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发帖数: 5516 | 1 An Update on Alexza Pharma (ALXA) - Analyst Blog
By Zacks
Jason Napodano, CFA
On October 10, 2010, the U.S. FDA issued a complete response letter (CRL) on
the approval of AZ-004 (Staccato loxapine) for the rapid treatment of
agitation in patients with schizophrenia or bipolar disorder. The FDA
raised four issues in the CRL with the new drug application for Adusuve:
1) The FDA raised concern on the clinical safety data from the three phase I
pulmonary safety studies with AZ-004 based on observed, dose-related post-
dose decreases in forced expiratory volume in one second (FEV1) in both
healthy subjects and in subjects with COPD and asthma. The dose-response
relates to a greater reduction in FEV1 following the second inhalation
relative to the first. The agency also noted that decreases in FEV1 were
recorded in healthy subjects who were administered device-only (no drug)
control versions of AZ-004.
- Initially this sounds pretty bad. The FDA is concerned with marked (>10%)
reductions in FEV1 in healthy patients, both on drug and placebo. The CRL
calls into questions the potential safety of not only AZ-004 (Staccato
loxapine) but the Staccato device itself.
Alexza ( ALXA ) has spent the past month and a half analyzing the data from
the pulmonary safety programs and from the phase III trial. The company has
hired outside consultants to help analyze if there is a safety concern with
Staccato or AZ-004. Management's conclusion is that if there is a safety
concern, it can be adequately managed with restrictive labeling or a REMS
program post-approval. Previously management has spoken about a “
fundamentally different view” of the data from the FDA. Management will
get its chance to convince the FDA face-to-face at a meeting in two weeks.
Some ammunition on management's side:
1. All respiratory symptoms that developed after treatment in the phase I
study were either self-limiting (resolved spontaneously) or readily managed
with an inhaled bronchodilator.
2. No intravenous intervention was necessary due to respiratory side-effects
in either the phase I pulmonary safety study or the pivotal phase III
program.
3. There were no serious adverse events (SAEs) in the phase I or the phase
III pivotal program. Respiratory events in the phase III program (~750
patients) were less than 2%.
4. We note that during the clinical trials, use of standard bronchodilators
was prohibited while on drug.
Management does not believe there are significant pulmonary safety issues
that would prevent approval of AZ-004. It is clear that in patients with
already impaired lung function, such as asthma or COPD, a REMS program must
be put into place to reduce risk. This REMS program can be expanded to
include use in patients with healthy airways to satisfy the FDA's concerns.
This issue is clearly something the company believes can be managed with
labeling, a REMS program, and post-approval through a phase IV study.
2) The CRL raised issues relating to the suitability of the stability
studies undertaken by Alexza. Management conducted a 12-month accelerated
and 12-month standard stability program. The proposed stability of the
product is 18 to 24 months.
- We note that the supply chain for the Staccato device has changed
dramatically over the past 24 months. Management noted a number of
component suppliers going out of business. Management has shifted around
manufacturing piece of the device from small (unreliable) firms to larger (
financially stable) organizations and brought final assembly in-house. This
includes the foil wrap film that surrounds the device. The FDA questions
the suitability of the data because many of the suppliers used to collect
the data have changed.
Alexza has begun a new accelerated and standard stability program following
the CRL in October 2010. Sufficient data should be collected in time for a
re-file around the middle of 2011. Management also noted that they can seek
approval with a lower shelf-life, of say 12 months, and then supplement
post approval to bring the shelf-life up to the desired 18 to 24 months. In
our view, this is a non-issue.
3) The CRL raised issues relating to the agency's pre-approval manufacturing
inspection.
- We note the inspection was only recently completed in August 2010.
Management submitted a response to the FDA's questions in September 2010.
Much of this information was not included in the CRL letter. Questions
following a pre-approval manufacturing inspection, especially for a brand
new drug-device combination, are common. Alexza believes that all of the
questions on the pre-approval manufacturing inspection have already been
address or can be address with the FDA at a face-to-face meeting. Similar
to the stability issues, we do not believe this is a significant or rate-
limiting issue.
4) Because AZ-004 incorporates a novel delivery system, the CRL also
included input from FDA's Center for Devices and Radiological Health (CDRH).
CDRH requested a human factors study and related analysis to validate that
the product can be used effectively in the proposed clinical setting.
- Alexza did not submit a standard human factor study as part of the new
drug application. Instead, management submitted data from over 1,600
patients in the clinical setting, including roughly 750 patients from the
phase III pivotal program.
