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v**********m
发帖数: 5516 | 1 DNDN，理由银杏大牛说过http://www.mitbbs.com/clubarticle/pennystock/31547287_3.html；我自己的家庭作业结果也跟银杏差不太多，唯一不同的是也许大公司对therapy的收购意愿可能不如对单个药物的强烈。Marketing是关键。
ARNA，年底resubmit，等待prerun，药物机理非常solid，老鼠癌症问题会在resubmit
之前被新实验结果完美掩盖，新投资（投机）的钱会涌入。
SNV，明年一季度的季报会好转，公司内部持有在增加，风险是tarp的债，也许会增发
。最近pump的文章很多。 | K********g
发帖数: 9389 | 2 Pump效果不佳。哈哈哈哈
resubmit
【在 v**********m 的大作中提到】
: DNDN，理由银杏大牛说过http://www.mitbbs.com/clubarticle/pennystock/31547287_3.html；我自己的家庭作业结果也跟银杏差不太多，唯一不同的是也许大公司对therapy的收购意愿可能不如对单个药物的强烈。Marketing是关键。
: ARNA，年底resubmit，等待prerun，药物机理非常solid，老鼠癌症问题会在resubmit
: 之前被新实验结果完美掩盖，新投资（投机）的钱会涌入。
: SNV，明年一季度的季报会好转，公司内部持有在增加，风险是tarp的债，也许会增发
: 。最近pump的文章很多。
| v**********m
发帖数: 5516 | 3 SNV还是比较坚挺的。我在1.3-1.45之间做了两回。
【在 K********g 的大作中提到】
: Pump效果不佳。哈哈哈哈
:
: resubmit
| y***q
发帖数: 4147 | 4 头象太ws了，换一个帅一点的，pump效果要好一点 | v**********m
发帖数: 5516 | 5 熟男四十一朵花。
【在 y***q 的大作中提到】
: 头象太ws了，换一个帅一点的，pump效果要好一点
| w*******d
发帖数: 3714 | | v**********m
发帖数: 5516 | 7 新热点会来的。
【在 w*******d 的大作中提到】
: ARNA还有戏么。。。
| v**********m
发帖数: 5516 | 8 Arna pump新文。
http://seekingalpha.com/article/292994-is-arena-s-lorcaserin-on
Is Arena's Lorcaserin On Track For Approval In 2012?
28 comments | by: KLLJ Investments September 12, 2011 | about: ARNA
Arena Pharmaceuticals (ARNA) investors have had a tough road over the last
12 months since a negative vote by an Advisory Committee called to review
Arena’s lead drug candidate for the treatment of obesity – lorcaserin. The
stock was trading close to $7.00 a year ago heading into that fateful
Advisory Committee, down to under $2 after a negative vote foreshadowed a
Complete Response Letter (CRL) from the Food & Drug Adminstration (FDA).
ARNA has bounced between $1.25 and $1.60 for most of 2011. So will Arena
have a better chance of seeing lorcaserin approved in 2012 than it did in
2010?
According to recent reports, the U.S. Senate Committee on Appropriations has
instructed the FDA to report back by the end of March 2012 on the steps the
agency will take to support novel treatments for obesity. In this report
the Committee noted that the “lack of obesity medications is a significant
unmet medical need” and that they were “concerned with the absence of
novel medicines to treat obesity.” Any investor who has followed the
obesity space knows that of the three obesity drugs recently rejected by the
FDA; Vivus’ (VVUS) qnexa, Orexigen’s (OREX) contrave and Arena’s (ARNA)
lorcaserin – the only one that is a “novel” drug is lorcaserin. The other
two drugs were combination pills of existing compounds. Perhaps the efforts
by Arena investors last fall to express their concern to their
congressional representatives has paid off by increasing the pressure on the
FDA to look at obesity as a disease rather than a lifestyle problem.
Obesity continues to be the largest unmet medical need in the world and the
root cause of many of our biggest diseases including Type II diabetes &
heart disease. With 1/3 of American’s facing obesity – a safe and
effective novel treatment would become a mega-blockbuster. Given Arena’s $1
.25 share price, the Street clearly believes there is little chance
lorcaserin will ever be approved. So is this a stock worth buying? Let’s
examine the details of what was contained in Arena’s 2010 Complete Response
Letter to see where they stand in addressing each concern to allow the
company to refile their New Drug Application by the end of this year.
The committee listed four major points for Arena to address before they
could approve lorcaserin:
1) Diagnostic uncertainty in the classification of mammary masses in female
rats: On August 9, 2011 Arena announced results from a Pathology Working
Group's (PWG) re-adjudication of female rat mammary tumor diagnoses from a
two-year rat carcinogenicity study of lorcaserin. The PWG was able to
decisively demonstrate that there is no increased cancer risk to humans and
that the risk is actually lower than Arena originally estimated in their
first New Drug Application. The PWG results also show that the FDA-erred
when combining tumor types to determine cancer risk, a practice not
generally accepted in the medical community.
2) Unresolved exposure-response relationship for lorcaserin-emergent mammary
adenocarcinoma: Arena is still conducting a study, 3 months in duration,
that measures the increase in prolactin that lorcaserin may cause. An
increase in prolactin is an accepted cause of increased mammary risk.
However, given the results of the Pathology Working Group, this may no
longer be of concern since there is no statistically significant increase in
mammary risk for lorcaserin patients. Regardless, results of this study are
expected later this year and well prior to resubmission of the NDA.
