-First Presentation of Integrated Data Analyses From Two Pivotal Trials
-Data Shows Statistically Significant Improvement in Symptoms of NOH vs. Placebo
CHARLOTTE, N.C. and STOCKHOLM, Sweden, June 12, 2014 (GLOBE NEWSWIRE) -- Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) today announced the presentation of an integrated analysis of data from two pivotal multicenter, placebo-controlled, randomized clinical trials showing that NORTHERA™ (droxidopa) had demonstrated an acceptable safety profile and demonstrated a statistically significant difference in efficacy compared to placebo for improving the symptoms of neurogenic orthostatic hypotension (NOH) in a population comprised chiefly of patients with Parkinson's Disease (PD). The results were presented at the 18th International Congress of Parkinson's Disease and Movement Disorders (MDS) in Stockholm, Sweden, June 8-12, 2014.
NORTHERA was approved by the U.S. Food and Drug Administration on Feb. 18, 2014, for the treatment of orthostatic dizziness, lightheadedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been demonstrated. The continued effectiveness of NORTHERA should be assessed periodically. Symptomatic NOH is an orphan condition that affects an estimated 80,000 to 150,000 patients in the United States. As part of its New Drug Application, Chelsea submitted data from pivotal studies 301 and 306 in support of the safety and efficacy of NORTHERA. For MDS, data from these studies were integrated, analyzed and presented together, marking the first time these data were presented at a major medical meeting. MDS draws more than 4,000 physicians and medical professionals from more than 80 countries to view more than 1,600 scientific abstracts submitted by clinicians from around the world.
The posters, titled Integrated Efficacy of Droxidopa for Neurogenic Orthostatic Hypotension and Integrated Safety of Droxidopa for Neurogenic Orthostatic Hypotension, were presented at the Parkinson's disease dysautonomia Poster Session at MDS.
"Overall, 359 patients contributed data to the integrated efficacy analyses, 174 randomized to droxidopa and 185 to placebo. Patients on NORTHERA self-reported more improvements in NOH symptoms of dizziness/lightheadedness, feeling faint or the 'feeling that you are going to black out' compared to patients on placebo," said Robert A. Hauser, MD, Professor of Neurology, Molecular Pharmacology, and Physiology, and Director of the Parkinson's Disease and Movement Disorders Center, University of South Florida. "Patients on NORTHERA also showed improvements in standing systolic blood pressure at one week compared to patients on placebo."
Dr. Hauser was the lead author on the integrated efficacy poster.
Horacio Kaufmann, MD, Professor of Neurology and Medicine at New York University and Director of the Dysautonomia Center at NYU Langone Medical Center, was the lead author on the safety poster. "Droxidopa demonstrated an acceptable safety profile across these two pivotal induction design trials in patients in NOH, and data shows that adverse events were consistent across studies 301 and 306 and consistent with other studies of droxidopa," he said.
About Studies 301 And 306
In Study 301, adult patients with symptomatic NOH due to primary autonomic failure (PD, MSA, or PAF), DBH, or NDAN underwent an up-to-2-week titration of open-label droxidopa, so as to identify their optimal dose. Responders underwent a 7-day washout, followed by a 7-day double-blind trial of optimized treatment versus placebo (100–600 mg TID). In Study 306, adult PD patients with symptomatic NOH underwent an up-to-2-week titration of double-blind droxidopa or placebo, followed by an 8-week double-blind trial of maintenance treatment (100–600 mg TID).
In both studies, safety assessments included adverse-event (AE) monitoring. Blood pressure was assessed multiple times using the Orthostatic Standing Test (OST). Supine hypertension was defined as a systolic pressure >180 mmHg at all three observations during the 10-minute supine period of the OST. During the supine period, patients had their head and torso elevated at an angle of approximately 30 degrees.
Efficacy assessments were made at randomization and the end of week one of double-blind study-drug treatment, using the Orthostatic Hypotension Questionnaire (OHQ) comprised of the six-item Orthostatic Hypotension Symptom Assessment (OHSA) and the four-item Orthostatic Hypotension Daily Activity Scale (OHDAS). Data on standing systolic blood pressure was collected at all study-site visits when each subject had stood for three minutes after having been supine for 10 minutes.
