clinical candidates, including our imaging agent PGN650. Under the terms of
the development and commercialization agreement, we have elected to enter into a license agreement for the
PS-targeting antibody used to create PGN650, and therefore, are obligated to pay future milestones payments
of up to $1,971,000 based on the achievement of certain potential clinical development and regulatory
milestones, plus a low single digit royalty on net sales. We anticipate milestone obligations for PGN650
under this agreement to not exceed $101,000 during fiscal year 2013.
Mojojo, I have the smoking gun here about ASA404 (see below).
The upshot is that the phase II trial showed an increase in survival of 5.2 months with a hazard ratio of 0.73,
but a p-value of 0.33. So it had a good hazard ratio, but a bad p-value. Yet it was moved into phase 3 anyway.
Contrast that to the bavi phase 2 second-line NSCLC trial with an increase in survival of 6.5 months
(using the pooled data) with a hazard ratio of 0.52 and a p-value of 0.015.
Here is the phase 2 paper. British Journal of Cancer (2008) 99(12), 2006 – 2012
FREE: http://www.nature.com/bjc/journal/v99/n12/pdf/6604808a.pdf
"Median survival was 14.0 months in the ASA404-CP group and
8.8 months in the CP group (Figure 2). The risk of death was
reduced by 27% in the ASA404-CP group, with a hazard ratio of
0.73, 95% CI 0.39, 1.38, and P=0.33"
--------------------------------------------------------------------------------------------------------
From JCO August 1, 2011 vol. 29 no. 22 2952-2955.
Clinical Development of Vascular Disrupting Agents: What Lessons Can We Learn From ASA404?
Patricia M. LoRusso, Scott A. Boerner, Sally Hunsberger
[snip]
In phase I/II clinical trials, ASA404 showed promising results in
combination with paclitaxel/carboplatin for the treatment of NSCLC
and resulted in improved tumor response and increased time to disease
progression, partial response, and 5-month median survival advantage
in both patients with squamous NSCLC and those with
nonsquamous NSCLC. These promising early results prompted
examination of the combination in two global, large-scale, randomized
phase III clinical trials, named ATTRACT-1 (Antivascular Targeted
Therapy: Researching ASA404) and ATTRACT-2. ATTRACT-1
was designed to evaluate ASA404 in combination with paclitaxel and
carboplatin as first-line treatment for stage IIIB/IV NSCLC of squamous
or nonsquamous histology, whereas ATTRACT-2 evaluated the
combination as second-line treatment for patients with advanced
NSCLC. Both studies were designed with the primary end point of
determining whether the addition of ASA404 significantly extended
overall survival (OS).
In the article that accompanies this editorial, Lara et al describe
the results of the ATTRACT-1 trial, which was conducted at more
than 200 sites in 20 countries and involved 1,299 patients, 649 of
whom received ASA404. At interim analysis, no difference in OS was
observed between ASA404 and placebo arms, and the clinical trial was
halted for futility. In March 2010, a statement was released that indicated
that first-line ASA404 therapy had failed to meet the primary
end point of significantly extending OS for patients with advanced
NSCLC who were enrolled onto the ATTRACT-1 clinical trial. Similarly,
in November 2010, it was announced that there was no observed
improvement in OS with administration of ASA404 as second-line
treatment of patients with advanced NSCLC in the ATTRACT-2
phase III trial.
Should we be surprised that the phase III studies produced negative
results? Unfortunately, probably not. The basis of the decision to
move forward with a phase III study was likely heavily influenced by
results from the randomized phase II study of ASA404 plus paclitaxel/
carboplatin, including observed increases in median OS (8.8 months v
14 months, with a corresponding hazard ratio of 0.73), response rate,
and time to progression in the ASA404 arm (Table 1). However,
interpreting these statistics alone, without accounting for the variability
associated with them, can be misleading. The P value is essential to
weighing the evidence in a phase II study. It is the probability of
observing differences as extreme or more extreme than what were
observed, if the treatments are exactly the same. In the calculation of
the P value, the sample size and variability of the estimates are taken
into account. An alternative way to understand the P value of .33
that was observed in the phase II study of ASA404 is to consider
what would occur if 100 studies were run in the same population,
with each study having two treatment arms of 35 patients and both
arms receiving the chemotherapy regimens with different placebos.
[snip]
So what has this trial taught us about advancing novel
agents into the phase III arena? Carefully scrutinizing phase II
data and defining efficacy differentials may be pivotal to decrease
the failure rate of future phase III trials. Excitement over
differences in median survival must be tempered when P values
indicate the differences have a high probability of being a result
of chance. Minimizing the failure rate can save valuable resources,
not only in terms of funding, but as it relates to patients
as well. Even if there is no evidence of increased toxicity or
alterations in quality of life between the novel combination and
standard arms, randomly assigning a patient to a phase III trial
still requires a valuable time commitment from a patient who is
racing against the clock. Additionally, such patients could have
been considered for alternative trials that, predicated on possible
patient preselection, may have resulted in a significantly
improved outcome for them. Whenever possible, defining appropriate
patient subsets for protocol recruitment may be the
tool that significantly influences failure rates, heightens enthusiasm
for additional trial recruitment, and, most importantly,
increases patient survival. So why are many positive phase II
trials not resulting in positive phase III trials? Perhaps it is
because, in those situations wherein positive subsequently begets
negative, we may never have had a truly positive phase II
trial to begin with.