3) Unidentified mode of action and unclear safety margin for lorcaserin-
emergent brain astrocyloma: On August 2, 2011 Arena announced the completion
of a clinical study that measured lorcaserin concentrations in human
cerebrospinal fluid (CSF) and plasma and related data analyses. In this
study, Arena was able to conclusively demonstrate that the exposure to the
human brain with lorcaserin was 5X lower than in the brains of rats. This
provides the data necessary to show that there is absolutely no increased
risk of brain cancer in humans.
4) The agency wanted to review results of Arena’s BLOOM-DM trial to see
effect of lorcaserin with Type II diabetics: The results of this study were
released in November 2010 and were quite impressive. Not many people thought
that lorcaserin would have much success in this population that tends to
have a difficult time losing weight. After 52-weeks of treatment, 37.5% of
patients taking lorcaserin lost at least 5% of their body weight, more than
double the 16.1% who did so in placebo and meeting the FDA criteria for
approval of a weight-loss drug. In addition, over 16% of lorcaserin patients
lost over 10% of their body weight compared to just 4.4% on placebo.
Diabetes drugs are measured by their ability to lower HbA1c and those on
lorcaserin lowered HbA1c by .9% compared to .4% on placebo. This is
significant because a reduction in HbA1c of .9% is similar to a number of
diabetes-specific treatments. To have such an impressive reduction of HbA1c
could make lorcaserin a first line treatment for Type II diabetics and pre-
diabetics – a population of over 70M Americans.
It is important to note that the FDA expressed no concern in the CRL with
heart safety like they did for qnexa and contrave. Arena conducted extensive
heart safety testing in their trials understanding that there was great
concern in the aftermath of the Phen-Fen debacle around the potential for
heart-valve damage. Arena apparently made the agency comfortable that there
was no increase in heart valve risk to patients who took lorcaserin, since
there was no language in the CRL expressing any concern in this regard.
Lorcaserin is the only treatment that has been recently up for review that
not only doesn’t increase risk to the heart, it actually decreases it.
I spoke with Arena last week and the company is still very confident they
will be able to refile their NDA for lorcaserin prior to the end of 2011,
which would start a 6-month review and 2nd PDUFA in mid-2012. Our Congress
is now pressuring FDA to approve “novel” new agents to fight obesity.
Lorcaserin is the only novel new drug that will be up for approval anytime
soon. It has virtually no risk associated with it, given the updated study
results and is effective for a significant amount of the population. It
lowers cardiovascular risk, HbA1c, waste circumference and reduces the need
for anti-lipids, anti-hypertensives and potentially other diabetes
treatments. It has the potential to also be used for other indications over
time including smoking cessation or other addictives.
Given that Arena appears to be on-track to answer all of the FDA’s concerns
listed in the CRL and refile by the end of 2011, it is a good speculative
play and I purchased a nice position over the last 2 months. If they
continue on this path and refile in December, you could see a good move
north of $3 in Q1 2012 and it might recover to the $5-7 range as it
approaches a 2nd PDUFA in June 2012 – a +400% return from here. I’ll plan
on taking some profit prior to the next FDA action date but lorcaserin
stands a far better chance of approval in 2012 than it did this time last
year. Approval could launch ARNA north of $20 in a hurry and it stands a
good chance of major blockbuster status once on the market. That to me is
worth a speculative play on a $1.25 stock. At this level, Arena is trading
like a never-expiring zero strike call option.
Disclosure: I am long ARNA. | v**********m
发帖数: 5516 | 9 楼上文章的comments
Not yet but stay tuned. But a definite fact and you can review it in the FDA
's analysis in the briefing document is that there was no SS of astrocytomas
in male rats or female rats.
Dr. Alavi had concerns about how Arena calculated the exposure margin for
Lorcaserin, that is why it appeared in the CRL. When Arena met directly with
the FDA on December 15th and 16th at the FDA, both Arena and the FDA agreed
on the CSF methodology and the number of participants that would be
acceptable. The FDA agreed on the study design and protocols.
I know, that does not mean they have to accept their results or the results
of the PWG, but I would think that with their involvement and also with the
fact that Dr. Alavi was wrong in his analysis of the rat tumor data. My bet
would be on the FDA accepting the results...
One other thing, not necessarily related to Arena but related to Obesity in
general is the Obesity Project that is being conducted by George Washington
University under the direction of the FDA - directly from Dr. Woodcock's
office - in my opinion, will go a long way to having the FDA rethink their
thinking on obesity drugs.
This project will focus on researchers from GWU meeting directly with
obesity patients, obesity specialists, obesity groups, cardio and diabetes
medical doctors, etc. Part of the discussion will be focused on how much
risk both patients and doctors are willing to take with regards to a obesity
medication or procedure.
I think the environment is changing for Arena and Lorcaserin. Yes, it is not
reflected in the stock price and probably won't be reflected in the stock
price until next year.
BTW, I hope that the this changing environment helps both Vivus and Orex. I
think doctors having more than one tool in their toolbox is perfectly fine.
One patient might respond better to Qnexa, another to Lorcaserin and another
to Contrave
12 Sep, 06:21 PM0
#
psych Comments (2)
Re: the lung mets, statistically, if you have 100 possible things that can
hit statistical significance, it is not surprising that something pops up.
What should be important, I think, would be some logic to the cause, and
there doesn't seem to be one. At this time we have major scientists in the
obesity community correctly stating that the FDA's hyper-cautious stance is
hurting the country. We need an obesity drug, and self-centered bureaucratic
concerns aside, even in a worst-case scenario, it makes sense to save 15
lives from obesity-related complications even if we have to tolerate the
risk of losing one to some possible complications from a drug. At some point
the FDA has to show some courage and science and common sense ought to
prevail, right?