Efficacy Results
Overall, data from 359 subjects, including 263 with underlying Parkinson's disease, contributed to the integrated efficacy analyses. For analyses of subjects' self-ratings on OHSA Item 1 ("dizziness/lightheadedness, feeling faint, or feeling like you might black out," on average over the preceding week), data from 174 droxidopa and 185 placebo recipients (including 127 and 136 with underlying PD) were analyzed. From randomization to the end of double-blind Week 1, the mean score change was –2.5 ±3.1 versus –1.3 ±2.9 units (p<0.001) and 55.2 percent versus 35.1 percent of the subjects had improvements of greater than 50 percent (p<0.001). The proportions of subjects with improvements of ≥1, ≥2, ≥3, or ≥4 units were also significantly greater among droxidopa recipients than among placebo recipients.
For standing systolic blood pressure analyses, data from 173 patients on droxidopa and 184 patients on placebo were analyzed. From randomization to the end of double-blind Week 1, the mean change was +8.6 ±20.5 versus +0.9 ±18.5 mmHg (p<0.001). The proportions of subjects with increases of ≥5, ≥10, ≥15, or ≥20 mmHg were also significantly greater among droxidopa recipients than among placebo recipients.
Safety Results
During double-blind treatment, the overall incidence of reported adverse events was 18.5 percent for patients on droxidopa versus 14.8 percent for patients on placebo in Study 301 for up to 1-week exposure, and 79.8 percent versus 80.6 percent, respectively, in Study 306 up to 10-week exposure. Headache was the only type of AE that was reported in greater than 5 percent of patients from both trials while on double-blind droxidopa or placebo. In study 301, 7.4 percent of patients on droxidopa reported headaches compared to 0 on placebo; and in study 306, 13.2 percent of patients on droxidopa reported headaches compared to 7.4 percent of patients on placebo.
During study-drug titration, the overall incidence of reported AEs was 38 percent for open-label droxidopa in study 301, 55.3 percent for double-blind droxidopa in study 306, and 43.5 percent for double-blind placebo in study 306.
Across the studies, 5.6 percent of the pooled droxidopa group (11 of 195) and 3.2 percent of the pooled placebo group (6 of 189) had a systolic blood pressure >180 mmHg at all 3 observations during a 10-minute supine period.
About symptomatic neurogenic orthostatic hypotension (NOH)
It is estimated that 80,000 to 150,000 patients suffer from symptomatic NOH in the U.S. Symptomatic NOH is a chronic disorder that is caused by an underlying neurogenic disorder, such as Parkinson's disease, multiple system atrophy or pure autonomic failure. Symptoms of NOH may include dizziness, lightheadedness, blurred vision, fatigue, poor concentration, and fainting episodes when a person assumes a standing position. These symptoms can severely limit a person's ability to perform routine daily activities that require standing or walking for both short and long periods of time.
About NORTHERA (droxidopa)
NORTHERA is the first and only therapy approved by the FDA that demonstrates symptomatic benefit in adult patients with NOH caused by primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure), dopamine beta hydroxylase deficiency and non-diabetic autonomic neuropathy. NORTHERA is expected to be launched in the second half of 2014.
NORTHERA carries a boxed warning for supine hypertension. The most common adverse events experienced in controlled studies were headache, dizziness, nausea, hypertension and fatigue. Please see NORTHERA full Prescribing Information at www.chelseatherapeutics.com, and Important Safety Information below.
The NORTHERA approval was granted under the FDA's accelerated approval program, which allows for conditional approval of a medicine that fills a serious unmet medical need, provided additional confirmatory studies are conducted. The package insert indicates that effectiveness beyond two weeks of treatment has not yet been demonstrated; therefore the continued effectiveness of NORTHERA in patients should be assessed periodically. A multi-center, placebo-controlled, randomized study, which is designed with the goal of definitively establishing the durability of the clinical benefits of NORTHERA, has been preliminarily agreed to with the FDA.
IMPORTANT SAFETY INFORMATION
WARNING: SUPINE HYPERTENSION
See full prescribing information for complete boxed warning. Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses. Elevating the head of the bed lessens the risk of supine hypertension, and blood pressure should be measured in this position. If supine hypertension cannot be managed by elevation of the head of the bed, reduce or discontinue NORTHERA.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Supine Hypertension: NORTHERA therapy may cause or exacerbate supine hypertension in patients with NOH, which may increase cardiovascular risk if not well-managed.
