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Update On Midodrine (Proamatine Under Shire Pharma) Saga


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PR Newswire

PHILADELPHIA, March 29, 2012

PHILADELPHIA, March 29, 2012 /PRNewswire/ --

Shire plc (LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company, reaffirms its commitment to patients as set forth in its recent agreement with the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) to conduct two additional clinical trials to verify and describe the clinical benefit of midodrine HCI.

Midodrine HCl, approved in 1996 under Subpart H (an accelerated approval process) for the treatment of symptomatic orthostatic hypotension (SOH), will remain available to patients who rely on this medicine while Shire's trials are conducted. To read the Midodrine Update from FDA please see the FDA website. Currently there are no alternative FDA-approved treatments for SOH.

"Our agreement with the FDA on clinical trials protocols to confirm the clinical benefit of midodrine is a good outcome and in the best interest of patients who rely on this medicine to manage their SOH symptoms," said Jeffrey Jonas, M.D., Senior Vice President of Research & Development for Shire. "Our agreement is especially important in light of the recent FDA Complete Response Letter for the New Drug Application (NDA) for droxidopa, a competitor investigational product, for the treatment of symptomatic neurogenic orthostatic hypotension in certain patient types. We appreciate the FDA's agreement to keep midodrine HCI on the market while we conduct the agreed upon trials."

Shire is the NDA holder for midodrine HCl, which had been marketed by Shire until 2010 under the brand name ProAmatine®. Shire has no financial interest in midodrine, and no longer manufactures, distributes or markets the brand name version of midodrine HCI, ProAmatine. Beginning in 2003, midodrine has been manufactured and distributed by generic pharmaceutical companies. As the NDA holder, Shire has continued to invest in the needed regulatory processes and has worked diligently with the FDA to develop this now agreed path forward that may permit midodrine to maintain its marketing authorization thus allowing it to remain available for patients who critically need this medicine.

"Even though Shire no longer generates revenue from midodrine, we've agreed to invest more time and resources in additional clinical trials because we know it's the right thing to do for patients," added Jonas. "Preliminary work on these two midodrine trials is underway and we anticipate completion in the first half of 2014."

With the 1996 Subpart H accelerated approval of midodrine for the treatment of SOH came a post-approval commitment by Shire to conduct two clinical trials to verify and describe the clinical benefit of midodrine HCI. The initial approval was based on midodrine's demonstrated ability to significantly raise blood pressure in patients with SOH. In 2000, Shire acquired the medicine and completed two clinical post-marketing trials as required and submitted the results to FDA in 2005. FDA took the position that those two trials were inadequate and requested that additional trials be completed. The agreement of the two additional clinical trials announced here is the outcome of the FDA request following the Shire submission of the 2005 data.

Important Safety Information

Warning: Because ProAmatine® can cause marked elevation of supine blood pressure, it should be used in patients whose lives are considerably impaired despite standard clinical care. The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

CONTRAINDICATIONS

ProAmatine® is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. ProAmatine® should not be used in patients with persistent and excessive supine hypertension.

Please see Full Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.FDA.gov/medwatch or call 1-800-FDA-1088

Notes to editors

SHIRE PLC

Shire's strategic goal is to become the leading specialty biopharmaceutical company that focuses on meeting the needs of the specialist physician. Shire focuses its business on attention deficit hyperactivity disorder, human genetic therapies, gastrointestinal diseases and regenerative medicine as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results. For further information on Shire, please visit the Company's website: http://www.shire.com.

"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORM ACT OF 1995

Statements included herein that are not historical facts are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, the Company's results could be materially adversely affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of research, development, approval, reimbursement, manufacturing and commercialization of the Company's Specialty Pharmaceuticals, Human Genetic Therapies and Regenerative Medicine products, as well as the ability to secure new products for commercialization and/or development; government regulation of the Company's products; the Company's ability to manufacture its products in sufficient quantities to meet demand; the impact of competitive therapies on the Company's products; the Company's ability to register, maintain and enforce patents and other intellectual property rights relating to its products; the Company's ability to obtain and maintain government and other third-party reimbursement for its products; and other risks and uncertainties detailed from time to time in the Company's filings with the Securities and Exchange Commission.

For further information please contact:

Gwen Fisher

gfisher@shire.com

+1-484-595-9836

SOURCE Shire plc

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Chelsea Therapeutics' CEO Hosts Conference to Discuss FDA's CRL to Northera (Transcript)

March 29, 2012

Chelsea Therapeutics International Ltd. (CHTP) FDA Issues Complete Response Letter Regarding Northera's NDA March 29, 2012 8:00 AM ET

Operator

Good day ladies and gentlemen and an welcome to the Chelsea Therapeutics March 29th conference call. At this time all participant lines are in a listen-only mode. Later we will conduct the question-and-answer session and instructions will be given at that time. (Operator Instructions). As a reminder this conference is being recorded. I would now like to turn the conference over to your host, Ms. Kate McNeil, please go ahead.