12 Sep, 11:30 AM0
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psych Comments (2)
Re: the lung mets, if you have 100 things that could possibly happen, it's
not surprising that something pops up, is it? We have major scientists in
the obesity community correctly saying that the FDA's hyper-cautious stance
is hurting the county. Self-centered bureaucratic concerns aside, the FDA
needs to have the courage to risk losing one life to possible unproven
complications of a drug to save 15 lives from obesity-related complications.
Common sense and science ought to prevail at some point, no?
12 Sep, 11:43 AM0
#
PEhrlich Comments (443)
I'd agree that multiple hypothesis testing is always an issue in safety
testing. But this was a 2 year carcinogenicity study, and what was seen was
an increase in metastatic tumors in both lorcaserin treatment groups (no
lung mets were seen in the placebo group).
If they had seen a small increase in diabetes or infections in a
carcinogenicity study you'd have a stronger argument.
12 Sep, 12:12 PM0
#
PhillyDan Comments (151)
PhillyDan
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The lung mets is not an issue. The lung mets did not increase and that is an
error in your comments. The lung mets were basically the same as in the
original filing. The FDA did not make an issue of the lung mets then and
will not now.
I will be back with more on this subject since you are totally wrong in your
judgement.
12 Sep, 01:40 PM0
#
PEhrlich Comments (443)
Dan, if you think the FDA cannot bring up additional issues that were not in
the original CRL, you are not sufficiently familiar with the Agency's
history. Next time you visit Arena, you might try walking down the street
and discussing this issue with the folks at Amylin.
12 Sep, 02:22 PM0
#
PhillyDan Comments (151)
PhillyDan
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From a very high level person involved with the CRL at Arena:
"Sprague Dawley rats get a LOT of spontaneous tumors, and our control group
was no exception. The lorcaserin rats had a similar spectrum of tumors to
the controls—they are not listed in the briefing book because they were not
increased over control. Some of these spontaneous tumor types can
metastasize, and some can go to lung.
The PWG did not provide the primary source for any lung mets except the
mammary, since no other primary tumor type was increased over control in the
lorcaserin animals. So, all of the non-mammary lung mets are from a variety
of other primary sites--none of which was increased over control in
incidence. "
Once again, the lung mets are not an issue and the FDA agrees with this. The
reason why the PWG did not provide the primary sources for the other sites
is because the FDA only was interested in the lung mets from the mammary
sites.
The initial report had 19 total lung mets from both Mammary and non-Mammary
Gland origin. The PWG report had 20 total lung mets from both Mammary and
non-mammary gland origin. 9 of those lung mets were from non-mammary origin
which as the comments above were not increased in incidence over control.
In addition, those 9 lung mets could have come from only 4 or 5 rats out of
270 rats. Not even close to SS!
The 11 lung mets from mammary origin again could have come from only 5 rats
out of 270. in addition, 5 of the lung mets came from the 24x dosage and 5
from the 82x dosage.
In addition, since the PWG report shows no SS for malignant tumors in the
low and med dose and only SS for the 82x dosage, the PWG report shows that
there is no risk of cancer in humans from Lorcaserin; therefore, there is no
risk from lung mets.
Adding to this in case you come back with the increase in benign tumors,
remember benign tumors do not progress to malignant tumors. Dr. Daniel can
provide more research on this aspect along with Arena and even the FDA knows
this.
I am very familiar with the agencies history. But this will not be an issue
that will come up at all.
When Arena proves the prolactin hypothesis, which I strongly believe they
will, then the whole cancer issue is closed. Why?
The FDA already knows that prolactin increases in humans has very little to
no cancer risk for humans. The FDA reviewer said as much in the briefing
documents.
Yes, the FDA could bring up issues but they are going to have to dig very
deep to find them. Why? There is no valvulopathy risk, the receptor studies
(probably completed) on the 2a and 2b receptors will reinforce even more the
fact that Lorcaserin is highly selective for the 2c receptor and has little
or no affinity for the 2b receptor. You wouldn't want to bet against me on
this one. Not being smart, but that walking down the street deal provides
some insightful information.
The Bloom DM studies adds mucho benefit in the 0.9% reduction in A1C and 27%
in FG levels is significant. As noted by the author, these results are
equal to or better than a number of current T2DM drugs on the market. I know
, I was at the ADA Conference in June and did the research my self.
I also met Ed Sussman who lost 52 lbs. in the Bloom-DM study and dropped 4
out of 5 meds. He is still doesn't know if he was on drug or control. But
since he did not follow the exercise program that much, my guess is the drug
. He regained 10 pounds but lost it again. Ed who was a lifelong nail biter
has stopped biting his nails since being in the study. A coincidence,
perhaps, but then the Duke study on rats with regards to tobacco and how
they got SS results on rats staying away from tobacco/nicotine.
I do appreciate your civility and playing devil's advocate and who knows you
might turn out to be right in the long run, but time will tell.
In fact, by this time next year we will know.
12 Sep, 06:03 PM0
#
taxed2much Comments (97)
"I think the increase in lung mets seen in the readjudicated rat study
represents a significant hurdle, as does the indirect (and therefore not "
conclusive") determination of lorcaserin levels in the brain. "
This is an argument presented by people who have a biased agenda against
Lorcaserine. Either you're biased and therefore should be disregarded or you
are ignorant of the fact that there is no possible way to take direct brain
samples of volunteers for that study. Get real, cerebral spinal fluid is
the closest you can get to taking actual brain tissue samples. What you
vaguely suggest with your ignorance is to perform brain biopsies on healthy
test subjects. Are you insane? Personally I think the FDA forcing Arena to
do the spinal taps for the fluid that conclusively did prove the point that
brain cancer is a non risk were way out of line when considering the safety
of volunteers. It is why the study only used a very minimal number of them.