To change the subject I am thinking ahead to after we have a partner and the phase 3 for second-line NSCLC is started.
My preference would be to start a phase 3 for second-line metastatic breast cancer with bavi + docetaxel.
We have data from the phase IIa trial in MBC using bavi + doceatxel and it looked pretty good. Seems like this
would be the logical next indication. I am also thinking about what new cancer ISTs might be interesting.
I have done some reading on relapsed multiple myeloma. Bavi + velcade might be a good pair to try.
Any other ideas?
I wish I knew more about this. It is pretty much a black box. Any good references?
and as time goes on the effect will get smaller and smaller as the total number of deaths increases?
Or if the other phase 2 trial had a highly statistically significant increase in MOS?
I don't think it takes a genius to understand that if 70% of the control arm patients have
died, then the median (50%) overall survival of the control arm isn't going to change.
The doubters all seem to be basing their red flags on the old paradigm. They think
of bavituximab as if it were a small molecule drug. So when the MOS is much better than
the old rule MOS = 2 X PFS they don't understand how it could be true, so there must
be something wrong, or worse. They fail to take the time to learn anything about the
unique MOA that bavi has. They understand that it is an antibody and the target is PS, but
fail to understand anything else about it. For example, that by targeting the tumor
vasculature the effects of the antibody are greatly magnified when each blood vessel
feeds hundreds, or thousands, of tumor cells downstream. The fact that bavi can
both block the immunosuppressive effects of PS, and at the same time switch the tumor
associated macrophages (TAMs) from type M2 to M1, and cause dendritic cells
to mature, and reduce the numbers of myeloid-derived suppressor cells (MDSCs), and
allow adaptive immunity to work again, is totally lost on them. There is plenty of info out
there if they would care to make the effort to learn something new. For example:
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=78445110
I expect that the MOS estimate will get better, since it is interim data. Of course,
the control MOS was reached quite a while ago and won't change.
The story so far has been about triggering the MOS in the Bavi arms. There may be 5 or 6
patients to go there. However, that means 50% will still be alive, whereas we know the
control arm has about 30% still alive, and likely less by the time the MOS is triggered
for the treatment arms. The really interesting thing will be to see if there is a residual
number of treatment patients that remain alive after the control arm patients have all died.
I am hoping that maybe 15-20% of the bavi patients remain alive into the future. I don't know
if it will be possible to monitor these patients unless they are taking bavi as maintenance therapy.
Thanks I found it online.
Does anyone remember the comments King made about squamous cell lung cancer
in answer to a question during a conference call? Was that in the July call?
I can't seem to find the transcript. CJ is there a link? Thanks.
You think they are "journalists"? That is a joke!
Is the share price being totally manipulated here? Despite the incredible data presented people seem
to want to discount it as being unbelievable. I ask, just what will you believe if not the results from a randomized,
placebo controlled, double-blind study done in many places across many countries? Does that sound like
something that could be faked? I can't believe what some people will believe, or pretend to believe.
I think this is possible at all because bavi has a unique MOA that very few people seem to understand.
They can put forth falsehoods because there are too few people who realize what a bunch of BS it is and
will call them on it. It is not about fairness and presenting both sides when there is a true difference of opinion,
but about distortion and misinformation to gain some advantage, i.e. greed.
Nice to read something constructive amongst the noise.
Correction from the CC transcript, Garnick
"Having personally been involved in the evaluation of over 30 Phase II trials over my career, none of which ever achieved statistical significance, including many of today's blockbuster biotech products; I am personally extremely pleased with the quality of this data and the clarity with respect to advancing bavituximab in Phase III trials, which it provides."
The question on the CC about the control arm MOS of 5.6 months was I thought dealt with decisively.
Here is an abstract of a trial which compared Tarceva with docetaxel and pemetrexed for second-line NSCLC.
Note the MOS for each.
Lancet Oncol. 2012 Mar;13(3):300-8. Epub 2012 Jan 24.
Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.
Ciuleanu et al.
Abstract
BACKGROUND: Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC.
FINDINGS: Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR] 0·96, 95% CI 0·78-1·19; log-rank p=0·73). The adverse-event profile of each group was in line with previous studies.
INTERPRETATION: No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed. Since the toxicity profiles of erlotinib and chemotherapy differ, second-line treatment decisions should take into account patient preference and specific toxicity risk profiles.
