Orexigen® Therapeutics, Inc. (Nasdaq: OREX), a biopharmaceutical company focused on the treatment of central nervous system disorders, including obesity, announced completion of enrollment in NB-303 and NB-304, the final two Phase III clinical trials for Contrave®, its lead obesity product candidate. Today's announcement marks the completion of patient enrollment for the full Contrave Phase III program, keeping Contrave on track for an NDA submission to the FDA in late 2009. The Contrave clinical development program includes four Phase III clinical trials evaluating a variety of obesity and metabolic-related outcome measures. Orexigen previously announced that enrollment was completed in NB-301 and NB-302.
NB-303 is a placebo-controlled, 56-week clinical trial designed to analyze the efficacy, safety and tolerability of Contrave at the expected standard dose with the opportunity for patients to switch to a higher dose if they do not respond after 28 weeks of therapy. This trial is being conducted at 36 centers nationwide and has randomized approximately 1495 patients.
NB-304 is a placebo-controlled, 56-week clinical trial designed to analyze the efficacy, safety and tolerability of Contrave in obese patients with Type II diabetes. Recent studies have demonstrated that obesity is a leading risk factor for diabetes, and this trial is designed to evaluate weight loss and factors related to glucose metabolism. This trial is taking place at 51 centers nationwide and has randomized approximately 500 patients.
"Completing enrollment for the entire Contrave Phase III program on schedule is a profoundly important milestone for the Company. Equally important has been the attention given to the quality execution of these studies by both the Orexigen team and our clinical investigators," said Orexigen President and CEO, Gary Tollefson, MD, Ph.D. "Beyond the standard measures of efficacy, safety and tolerability, we have designed the Contrave Phase III clinical trials to address a number of the key secondary metabolic and behavioral endpoints that complicate are often associated with obesity."
Orexigen previously announced completion of enrollment in its NB-301 trial in November 2007 and its NB-302 trial in April 2008. NB-301 is a placebo-controlled, 56-week clinical trial designed to analyze the efficacy, safety and tolerability of two doses of Contrave in generally healthy obese patients. NB-302 is a placebo-controlled, 56-week clinical trial designed to analyze the efficacy, safety and tolerability of Contrave when combined with an intensive behavior modification protocol.
Contrave is a proprietary fixed dose combination of bupropion sustained release (SR) and the Company's novel formulation of naltrexone SR in a single tablet. Orexigen chose these two constituent drugs based on preclinical data that suggested that they act synergistically to initiate and sustain weight loss. Results from the first Phase III clinical trial are anticipated in late 2008 or early 2009.
About Orexigen Therapeutics
Orexigen® Therapeutics, Inc. is a biopharmaceutical company focused on the development of pharmaceutical product candidates for the treatment of central nervous system disorders, including obesity. Orexigen's lead combination product candidates targeted for obesity are Contrave®, which is in Phase III clinical trials, and Empatic™, which is in the later stages of Phase II clinical development. Both product candidates are designed to take advantage of the company's understanding of how the brain appears to regulate appetite and energy expenditure, as well as the mechanisms that come into play to limit weight loss over time. Each product candidate is designed to act on a specific group of neurons in the central nervous system with the goal of achieving appetite suppression and sustained weight loss. Further information about the company can be found at http://www.Orexigen.com.
Forward-Looking Statements
Orexigen cautions you that statements included in this press release that are not a description of historical facts are forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "indicates," "will," "intends," "potential," "suggests," "assuming," "designed," "projects" and similar expressions are intended to identify forward-looking statements. These statements are based on the Company's current beliefs and expectations. These forward-looking statements include statements regarding enrollment, timing, execution and completion of clinical trials of Contrave, the timing of an NDA submission with the FDA for Contrave, the efficacy and safety of Contrave, and the potential to obtain regulatory approval for, and effectively treat obesity with, Contrave. The inclusion of forward-looking statements should not be regarded as a representation by Orexigen that any of its plans will be achieved. Actual results may differ from those set forth in this release due to the risk and uncertainties inherent in the Company's business, including, without limitation: the progress and timing of the Company's Contrave clinical trials or the development of Contrave; the potential for adverse safety findings relating to Contrave to delay or prevent regulatory filings; and its licensors may not be able to obtain, maintain and successfully enforce adequate patent and other intellectual property protection of its product candidates; and other risks described in the Company's filings with the Securities and Exchange Commission (SEC). You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Orexigen undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995.
http://www.Orexigen.com
View drug information on Naltrexone Hydrochloride Tablets.
VION PHARMACEUTICALS, INC. (Nasdaq: VION) announced the start of an investigator-sponsored Phase I/II clinical trial of its lead anticancer agent Cloretazine(R) (VNP40101M) in combination with cytarabine in elderly patients with previously untreated acute myelogenous leukemia (AML) and high-risk myelodysplastic syndromes (MDS). The trial is being conducted under the direction of Ellen K. Ritchie, M.D. at The Weill-Cornell Medical College in New York City. Co- investigators for the study are Eric Feldman, M.D. and Gail Roboz, M.D.
The objectives of the trial are: (i) to define the maximum tolerated dose (MTD) of Cloretazine(R) (VNP40101M) when given in combination with cytarabine to AML and high-risk MDS patients over the age of 60, and (ii) to evaluate this combination further for safety and efficacy in a larger cohort of patients. Cloretazine(R) (VNP40101M) will be given as a 30 - 60 minute infusion on day 1 approximately 3-4 hours after the start of the cytarabine infusion. Cytarabine will be administered as a continuous infusion of 100 mg/m2/day for 7 days. In the Phase I portion of the study, dose escalation will be done in cohorts of at least 3 patients and the maximum tolerated dose (MTD) identified in the Phase I segment will be used in the Phase II segment of the study.
Ann Cahill, Vice President, Clinical Development, commented, "It is important for us to continue to study Cloretazine(R) (VNP40101M) in combination with different doses and schedules of cytarabine, the most widely used drug in the treatment of AML. In addition, we want to evaluate Cloretazine(R) (VNP40101M) in a broader group of elderly patients than are currently being studied in our pivotal trial of Cloretazine(R) (VNP40101M) as a single agent." Ms. Cahill concluded, "Cloretazine(R) (VNP40101M) has shown activity in AML and MDS, warranting further study in the treatment of these devastating conditions as both a single agent and in combination with other therapies."
Dr. Ritchie commented, "We are enthusiastic to begin exploring this regimen for AML and MDS patients that are over the age of 60. As standard therapies for these individuals have shown to be inadequate, there exists a need for our continued attention to research and development of new treatment options. Preliminary clinical trials using Cloretazine(R) (VNP40101M) in combination with cytarabine have demonstrated favorable activity and compelling evidence for further study. The knowledge gained from this research study will bring us closer to our goal of finding the best possible treatment for our patients that will extend the length as well as improve the quality of their lives."
Vion Pharmaceuticals, Inc. is committed to extending the lives and improving the quality of life of cancer patients worldwide by developing and commercializing innovative cancer therapeutics. Vion has two agents in clinical trials. Cloretazine(R) (VNP40101M), a unique alkylating agent, is being evaluated in a Phase II pivotal trial as a single agent in elderly patients with previously untreated de novo poor-risk acute myelogenous leukemia. Clinical trials of Cloretazine(R) (VNP40101M) with temozolomide in brain tumors, and with stem cell transplantation in advanced hematologic malignancies, are also being conducted. Triapine(R), a potent inhibitor of a key step in DNA synthesis, is being evaluated in clinical trials sponsored by the National Cancer Institute. For additional information on Vion and its product development programs, visit the Company's Internet web site at http://www.vionpharm.com.
This news release contains forward-looking statements. Such statements are subject to certain risk factors which may cause Vion's plans to differ or results to vary from those expected, including Vion's potential inability to obtain regulatory approval for its products, particularly Cloretazine(R) (VNP40101M), delayed or unfavorable results of drug trials, the possibility that favorable results of earlier preclinical studies or clinical trials are not predictive of safety and efficacy results in later clinical trials, the need for additional research and testing, the inability to manufacture product, the potential inability to secure external sources of funding to continue operations, the inability to access capital and funding on favorable terms, continued operating losses and the inability to continue operations as a result, and a variety of other risks set forth from time to time in Vion's filings with the Securities and Exchange Commission, including but not limited to the risks attendant to the forward-looking statements included under Item 1A, "Risk Factors" in Vion's Form 10-K for the year ended December 31, 2007. In particular, there can be no assurance as to the results of any of the Vion's clinical trials, that any of these trials will continue to full accrual, or that any of these trials will not be discontinued, modified, delayed or ceased altogether. Except in special circumstances in which a duty to update arises under law when prior disclosure becomes materially misleading in light of subsequent events, Vion does not intend to update any of these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.