The safety of doing that when weighing the costs if something went wrong
would easily make Arena go out of business in teh blink of an eye. And you
are suggesting they should actually cut into someones brain to get a direct
sample. How about you volunteer for that since you obviously don't use yours.
12 Sep, 12:25 PM0
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PEhrlich Comments (443)
I guess the way I look at it is that the purpose of the rat carcinogenicity
study is to look for possible cancer risks. You get a passing score if 1)
you don't see an increase in tumors, or 2) you can convincingly show that
any increase you do see is not relevant to humans.
I agree that it is not possible to measure brain levels directly. But all
that means is that neither #1 nor #2 applies. The FDA is not obligated to
approve the drug simply because technical issues prevent Arena from
demonstrating that it is safe. That's not the way the law is written.
12 Sep, 12:50 PM0
#
PhillyDan Comments (151)
PhillyDan
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The bottom line from 5 independent pathologists, who did the re-adjudication
and 3 independent pathologists that did the initial adjudication of the
study is that there is no SS of tumors vs. placebo.
Therefore, Arena gets a passing score. The lung mets are not an issue and
the FDA was only interested in lung mets that developed from the malignant
mammary tumors not from other sources. There were 21 total lung mets both
from mammary origin and "other" origin, which was about the same total in
the initial NDA.
In addition, you notice that there was no re-adjudication of male rats where
the brain tumors occurred, most of them at the highest dosage level of 82X.
Once again, the FDA agreed with Arena's analysis that there was no SS
regarding the brain tumors with respect to placebo. They only wanted a more
accurate indication of the brain concentrations of Lorcaserin. BTW, the FDA
agreed with Arena that only ten volunteers is necessary.
You obviously have not done much research on the facts in this situation.
12 Sep, 02:02 PM0
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PEhrlich Comments (443)
Dan, I think if you are arguing that the FDA is not interested in tumors,
you should think this over more carefully.
There was no need to readjudicate the brain tumors because there was no
discrepancy in the tumor count like there was with the malignant vs. benign
mammary tumors. The outstanding issue with the brain tumors is whether
efficacious doses of loracaserin produces brain levels that are greater than
1/25 the brain levels that were associated with brain tumors in the rats.
Its possible the FDA will accept the CSF data as sufficient, but I don't
think its a slam dunk.
12 Sep, 02:29 PM0
#
domndan Comments (8)
This is in response to Perhlich
First of all, novel is defined in the following manner- "new and different,
often in an interesting, unusual or inventive way".
That is, original, different, innovative, unique. Lorcaserin, as a 5HT2c
agonist, fits this description perfectly as it would any new and innovative
drug.
Second, there is one major misunderstanding in your concern about the lung
metastasis. First, this was known at the time of the ADcomm meeting in
September of 2010. This is issue was not discussed at all in the FDA
briefing document. You must ask yourself why? There is one very good reason.
NONE OF THESE NON-MAMMARY TUMORS WERE INCREASED OVER CONTROLS IN THE 2 YEAR
CARCINOGENICITY STUDIES. If there is no increased incidence of these non-
mammary gland tumors then there is no increased risk for humans. I hope you
understand the impact of this statement. These tumors represent no human
risk which, by the way, was recognized by the FDA and in fact, the CAC
conclusion was that only mammary tumors were increased over control. The
incidence of lung metastasis in the non-mammary group included multiple
primary tumors - none of which had increased incidence over controls in the
two year study and were not significant - and this is why the PWG did not
state the primary tumors. Remember for Historical tumor data on rats there
are approximately 80 different tumor types that were reported in 473 rats in
one NTP study that was recently published. Therefore it is extremely likely
that the incidence of non-mammary tumors that you are concerned about
included multiple primary tumors, i.e. one met came from thyroid cancer, one
met came from ovarian cancer, etc. Do you see why this is insignificant?
Finally, cancer research is demonstrating that there are tissue-specific
metastatic prototypes that are not only associated with but promoted by
specific genes that pre-exist in the primary tumor. Metastasis has a genetic
basis and these genes are responsible for the mechanism associated with
metastasis from the primary tumors to the target tissues.
Why is this important? Lorcaserin could not be implicated in the metastatic
potential of these tumors because lorcaserin and its major metabolite were
not found to be genotoxic from the FDA BD under the section "Genotoxicity
and Carcinogenicity Assessment for Lorcaserin" page 83which states “
Lorcaserin and its major sulfated metabolite (APD244208) showed no evidence
of genotoxic effects in a standard battery of bacterial and mammalian
systems.” Lorcaserin would need to be genotoxic to be implicated in
metastatic potential of primary tumors. Again, the FDA was not concerned
about metastasis in the FDA briefing document or in the CRL. Why because it
is a non-issue – the tumors that caused these metastasis were not increased
in incidence over controls in the 2 year study.
Finally, Astrocytoma margin of safety drug levels (where there are no brain
tumors present) in human studies showed that lorcaserin was safe – the
margin of safely was found to be 20-28x the clinical dose. The CSF study
demonstrated that very little lorcaserin is concentrated in the CSF – 1.7
times as compared to plasma. In comparison, the rats brain concentration was
29x that of the plasma and the reason for the increase in astrocytomas in
the rat brain. In the original findings, the monkey brain to plasma
concentrations resulted in a 17x the clinical dose margin of safety. The FDA
was only concerned that Arena demonstrate a margin of safety dose, nothing
else. All your speculation has nothing to do with the FDA’s interest.