According to management, the protocols for these studies are pretty
straightforward with clearly validated endpoints. The operation of the
trial can be outsourced to an organization that handles these programs and
conducted rather quickly. Alexza has been in conversation with a handful of
these “FDA approved” centers and plans to begin the study early next year
. A Human Factors Study in approximately 30-40 patients can be completed in
less than two months time at a cost of less than $500K. We do not believe
this is a significant or rate-limiting issue.
Of the four issues raised by the FDA, we believe Alexza has answered or will
be in position to answer three of them (stability, manufacturing, and use)
by the middle of 2011. The wild-card remains the pulmonary safety and
whether or not the FDA requires Alexza to conduct additional pulmonary
safety studies prior to granting approval. Alexza's plan is to address the
issue through product labeling and a REMS program post approval.
Despite remaining big fans of the Staccato device and our belief that
management can work through the above issues with the FDA, we have a Neutral
rating on Alexza Pharma while we wait for the next update. Management has
not yet had a chance to speak with the FDA. Although meeting with the FDA
could result in a positive development for the stock, the soonest we see a
possible re-file on AZ-004 would be May / June 2011. This potentially puts
another FDA action on the product during the back half of 2011. We should
have additional information from the company on this strategy after the face
-to-face meeting schedule for later this month. Our target is $2 per share.
Read more: http://www.benzinga.com/10/12/666450/an-update-on-alexza-pharma-alxa-analyst-blog#ixzz1RLEc6FXg | v**********m
发帖数: 5516 | 2 http://seekingalpha.com/article/270094-biotech-some-crl-recipie
Alexa Pharmaceuticals (ALXA) Market Cap $102.4 Million 05/13/11 at 1.42 PPS
Alexa received its CRL on October 11, 2010 for its lead product, AZ-004, for
reducing agitation in patients with schizophrenia or bipolar disorder. The
active ingredient in their Staccato device that emits an aerosol spray to be
inhaled by the patient is loxapine, a drug already approved for use as an
antipsychotic medication. The two Phase III trials leading up to the NDA met
all primary endpoints. However, the FDA expressed concern in the CRL that
there were observed, dose-related post-dosage decreases in forced expiratory
volume in one second, or FEV1, in healthy subjects and in subjects with
COPD and asthma. A similar effect was seen in patients receiving placebo
solutions also from the Staccato device. In a January 18 release, Alexa
noted that it had submitted an information packet to the FDA already
addressing the concerns of safety, noting that the pulmonary changes were
likely background events in the patient population and that the extensive
and repeated pulmonary testing may have even caused some of the observations
. Alexa recently stated that it intends to resubmit the NDA in July of 2011
and expects a PDUFA date in early 2012. There were less significant items
mentioned in the CRL that Alexa believes it can address pertaining to "at
risk" patients via risk management, and that plan will be included in the
NDA resubmission in July. Relative to Biodel and MannKind, Alexa's CRL was a
fairly soft one and the company's financials are likely adequate due to a
recent $16.1 million stock offering on May 3 to fund them through the
apparent PDUFA date in 1Q 2012. As of March 31, Alexa had consolidated cash,
cash equivalents and marketable securities of $31.8 million with a 1Q cash
burn of $8.4 million. Alexa is also planning on submitting a Marketing
Authorization Application (MAA) to the European Medicines Agency (EMA) for
marketing approval for the Staccato device in late 3Q 2011 as well. A lot is
on the line for Alexa with pressure to get the device/drug combination
approved to help legitimize their Staccato device and to help their own
financials out. With the approval, all the licensing partnerships they've
been trying to gain would be a huge step closer to reality. | v**********m
发帖数: 5516 | 3 http://www.reuters.com/finance/stocks/ALXA.W/key-developments/a
Alexza Pharmaceuticals, Inc. Prices $16.1 Million Registered Direct Offering
Tuesday, 3 May 2011 08:30am EDT
Alexza Pharmaceuticals, Inc. announced that it has entered into a definitive
agreement with three institutional investors, including RA Capital
Management and Tavistock Life Sciences, to raise approximately $16.1 million
in gross proceeds in a registered direct offering through the sale of
common stock and warrants. The Company agreed to sell a total of 11,927,034
units, each unit consisting of (i) one share of common stock and (ii) one
warrant to purchase 0.35 of a share of common stock, at a purchase price of
$1.35 per unit. The warrants will be exercisable six months after issuance
at $1.755 per share and will expire five years from the date of issuance.
