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  1. Chelsea Drops While Trying To Prevent Falls April 10, 2012 http://seekingalpha.com/article/487471-chelsea-drops-while-trying-to-prevent-falls On March 28, 2012 Chelsea Therapeutics (CHTP) received a complete response letter (CRL) from the Food and Drug Administration (FDA) for the company's new drug application (NDA) for Northera (droxidopa) to treat people suffering from symptomatic neurogenic orthostatic hypotension (NOH). In the CRL the FDA asked Chelsea to conduct another study which can demonstrate the drug continues to work for patients over a two to three month period. Trial 306b Waiting in the Wings Investors will undoubtedly be wondering if the 306b study Chelsea is currently conducting might be sufficient to demonstrate the durability of effect the FDA wants to see. The short answer is perhaps. The longer answer is, first and foremost, Chelsea would need to negotiate with the FDA regarding the trial's endpoints. 306b does measure the mean change in the composite OHQ, the primary endpoint used in the highly successful 301 study, but as a secondary endpoint. 306b simply isn't powered to use the same endpoints 301 did. Currently, the primary endpoint in 306b is the comparison between drug and placebo on the rate of patient reported falls from baseline till the end of study. Investors should realize there is increased trial risk with 306b because it is only enrolling Parkinson's (PD) patients while 301 enrolled patients suffering not only from PD but also multiple systems atrophy (MSA) and pure autonomic failure (PAF). Treating different patient populations increases the chances of unexpected trial results. This is further complicated by the fact that in trial 302 PD patients were the most responsive while in 301 they were the least responsive. Assuming the company and the FDA agree on the suitability of study 306b, investors will then want to focus on whether the trial can successfully blunt the management theorized carryover effect resulting in higher than anticipated placebo responses. High placebo responses have been blamed for trials 302 and 303 failing to meet statistical significance. A quick overview of NOH and Northera is likely a good idea here. NOH is a sudden fall in blood pressure when standing from a sitting or lying position. Symptoms include lightheadedness, dizziness, blurred vision, falling and syncope. NOH is a disorder of the nervous system resulting from a deficient release of norepinephrine. Norepinephrine is the neurotransmitter that signals blood vessels to constrict. Normally, when we stand, norepinephrine gets pumped out of our neurons and tells the vasculature in our brain to constrict. This keeps us from becoming dizzy when we stand up. When we sit back down the norepinephrine that is still in our system and was not metabolized gets reabsorbed. When we sit, the blood pressure in our brain comes back down and everything returns to normal. Northera is a precursor or prodrug to norepinephrine. When taken it is directly metabolized and turned into norepinephrine and stored in the neurons. Study 302 and 303 both sported a withdrawal design. All patients were given Northera initially and then randomized into either a group which continued to receive the drug or a group given a placebo. The placebo group performed better than expected and Chelsea believes this is because Northera replenished norepinephrine levels to the point that the neurons stored the neurotransmitter for later use. Both trials didn't run long enough for these placebo patients to stop benefiting from having previously taken the drug. Unfortunately, 306b is designed so all patients will receive varying doses of Northera for up to two weeks initially before being randomized to continue receiving the drug or a placebo. Fortunately, the drug vs. placebo period lasts eight weeks. Hopefully, this is more than enough time for any carryover effect to cease. Durability of Effect At the Advisory Committee meeting both the panel members and FDA staff felt Study 301 on its own would have been sufficient for approval but the lack of long-term benefit from 303 called this into question. Can 306b show durability of effect over two or three months? It should be able to but only if it actually exists. The interim data from 306, now referred to as 306a, showed there was a greater difference between placebo and drug after one and two weeks than at the end of eight weeks. Both 302 and 301 studies were significantly shorter than eight weeks and both yielded very good data. Management alluded to the age of the patients and hinted at the untrustworthiness of their responses. Decide for yourself the merit of this positioning. Personally, I would like a closer look at the falls data. If the rate of falls increased week after week in the drug arm then maybe we are looking at diminishing returns. Black Box Warning In the CRL the FDA also recommended a black box warning related to supine hypertension be included in the labelling. They indicated this warning could be removed with supportive data derived from patients while they are lying completely flat. Interestingly, the standard of care (SOC) is to measure supine hypertension on a tilt table at 30 degrees. In 306b Chelsea is collecting data based on the SOC but not while patients are completely flat. Midodrine, the current, but lacking, SOC drug for NOH also has a warning of supine hypertension so Northera would lose a nice market differentiator if it ended up with the same warning. At the very least, Chelsea hopes to convince the FDA to use language that differentiates the risk between the two drugs since data to this point shows a much higher prevalence of supine hypertension using Midodrine than using Northera. A New Trial? Management hopes to talk with the FDA within sixty days about a variety of topics. Any news supporting the viability of 306b as a pivotal study will undoubtedly push the stock higher but given the challenges and risks associated with that study a new trial might be the surest way to proceed. Chelsea wants to eventually obtain a much coveted falls label claim for Northera but the FDA has already stated an additional trial beyond 306b would be required for support. A new trial enrolling the proper patients, using proper co-primary endpoints, using induction over withdrawal design, and lasting two to three months as the FDA requests sounds less risky than counting on 306b to deliver the goods. However, management may feel a quicker yet still realistic path to market is to change the current 306b trial and get it approved with the supine hypertension black box label warning. Passing Around the Hat Despite guiding cash is sufficient to last into 2013, the company is going to need to raise more funds. They ended March 2012 with over $50 million. Negotiations with the FDA and potential changes to 306b will require more time and money. A brand new trial would likely take two years to run and cost over $28 million. My guess is the company will wait until late June or early July to raise cash. News from talks with the FDA about 306b might come early June and data from the CH-4051 phase 2 trial in Rheumatoid Arthritis is due later that same month. Will management roll the dice on a higher stock price after these events? I think the bigger question is what they decide to do with 306b after input from the FDA.
  2. 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 Read more: http://www.digitaljournal.com/pr/644817#ixzz1rYZbelq0
  3. The FDA has updated their docket on Midodrine "FDA/OC Letter to Parties from the Office of the Commissioner, dated January 23, 2012" http://www.regulations.gov/#!documentDetail;D=FDA-2007-N-0475-0037 click on the "view attachment" PDF icon to read it I don't have the congitive capacity right now to figure out what it means LOL.
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