Daniel
UCLA MD
12 Sep, 02:04 PM0
#
PEhrlich Comments (443)
Daniel, thanks for your thoughtful reply.
I would appreciate any direct links to Pubmed references that you can supply
to the CNS penetration articles, they are hard to look up from the author's
last name only. From my own knowledge and from your comments below, I would
think the case is more favorable for lorcaserin if the relative absence of
the compound from the CNS can be attributed to strong(er) binding to serum
proteins (in rats relative to humans). Because at steady state, there is a
pseudo equilibrium of the drug partitioning between the plasma and the brain
, n'est pas? The CSF levels are not relevant unless one can persuasively
argue that the factors keeping the compound out of the CSF will also act to
keep it out of the brain.
There are certainly examples of compounds which promote tumors by non-
genotoxic mechanisms. Estrogen and phorbol esters come immediately to mind
as examples. So I don't think one can on first principles discount the
possiblity of metastasis promotion by a non-genotoxic mechanism.
Half of the US population will be diagnosed with cancer at some point in
their lives, and metastasis is the primary means by which surgically curable
cancers become incurable. So it is difficult for me to believe that the FDA
would not see this as a serious issue.
12 Sep, 04:05 PM0
#
domndan Comments (8)
PEhrlich
Thanks for your comments. And you are correct that there compounds that "
promote tumors", and I take this to mean that are carcinogenic. However, the
carcinogens and the mechanisms involved in the neoplastic process are
distinct from the the mechanisms that promote metastasis. However, this
topic is well beyond this discussion. If you review the current literature
on the theories related to metastasis and why companies are developing drugs
that inhibit certain kinases that are encoded by the proto-oncogenes c-MET
and SRC involved in the metastatic processes of many tumors.
And you are correct that CSF levels are not accurate predictors of CNS
levels. The CSF is separated from the blood by the blood-cerebrospinal fluid
barrier (BCSFB), which is formed by a continuous layer of polarized
epithelial cells that line the choroid plexus. Of particular note is that
the BCSFB is less quantitatively important than BBB transport in respect of
most drugs that partition into the brain. Although there have been several
reports on the use of CSF as a surrogate for the measurement of unbound drug
concentrations in the brain (Liu, Smith, et al. 2006; Lin 2008; Liu, Chen
and Smith 2008; Liu, Van Natta, et al. 2009;) it is not yet clear whether
ISF (interstitial fluid - fluid that surrounds brain tissue directly) and
CSF concentrations can be accurately compared. Indeed, there are several
reasons why ISF and CSF concentrations may differ (Shen, Artru, and Adkison
2004): 1) the ependymal lining the ventricles allows diffusional exchange
from the CSF to the brain interstitium and the contribution of this exchange
to the overall distribution of drugs is likely to be small; 2) the exchange
between ISF and CSF is only diffusional (there are no facilitated transport
mechanisms); 3) this exchange is counteracted by bulk flow of brain ISF to
the CSF; 4) the diffusion distance from the CSF to most brain tissue is also
considerably further than between the brain capillaries; 5) the concurrent
transport of a drug across the BBB is likely to have a dominant effect on
brain tissue concentrations after systemic administration because of the
large area of the BBB and the short distance between brain capillaries.
However, CSF levels are still useful to demonstrate reasonable drug
concentrations in the brain. The issue becomes more important when drugs are
being developed that have their mechanism of action directly on specific
CNS sites - knowledge of concentrations of these drugs is essential. However
, when we are trying to determine margin of safety levels, CSF to plasma
ratios and brain homogenate to plasma ratios are acceptable methods.
And this is what the scientific community accepts. So we can argue how
accurate the CSF levels are relative to CNS levels until we are blue, unless
we can discover a more accurate method, ie direct sampling of the ISF, then
we have to accept the current methods also.
Daniel
UCLA MD
12 Sep, 05:18 PM0
#
PEhrlich Comments (443)
Daniel,
Here are some interesting papers that appear to describe small molecule
enhancers of tumor metastasis that are not genotoxic. One of them turned out
to be estrogen, another identified from cigarette smoke acts through the AH
receptor.
www.ncbi.nlm.nih.gov/p...
www.ncbi.nlm.nih.gov/p...
As you might imagine, there's a lot more work out there focused on the
discovery of small molecule INHIBITORS of metastasis.
12 Sep, 08:33 PM0
#
domndan Comments (8)
Again, the point is that the metastasis reported are not indicators of human
risk. These metastasis came from nonmammary primary tumors that were not
statistically significant in the 2 year carcinogenicity studies, incidence
of these tumors in female rats were did not have an increased incidence over
controls. Please read the FDA briefing document if this is not being
understood. If the primary tumors were not increased over controls then why
would the metastasis of various tumors, and it could be one metastasis per
tumor involving multiple tumors - tumors that have different tumorigenic
mechanisms be significant. I will say it one last time - the lung metastasis
from nonmammary tumors from primary tumors that were not significantly
increased in the two year carcinogenicity studies have no relevance to human
risk - PERIOD. Just ask any nonclinical toxicologist worthy of the title
and they will confirm this. Thanks for your responses and intelligent
observations however I don't think you understand the clinical significance
that nonprimary tumors, of which there are many that afflict rats, were NOT
increased in incidence over controls in the two year study!!! This is the
KEY.
Daniel
UCLA MD
12 Sep, 11:19 PM0
#
domndan Comments (8)
Again, neither of these two papers exclude genotoxicity or genetic related
mechanisms.