Hyperpyrexia and Confusion: Postmarketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported in Japan with NORTHERA use. Observe patients carefully when the dosage of NORTHERA is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.
Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure: NORTHERA therapy may exacerbate symptoms in patients with existing ischemic heart disease, arrhythmias, and congestive heart failure.
Allergic Reactions: This product contains FD+C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD+C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
ADVERSE REACTIONS
The most common adverse reactions (greater than 5 percent) were headache, dizziness, nausea, hypertension, and fatigue.
DRUG INTERACTIONS
Administering NORTHERA in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension; Dopa-decarboxylase inhibitors may require dose adjustments for NORTHERA.
USE IN SPECIAL POPULATIONS
Clinical experience with NORTHERA in patients with severe renal function impairment (GFR less than 30 mL/min) is limited; There are no adequate and well controlled trials of NORTHERA in pregnant women; Women who are nursing should choose nursing or NORTHERA; The safety and effectiveness of NORTHERA in pediatric patients have not been established; No overall differences in safety or effectiveness were observed between subjects aged 75 years and older, and younger subjects in clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
About Chelsea Therapeutics
Chelsea Therapeutics (Nasdaq:CHTP) is a biopharmaceutical development company that acquires and develops innovative products for the treatment of a variety of human diseases, including central nervous system disorders. Chelsea acquired global development and commercialization rights to droxidopa (L-DOPS), or NORTHERA, from Dainippon Sumitomo Pharma Co., Ltd. in 2006, excluding Japan, Korea, China and Taiwan. For more information about the Company, visit www.chelseatherapeutics.com.
As previously announced, pursuant to the Agreement and Plan of Merger, dated as of May 7, 2014 (Merger Agreement), by and among Chelsea, H. Lundbeck A/S (Lundbeck), and Charlie Acquisition Corp., an indirect wholly owned subsidiary of Lundbeck (Acquisition Sub), Lundbeck has commenced a tender offer (Offer) to purchase all of the outstanding shares of Chelsea. Lundbeck and Acquisition Sub have filed a tender offer statement on Schedule TO (as amended, the Schedule TO), including an offer to purchase, a letter of transmittal and related documents, with the Securities and Exchange Commission (SEC), and Chelsea has filed a Solicitation/Recommendation Statement on Schedule 14D-9 (as amended, the Statement) with respect to the Offer. The Offer will only be made pursuant to the offer to purchase, the letter of transmittal and related documents filed as a part of the Schedule TO. Subject to Acquisition Sub's irrevocable acceptance for payment in the Offer of at least a majority of Chelsea's common stock outstanding on a fully diluted basis and to the satisfaction or waiver of certain other customary conditions, Acquisition Sub will merge with and into Chelsea (Merger) and, subject to certain exceptions, each Chelsea share not tendered in the Offer will be cancelled and converted into the right to receive in the Merger the same consideration per share paid in the Offer.
Safe Harbor/Forward-Looking Statements
The above information contains forward-looking statements, including without limitation statements regarding the planned completion of the Offer and the Merger.
Some of these forward-looking statements may contain words like "believe," "may," "could," "would," "might," "possible," "will," "should," "expect," "intend," "plan," "anticipate," or "continue," the negative of these words, or other terms of similar meaning or they may use future dates. These statements are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, risks and uncertainties related to: the timing of the transaction; diversion of the attention of Chelsea's management away from Chelsea's day-to-day business operations; the percentage of Chelsea's stockholders tendering their shares in the Offer; the possibility that competing offers will be made and the effects of provisions in the Merger Agreement that could discourage or make it difficult for competing offers to be made; the possibility that various closing conditions for the transaction 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; the effects of disruption caused by the transaction making it more difficult to maintain relationships with employees, collaborators, vendors and other business partners; stockholder litigation in connection with the transaction resulting in significant costs of defense, indemnification and liability; and other risks and uncertainties discussed in Chelsea's filings with the SEC, including the "Risk Factors" sections of Chelsea's Annual Report on Form 10-K for the year ended December 31, 2013 and Quarterly Report on Form 10-Q for the quarter ended March 31, 2014, as well as the Statement and the tender offer documents filed by Lundbeck and Acquisition Sub. Chelsea undertakes no obligation to update any forward-looking statements as a result of new information, future developments or otherwise, except as expressly required by law. All forward-looking statements in this document are qualified in their entirety by this cautionary statement.