Kate McNeil

Thank you, operator. Good morning and thank you all for joining us to discuss our Northera new drug application for the treatment of symptomatic neurogenic orthostatic hypotension and the complete response letter received yesterday from the US Food and Drug Administration. Our press release regarding the FDA’s decision can be found on our website www.chelseatherapeutics.com. Joining me from Chelsea is Dr. Simon Pedder, President and Chief Executive Officer; Chief Financial Officer Mr. Nick Riehle; Chief Medical Officer Dr. Bill Schwieterman; Chief Scientific Officer Arthur Hewitt; VP of marketing and sales Mr. Keith Schmidt; and our Chief Operating Officer, Joe Oliveto.

Following formal remarks by Dr. Pedder, the conference call will be open for questions. Now before I turn the call over to Dr. Pedder, let me note that some of the remarks that you will hear today may contain forward-looking statements about the company's performance, actual future results might differ materially from those projected in the forward-looking statements. Additional information concerning these factors that could cause actual results to materially differ from those in these forward-looking statements contained in our SEC filings and periodic reports under the Securities and Exchange Act of 1934 as amended, copies of which are available on our website or may be requested directly from the company. And with that said I'll turn the call over to Dr. Pedder.

Dr. Simon Pedder

Thank you Kate and thanks to everybody for joining our call today. As we announced late yesterday, the US Food and Drug Administration has issued a complete response letter related to our new drug application for Northera also known as droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension or NOH. This morning we would like to take you through each of these issues identified in last night's press release and answer questions you may have regarding the complete response letter or our path forward. Before we get into detail of the agency's response I would like to remind everyone that while we have had the opportunity to review the letter in detail, we of course have not had the opportunity to follow up or speak to anyone at the FDA.

In that respect some of our discussion will involve speculation until we consult with the agency on their recommendations. While the complete response letter identified several requests and recommendations, the principle request and the one with the greatest impact for Chelsea was the request for an additional efficacy data to support the findings of our pivotal study, Study 301 and to demonstrate the durability of effect the over a two to three-month period. The complete response letter detailed the agency's guidelines for an approval based on a single persuasive study and highlighted that Study 301 was positive and achieved a typically persuasive outcome on the OHQ, Orthostatic Hypotension Questionnaire.

They further acknowledged that that their guidance is open to the possibility of a single study approval in indications which there is an unmet serious medical need. And that NOH as a condition which is still [awaiting] symptoms with limited treatment options could be a condition for which they will consider an approval based on the results of one study. The letter also states that 301 has many of the characteristics of a single adequate well-controlled study that could make it adequate to support effectiveness.

However the agency's review of the data concluded that there were some subgroups namely women, older patients, US patients and those with Parkinson demonstrated less persuasive results following treatment with Northera and I will note separately that a majority of 301 was conducted in Ex US and that a majority of the US patients participating in the study were through consultation.

They further indicated that these inconsistencies, the results of Study 303 and 303 undercuts the persuasiveness of 301. Finally the letter raised some concerns regarding what they determined to be a disproportionate large favorable effect of one site on the outcome of Study 301. While we would agree that these results impacted the outcome of the 301 our analysis shows that consistent treatment effect is seen across the positive majority of the participating sites and that adjusted for the overall number of participants, results of Study 301 excluding the site would have been persuasive.

The letter also emphasizes the agency's interest in data that adequately demonstrates the durability of the effect. As you'll recall this was also a significant discussion point, both in the agency's briefing document and subsequent advisory committee meeting where the panel ultimately concluded the potential treatment benefits coupled with a significant unmet medical need warranted approval of Northera and outweighed the need for additional study concerning durability prior to the approval ultimately recommending approval of our NDA.

Given the need to provide evidence of durability of effect, the agency suggested an additional data supporting the NDA should be from a study designed to demonstrate durability of effect over a 2 to 3 month period and recommended we consult with the agency on the specific study design elements including endpoint measures to be used in future trials. While the FDA did not make reference to the company's ongoing Study 306 we believe that data from this trial could potentially meet the criteria for clinical efficacy and durability of effect data identified in the Complete Response Letter.