The lung cancer paper states "Direct genotoxicity induced by cigarette smoke
leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of
cigarette smoke also act as modulators altering cellular functions. These
two effects underlie the mechanisms of tumor promotion and progression"
First it states that both - genotoxicity and epigenetic effects of cigarette
smoke are involved in tumor promotion and progression. Second,epigenitic
effects involve tissue-specific metastatic phenotypes that are not only
associated with but promoted by specific genes that pre-exist in the primary
tumor. The primary tumors that were the source of the non-mammary lung mets
already have the genes that encode the proteins necessary for the multiple
steps involved in the affinity for specific tissues, in invasion,
angiogenesis (formation of new blood vessels) and growth of the tumor cells
in the new tissue. Lorcaserin would have to have multiple properties to
effect mestastasis in multiple tumors. Do tobacco carcinogens cause multiple
tumors from multiple sites in the body? Of course not but this is what you
are suggesting about lorcaserin.
The estrogen paper states "E2 significantly increased size, induced
progesterone receptors, and promoted lymph node metastasis, confirming that
ERs are functional and foster aggressiveness." This clearly states that it
is the estrogen receptors that are responsible for tumor metastasis. E2 -
estrogen - stimulates the receptor and the receptor responds with
aggressiveness.
ER (estrogen receptors) are inherited and therefore genetic.
The whole neoplastic process is complex and poorly understood however it is
clear from the above sources that both genotoxicity and inherited phenotypes
are involved in the process.
It is a stretch to suggest that lorcaserin is so multifaceted that it was
able to have universal receptor proprieties that could effect multiple tumor
genes that are pre-existent in multiple primary tumors and promote tissue-
specific metastatic phenotypes. This would be remarkable. Remember, we are
not talking one tumor causing all the metastasis but various tumors were
involved.
Daniel
UCLA MD
13 Sep, 12:10 AM0
#
PEhrlich Comments (443)
Thank you Daniel. I"m not sure we aren't arguing past each other to some
extent, but I appreciate your thoughts.
13 Sep, 03:58 AM0
#
William Haynes Comments (21)
Your point about mammary cancer is not quite correct. You said:
'The PWG was able to decisively demonstrate that there is no increased
cancer risk to humans and that the risk is actually lower than Arena
originally estimated in their first New Drug Application.'
That misses some subtle points, like there IS an increase at the highest
dose.
Here is the press release from Arena:
'The PWG consisted of five pathologists contracted by Arena. Arena consulted
the US Food and Drug Administration (FDA) in selecting these pathologists.
According to the PWG's re-adjudication, the incidence of adenocarcinomas was
numerically lower than the control group in both the lorcaserin low (10 mg/
kg/day) and mid (30 mg/kg/day) dose groups and was statistically higher than
the control group in the lorcaserin high (100/kg/day) dose group, and the
incidence of fibroadenomas was statistically higher than the control group
for all three lorcaserin dose groups.'
AND
'It is important to note that the FDA may have a different interpretation of
the re-adjudication and subsequent conclusions of the PWG. There may be
other factors in addition to incidence that may contribute to the FDA's
assessment of human risk for the finding of mammary tumors in female rats.
The information reported in this press release summarizes a report
containing voluminous and detailed data that will be reviewed by the FDA.
The FDA may analyze or weigh the importance of data from the report
differently than the PWG or Arena.'
12 Sep, 05:23 PM0
#
sts66 Comments (72)
"hat misses some subtle points, like there IS an increase at the highest
dose. "
So what? The human dose doesn't come anywhere close to the highest dose, and
the data shows LESS cancers in the low and mid doses compared to the
placebo control group. Lorc, a cure for cancer? Whodathunkit....
"the incidence of fibroadenomas was statistically higher than the control
group for all three lorcaserin dose groups."
Again, so what? Fibroadenomas are benign growths, not cancerous tumors. Also
suggest you don't try to tangle with Dr. Dan, you *will* lose the argument.
12 Sep, 06:02 PM0
#
KLLJ Investments Comments (45)
Thanks for all of the excellent commentary, especially from Dan and Dr.
Daniel. I think we can all state with certainty that there are no sure
things in biotech investing. The FDA can come up with new concerns or a
number of other stumbling blocks to keep lorcaserin from ever getting
approved. Lorcaserin will hurt the sales of many major drugs and big pharma
(outside of Eisai) don't want to see it approved. However, sentiment has
shifted since 2010 for this space and Congress has taken notice. Given the
currently available data and progress Arena has mad to address the points
made from the CRL, the chances for approval are far greater now then they
were last year. If the Street thought ARNA had a chance, the stock would be
10X higher than it is now. The fact is they don't so are they wrong or are
ARNA longs wrong? Time will tell but for me it is worth a gamble with the
stock under $2. There is plenty of room to run pre-PDUFA if ARNA can in fact
file by the end of the year regardless if you hold through the FDA decision
.... | w*******d
发帖数: 3714 | 10 关键我们局外人还是看不清楚这个老鼠肿瘤的问题到底算解释清楚了没有，这个要靠内
行来评论了，FDA事实上往往是不理性的 | | | f*****g
发帖数: 312 | 11 这个头像是熟萎男
【在 v**********m 的大作中提到】
: 熟男四十一朵花。
| v**********m
发帖数: 5516 | 12 Arna近期会拉一拉。
【在 f*****g 的大作中提到】
: 这个头像是熟萎男
| K********g
发帖数: 9389 | 13 真的拜托你换一个头像吧
【在 v**********m 的大作中提到】
: Arna近期会拉一拉。
| v**********m
发帖数: 5516 | 14 哈哈。老牛真受不了了？
这个怎么样？
【在 K********g 的大作中提到】
: 真的拜托你换一个头像吧
| v**********m
发帖数: 5516 | 15 snv insider transactions
Aug 10, 2011 STELLING KESSEL DOfficer 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 PROCHASKA JOSEPH J JRDirector 5,898 Direct
Acquisition (Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 BRUMLEY FRANK WDirector 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 CAMP ELIZABETH WDirector 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 PURCELL J NEALDirector 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 YANCEY JAMES DDirector 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 ANTHONY RICHARD EDirector 5,898 Direct Acquisition
(Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 LAMPTON MASON HDirector 5,898 Direct Acquisition (
Non Open Market) at $1.27 per share. 7,490
Aug 10, 2011 GOODRICH T MICHAELDirector 5,898 Direct Acquisition
(Non Open Market) at $1.27 per share. 7,490
Aug 9, 2011 PERRY CURTIS JOfficer 25,000 Direct Purchase at $1.