I think the genetics issue is a non-issue. The survival effect is way too big to be explained
by any small imbalances. If Asian patients with NSCLC live longer on chemo then it is
possible that they lived even longer with chemo + bavi, along with all the other patients.
It was noted on the call that all three arms had 90-92% stage 4 patients, which I
believe is larger than most trials. That these survival results were obtained with that
patient group is even more amazing, and might be the reason the control group's
survival was relatively short.
Garnik said that he had personally been involved with 20 phase 2 trials and had never
seen one that had statistically significant survival data, until now. To me nothing
more needs to be added. I also find the imbalance issue to be over blown. There were some
small imbalances that would tend to cancel each other out, but the magnitude of the survival
data blows away any small effects due to imbalances, if they exist. Not to criticize,
but you seem to want to find things to worry about. I say ignore all the idiots out there
and concentrate on the huge upside here.
Thanks for counting the events and your PM reply.
I like to think of it as
control arm 13 alive/38; -6
1 mg/kg arm 22 alive/40; +2
3 mg/kg arm 23 alive/39; +4
No matter how you slice it Bavi works.
I just think you have to always be moving forward with the latest, and best, treatments otherwise
you can be left behind. That is why I don't think anyone would suppress bavi development. Also, Avastin
doesn't work on everything. Look at the withdrawal of approval for metastatic breast cancer. That is a big
hole Bavi could fill considering how well the Bavi trial on MBC went, something you have brought up repeatedly.
My bet is for Roche, we'll just have to wait a little longer to see.
Thurly, sorry, but I just don't buy this argument. If I was Roche, and I had bavi ,and it had been shown
to have much better survival than anything else, then I would be pushing development of bavi,
not delaying it. With a much better product you can take market share away from your competitors.
There are only so many cancer patients, the only way to grow your share is to take them away from
your competition, sitting on bavi won't do that.
I would favor a deal with Roche because they have Genentech which has the best researchers in the
biotech world. I think the combination of brains and money could move bavi along faster than any other company.
Since generic docetaxel is available to anyone, why would there be an advantage to partner with Sanofi over
another company which also has a good distibution network?
I don't see the logic here. If Roche had Bavi then as it got approved for different indications it would just
be substituted for any other treatment. So the revenue stream would continue, it would just be coming
from bavi instead of avastin, for example.
Yes, that is the ultimate goal. Remember that > 90% of all the patients had stage 4 disease (metastatic).
If a trial were done with stage 3 patients only it would be interesting to see if adding bavi to chemo could
actually prevent the transition from stage 3 to stage 4 and ultimately death.
I think you are referring to the Avastin trial that was the basis for first-line approval and combined Avastin
with carboplatin and paclitaxel, so any comparison of the survival curves wouldn't really mean anything.
Thanks mojojo for the graph. It looks like it took about 4.5 months before the curves of the treatment
and control arms separated and then diverged. At 3 months they are on top of each other. Would you
take this as a sign of delayed separation? The treatment phase lasted 18 weeks (4.1 months). I take it
that the remaining patients alive at the time of this interim analysis have been censored, isn't that how it works?
I do. Try hotels.com for good rates. I will be at the
Best Western Plus Orange County Airport North
I got a room with King-size bed for $83/night.
I agree. I suspect that lung cancer patient advocacy groups will notice.
http://www.nationallungcancerpartnership.org/
As for the Asian patients, do they live longer if you control for both ECOG PS and stage of disease?
Here are baselines for ECOG PS and Stage 4 and their survivals for this trial (Hanna et al 2004).
Note that the percentage of Stage 4 patients is 75% vs 91% for bavi, and that stage 4 patients had a
shorter survival, as reflected in our control arm (90% stage 4). The distrbution of PS 0 or 1, and 2
is identical to our control arm and bavi 1mg/kg arm. All in all, I would say that the bavi arms did remarkably
well even though they had a higher percentage of sick patients and those with stage 4 disease.
Wouldn't you agree?
I recalculated including the pooled numbers and for PS of 0 or 1. If you look at the bottom row
you can see that the 3 mg/kg arm and the pooled arms both have a smaller percentage of patients
with PS = 0 or 1 than the control arm, and that the 1 kg/mg arm has exactly the same percentage.
Based on the pooled numbers it seems that the control arm has the advantage, as you said.
Here is the ECOG status taken from today's slides from Peregrine.
I would say that the 3 mg/kg arm had sicker patients than the control arm,
but the 1 mg/kg arm had patients that were healthier, so pooled it might be
a wash. I think this is just a reflection of the relatively small size of the patient group.
I think we got what was needed for the AA. Now I would like to see a paper in NEJM about the trial from
Gerber and Thorpe. Want those oncologists to be chomping at the bit to try Bavituximab.
What could they name Bavituximab? Bavitin?
Where are those people who were always talking up hazard ratios and how this trial was a bust????