frontiers
12年前
Levadex has shown heart valve changes in P3 trials (3 pts with issues out of 638 pts)
Source : http://www.mappharma.com/file.cfm/124/docs/Cardiac_Web.pdf
Excerpt
Assessment of Cardiac Safety of MAP0004 Orally Inhaled Dihydroergotamine (DHE)
The cardiac safety of MAP0004 was assessed in clinical studies
Echocardiograms and electrocardiograms were reviewed by Board Certified
Cardiologists at a central reading center
Three MAP0004 treated subjects (out of 638) had changes in vavular regurgitation (two of tricuspid valve and one of mitral valve) vs. none in placebo treated subjects (out of 217). Changes were not considered clinically relevant.
Comments
Sounds similar to the phenfen story from Wyeth ? Initial reports were on heart valve changes and ignored till some phenfen users died. The initial reports for Levadex note changes but they are not clinically relevant. The same story happened with Redux. Has MAPP done follow-up biopsy on the affected valves to rule out fibrotic changes ? No, they did not do this.
Both fenfluramine and dihydroergotamine are 5HT 2B agonists, fenfluramine has greater agonist action meaning dihydroergotamine (DHE) is partial agonist, LSD, a compound related to DHE is a full agonist. But fenfluramine and DHE bind 5HT 2B equally well. Like Redux, DHE as Migranal or Dihydergot carry a warning for cardiac valvulopathy (see label for Migranal). The FDA may consider the heart valve findings for Levadex negatively. The issue becomes relevant as Levadex has shown issues in a relatively small number of patients, placebo has no such cases. Effect of exposure is one more thing that the FDA will look at. Levadex, if approved, will increase the use of DHE further than what Migranal has done (Vernalis does not promote as well enough) and the heart valve issue becomes a real concern.
The 6 month dog toxicology study with Levadex did not show any issues. However, the study did not use known heart valve disease causing agents as controls, fenfluramine as positive control and cyproheptadine as negative control. Should controls fail to show expected results, dog model would be invalid for cardiac valve disease. SD rat and cynomolgous monkey have been shown to be meaningful. A good reference for drug induced valvulopathy is a recent GSK presentation. (http://www.toxpathindia.com/docs/fourth_conference_2012/Elangbam_Drug-induced%20Valvulopathy.pdf). It lists DHE as causing Drug Induced Valvulopathy.
Levadex subjects the lung and heart to higher levels of DHE compared to Migranal Nasal Spray as delivery of DHE through Levadex is pulmonary absorption while Migranal is nasal cavity based absorption and more distributed before reaching the heart. Both bypass hepatic extraction. Both are equally effective at treating acute migraine based on P3 data (comparison across trials unfortunately). Levadex is not a big advance over Migranal in this regard.
In the Migranal NDA comments (NDA 20148, documents at FDA site), the FDA notes that while oral, intra-venous, intra-muscular and sub-cutaneous forms of DHE are already marketed, the FDA considers nasal spray different for two reasons. Firstly, the delivery method subjects the nasal cavity to high levels of drug and nasal toxicity becomes relevant. Secondly, DHE is used sparingly in current forms as oral is not very effective and injected forms are delivered by HCP. With a nasal spray approval, use will increase due to convenience and hence, performing rigorous studies to study risks is needed. The FDA gave Novartis a non-approvable letter and noted that nasal delivered carcinogenicity studies in rodents are needed for approval. In the case of Levadex, MAPP has done the 6 month Levadex dog toxicology study but this may not address the relevant lung and heart exposure issue with respect to valve pathology as the dog model is not validated for such effects. The FDA may delay approval till human studies for cardiac valve disease studies are done by MAPP considering that duplication in an animal model may be problematic. A 2 year study with 5000 patients against placebo is a guess.