EntreMed, Inc. (Nasdaq: ENMD), a clinical-stage pharmaceutical company developing therapeutics for the treatment of cancer and inflammatory diseases, announced that Dana-Farber Cancer Institute has joined the University of Colorado Cancer Center in conducting a Phase 1 study of ENMD-2076 in advanced cancer patients. Dr. Geoffrey Shapiro, Dana-Farber Cancer Institute, and Dr. Wells Messersmith, University of Colorado Cancer Center, will serve as co-principal investigators for the study.
Safety and tolerability of orally administered ENMD-2076 in refractory cancer patients will be assessed in this Phase 1 study. A secondary objective for the study will be to determine a dose-dependent response to treatment with ENMD-2076 through the evaluation of pharmacokinetic parameters.
ENMD-2076 is a novel, selective kinase inhibitor with potent activity against Aurora A and tyrosine kinases linked to the promotion of cancer and inflammatory diseases. ENMD-2076 acts through multiple pathways, resulting in both antiproliferative activity and the inhibition of angiogenesis. ENMD-2076 has demonstrated substantial, dose-dependent efficacy as a single agent in multiple preclinical models, including tumor regression in breast, colon, and leukemia models. Importantly, ENMD-2076 is an oral agent that has shown an acceptable toxicity profile in preclinical studies without cardiovascular toxicity.
Carolyn F. Sidor, MD, MBA, EntreMed Vice President and Chief Medical Officer commented on the study, "Both clinical trial sites are now enrolling and treating patients with our selective kinase inhibitor. We believe that this product candidate has substantial potential as both a single agent and in combination with other approved cancer drugs. ENMD-2076 is unique-in-class because it not only inhibits Aurora A selectively, it also inhibits a cluster of kinases that are important for tumor growth, particularly growth factor receptors critical to angiogenesis. ENMD-2076 has potent antitumor activity in multiple preclinical models, including both solid tumors and hematological cancers."
James S. Burns, EntreMed President & Chief Executive Officer commented, "Further development of ENMD-2076 is consistent with both our focus on investing behind oncology drug candidates with strong single-agent activity and our continuing interest in kinase inhibitors. In keeping with our 2008 goals of cash preservation and rigorous resource management, we intend to pay the $2 million Phase 1 milestone to Miikana shareholders in shares of EntreMed common stock. Our goals for this program over the next twelve months are to complete the clinical trial in solid tumor patients, initiate a clinical trial in patients with hematological cancers, and secure a pharmaceutical partner to help accelerate the development of ENMD-2076."
About EntreMed
EntreMed, Inc. is a clinical-stage pharmaceutical company developing therapeutic candidates primarily for the treatment of cancer and inflammation. MKC-1 is currently in multiple Phase 2 clinical trials for cancer. MKC-1 is an oral cell-cycle regulator with activity against the mTOR pathway. ENMD-1198, a novel antimitotic agent, and ENMD-2076, a selective kinase inhibitor, are in Phase 1 studies in advanced cancers. The Company also has an approved IND application for Panzem(R) in rheumatoid arthritis. EntreMed's goal is to develop and commercialize new compounds based on the Company's expertise in angiogenesis, cell-cycle regulation and inflammation -- processes vital to the treatment of cancer and other diseases, such as rheumatoid arthritis. Additional information about EntreMed is available on the Company's web site at http://www.entremed.com and in various filings with the Securities and Exchange Commission.
Forward Looking Statements
This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act with respect to the outlook for expectations for future financial or business performance (including the timing of royalty revenues and future R&D expenditures), strategies, expectations and goals. Forward-looking statements are subject to numerous assumptions, risks and uncertainties, which change over time. Forward-looking statements speak only as of the date they are made, and no duty to update forward-looking statements is assumed. Actual results could differ materially from those currently anticipated due to a number of factors, including those set forth in Securities and Exchange Commission filings under "Risk Factors," including risks relating to the need for additional capital and the uncertainty of additional funding; variations in actual sales of Thalomid(R), risks associated with the Company's product candidates; the early-stage products under development; results in preclinical models are not necessarily indicative of clinical results, uncertainties relating to preclinical and clinical trials; success in the clinical development of any products; dependence on third parties; future capital needs; and risks relating to the commercialization, if any, of the Company's proposed products (such as marketing, safety, regulatory, patent, product liability, supply, competition and other risks).
Bayer HealthCare AG and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced that the first patient has been dosed in the VIEW 2 trial, a second Phase 3 clinical study in a development program evaluating VEGF Trap-Eye for the treatment of the neovascular form of Age-related Macular Degeneration (wet AMD), a leading cause of blindness in adults.
VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) will enroll approximately 1,200 patients in up to 200 centers in Europe, Asia Pacific, Japan and Latin America. The first Phase 3 trial, VIEW 1, began enrolling patients in August 2007 in the United States and Canada. Both VIEW 1 and VIEW 2 are designed to evaluate the efficacy and safety of VEGF Trap-Eye administered by intravitreal injection, at dosing intervals of 4 and 8 weeks. The development program will include visual acuity endpoints and anatomical endpoints, including retinal thickness, a measure of disease activity. The trial is intended to establish non-inferiority of VEGF Trap-Eye with Lucentis(R)* (ranibizumab), an antiangiogenic agent approved for use in wet AMD in major markets globally.
Wet AMD accounts for about 90 percent of all severe AMD-related vision loss. It occurs when abnormal blood vessels in the eye leak fluid and blood into the macula, the area of the retina that allows for vision of fine details. This can lead to a rapid loss of central vision with continued progression.
"Results from the Phase 2 study have shown that VEGF Trap-Eye has the potential to significantly reduce retinal thickness and improve vision," said Kemal Malik, MD, Head of Global Development and member of the Bayer HealthCare Executive Committee. "Dosing of the first patient in this confirmatory Phase 3 trial is an important milestone for this compound intended to treat a devastating ocular disease that impacts millions of people worldwide."
"New therapies are still needed to provide optimal care to those patients with wet AMD," said George D. Yancopoulos, M.D., Ph.D., President of Regeneron Research Laboratories. "This global Phase 3 clinical program will provide additional data to further evaluate the efficacy and safety of VEGF Trap-Eye using different dosing regimens."
Bayer HealthCare and Regeneron are collaborating on the global development of VEGF Trap-Eye for treatment of wet AMD, diabetic eye diseases, and other ocular diseases and disorders. Once approved, Bayer HealthCare will market VEGF Trap-Eye outside the U.S., where the parties will share equally in profits from any future sales of VEGF Trap-Eye. Regeneron maintains exclusive rights to VEGF Trap-Eye in the U.S. VIEW 2 primary analysis results are anticipated in 2011.
About VIEW 2
In the first year, the VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) study will evaluate the safety and efficacy of VEGF Trap-Eye at doses of 0.5 milligrams (mg) and 2.0 mg administered at 4-week intervals and 2.0 mg at an 8-week dosing interval, including one additional 2.0 mg dose at week four. Patients randomized to the ranibizumab arm of the trial will receive a 0.5 mg dose every 4 weeks. After the first year of treatment, patients will continue to be followed and treated for another year on a flexible, criteria-based extended regimen with a dose administered at least every 12 weeks, but not more often than every 4 weeks until the end of the study.
The primary endpoint of the study is the proportion of patients treated with VEGF Trap-Eye who maintain vision at the end of one year, compared to ranibizumab patients. Visual acuity is defined as the total number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, a standard chart used in research to measure visual acuity. Maintenance of vision is defined as losing fewer than three lines (equivalent to 15 letters) on the ETDRS chart. Key secondary endpoints include the mean change from baseline in visual acuity as measured by ETDRS and the proportion of patients who gained at least 15 letters of vision at week 52.
Phase 2 Clinical Data
In a Phase 2 trial in 157 patients, announced in October 2007 at the Retina Society Conference in Boston, VEGF Trap-Eye met both primary and secondary key endpoints: a statistically significant reduction in retinal thickness (a measure of disease activity) after 12 weeks of treatment compared with baseline and a statistically significant improvement from baseline in visual acuity (ability to read letters on an eye chart).
Following the initial 12-week fixed-dosing phase of the trial, patients continued to receive therapy at the same dose on a PRN (as needed) dosing schedule based upon the physician assessment of the need for re-treatment in accordance with pre-specified criteria. At the 2008 meeting of the Association for Vision and Ophthalmology (ARVO), it was reported that, on average, patients on the PRN dosing schedule maintained the gain in visual acuity and decrease in retinal thickness achieved at week 12 through week 32 of the study.
