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v**********m
发帖数: 5516 | 1 Investment Considerations
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.
Disclosure: I have no positions in any stocks mentioned, and no plans to
initiate any positions within the next 72 hours. | y***q
发帖数: 4147 | 2 好长，看了一半看不下去了。
expects
a
【在 v**********m 的大作中提到】
: Investment Considerations
: 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.
| K********g
发帖数: 9389 | 3 你估计看不懂吧。
【在 y***q 的大作中提到】
: 好长，看了一半看不下去了。
:
: expects
: a
| w*********7
发帖数: 2883 | 4 怎么这样啊， google 翻译， 怎么都能看懂吧
【在 K********g 的大作中提到】
: 你估计看不懂吧。
| y***q
发帖数: 4147 | 5 1分
等我换电脑打
【在 K********g 的大作中提到】
: 你估计看不懂吧。
| H******k
发帖数: 690 | 6 Seeking alpha article, Aug 30, 2011
10 Biotech Stocks Being Dumped By Big Money Managers
http://seekingalpha.com/article/290509-10-biotech-stocks-being- |
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