Zecuity is a far safer option for treating acute migraine and a true advance over sumatriptan oral, sc or nasal. Levadex is another version of Migranal. Novartis has divested Migranal to Vernalis without completing 2 year nasal spray rat carcinogenicity studies that the FDA required as a post market commitment. Novartis submitted a preliminary 2 year nasal carcinogenicity report just prior to approval that the FDA did not review at approval (noted in documents) but Novartis did not provide a full report as needed. The label for Migranal till today notes that rat nasal delivered carcinogenicity studies are not available. This baggage goes with Levadex. MAPP is not submitting these either as they are using the 505 (b) (2) pathway inappropriately, what is needed is a full new NDA through the (505) (b) (1) pathway. Migranal pulmonary and cardiac fibrosis issues will appear on the Levadex label if MAPP used 505 (b) (2) as planned. Removal of pulmonary and cardiac fibrosis will be a gift to the lawyers. This pulmonary and cardiac fibrosis warning for long term use on the Levadex Label will make the clean Zecuity Label appealing for physicians and their patients.
Another recent example of a drug with 5HT 2B binding is lorcaserin. The FDA gave Arena a CRL and called for an Advisory Committee Meeting. One of the issues for discussion at the Advisory Committee Meeting was the heart valve fibrosis (see briefing document). Lorcaserin is a new chemical entity without past experience. DHE in Levadex is an existing drug and has shown cardiac fibrosis and 5HT 2B binding to be as potent as pergolide, an agent withdrawn due to pulmonary and cardiac fibrosis. The FDA cannot ignore considering that heart valve changes were seen in rather small P3 Levadex trials.
SoonerBrn
12年前
Congrats to all shareholders!!!
IRVINE, Calif. & MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)--
Allergan, Inc. (AGN) and MAP Pharmaceuticals, Inc. (MAPP)
today jointly announced that they have entered into a definitive merger
agreement whereby Allergan will acquire 100% of the shares of MAP
Pharmaceuticals for a price of $25.00 per share. MAP Pharmaceuticals is
a biopharmaceutical company focused on developing and commercializing
new therapies in Neurology, including LEVADEX®, an orally inhaled drug
for the potential acute treatment of migraine in adults. LEVADEX® is
currently under review with the U.S. Food and Drug Administration (FDA).
The transaction, which has been unanimously approved by the boards of
directors of both companies, will be accomplished pursuant to a cash
tender offer followed by a second step merger. The per share cash offer
price represents a 60% premium over MAP’s closing stock price on the
Nasdaq Stock Market of $15.58 on January 22, 2013, and represents a
total equity value of approximately $958 million, on a fully-diluted
basis. The acquisition is expected to close late in the first quarter or
in the second quarter of 2013.
“One of the key drivers of Allergan’s continued success is our focus on
medical specialties where we have extensive knowledge of physician and
patient needs, and can provide a broad portfolio of products,” said
David E.I. Pyott, Chairman of the Board, President and Chief Executive
Officer, Allergan. “Allergan has a record of leadership in the
Neurosciences field and, according to a recent physician survey, is now
perceived as the #1 company in prophylactic migraine management by
physicians. During the past few years, Allergan has received regulatory
approvals in 56 countries for BOTOX® for use in the treatment of chronic
migraine. As a result, thousands of patients who suffer from chronic
migraine have benefited from this important treatment option. We plan to
capitalize on this depth of expertise in Neurology as we continue the
global development of LEVADEX® as a potential acute treatment for
migraine that is complementary to BOTOX® and use MAP’s proprietary drug
particle and inhalation technologies to generate new pipeline
opportunities.”
“Through our dedicated employees at MAP Pharmaceuticals, we have made
tremendous progress to date with our lead product candidate, LEVADEX®,
enabling us to realize substantial value for our stockholders through
this transaction,” said Timothy S. Nelson, President and Chief Executive
Officer, MAP Pharmaceuticals. “We are pleased that we and Allergan share
similar values and a common vision in neuroscience that make for a
strong cultural and scientific fit between our companies. We believe
this acquisition by our partner Allergan will increase the potential for
our product candidates to make a meaningful difference for patients we
have worked so hard to serve.”
In January 2011, Allergan entered into a collaboration agreement with
MAP to co-promote LEVADEX®, contingent upon potential regulatory
authority approvals in the U.S. and Canada, to neurologists and pain
specialists in these markets. In May 2011, MAP initially submitted a New
Drug Application (NDA) for LEVADEX® to the FDA. In October 2012, MAP
resubmitted its NDA, which included additional data and provided
responses to FDA comments. In November 2012, MAP announced that its NDA
resubmission for LEVADEX® was accepted for filing by the FDA and that
the FDA has classified the resubmission as a complete Class 2 response
and has set a goal date of April 15 th , 2013 under the
Prescription Drug User Fee Act (PDUFA).