About VEGF Trap-Eye
Vascular Endothelial Growth Factor (VEGF) is a naturally occurring protein in the body whose normal role is to trigger the formation of new blood vessels (angiogenesis) to support the growth of the body's tissues and organs. It has also been associated with the abnormal growth and fragility of new blood vessels in the eye, which lead to the development of wet AMD. VEGF Trap-Eye is a fully human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PIGF) and VEGF-B. VEGF Trap-Eye is a specific and highly potent blocker of these growth factors. Blockade of VEGF can prevent abnormal blood vessel formation as well as vascular leak and has proven beneficial in the treatment of wet AMD.
About Wet AMD
Age-related Macular Degeneration (AMD) is a leading cause of acquired blindness. Macular degeneration is diagnosed as either dry (non-exudative) or wet (exudative). In wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes disruption and dysfunction of the retina creating blind spots in central vision, and it can account for blindness in wet AMD patients. Wet AMD is the leading cause of blindness for people over the age of 65 in the U.S. and Europe.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world's leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business operates under the name Bayer Schering Pharma AG. Bayer HealthCare's aim is to discover and manufacture products that will improve human and animal health worldwide. Find more information at http://www.bayerhealthcare.com.
Bayer Schering Pharma is a worldwide leading specialty pharmaceutical company. Its research and business activities are focused on the following areas: Diagnostic Imaging, General Medicine, Specialty Medicine and Women's Healthcare. With innovative products, Bayer Schering Pharma aims for leading positions in specialized markets worldwide. Using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life. Find more information at http://www.bayerscheringpharma.de.
About Regeneron
Regeneron is a fully integrated biopharmaceutical company that discovers, develops, and commercializes medicines for the treatment of serious medical conditions. In addition to ARCALYST(TM) (rilonacept) Injection for Subcutaneous Use, its first commercialized product, Regeneron has therapeutic candidates in clinical trials for the potential treatment of cancer, eye diseases, and inflammatory diseases, and has preclinical programs in other diseases and disorders. Additional information about Regeneron and recent news releases are available on Regeneron's Web site at http://www.regeneron.com.
Bayer HealthCare Forward Looking Statement
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at http://www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.
Regeneron Forward Looking Statement
This news release discusses historical information and includes forward-looking statements about Regeneron and its products, development programs, finances, and business, all of which involve a number of risks and uncertainties, such as risks associated with preclinical and clinical development of Regeneron's drug candidates, determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron's ability to continue to develop or commercialize its product and drug candidates, competing drugs that are superior to Regeneron's product and drug candidates, uncertainty of market acceptance of Regeneron's product and drug candidates, unanticipated expenses, the availability and cost of capital, the costs of developing, producing, and selling products, the potential for any collaboration agreement, including Regeneron's agreements with the sanofi-aventis Group and Bayer HealthCare, to be cancelled or to terminate without any product success, risks associated with third party intellectual property, and other material risks. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission (SEC), including its Form 10-Q for the quarter ended March 31, 2008. Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events, or otherwise unless required by law.
Scientists have developed a new class of drugs called the vaptans that could treat a large variety of conditions, including but not limited to painful menstrual periods, brain hemorrhage, certain psychotic disorders, and glaucoma. This was reported by Professor Guy Decaux, Erasmus University Hospital, Brussels, Belgium, and colleagues in a New Drug Class paper released on May 9, 2008 in The Lancet.
The vasopressin-receptor antagonists, dubbed vaptans, target the vasopressin hormonal feedback system. Vasopressin, also called ant-diuretic hormone or ADH, is an important part of regulation in the circulatory system and is integral to the balance of water in the body. As a fundamental part of hormonal control in the body, it is implicated in many different conditions. Vaptans can be administered orally or intravenously. They work by competing for the active sites on cells meant for vasopressin binding -- in this way, the vasopressin is blocked from acting, which earns them the title of vasopressin antagonists.
There are several subclasses of vaptan which are in development or complete. For one, relcovaptan has been tested in the treatment of several ailments: painful menstrual periods, known as dysmenorrhea; Raynaud's disease, a vascular disorder that sometimes restricts blood flow to the extremities; and tocolysis, when premature labor leads to premature birth.
Another subclass of vaptans, which targets a different cell receptor site, encompasses several drugs including mozavaptan, lixivaptan, satavaptan, and tolvaptan, all inducing water loss without the loss of mineral salts, which often accompanies other diuretics. These drugs are used to treat hyponatraemia, or sodium deficiency. Presently, conivaptan is the only vaptan approved by the FDA for treatment of this condition. Many from this category of drugs is also in development to treat several other problems, including renal failure in polycystic kidney disease, diabetic nephropathy, cirrhosis, and depression.
Finally, vaptans have been studied with promising results for the treatment of glaucoma, the inner-ear disorder Meniere's disease, brain hemorrhage, and small cell cancers.
Non-peptide arginine-vasopressin antagonists: the vaptans
Guy Decaux, Alain Soupart, Gilbert Vassart
The Lancet, Vol 371, May 10, 2008
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Written by Anna Sophia McKenney
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
Shire plc(LSE: SHP, Nasdaq: SHPGY), the global specialty biopharmaceutical company, has presented at a major scientific meeting findings from analyses of pivotal trial results of INTUNIV, a selective alpha-2A-agonist. This compound is an investigational once-daily medication, which is being evaluated for the treatment of the symptoms of Attention Deficit Hyperactivity Disorder (ADHD). The data demonstrated that INTUNIV showed significant efficacy in reducing ADHD symptoms for patients taking the medication when compared to patients taking placebo at all measured time points up to 24 hours postdose.
The U.S. Food and Drug Administration (FDA) issued an approvable letter on June 20, 2007, regarding INTUNIV. Shire is conducting additional clinical work which is designed to enhance the label. Upon approval, INTUNIV will be the first selective alpha-2A receptor agonist indicated for the treatment of ADHD that may provide an important treatment option for patients and physicians.
Summary of Analyses
The pooled analysis evaluated results from these patients on a weight adjusted mg/kg basis from two similarly designed, randomized, double-blind, forced-dose titration, multicenter phase III trials. The primary efficacy measure for both studies was change in the ADHD Rating Scale (ADHD-RS-IV) total score from baseline to endpoint. All patient groups treated with INTUNIV showed significantly greater improvement in ADHD-RS-IV total score from baseline to endpoint than the placebo group (P < .001). The ADHD-RS-IV is a standardized, validated test for assessing symptoms of ADHD and for assessing their response to treatment.
The analysis also studied duration of effect using the Conners' Parent Rating Scale-Revised Short Form (CPRS-R), which is a comprehensive scale that used observer and self-report ratings to help assess ADHD and evaluate behavioral issues in children and adolescents. The CPRS-R assessments were completed on specified days at approximately 6 PM (after school and before dinner), 8 PM (dinner through bedtime) and 6 AM (waking time/new dose administration time), which represented 12, 14 and 24 hours after the administration of the dose of INTUNIV, respectively. The data demonstrated significant improvement of ADHD symptoms based on total endpoint CPRS-R scores for all weight adjusted dose groups treated with INTUNIV when compared to placebo for all time periods (at 12 hours, P < = .001; at 14 hours, P < .001; and at 24 hours, P=.003).
A separate analysis of the same phase III studies evaluated the percentage of ADHD patients who responded to weight-adjusted treatment with INTUNIV versus those participants receiving placebo. Using the change in the ADHD-RS-IV total score from baseline to endpoint as the primary efficacy measure, responders were defined as those with a 25 percent reduction in score from baseline to endpoint. Findings from the analysis showed that all groups treated with INTUNIV responded to the medication in a shorter time period than the placebo group (14 days versus 20 days, respectively, P = .001).
In the phase III studies, adverse events (AEs) were reported in 80.7 percent of patients treated with INTUNIV and 71.8 percent of patients treated with placebo. Overall, the AEs were mostly mild to moderate in severity. Adverse reactions that appeared to be dose-related in patients given INTUNIV included upper abdominal pain, constipation, dizziness, dry mouth, hypotension, sedation, and somnolence. Serious AEs reported in these analyses were uncommon and rates were similar between patients treated with INTUNIV and patients treated with placebo (0.6% of the INTUNIV group and 0.7% of placebo group, respectively).