25 per share. 31,250
Aug 9, 2011 BRADLEY RICHARD YDirector 25,000 Direct Purchase at
$1.23 per share. 30,750
Aug 8, 2011 PERRY CURTIS JOfficer 27,800 Direct Purchase at $1.
21 per share. 33,638
Aug 8, 2011 PURCELL J NEALDirector 33,000 Direct Purchase at $1.
27 per share. 41,910
Aug 8, 2011 YANCEY JAMES DDirector 50,000 Direct Purchase at $1.
31 per share. 65,500
Aug 3, 2011 PERRY CURTIS JOfficer 55,000 Direct Purchase at $1.
68 per share. 92,400
Aug 3, 2011 BLANCHARD JAMES HDirector 111,088 Indirect
Acquisition (Non Open Market) at $0 per share. N/A
Aug 3, 2011 BLANCHARD JAMES HDirector 535,088 Indirect
Disposition (Non Open Market) at $0 per share. N/A
Aug 3, 2011 BLANCHARD JAMES HDirector 424,000 Direct Acquisition
(Non Open Market) at $0 per share. N/A
Aug 3, 2011 YANCEY JAMES DDirector 75,000 Direct Purchase at $1.
71 per share. 128,250
Aug 2, 2011 PROCHASKA JOSEPH J JRDirector 15,000 Direct Purchase
at $1.77 per share. 26,550
Aug 1, 2011 GULA ALLEN JOfficer 95,629 Direct Acquisition (Non
Open Market) at $0 per share. N/A
Jun 9, 2011 PAGE H LYNNDirector 543,379 Indirect Acquisition (
Non Open Market) at $0 per share. N/A
Jun 9, 2011 PAGE H LYNNDirector 543,379 Direct Disposition (Non
Open Market) at $0 per share. N/A | X*****s
发帖数: 2767 | 16 please stick to the old one. it's cool and charming.
【在 v**********m 的大作中提到】
: 哈哈。老牛真受不了了？
: 这个怎么样？
| v**********m
发帖数: 5516 | 17 靠，我不卖色的。
【在 X*****s 的大作中提到】
: please stick to the old one. it's cool and charming.
| b*****h
发帖数: 783 | 18 我印象中他们还没有开始老鼠肿瘤试验。
The
【在 v**********m 的大作中提到】
: Arna pump新文。
: http://seekingalpha.com/article/292994-is-arena-s-lorcaserin-on
: Is Arena's Lorcaserin On Track For Approval In 2012?
: 28 comments | by: KLLJ Investments September 12, 2011 | about: ARNA
: Arena Pharmaceuticals (ARNA) investors have had a tough road over the last
: 12 months since a negative vote by an Advisory Committee called to review
: Arena’s lead drug candidate for the treatment of obesity – lorcaserin. The
: stock was trading close to $7.00 a year ago heading into that fateful
: Advisory Committee, down to under $2 after a negative vote foreshadowed a
: Complete Response Letter (CRL) from the Food & Drug Adminstration (FDA).
| v**********m
发帖数: 5516 | 19 --------------------
转片旧文
Arena Pharmaceuticals (ARNA) is in the process of addressing issues raised
in the FDA’s complete response letter (CRL) of October 23, 2010 and expects
to file this response by year end. The company discussed its progress
during the second quarter conference call of August 9, 2011. Arena has
recently released results addressing two of the issues raised in regard to a
two-year carcinogenicity study in rats. One of these was the occurrence and
importance of mammary tumors in female rats and the other was detection of
astrocytomas in the brains of male rats. These were discussed at length on
the call.
I have listened to the conference call and this note summarizes the key
points that I think were made. I do not have a conclusion on whether the FDA
will conclude that Arena has satisfactorily addressed the concerns raised
in the CRL or will ask for more data. There is little in the way of
historical precedent to help form judgments. As is evident in this note,
Arena’s work has come a long way toward defining the issues and giving
greater comfort in the safety of this drug, but is it enough? The FDA seems
to be setting incredibly high safety requirements for all drugs and anti-
obesity agents in particular.
The market appears to be betting that the FDA will not approve Lorcaserin
and this is reflected in the stock price. In the event of acceptance of the
CRL and ultimate approval, the short term upside would appear to be much
greater than the downside if the drug is rejected. However, I have no clue
as to what the FDA may do and I am going to sit this one out.
Mammary Tumors in Female Rats
In the CRL, the FDA questioned Arena’s classification of benign versus
malignant mammary tumors in female rats in a two year carcinogenicity study
and as a result conservatively combined both the benign and the malignant
tumor types in their analysis. In order to answer this FDA concern, Arena
formed a pathology working group (PWG) of five pathologists agreed to by the
FDA to look at and re-adjudicate the classification of benign versus
malignant tumors in the original rat tissue samples. Each pathologist made
his own diagnosis and when there was disagreement a consensus was reached.