Assuming this transaction closes as planned, and approval of LEVADEX®
occurs on or before the PDUFA date of April 15 th , 2013,
Allergan anticipates that this transaction will be dilutive to 2013
earnings per share by approximately $0.07 and accretive to earnings per
share by the second half of 2014. Allergan will provide 2013 guidance on
its February 5, 2013 earnings call. Allergan currently anticipates that,
excluding this transaction, 2013 earnings per share growth expectations
will fall within our mid-teens growth aspiration.
Allergan expects to fund the transaction with a combination of cash on
hand, cash equivalents and short-term borrowings under its commercial
paper program. The transaction is not subject to any financing
contingency.
About the Cash Tender Offer
Under the terms of the definitive merger agreement, Allergan will
commence a cash tender offer to purchase all of MAP’s outstanding shares
for $25.00 per share, net to the seller in cash, without interest and
less any applicable withholding taxes. The tender offer will remain open
for at least 20 business days. The completion of the tender offer is
subject to the tender of at least a majority of MAP’s outstanding shares
of common stock (on a fully diluted basis), the expiration or
termination of the waiting period under the Hart-Scott-Rodino Antitrust
Improvements Act, and other customary closing conditions. The merger
agreement also provides for the parties to effect, subject to customary
conditions, a merger following the completion of the tender offer which
would result in all shares not tendered in the tender offer being
converted into the right to receive $25.00 per share, net to the holder
in cash, without interest and less any applicable withholding taxes. The
board of directors of MAP has unanimously agreed to recommend that MAP’s
stockholders tender their shares to Allergan in the tender offer. All of
MAP’s directors and executive officers and a major stockholder of MAP
affiliated with a director, collectively owning approximately 9 percent
of MAP’s outstanding common stock, have entered into a tender and
support agreement with Allergan committing to tender all of their MAP
shares in the tender offer and, if applicable, to vote in favor of the
merger.
In connection with this transaction, Goldman, Sachs & Co. is acting as
financial advisor and Gibson, Dunn & Crutcher LLP as legal advisor to
Allergan. Centerview Partners LLC is acting as exclusive financial
advisor and provided a fairness opinion to MAP Pharmaceuticals, and
Latham & Watkins LLP as legal advisor to MAP.
Investor Information Call
Allergan will host a 30-minute conference call on Wednesday, January 23,
2013, commencing at 8:00 a.m. Pacific Time (11:00 a.m. Eastern Time) to
discuss and provide additional information regarding the proposed
acquisition of MAP Pharmaceuticals.
You may participate in this call by dialing 1-888-677-5720 or call
1-312-470-0056 from international locations. A passcode, Allergan
Conference Call , will be required. David E.I. Pyott, Allergan’s
Chairman of the Board, President and Chief Executive Officer, will
comment on the proposed acquisition.
The live Web cast can be accessed through the Allergan Web site, www.Allergan.com,
beginning at 8:00 a.m. Pacific Time. A replay of the discussion will be
available soon after the call and can be accessed through www.Allergan.com,
1-800-365-4718 for domestic locations or 1-203-369-3119 for
international locations. A passcode will not be required for the replay.
The replay will be available for one week following the live call.
About MAP Pharmaceuticals, Inc.
MAP Pharmaceuticals is a biopharmaceutical company focused on developing
and commercializing new therapies to address undermet patient needs in
neurology. The Company is developing LEVADEX®, an orally inhaled
investigational drug for the acute treatment of migraine. The New Drug
Application for LEVADEX® is currently under review by the U.S. Food and
Drug Administration. MAP Pharmaceuticals has entered into a
collaboration agreement with Allergan, Inc. to co-promote LEVADEX® to
neurologists and pain specialists in the U.S. and Canada. The Company
also applies its proprietary drug particle and inhalation technologies
to generate new pipeline opportunities by enhancing the therapeutic
benefits of proven drugs, while minimizing risk by capitalizing on their
known safety, efficacy and commercialization history. Additional
information about MAP Pharmaceuticals can be found at http://www.mappharma.com.