---------------------------- Article adapted by Medical News Today from original press release. ----------------------------
About INTUNIV
INTUNIV, a once-daily formulation of guanfacine, provides a controlled, steady delivery of drug throughout the day with a delivery system that is designed to minimize the fluctuations between peak and trough concentrations as seen with immediate-release guanfacine. INTUNIV is not a controlled substance and does not appear to have a known mechanism for potential abuse or dependence.
Although other ADHD medications work indirectly in the prefrontal cortex, it has been shown that guanfacine, the active ingredient in INTUNIV, works directly by binding selectively to alpha-2A adrenergic cell receptors located in the prefrontal cortex. The prefrontal cortex is an area of the brain associated with executive functioning, ie, working memory, behavioral inhibition, regulation of attention, distractibility, impulsivity, and frustration tolerance. The selective alpha-2A agonist strengthens working memory and prefrontal cortex neuronal firing. This research supports the use of guanfacine for the treatment of ADHD.
Safety data showed that adverse events reported by participants using INTUNIV were generally mild to moderate in severity, with the most common side effects being sedative in nature. Sedation-related, treatment-emergent adverse events were among the most common but emerged in the first two weeks and were usually transient and mild or moderate in severity. Treatment-related adverse events greater than 10 percent included somnolence (32 percent), headache (26 percent), fatigue (18 percent), upper abdominal pain (14 percent) and sedation (13 percent). Small to modest changes in blood pressure, pulse rate, and ECG parameters were observed.
About ADHD
ADHD is one of the most common psychiatric disorders in children and adolescents. Approximately 7.8 percent of all school-aged children, or about 4.4 million U.S. children aged 4 to 17 years, have been diagnosed with ADHD at some point in their lives, according to the U.S. Centers for Disease Control and Prevention (CDC). The disorder is also estimated to affect 4.4 percent of U.S. adults aged 18-44 based on results from the National Comorbidity Survey Replication, a nationally representative household survey, which used a lay-administered diagnostic interview to assess a wide range of DSM-IV disorders. ADHD is a neurobiological disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. To be properly diagnosed with ADHD, a child needs to demonstrate at least six of nine symptoms of inattention; and/or at least six of nine symptoms of hyperactivity/impulsivity; the onset of which appears before age 7 years; that some impairment from the symptoms is present in two or more settings (e.g., at school and home); that the symptoms continue for at least six months; and that there is clinically significant impairment in social, academic or occupational functioning and the symptoms cannot be better explained by another psychiatric disorder.
Although there is no "cure" for ADHD, there are accepted treatments that specifically target its symptoms. The most common standard treatments include educational approaches, psychological or behavioral modification, and medication.
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 and hyperactivity disorder (ADHD), human genetic therapies (HGT), gastrointestinal (GI) and renal diseases. The structure is sufficiently flexible to allow Shire to target new therapeutic areas to the extent opportunities arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in niche markets with strong intellectual property protection either in the US or Europe. Shire believes that a carefully selected 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, Shire's results could be materially affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of pharmaceutical research, product development including, but not limited to the successful development of JUVISTA(R) (Human TGF(beta)3) and velaglucerase alfa (GA-GCB); manufacturing and commercialization including, but not limited to, the establishment in the market of VYVANSE(TM) (lisdexamfetamine dimesylate) (Attention Deficit and Hyperactivity Disorder ("ADHD")); the impact of competitive products, including, but not limited to, the impact of those on Shire's ADHD franchise; patents, including but not limited to, legal challenges relating to Shire's ADHD franchise; government regulation and approval, including but not limited to the expected product approval date of INTUNIV(TM) (guanfacine extended release) (ADHD); Shire's ability to secure new products for commercialization and/or development; and other risks and uncertainties detailed from time to time in Shire plc's filings with the Securities and Exchange Commission, including Shire plc's Annual Report on Form 10-K for the year ended December 31, 2007.
Genzyme Corp. (Nasdaq: GENZ) reported that a preliminary analysis of data from an ongoing open-label Phase 2 clinical trial of its investigational oral therapy Genz-112638 showed that the compound produced a meaningful impact on key clinical manifestations of Gaucher disease. The results highlight the potential of this compound to become an innovative treatment option for Gaucher disease.
Genzyme's Cerezyme(R) (imiglucerase for injection), the standard of care for patients with Type 1 Gaucher disease, is administered through intravenous infusions. The company is developing Genz-112638, a capsule taken orally, to provide a convenient treatment alternative for patients and to provide a broader range of treatment options for physicians.
The primary analysis period of the Phase 2 study of Genz-112638 is scheduled to conclude later this year, and the results for all trial participants will be available in the first quarter of 2009. The study included 26 adults with Type 1 Gaucher disease at medical centers in North America, South America, Europe and Israel. It was designed to evaluate the efficacy, safety and pharmacokinetics of the compound over one year. Nearly all study participants had completed six months of treatment when the preliminary analysis was conducted, and approximately half of the participants had completed one year of treatment.
The preliminary analysis showed that Genz-112638 produced promising efficacy results at six months and that these results continued to improve through one year of treatment:
-- At six months, spleen volumes had decreased from baseline by a mean of 27 percent among the 21 patients for whom data were available. Spleen volumes had decreased by 40 percent among 11 patients with available data at one year.
-- At six months, hemoglobin levels had increased from baseline by a mean of 0.9 grams per deciliter of blood among 17 patients for whom data were available. Hemoglobin levels had increased by 1.3 grams per deciliter among 13 patients with available data at one year.
-- Platelet counts increased from baseline by a mean of 18 percent among 17 patients treated for six months and by 34 percent among 13 patients with available data at one year.
-- Chitotriosidase levels decreased from baseline by a mean of 30 percent at six months among 20 patients and by 50 percent among 12 patients treated for one year. Chitotriosidase commonly serves as a biomarker of Gaucher disease burden, allowing physicians to monitor patient response to treatment.
These preliminary results are consistent with results observed for patients beginning enzyme replacement therapy.
The analysis showed that drug-related adverse events seen in the trial occurred in a small number of patients, were mild and transient in nature, and did not require any medical intervention. The drug-related adverse events were diarrhea, abdominal pain, tachycardia, and headache.
Genzyme is currently developing protocols for two Phase 3 trials that it expects to initiate early next year. One trial is expected to include untreated Gaucher patients, and the other is expected to include patients previously treated with Cerezyme.
"We have set a very high bar in trying to develop an oral therapy for Gaucher disease given the remarkable impact that Cerezyme has had," said David P. Meeker, M.D., Genzyme's president of Lysosomal Storage Disorder Therapeutics. "We are excited by the potential of Genz-112638. The data we collect from this study and from the Phase 3 program will provide guidance on the roles that this compound may play in treating and maintaining patients with Gaucher disease."
Genzyme reported the results from the preliminary analysis of the Phase 2 study of Genz-112638 at its Analyst Day meeting held today in Boston.
About Gaucher disease
Gaucher disease is an inherited condition affecting fewer than 10,000 people worldwide. People with Gaucher disease do not have enough of an enzyme that breaks down a certain type of fat molecule called glucocerebrosidase. As a result, cells fill up with the undigested fat in different parts of the body, primarily the liver, spleen and bone marrow. Accumulation of Gaucher cells may cause spleen and liver enlargement, anemia, excessive bleeding and bruising, bone disease and a number of other signs and symptoms. The most common form of Gaucher disease, Type 1, does not affect the brain or nervous system.
About Genz-112638
Genz-112638, a novel glucosylceramide analog given orally, is designed to inhibit the enzyme glucosylceramide synthase, which results in reduced production of glucocerebroside. Glucocerebrosidase is the substance that builds up in the cells and tissues of people with Gaucher disease. In preclinical studies, the molecule has shown high potency and specificity. Based on its mechanism of action, which is independent of genotype, Genz-112638 is a potential therapy for all patients with Type 1 Gaucher disease. Initiation of the Phase 2 study of Genz-112638 in Gaucher disease followed completion of an extensive pre-clinical research effort and a Phase 1 program that involved more than 120 subjects in three separate studies. In addition to Gaucher disease, there are a variety of other conditions including Fabry disease that can be caused by malfunctions in the pathway targeted by this molecule. The compound is exclusively licensed from the University of Michigan and was developed with James A. Shayman, M.D.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 10,000 employees in locations spanning the globe and 2007 revenues of $3.8 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.
With many established products and services helping patients in nearly 90 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as immune disease, cardiovascular disease, and other areas of unmet medical need.