The PWG concluded that mammary fiber adenomas, which are benign tumors,
could be distinguished from the mammary adenocarcinomas, which are malignant
tumors. The PWG then concluded that the incidence of the malignant mammary
adenocarcinomas was not increased relative to control in the Lorcaserin low
and mid dose groups. The incidence of mammary adenocarcinoma was
statistically higher in the Lorcaserin high-dose group than in the control
group. The low dose was 10 mg/kg/day which is 7 times the exposure that
humans would encounter at the proposed human dose. The mid dose is 30 mg/kg/
day or 24 times and the high dose is 100 mg/kg/day or 82 times. These
results suggest that there is a margin of safety of at least 24 times the
proposed human dose.
Aggressiveness of Mammary Tumors
In the CRL, the FDA also requested additional information about the
aggressiveness of mammary adenocarcinoma. Some indicators of aggressiveness
include; (1) incidence, (2) the time to tumor development, (3) the frequency
of multiple tumors developing in individual rats and (4) the role of
metastases in tumor related mortality.
The PWG concluded that neither incidence nor time to tumor development
differed from controls at the low and mid Lorcaserin doses. However, both
reached significance at the high Lorcaserin dose. The PWG described the
frequency of mammary metastases as basically the same between control and
low-dose group and equivocally increased in the mid and high dose groups. It
does appear that there is an increase in lung metastases of mammary gland
origin at the mid dose. The lung metastases are only one way to look at
tumor aggressiveness and it is difficult to determine what weight the FDA
will give this issue.
Mechanism of Action
Arena continues to investigate a mechanism for mammary tumors in rats and
has repeatedly said that it believes that it is probably irrelevant to
humans. The company is conducting a series of studies that are intended to
test the hypothesis there is a causal relationship between Lorcaserin,
prolactin and mammary tumor development in rats. No one experiment is
expected to be conclusive and conclusions will be drawn from the aggregate
data of several studies. This raised the concern of some investors as to
whether the prolactin hypothesis is not as solid as was originally implied
by the company. The longest duration of any study is three months and Arena
anticipates having final data and reports late this year. This timeline
should enable the company to submit its complete response around year end.
There was a discussion with the FDA on whether Arena might need one-year
studies to assess the hypothesized prolactin mechanism. Arena feels that the
one-year suggestion by the FDA was just that, a suggestion, in case the
company could not show what was needed in three months. Arena doesn’t
anticipate initiating a longer term study for the female rats.
Brain Astrocytoma
The work related to brain astrocytoma in male rats was done to provide
greater confidence in the exposure margin for human as compared to rats
through estimating Lorcaserin brain levels in the two species. In a protocol
submitted to the FDA, brain concentrations of Lorcaserin were measured in
cerebrospinal fluid of nine obese volunteers. Arena concluded that humans
concentrate Lorcaserin in cerebral spinal fluid 14 times less than do rats.
The plasma concentrations at which astrocytomas occurred in rats was at five
times the anticipated human clinical exposure. This suggests a safety
margin of 70 times the proposed human dose and far beyond the margin that
was previously estimated based on plasma exposure alone.
Components of Response to Complete Response Letter
Arena’s planned response to the CRL incorporated seven activities, of which
most are complete and the company anticipates that all will be completed by
year end in time to file a CRL.
1. To establish certainty in the classification of mammary tumors in
female rats. The PWG’s re-adjudication is now complete and showed that at
the low and mid dose, the malignant tumors in these rats were really no
different than control animals and only at the highest dose was there a
statistically significant increase.
2. To more accurately estimate the exposure margin for brain astrocytomas
observed in male rats. The human CSF study and related analyses that will
help to establish a new estimate are now complete.
3. To investigate a mechanism for mammary tumors and the mechanistic
studies are underway. Arena has made good progress thus far, and should have
the work completed by yearend.
4. To address the FDA's concern that mammary adenocarcinomas in female
rats appear to be more aggressive with Lorcaserin administration. Arena
believes that the data from the PWG's re-adjudication will help address this
issue. Perhaps the greatest uncertainty is the occurrence of lung
metastases in the mid dose range.
5. To incorporate the final study report from BLOOM-DM into the overall
benefit risk assessment of Lorcaserin. This has been completed.
6. To further assess abuse potential. Dosing in two preclinical studies
is now complete, and the company expects to have the final study reports
later this year.
7. To further define receptor selectivity. This work is ongoing, but
should be done by year end.
-----------------------
【在 b*****h 的大作中提到】
: 我印象中他们还没有开始老鼠肿瘤试验。
:
: The
| b*****h
发帖数: 783 | 20 ARNA 的确在逐步解决fda提出的问题。
我觉的关键问题是老鼠生肿瘤的机制问题。
这个文章中提到的Mechanism of Action那部分。
FDA 要求arna 做一个不少于3个月的老鼠试验，并且建议另外做一个1年的老鼠试验。
FDA要求试验前先和fda确认protocol。
在公司5/10的ER中，可以看出试验还没有开始。
后面没看到公司有关这个老鼠肿瘤机理试验的update
expects
a
and
of
【在 v**********m 的大作中提到】
: --------------------
: 转片旧文
: Arena Pharmaceuticals (ARNA) is in the process of addressing issues raised
: in the FDA’s complete response letter (CRL) of October 23, 2010 and expects
: to file this response by year end. The company discussed its progress
: during the second quarter conference call of August 9, 2011. Arena has
: recently released results addressing two of the issues raised in regard to a
: two-year carcinogenicity study in rats. One of these was the occurrence and
: importance of mammary tumors in female rats and the other was detection of
: astrocytomas in the brains of male rats. These were discussed at length on
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