As you'll recall, Study 306b is an ongoing 10-week double-blind placebo-controlled trial evaluating Northera in patients with symptomatic neurogenic OH associated with (inaudible). The primary endpoint for this trial is the reduction in the rates of fall per patient per week. However the study is also designed to assess the benefit of Northera in the treatment population using both OHSA Item 1 which measures dizziness, light headedness, feeling faint or feeling like you might blackout as well as the OHQ composite which is a more global assessment of symptomatic and functional benefits.

Since the letter was not specific with regard to the design of a longer confirmatory study, we will need to speak to the agency regarding the suitability of 306b to meet their request. This discussion will of course involve discussion regarding the primary endpoint and if that would be necessary or possible to a co-primary endpoint including both [fall] and either OHSA Item 1 or the OHQ or change in the endpoint altogether.

Until we have these discussions, it is difficult to speculate in great detail as what will be the final path forward or the time forward towards the possible approval. However preliminary estimates suggest that given our enrolment in 306b, the time required to prepare the result with submissions, we could potentially submit a major amendment to our NDA as early as first quarter of next year. Once we have designed our path forward with the agency we will of course look to update you with more vision at the timeline through submissions and potential approval.

Now, in addition to the clinical request made by the agency there were a number of additional requests and recommendations made in the complete response letter. For the most part these are not issues that will prevent approval or time-to-market. As we indicated in the press release, the agency would like to see additional bioequivalence work in order to approve the 300 milligram capsule. Just to clarify, our clinical trials were conducted using combinations of 100 milligrams and 200 milligram capsules.

Our interest in approving a 300 milligram capsule would simply be for ease of administration and we could certainly launch with only 100 and 200 milligram capsules. Of course, given that we will be working to complete clinical requirements for approval, conducting the necessary bioequivalence work to approve the 300 milligram capsule shouldn't be an issue and we anticipate this could be really accomplished prior to an FDA approval of Northera.

Finally, the complete response letter included draft recommendations regarding our labeling. I would like to emphasize that, we did not have an opportunity to engage in meaningful discussions with the agency regarding our label. So while these recommendations are informative they are not final and would not certainly be dependent on the final outcome of future studies and the collected datasets.

As we set forth in the press release, the agency recommendation, narrowing the scope of symptomatic benefits claim to emphasize dizziness, lightheadedness, feeling faint or feeling like you may black out, as the clinical benefits associated with Northera treatment. The only other item of note in the labeling recommendations was that the FDA at this time made a preliminary recommendation to include a black box warning related to supine hypertension. However, the letter indicates such a black box warning could be reconsidered a suitable data, demonstrating lack of severe hypotension, were provided.

As you may recall this topic came up during the advisory committee at a time which we explained that, in keeping up with the standard of care and clinical practice. Patients are advised to maintain a 30 degree head-up tilt in a more supine position. Panelistsin the agency expressed interest in testing supine hypertension in patients, when they are in a fully prone position. Given the convincing nature of lack of severe supine hypotension, relative to placebo in our clinical trial, we would expect to see a similar lack of significant, severe, supine hypotension compared to the placebo in a fully prone position. We look forward to get a better understanding from the agency to the scope of the data they would be interested in seeing, in order to remove the potential black box warning from our draft label.

That said, as you are well aware Midodrine has a similar black box warning, though ultimately this is not a significant competitive disadvantage. None of the recommended label changes included discussions around the black box warning, meaningful change or meaningful change apart from pricing or potential market opportunity for Northera. We look forward at the appropriate time to continuing discussions with the agency regarding a potential label for Northera.

Finally, with respect to the complete response later from the agency, I would like to point out that beyond continuing to provide complete safety data as our clinical program progresses, the letter did not identify any outstanding safety concerns related to our NDA submission. We think this is particularly significant in the light of the briefing document issued by the agency before the advisory panel meeting and the emphasis in those documents on safety and are pleased that the data presented during the panel meeting appears to have mitigated these initial concerns related to our submission.

Before I open up the call for questions, I would like to take a minute to share our gratitude for physicians, nurses, study coordinators who conducted our clinical trial and especially the patients, who participated in medical science to help bring this drug to market by participating in our extensive clinical program to-date.

In closing, I would like to emphasize our faith in Northera remains strong as ever. The testimony we have heard from patients regarding the profound effects, they’ve experienced participating in our clinical trials is among the most moving I’ve had the privilege to hear.

Though yesterday’s response from the agency was indeed a setback, we’re committed to doing our best to help those that continue to suffer from symptomatic neurogenic OH, patients who have been waiting for long treatment options to help alleviate their mediated symptoms. We recognize that Northera may meet an unmet significant need for those patients and continue to look forward to bring in this product to these patients.

Now, I would like to turn the call over to questions. Operator?

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