Safe Harbor
This press release contains forward-looking statements regarding Genzyme's future business plans including, without limitation, statements about the potential uses and benefits of Genz-112638; when final results from the Phase 2 study will be available; and future clinical trial plans and potential uses of the data from such clinical trials. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: the actual timing of the completion of the analysis of clinical study results; Genzyme's ability to accurately understand and predict the outcome and impact of its clinical studies related to Genz-112638; Genzyme's ability to continue to support its clinical and other development efforts related to Genz-112638; the actual efficacy and safety of Genz-112638; the outcome of discussions with regulatory authorities regarding clinical studies of Genz-112638; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Annual Report on Form 10-K for the year ended December 31, 2007. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of today's date and Genzyme undertakes no obligation to update or revise the statements.
Genzyme(R) and Cerezyme(R) are registered trademarks of Genzyme Corporation. All rights reserved.
Shire plc (LSE: SHP, Nasdaq: SHPGY), the global specialty biopharmaceutical company, announced findings from a new data analysis that was conducted to examine treatment differences with DAYTRANA(TM) (methylphenidate transdermal system) between boys and girls aged 6 to 12 years with Attention Deficit Hyperactivity Disorder (ADHD). The findings from the analysis reaffirmed that DAYTRANA has an established safety profile and effectively controlled ADHD symptoms in both boys and girls for the duration of the study. Results from this analysis were presented at a national scientific medical meeting in Washington, D.C.
"This analysis further demonstrates that DAYTRANA has a recognized safety profile and is an effective treatment for ADHD symptoms in both boys and girls with the disorder," said Robert Findling, M.D., investigator of the analysis and Director of the Division of Adolescent and Child Psychiatry at University Hospitals Case Medical Center and Professor of Psychiatry at Case Western Reserve University. "The findings are significant because only a relatively modest amount of work has been done to examine the effects of ADHD treatments by gender. This is an important consideration for parents because not only do they need to recognize that ADHD symptoms present differently in girls than in boys, but also because it is important to understand the role of treatment for both sexes."
According to the U.S. Centers for Disease Control and Prevention (CDC), a national survey conducted in 2003 showed that 11 percent of boys have been diagnosed with ADHD, in contrast to 4.4 percent of girls. Additional studies suggest the prevalence of ADHD in girls is critically underestimated and that many school-aged girls with the disorder are undiagnosed and under treated. This may be due to the fact that girls tend to show less disruptive ADHD symptoms such as inattention (e.g., inability to focus, organize and finish tasks), while boys tend to exhibit disruptive symptoms such as hyperactivity and impulsivity (e.g., restlessness, interrupting, impulsive decisions). In children, ADHD may interfere with paying attention in school, completing homework or making friends. Difficulties experienced by these children may continue into adulthood.
Summary of Analysis Findings
This analysis was conducted using data from an open-label, flexible dose, 12-month extension study in which 326 children received DAYTRANA. Children who enrolled in this study previously participated in other studies in which they received DAYTRANA, osmotic-release oral system (OROS) methylphenidate or placebo as part of the study design. The primary objective of this study was to investigate the long term safety profile of ADHD treatment with DAYTRANA, and the secondary objective examined the efficacy of the medication between genders. This subanalysis was conducted to examine treatment differences between boys and girls receiving DAYTRANA.
Adverse events were reported in a higher percentage of boys than girls in all dose groups; however, they were generally comparable between genders. Further, no clinically significant differences in adverse events were noted between boys and girls. Adverse events were typically mild or moderate and consistent with stimulant treatment. The most common adverse events included decreased appetite, headache, upper respiratory tract infection, cough, fever and decreased weight.
In the study, the efficacy of DAYTRANA was measured using the ADHD Rating Scale (ADHD-RS-IV), the Clinical Global Impressions-Improvement (CGI-I) scale and the Parent Global Assessment (PGA) rating scale and measurement results were found to be statistically significant on all scales. In the analysis, boys had a 41 percent change on the ADHD-RS-IV (as calculated from a mean baseline score of 11.6, with a mean change from baseline to endpoint of -4.8) and girls had a 23 percent change on the scale (as calculated from a mean baseline score of 11.3, with a mean change from baseline to endpoint of -2.6). Lower scores on the ADHD-RS-IV reflect an improvement in symptom control.
On the CGI-I scale, clinicians rated 83 percent of boys and girls "improved" or "very much improved" at the end of the study compared to week one. Additionally, the PGA rating scale showed that 78 percent of boys and girls "improved" or "very much improved" at the end of the study compared to week one. The results in both the CGI-I and PGA scale were comparable between boys and girls.
Dr. Findling added, "These positive findings, along with previously presented research, reinforces that the ADHD patch is an important treatment option for children, especially those who may benefit from an ADHD medication that can accommodate their changing daily needs."
DAYTRANA is the first and only non-oral medication for treating ADHD in children aged 6 to 12 years. Parents can adjust the wear time up to 9 hours under the physician's advice to accommodate for their child's varying weekdays, weekend and vacation schedules. DAYTRANA is available in four dosage strengths -- 10 mg, 15 mg, 20 mg and 30 mg -- all designed for once-daily use.
While this study evaluated the safety and effectiveness of DAYTRANA for up to 12 months, DAYTRANA has not been studied versus placebo for longer than 7 weeks. Physicians, who prescribe DAYTRANA for long-term use, should periodically re-evaluate patients to assess the usefulness of DAYTRANA for the individual patient.
This analysis was supported by Shire Development Inc.
Additional information about DAYTRANA and Full Prescribing Information are available at http://www.DAYTRANA.com.
ADHD-RS-IV assesses 18 individual symptoms of ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR(R)), a publication of the American Psychiatric Association.
The CGI-I scale is a standard assessment used to rate the severity of a patient's illness and improvement over time.
The PGA is a scale that measures overall improvement as assessed by parents.
DAYTRANA(TM) is a trademark of Shire Pharmaceuticals Ireland Limited.
Important Safety Information
Tell your doctor about any heart conditions, including structural abnormalities, your child or a family member may have. Inform your doctor immediately if the child develops symptoms that suggest heart problems, such as chest pain or fainting.
DAYTRANA should not be used if the child has: significant anxiety, tension, or agitation; allergies to methylphenidate or other ingredients of DAYTRANA; glaucoma; discontinued in the last 14 days or is taking a monoamine oxidase inhibitor (MAOI); tics, or family history or diagnosis of Tourette's syndrome.
Tell your doctor before using DAYTRANA if the child: is being treated for or has symptoms of depression (e.g. sadness, worthlessness or hopelessness) or bipolar disorder; has family history of tics; has abnormal thoughts or visions, hears abnormal sounds or has been diagnosed with psychosis; has had seizures or abnormal EEGs; has or has had high blood pressure; exhibits aggressive behavior or hostility. Tell your doctor immediately if the child develops any of these conditions/symptoms while using DAYTRANA.
In clinical studies, side effects were generally mild to moderate. The most common side effects reported with DAYTRANA were decreased appetite, sleeplessness, sadness/crying, twitching, weight loss, nausea, vomiting, tics and affect lability (mood swings). Aggression, new abnormal thoughts/behaviors, mania and growth suppression have been associated with use of drugs of this type. Tell your doctor if the child has blurred vision while using DAYTRANA.
Abuse of DAYTRANA can lead to dependence.
DAYTRANA should be applied daily to clean, dry skin, which is free of any cuts or irritation. Skin redness or itching is common with DAYTRANA. Allergic skin rash may occur.
About ADHD
ADHD is one of the most common psychiatric disorders in children and adolescents. Approximately 7.8 percent of all school-aged children, or about 4.4 million U.S. children aged 4 to 17 years, have been diagnosed with ADHD at some point in their lives, according to the U.S. Centers for Disease Control and Prevention (CDC). The disorder is also estimated to affect 4.4 percent of U.S. adults aged 18-44 based on results from the National Comorbidity Survey Replication, a nationally representative household survey, which used a lay-administered diagnostic interview to assess a wide range of DSM-IV disorders. ADHD is a neurobiological disorder that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of development. To be properly diagnosed with ADHD, a child needs to demonstrate at least six of nine symptoms of inattention; and/or at least six of nine symptoms of hyperactivity/impulsivity; the onset of which appears before age 7 years; that some impairment from the symptoms is present in two or more settings (e.g., at school and home); that the symptoms continue for at least six months; and that there is clinically significant impairment in social, academic or occupational functioning and the symptoms cannot be better explained by another psychiatric disorder.
Although there is no "cure" for ADHD, there are accepted treatments that specifically target its symptoms. The most common standard treatments include educational approaches, psychological or behavioral modification, and medication.