About Allergan, Inc.
Allergan is a multi-specialty health care company established more than
60 years ago with a commitment to uncover the best of science and
develop and deliver innovative and meaningful treatments to help people
reach their life’s potential. Today, we have approximately 10,800 highly
dedicated and talented employees, global marketing and sales
capabilities with a presence in more than 100 countries, a rich and
ever-evolving portfolio of pharmaceuticals, biologics, medical devices
and over-the-counter consumer products, and state-of-the-art resources
in R&D, manufacturing and safety surveillance that help millions of
patients see more clearly, move more freely and express themselves more
fully. From our beginnings as an eye care company to our focus today on
several medical specialties, including eye care, neurosciences, medical
aesthetics, medical dermatology, breast aesthetics, obesity intervention
and urologics, Allergan is proud to celebrate more than 60 years of
medical advances and proud to support the patients and physicians who
rely on our products and the employees and communities in which we live
and work. For more information regarding Allergan, go to: www.allergan.com.
Forward-Looking Statements
This press release contains "forward-looking statements," relating to
the acquisition of MAP Pharmaceuticals by Allergan. All statements other
than historical facts included in this press release, including, but not
limited to, the statements by Mr. Pyott and Mr. Nelson and other
statements regarding the timing, and the closing of the tender offer and
merger transactions, the expected benefits of the transaction, the
expected dilution and accretion to earnings, the anticipated 2013
earnings per share growth expectations, Allergan’s plans to operate MAP
and any assumptions underlying any of the foregoing, are forward-looking
statements. These statements are based on current expectations of future
events. If underlying assumptions prove inaccurate or unknown, or
unknown risks or uncertainties materialize, actual results could vary
materially from Allergan's or MAP’s expectations and projections. Risks
and uncertainties include, among other things, uncertainties as to the
timing of the tender offer and merger; uncertainties as to how many of
MAP’s stockholders will tender their stock in the tender offer; the
possibility that various closing conditions to the tender offer and
merger transactions may not be satisfied or waived, including that a
governmental entity may prohibit, delay, or refuse to grant approval for
the consummation of the transaction; that the FDA or other regulatory
authorities do not approve LEVADEX® in the manner desired by MAP and
Allergan, on a timely basis, or at all; that there is a material adverse
change to MAP; that the integration of MAP’s business into Allergan is
not as successful as expected; the failure of Allergan to achieve the
expected financial and commercial results from the transaction; other
business effects, including effects of industry, economic or political
conditions outside the company’s control; transaction costs; actual or
contingent liabilities; as well as other cautionary statements contained
elsewhere herein and in the companies’ periodic reports filed with the
SEC including current reports on Form 8-K, quarterly reports on Form
10-Q and annual reports on Form 10-K. Given these uncertainties, you
should not place undue reliance on these forward-looking statements,
which apply only as of the date of this press release. Allergan and MAP
expressly disclaim any intent or obligation to update these
forward-looking statements except as required by law. Additional
information about Allergan is available at www.allergan.com
or you can contact the Allergan Investor Relations Department by calling
714-246-4636. Additional information about MAP is available at www.mappharma.com.
Additional Information and Where to Find It
The tender offer described in the release has not yet commenced and the
release is neither an offer to purchase nor a solicitation of an offer
to sell shares of common stock of MAP. At the time the tender offer is
commenced, Allergan and its new wholly owned subsidiary, Groundhog
Acquisition, Inc., will file with the SEC a Tender Offer Statement on
Schedule TO, and MAP will file a Solicitation/Recommendation Statement
on Schedule 14D-9 with respect to the tender offer. MAP stockholders and
other investors are strongly advised to read the tender offer materials
(including the Offer to Purchase, the related Letter of Transmittal and
certain other tender offer documents) and the
Solicitation/Recommendation Statement because they will contain
important information which should be read carefully before any decision
is made with respect to the tender offer. The Tender Offer Statement and
the Solicitation/Recommendation Statement will be available for free at
the SEC’s website at www.sec.gov.
Free copies of these materials and other tender offer documents will be
made available by the information agent for the tender offer.