The shares of common stock and warrants are immediately separable and will
be issued separately. Alexza estimates that net proceeds from the offering
will be approximately $15.8 million, after deducting estimated offering
expenses. The Company intends to use the net proceeds from the sale of the
securities primarily for general corporate purposes, including regulatory
activity, clinical trial, research and development, general and
administrative and manufacturing expenses. | v**********m
发帖数: 5516 | 4 http://seekingalpha.com/article/229617-alexza-s-crl-offers-long
The FDA showed it was playing hardball this October by delivering two
completes response letters (CRLs) last Friday – one to Jazz Pharmaceuticals
(JAZZ) and the other to Alexza Pharmaceuticals (ALXA). While the Jazz CRL
was generally expected, Alexza Pharmaceuticals was widely expected to gain
approval on first pass - RBC even stated odds of approval as high as 65%. As
a result, the share price took a 55% haircut in the first day of trading
after its rejection and continues downward today. While making a play on
this stock before Alexza reports its discussions with the FDA about the CRL
is a risky proposition, those that buy at these low prices stand to be
handsomely rewarded when the uncertainty is resolved.
The issues brought up in the CRL according to the conference call held this
morning appear to be based on the following four points.
1. Pulmonary safety
2. Suitability of stability studies
3. Manufacturing facility inspections
4. Validation that product can be used effectively in the setting
proposed in the label
The suitability of stability studies and manufacturing facility inspections
appear to be rather innocuous. The stability studies are rather
straightforward and the company has completed both 12-month standard and 12-
month accelerated stability programs. Manufacturing concerns are relatively
common – especially when dealing with new drug delivery platforms – and
management believes those concerns can be resolved in a face-to-face meeting
with the FDA. It would appear that the data to address both of these claims
is readily available and the management has stated is does not expect
either of these issues to be rate limiting.
The validation that the product can be used effectively was raised by the
Center for Devices and Radiological Health and it’s a reasonable concern.
After all, AZ-004 is a treatment for agitation in bipolar and schizophrenic
patients. Will a psychologically agitated patient be able to effectively use
the device?
Alexza did not include a human factor study in its new drug application (NDA
); instead relying on what the company thought was comprehensive phase III
data showing that the treatment could be used effectively. Performing the
now requisite study, however, does not appear to be particularly time
consuming. The company has stated that the study has already designed and
that the study could be completed by the end of the year.
The big concern, then, is the pulmonary safety issue. This has, apparently,
caught the company completely off guard as there were no communications
specifically about pulmonary safety between the FDA and Alexza for quite
some time. This concern lies primarily in the drug treatment arm of patients
with asthma and chronic obstructive pulmonary disease. Reductions in FEV1 (
force expiratory volume in one second – a measure of lung function) were
higher in both placebo and treatment groups, but higher in the treatment arm.
The important thing to note, however, is that there were no severe adverse
events (SAEs) and all events were self-limiting or readily managed with an
inhaled bronchodilator. Total respiratory events in the phase III study were
less than 2%. While the concern stands to bring doubt to the entirety of
Alexza’s inhalable drug platform, it is not something that can’t easily be
managed through excluding patients with existing impaired lung function or
through new labeling to warn of possible contraindications. And again, none
of the adverse events were considered serious – patients or doctors can
simply opt out of the AZ-004 treatment is the events are particularly
bothersome.
While losing a year or two of marketability on the front end of a product
life span can be particularly costly, it does not justify a 55% drop in
share value. The FDA is conducting its own due diligence and siding with
caution for a relatively new platform for drug delivery. The CRL does not
bring long term doubt into AZ-004 or the Staccato platform as a whole. Those
that buck the trend and buy into the currently depressed share values
should stand to profit handsomely in the long term. | v**********m
发帖数: 5516 | 5 http://www.mitbbs.com/clubarticle/pennystock/31535995_3.html
发信人: JustinCase (JustinCase), 信区: pennystock
标 题: 可以建仓ALXA了
发信站: BBS 未名空间站 (Tue May 24 20:38:30 2011, 美东)
1.25-1.35可以建仓ALXA,7月份FDA resubmission,之后应该会进入上升通道.年内到2应
该没有问题.
欢迎大家讨论. | H******k
发帖数: 690 | 6 Why it dropped so much today? | v**********m
发帖数: 5516 | 7 MM心思海底针。
【在 H******k 的大作中提到】
: Why it dropped so much today?
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