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 and hyperactivity disorder (ADHD), human genetic therapies (HGT), gastrointestinal (GI) and renal diseases. The structure is sufficiently flexible to allow Shire to target new therapeutic areas to the extent opportunities arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in niche markets with strong intellectual property protection either in the US or Europe. Shire believes that a carefully selected 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, Shire's results could be materially affected. The risks and uncertainties include, but are not limited to, risks associated with: the inherent uncertainty of pharmaceutical research, product development including, but not limited to the successful development of JUVISTA(R) (Human TGF(beta)3) and velaglucerase alfa (GA-GCB); manufacturing and commercialization including, but not limited to, the establishment in the market of VYVANSE(TM) (lisdexamfetamine dimesylate) (Attention Deficit and Hyperactivity Disorder ("ADHD")); the impact of competitive products, including, but not limited to, the impact of those on Shire's ADHD franchise; patents, including but not limited to, legal challenges relating to Shire's ADHD franchise; government regulation and approval, including but not limited to the expected product approval date of INTUNIV(TM) (guanfacine extended release) (ADHD); Shire's ability to secure new products for commercialization and/or development; and other risks and uncertainties detailed from time to time in Shire plc's filings with the Securities and Exchange Commission, including Shire plc's Annual Report on Form 10-K for the year ended December 31, 2007.
Although once considered to be a disorder only seen in children, Attention Deficit Hyperactivity Disorder (ADHD) is now known to be a condition associated with a wide range of functional impairments throughout the lifespan(1). In the US, the overall prevalence of ADHD in adults is estimated to range between 3.4% and 4.4%(2), and between 30 and 70% of children with ADHD continue to exhibit symptoms into adult years(3).
Today at the 161st Annual Meeting of the American Psychiatric Association (APA) there were new insights provided into treatment of adult ADHD with OROS(R) methylphenidate (MPH) HCl Extended-release Tablets. The findings included efficacy and safety sub-analyses from a randomized, double-blind, placebo-controlled, dose-titration trial completed in 2007 and final results from a long-term, open-label safety trial.
"What we're learning more and more is that adult ADHD, while considered the same medical condition as pediatric ADHD, often has a strikingly different patient impact due to what can be a lifetime of functional impairment related to individualized symptoms," noted Lenard Adler, M.D., Director of the Adult ADHD Program at the NYU Langone Medical Center and Associate Professor of Psychiatry, Neurology and Child and Adolescent Psychiatry at the NYU School of Medicine. Dr. Adler* participated as an investigator in the long-term, open-label trial and was the lead investigator of the placebo-controlled dose-titration trial presented in October 2007. In that study, 226 patients with ADHD ages 18-65 were randomized to receive placebo or OROS(R) MPH (36 to 108 mg/day) for seven weeks; results showed significant improvements with OROS(R) MPH in symptom management compared to placebo.
Efficacy Findings from Short-Term, Dose-Titration Trial
In sub-analysis findings from that study presented today, OROS(R) MPH demonstrated efficacy in the study population. Specifically, OROS(R) MPH demonstrated significant efficacy in adults with ADHD across the dose range studied (36 to 108 mg/day) and consistency in symptom evaluation between clinicians (using the Adult ADHD Investigator Symptom Rating Scale [AISRS]) and patients (using the Conners' Adult ADHD Rating Scale-Self Report, Short Version [CAARS-S:S]).
"What's important about these data is that patients and clinicians in this study showed clear agreement on how each viewed the severity of the condition being treated, as well as the patient response to the medication being tested," notes Joseph M. Palumbo, M.D., Franchise Medical Leader in Psychiatry, Johnson & Johnson Pharmaceutical Research & Development, LLC (J&JPRD). "What we saw in patients' responses to treatment across the dose range studied suggest that adults with ADHD may benefit from more personalized treatment options."
Safety and Cardiovascular Data
Other findings presented today showed OROS(R) MPH to be well tolerated, with no unexpected cardiovascular effects associated with OROS(R) MPH in the study populations of the short-term dose-titration trial as well as the long-term, open-label trial. Consistent with Food and Drug Administration class labeling for all stimulant ADHD medication, which states that patients with serious cardiovascular illness should generally not be treated with stimulants, patients with a history of serious cardiovascular illness were excluded from both the short-term dose-titration study and the long-term open-label trial. Throughout both trials, heart rate and blood pressure were monitored during the titration period and the dose was reduced if certain cut-off heart rate or blood pressure values were reached. The long-term, open-label trial included an ECG every three months.
Final results from the open-label trial conducted for up to one year showed that in the study population of 550 patients, mean increases in blood pressure (BP) and heart rate (HR) observed with OROS(R) MPH were consistent with those seen in other data from the methylphenidate class. Mean systolic and diastolic blood pressure increased by 2.6 mmHg and 1.9mmHg, respectively and mean heart rate increased by 4.1 beats per minute (bpm).
Overall, cardiovascular-related adverse events occurred in 23.3% of patients and mainly consisted of BP and HR increases. There was no evidence of a treatment effect in any ECG assessment aside from an increase in HR. No deaths, heart attacks or strokes were reported and no unexpected safety findings were noted.
The safety profile of OROS(R) MPH in the long-term, open-label study's dose range of 36 mg to 108 mg per day, was consistent with that seen in shorter-term trials in adults. Adverse events with an incidence greater than 10% included decreased appetite, headache, insomnia, dry mouth, anxiety, upper respiratory tract infection, nausea, increased heart rate and irritability.
Additionally, a cardiovascular sub-analysis from the short-term dose-titration study of OROS(R) MPH versus placebo showed no clinically significant mean changes from baseline in blood pressure, heart rate or ECG parameters. The cardiovascular effects noted in this sub-analysis were consistent with those previously documented in other data from the MPH class.
Data from this sub-analysis showed similar mean changes from baseline in systolic and diastolic BP for OROS(R) MPH and placebo groups. Systolic mean change from baseline was -1.2 mmHg for OROS(R) MPH vs. -0.5 mmHg for placebo; diastolic mean change from baseline was +1.1 mmHg for OROS(R) MPH vs. +0.4 mmHg for placebo. Mean change in pulse from baseline was greater for the OROS(R) MPH group, with +3.6 beats per minute (bpm) vs. -1.6 bpm in placebo. Increased BP was the only cardiovascular adverse event reported in greater than 10% of OROS(R) MPH patients (10% for OROS(R) MPH vs. 5.2% for placebo). BP or HR increase led to down titration in 4.5% (5/110) of OROS(R) MPH patients and 0.9% (1/116) of placebo patients.
The studies were presented and sponsored by J&JPRD, which filed for U.S. approval of OROS(R) MPH for the treatment of adult ADHD last year.
The following New Research Posters on OROS(R) MPH will be presented at APA:
NR6-019: Cardiovascular Safety Data From a Long-Term, Open-Label Study of OROS(R) MPH in Adults with ADHD
NR6-017: A Long-Term Safety Study of OROS(R) Methlyphenidate in Adults with ADHD
NR6-034: Cardiovascular Effects of OROS(R) MPH in a Dose-Titration Study of Adults with ADHD
NR6-014: Treatment Response with OROS(R) MPH in a Dose-Titration Study of Adults with ADHD
NR6-010: Clinician-Rated and Patient-Rated Symptom Improvement in a Double-Blind, Placebo-Controlled, Dose-Titration Study of OROS(R) MPH in Adults with ADHD
NR6-005: Efficacy of OROS(R) MPH in a Double-Blind, Placebo-Controlled, Dose-Titration Study of Adults with ADHD: Secondary Endpoints
Dr. Adler has been a consultant, served on advisory boards and received research grants from J&JPRD and McNeil Pediatrics(TM), Division of Ortho- McNeil-Janssen Pharmaceuticals, Inc.
About ADHD
Attention Deficit Hyperactivity Disorder (ADHD) is a common and treatable neuropsychiatric condition, which includes inattention, hyperactivity and impulsivity. According to the National Institutes of Mental Health (NIMH), ADHD is one of the most common mental disorders in childhood. It affects an estimated four million children and adolescents in the United States.
Important Safety Information
OROS(R) MPH should not be taken by patients with: significant anxiety, tension or agitation; allergies to methylphenidate or other ingredients in OROS(R) MPH; glaucoma; Tourette's syndrome, tics or family history of Tourette's syndrome. Abuse of methylphenidate may lead to dependence. Tell your health care professional if your child has had problems with alcohol or drugs, has had depression, abnormal thoughts or visions, bipolar disorder, seizures, high blood pressure or has had any heart problems or defects. If your child develops abnormal thinking or hallucinations, abnormal, extreme moods and/or excessive activity, or if aggressive behavior or hostility develops or worsens while taking OROS(R) MPH, consult your health care professional. The most common adverse events reported in children receiving up to 54 mg were headache, upper respiratory tract infection and abdominal pain. The most common adverse events reported by adolescents receiving up to 72 mg were headache, accidental injury and insomnia.