In addition to the Offer to Purchase, the related Letter of Transmittal
and certain other tender offer documents, Allergan and MAP file annual,
quarterly and special reports, proxy statements and other information
with the SEC. You may read and copy any reports, statements or other
information filed by Allergan and MAP at the SEC public reference room
at 100 F Street, N.E., Washington, D.C. 20549. Please call the
Commission at 1-800-SEC-0330 for further information on the public
reference room. Allergan’s and MAP’s filings with the SEC are also
available to the public from commercial document-retrieval services and
at the website maintained by the SEC at www.sec.gov.
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http://finance.yahoo.com/news/allergan-inc-acquire-map-pharmaceuticals-013500252.html
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surf1944
12年前
MAP Pharma: Shorts Should Beware
MAP Pharmaceuticals (MAPP) received a Complete Response Letter (CRL) from the FDA on March 26th, 2012. The FDA cited, "that the Company address issues relating to chemistry, manufacturing and controls (CMC) and observations from a recent facility inspection of a third party manufacturer." These issues raised by the FDA seem to be minor, and MAPP will be meeting with the FDA to learn more on how they can resolve them. The FDA is not requiring any additional safety or efficacy studies.
On March 11th, I wrote an article entitled "MAP Pharma: Making Money From Migraines", where I wrote I expected approval. I was wrong; however, I brought up the fact that FDA might bring up red flags on minor issues. Since the rejection, MAPP's stock price has slid lower, from 17 to 12, as investors have yet to receive clarity of when Levadex could receive approval. Currently, expectations for approval range from 4Q 2012 to 1H 2013.
Investors continue their wait for MAPP's meeting with the FDA. We know MAPP requested a meeting with the FDA and this meeting was granted to discuss the CRL. By law, the FDA has 14 days to accept or reject the meeting with a company and another 60 days to have this meeting. By simple math, that means 74 days is the maximum timeline after the rejection for MAPP to know additional details about the rejection. That 74th day would fall on June 9th, 2012.
Short sellers have been pressing the stock lower, as they don't expect approval until 2013. They also expect that MAPP will need to raise more cash, which I feel is not necessary (more details later). These short sellers should be getting a little nervous as we finally receive clarity on when MAPP will resubmit for approval. If it ends up being late 2012, shorts will be scrambling to buy back their short positions.
Short sale data has shown that short interest in MAPP has grown from 1.8M shares before the rejection to more than 4.8M shares as of May 15th. That is more than 22 days of volume to cover and 19% of the current float is short. As June 9th approaches, I expect some short sellers to cover and longs to reenter positions.
Bears in MAPP continue to raise the concern that the company won't get approval until Q2 2013 and would need to issue shares to have enough capital to launch their drug. As of March 31st, MAPP had $79M in cash on their balance sheet. They've guided to operating cash expenses of $35-$37M for the rest of the year, leaving the company with $42-44M in cash at the end of 2012. At this same burn rate, MAPP's cash position would be down to roughly $15-20M by middle of 2013.
What shorts are missing is that Allergan (AGN) partnered with MAPP on sales through neurologists and pain specialists in the US and Canada only. Based on approval, MAPP will be receiving $97M more in payments based on regulatory milestones (i.e. approval). This would give them more than $110M in cash if they were to have worst case scenario of Q2 2013 approval from the FDA. Either way, I doubt MAPP would need to raise cash between now and approval.
Also, MAPP remains un-partnered for the remaining U.S. sales (not covered in AGN agreement) and all ex-US sales. Any type of partnership will bring in huge sums of cash, again thwarting the thesis of short sellers. Willing partners might are more likely to strike a deal with MAPP now that the FDA has pulled the worst case scenario of Levadex never reaching approval off the table.
At its current share price, MAPP remains an attractive acquisition candidate and investment. The share price could remain weak in the near term as the timeline of FDA approval is still unknown. I remain an advocate of selling $12.50 or $10 put options. I previously mentioned in my March 11th article that I was short puts, and anyone who pursued this strategy is still seeing solid profits despite MAPP's sagging price. In the end, the worst case scenario for MAPP was taken off the table by the FDA, and upon approval shares of MAPP will be over $20 for good.
Disclosure: I am short MAPP puts.
http://seekingalpha.com/article/622211-map-pharma-shorts-should-beware?source=yahoo
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