Johnson & Johnson Pharmaceutical Research & Development, LLC (J&JPRD) is part of Johnson & Johnson, the world's most broadly based producer of healthcare products. J&JPRD is headquartered in Raritan, NJ, and has facilities throughout Asia, Europe and the United States. J&JPRD is leveraging drug discovery and drug development in a variety of therapeutic areas to address unmet medical needs worldwide.
McNeil Pediatrics(TM), Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is committed to meeting the needs of pediatric medicine through the development of therapies specifically formulated for children. McNeil Pediatrics(TM) markets OROS(R) methylphenidate HCL for treatment of children and adolescents with ADHD in the US. McNeil Pediatrics(TM) is continuing to explore other new therapies to meet the special needs of children and the pediatric community. Visit http://www.mcneilpediatrics.net for more information.
OROS(R) is a registered trademark of ALZA Corporation.
References
1: Kessler RC et al, Journal of American Occupational Environmental Medicine 2005
2: Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: Results from the National Comorbidity Study replication. Am J Psychiatry 2006;163:716-23.insert reference
3: NIMH website, Silver LB. Attention-deficit hyperactivity disorder in adult life. Child and Adolescent Psychiatry Clinics of North America, 2000:9:3: 411-523
New Phase 1 clinical trial results for NKTR-118 (oral PEG-naloxol) were presented by Nektar Therapeutics (Nasdaq: NKTR) this week at the Annual Meeting of the American Pain Society (APS) in Tampa, Florida. In this multiple-dose Phase 1 study, oral NKTR-118 was shown to have substantial oral bioavailability with rapid absorption and an extended half-life that is up to ten times the known half-life of unPEGylated naloxone.
NKTR-118 is Nektar's proprietary peripheral opioid antagonist candidate currently in a Phase 2 trial in patients with opioid-induced bowel dysfunction (OBD), including opioid-induced constipation. Nektar's advanced small molecule PEGylation technology has been shown to reduce NKTR-118's penetration across the blood-brain barrier, an important potential advance for this and many other potential therapies.
"For the first time, it has now been shown that Nektar's proprietary PEGylation technology can be used to enhance oral bioavailability for a small molecule drug," said Timothy A. Riley, Ph.D., Vice President of PEGylation Research at Nektar. "In addition, this PEGylated drug exhibited an exceptionally long half-life of eleven hours, enabling a once-daily dosing regimen for NKTR-118 as an oral therapy."
NKTR-118 was also shown to be safe and generally well-tolerated at doses up to 250 mg twice daily, with no serious or severe adverse events. The pharmacokinetics of NKTR-118 were dose-proportional and the observed terminal half-life of the drug was approximately eleven hours, independent of dose. This compares to a known half-life of between 45 and 100 minutes for naloxone.(1) At all dose levels, NKTR-118 was rapidly absorbed after oral administration, as evidenced by a steep increase of plasma NKTR-118 concentration. Plasma concentrations of NKTR-118-glucuronide were approximately 100-fold less than plasma NKTR-118 concentrations. Studies have shown that the bioavailability of oral naloxone is limited by first-pass metabolism of naloxone.(1)
"The prevalence and impact of opioid-bowel dysfunction among chronic pain patients are underestimated today," said Sunil J. Panchal, M.D., President of the National Institute of Pain and the Coalition for Pain Education (COPE) Foundation. "The condition can have a serious deleterious impact on a patient's quality of life and can also limit chronic pain management treatments. There is a clear need for an oral therapy that targets the underlying cause of OBD while preserving the desired analgesic effects of opioid treatment."
About the Phase 1 Clinical Trial
The primary objective of this Phase 1 multi-dose, double-blind, randomized, placebo-controlled study was to evaluate the safety and tolerability of multiple doses of oral NKTR-118 in healthy human subjects not receiving opioid therapy. A total of 32 subjects enrolled in the trial. The secondary objective of the trial was to evaluate the pharmacokinetics of oral NKTR-118 and its metabolite (NKTR-118 glucuronide) following twice-daily oral administration for seven days. Escalating doses up to 250 mg twice daily were studied. Subjects were randomized 3:1 to NKTR-118 or placebo twice daily (every 12 hours) for seven days, with a single dose on the eighth day.
Prior Clinical Study Results for NKTR-118
Nektar previously presented results from a proof-of-principle, single-dose Phase 1 study at the American College of Clinical Pharmacology Meeting (ACCP) conference in September of 2007. In this proof-of-principle study, single oral doses of NKTR-118 antagonized morphine-induced delay in gastrointestinal transit time demonstrating the potential of the drug to relieve constipation. Further, no diminution of morphine-induced miosis, a CNS effect, was observed at single oral doses of NKTR-118 of 125 mg or less. In addition, NKTR-118 at single doses up to 1,000 mg was well-tolerated. The drug was rapidly absorbed with dose-proportional pharmacokinetics over the 8-1,000 mg dose range.
About NKTR-118
Oral NKTR-118 is currently in a Phase 2 study to evaluate the efficacy, safety and tolerability of once-daily doses in patients with opioid-induced constipation (OIC). The investigational drug combines Nektar's advanced small molecule PEGylation technology platform with naloxol, a derivative of the opioid-antagonist drug, naloxone. In a Phase 1 clinical study, Nektar's PEGylation technology has been shown to reduce penetration of oral NKTR-118 across the blood-brain barrier, an important potential advance for this and possibly many other small molecule therapies.
The antagonist NKTR-118 targets mu-opioid receptors within the enteric nervous system, which mediate OBD, a symptom complex resulting from opioid use that encompasses constipation, bloating, abdominal cramping, and gastroesophageal reflux. Constipation is the hallmark of this syndrome, and is generally its most prominent component. Many studies indicate that a high percentage of patients receiving opioids are likely to experience significant constipation and other symptoms of OBD. According to IMS Health, about 230 million prescriptions were written for opioids in 2007 in the United States, alone.
Currently, there are no specific oral drugs approved that are indicated to treat OIC. Stool softeners or laxatives may be ineffective for many patients with OIC and they are often associated with side effects like diarrhea and stomach cramps. OBD and OIC can significantly impact quality of life and increase healthcare utilization. A meta-analysis of available randomized, placebo-controlled trials of non-cancer patients receiving opioids for moderate-to-severe pain revealed that constipation is one of the most common opioid-related side effects.(2)
Nektar PEGylation Platform
Nektar PEGylation technology can enhance the properties of therapeutic agents by increasing drug circulation time in the bloodstream, decreasing immunogenicity and dosing frequency, increasing bioavailability and improving drug solubility and stability. It can also be used to modify pharmaceutical agents to preferentially target certain systems within the body and reduce penetration of drug across the blood-brain barrier. It is a technique in which non-toxic polyethylene glycol (PEG) polymers are attached to therapeutic agents, and it is applicable to most major drug classes, including proteins, peptides, antibody fragments, small molecules, and other drugs.
Nektar PEGylation technology is also used in eight additional approved partnered products in the U.S. or Europe today, including UCB's Cimzia for Crohn's disease, Roche's PEGASYS(R) for hepatitis C and Amgen's Neulasta(R) for neutropenia.
About Nektar
Nektar Therapeutics is a biopharmaceutical company that develops and enables differentiated therapeutics with its industry-leading PEGylation and pulmonary drug development platforms. Nektar's technology and drug development expertise have enabled nine approved products for partners, which include leading biopharmaceutical companies. Nektar is also developing a robust pipeline of its own high-value therapeutics that addresses unmet medical needs by leveraging and expanding its technology platforms to improve known molecules.
This press release contains forward-looking statements regarding the potential of the company's PEGylation technology platform and NKTR-118. These forward-looking statements involve important risks and uncertainties, including but not limited to: (i) preclinical testing and clinical trials for NKTR-118 are long, expensive and uncertain processes, (ii) because the NKTR-118 product development program is in the early phases of clinical development, the risk of failure is high and can occur at any stage of development, (iii) the company may fail to obtain regulatory approval of NKTR-118, (iv) potential competition from approved drugs or drugs under development that may be safe and effective for the same indication as that targeted by NKTR-118, and (v) the company's patent applications for NKTR-118 may fail to issue; patents that have issued may not be enforceable; or unanticipated intellectual property licenses from third parties may be required in the future. Other important risks and uncertainties are detailed in the company's reports and other filings with the SEC; including its most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q. Actual results could differ materially from the forward-looking statements contained in this press release. The company undertakes no obligation to update forward-looking statements, whether as a result of new information, future events, or otherwise. No information regarding or presented at the scientific meetings referred to above (or contained at the Internet links provided herein) is intended to be incorporated by reference in this press release.
References
(1) Handel K, Schauben J, Salmone F, Naloxone. Annals of Emergency Medicine 1993; 12.7; 438-51
(2) Kalso et al., Opioids in chronic non-cancer pain; systematic review of efficacy and safety.
Patients receiving paliperidone extended-release tablets (paliperidone ER) spent significantly fewer days in the hospital, had significantly fewer emergency room and psychiatric-related office visits, and fewer psychotherapy sessions, compared with the year before starting treatment, according to a new analysis of data presented at the 161st Annual Meeting of the American Psychiatric Association (APA) in Washington, D.C.(1)
In the analysis, researchers retrospectively reviewed the charts of 79 of the patients who had participated in any of three multi-center, double-blind, randomized six-week trials of paliperidone ER and placebo, and were then entered into a 12-month open-label extension (OLE) phase. The investigators compared the number of days a patient was hospitalized for psychiatric reasons in the 12 months before being screened for the trial (pre-period) with those in the 12-month OLE phase (post-period) following administration of the first dose of paliperidone ER.(a) Most of the patients (70.9 percent) had received prior antipsychotic medication during the pre-period.
The results showed that patients taking paliperidone ER used significantly fewer healthcare resources after starting on the medication than in the one-year period before entering the trials. Patients had an average of 12 fewer hospital days (P=0.002), 0.3 fewer emergency room visits (P=0.038), two fewer psychiatric-related office visits (P<0.001) and 0.4 fewer psychotherapy sessions (P=0.004).
An economic analysis showed that the average costs savings for the reduced resource use with paliperidone ER was $7,411 per person-year, based on current Federal Medicare per diem base rates and 2007 Medicare unit costs, taking into account psychiatric-related hospitalizations, emergency room visits, psychiatric-related clinic visits and psychotherapy.
"Due to its chronic nature and the need for frequent hospitalization, schizophrenia is associated with significant economic burden," said Dr. Philip Janicak, Professor of Psychiatry, Rush University Medical Center and one of the lead investigators in the trial.(b) "Treating physicians, patients and their families would welcome treatment options that may help reduce resource use."
"We should keep in mind, important study limitations include the lack of a control group; pre/post design comparing historical data with data collected in the trials could create a bias due to the mismatch in settings; and patients may have had more frequent contact with treating physicians and investigators during the trial period which could favor the outcomes in the open-label phase. Therefore prospective studies should be conducted to confirm these findings," Dr. Janicak said.
A separate post-hoc analysis from those same three OLE studies also presented today examined employment status of patients with schizophrenia treated with paliperidone ER over the 52-week OLE period. A total of 1,012 patients 18 years and older with a diagnosis of schizophrenia were included. At their first and last visits, patients were placed into nine different occupational status categories.
The percentage of patients who reported employment during the open-label phase of the study increased throughout the 52-week study period. The number of patients who were employed full-time at their last visit almost doubled from 4.8 percent at the first visit to 8.8 percent, and the number of patients in any form of employment (including students, but excluding housewives or those retired) increased by 10.6 percent.
The studies were sponsored by Ortho-McNeil Janssen Scientific Affairs, LLC. Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. markets paliperidone ER in the U.S.
Paliperidone ER, an atypical antipsychotic medication, was first approved in the U.S. in December 2006. It is approved for the acute and maintenance treatment of schizophrenia in the U.S. and for the treatment of schizophrenia in the E.U.
Worldwide, it is estimated that 1 person in every 100 develops schizophrenia(2), one of the most serious types of mental illness. An estimated 2.4 million Americans have schizophrenia, with men and women affected equally.(3) The disease is marked by positive symptoms (hallucinations and delusions) and negative symptoms (depression, blunted emotions, and social withdrawal), as well as by disorganized thinking, speech and behavior.
Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., is based in Titusville, N.J. and is the only large pharmaceutical company in the U.S. dedicated solely to mental health. As the company celebrates its 50th year in mental health, it currently markets prescription medications for the treatment of schizophrenia, bipolar mania, and the treatment of symptoms associated with autistic disorder. For more information about Janssen, visit http://www.janssen.com.
IMPORTANT SAFETY INFORMATION FOR PALIPERIDONE ER
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Paliperidone is not approved for the treatment of patients with dementia-related psychosis.
Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal side effect reported with paliperidone and similar medicines. Call your doctor immediately if the person being treated develops symptoms such as high fever; stiff muscles; shaking; confusion; sweating; changes in pulse, heart rate, or blood pressure; or muscle pain and weakness. Treatment should be stopped if the person being treated has NMS.
One risk of paliperidone is that it may change your heart rhythm. This effect is potentially serious, and you should talk to your doctor about any current or past heart problems. Some medications interact with paliperidone. Please inform your healthcare professional of any medications or supplements that you are taking.
Tardive Dyskinesia (TD) is a serious, sometimes permanent side effect reported with paliperidone and similar medications. TD includes uncontrollable movements of the face, tongue, and other parts of the body. The risk of developing TD and the chance that it will become permanent is thought to increase with the length of therapy and the overall dose taken by the patient. This condition can develop after a brief period of therapy at low doses, although this is much less common. There is no known treatment for TD, but it may go away partially or completely if therapy is stopped.
High blood sugar and diabetes have been reported with paliperidone and similar medications. If the person being treated has diabetes or risk factors such as being overweight or a family history of diabetes, blood sugar testing should be performed at the beginning and throughout treatment with paliperidone. Complications of diabetes can be serious and even life threatening. If signs of high blood sugar or diabetes develop, such as being thirsty all the time, going to the bathroom a lot, or feeling weak or hungry, contact your doctor.
Paliperidone and similar medications can raise the blood levels of a hormone known as prolactin, causing a condition known as hyperprolactinemia. Blood levels of prolactin remain elevated with continued use. Some side effects seen with these medications include the absence of a menstrual period; breasts producing milk; the development of breasts by males; and the inability to achieve an erection. The connection between prolactin levels and side effects is unknown.
People with narrowing or blockage of the gastrointestinal tract (esophagus, stomach or small or large intestine) should talk to their healthcare professional before taking paliperidone.
Some people taking paliperidone may feel faint or lightheaded when they stand up or sit up too quickly. By standing up or sitting up slowly and following your healthcare professional's dosing instructions, this side effect may be reduced or it may go away over time.
Paliperidone may affect your driving ability; therefore, do not drive or operate machinery before talking to your healthcare professional. Avoid alcohol while on paliperidone.
Paliperidone should be used cautiously in people with a seizure disorder, who have had seizures in the past, or who have conditions that increase their risk for seizures.
Extrapyramidal Symptoms (EPS) are usually persistent movement disorders or muscle disturbances, such as restlessness, tremors, and muscle stiffness. If you observe any of these symptoms, talk to your healthcare professional.
Inform your healthcare professional if you are pregnant or if you are planning to get pregnant while taking paliperidone. Caution should be exercised when paliperidone is administered to a nursing woman.
Paliperidone may affect alertness and motor skills; use caution until the effect of paliperidone is known.
Paliperidone may make you more sensitive to heat. You may have trouble cooling off, or be more likely to become dehydrated, so take care when exercising or when doing things that make you warm.
Paliperidone should be swallowed whole. Tablets should not be chewed, divided, or crushed. Do not be worried if you see something that looks like a tablet in your stool. This is what is left of the tablet after all the medicine has been released.
The most common side effects that occurred with paliperidone were restlessness and extrapyramidal disorder (for example, involuntary movements, tremors and muscle stiffness).
(a) Because only 28 percent of patients completed the entire 12-month OLE phase, total person-years were calculated for the post-period to account for different lengths of observation compared with the pre-period.
(b) Dr. Janicak is a consultant to Janssen, Division of Ortho-McNeil- Janssen Pharmaceuticals, Inc.
References
(1) Janicak P, Wu J, Amatniek J et al., Changes in mental health resource use after initiation of paliperidone ER in patients with schizophrenia, presented at the 161st Annual Meeting of the American Psychiatric Association (APA), Washington, D.C.
(2) Royal College of Psychiatrists website: http://www.rcpsych.ac.uk/default.aspx?page=1643. Accessed April 14, 2008.
(3) American Psychiatric Association. Let's talk facts about schizophrenia.
