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ENews Vol 1 No 17 May 2009 Welcome to the National Information Centre for Metabolic Diseases Research News Sheet - Vol 1 No 16. The contents of this news sheet has been gathered from around the globe during our research to update our information on metabolic diseases. The contents are general and not specific to our vision.
Amicus Therapeutics Presents Positive Results From Phase 2 Extension Study of Amigal(TM) for Fabry Disease at ACMG 2009 Annual Meeting --Data provide support for expected Phase 3 program
CRANBURY, N.J., March 28, 2009 /PRNewswire-FirstCall via COMTEX News Network/ -- Amicus Therapeutics (Nasdaq: FOLD) announced today positive results from its ongoing Phase 2 extension study of its investigational drug, Amigal(TM) (migalastat HCL) for Fabry disease. The results will be presented at the American College of Medical Genetics (ACMG) 2009 Annual Meeting in Tampa, FL. Phase 2 Extension Study Overview:
Twenty-six subjects completed either 12 or 24 weeks of treatment during Phase 2 studies. Twenty-three of the 26 subjects continue to receive treatment in an ongoing extension study designed to evaluate the long term safety and efficacy of Amigal. Ten of the 23 subjects have been on treatment for at least 2 years and 4 subjects have been on treatment for more than 3 years.
Preliminary Results: Treatment with Amigal was generally well-tolerated, with no drug-related serious adverse events. The most common adverse events were headache, arthralgia and diarrhea.
Subjects identified as responders to Amigal at the completion of the Phase 2 studies continued to maintain elevated levels of the target enzyme (a-Gal A), as measured in white blood cells, and reduced levels of the target substrate (kidney GL-3), as measured in urine.
A reduction of GL-3 levels was also observed in interstitial capillary cells from kidney biopsies. Previously reported Phase 2 results indicated that little to no GL-3 was detected in these cells in most subjects prior to treatment with Amigal. The new data were obtained from the retesting of biopsies using an improved methodology. Preliminary results from the evaluation of modified doses and a new dosing regimen were also presented.
Derralynn Hughes, MA, DPhil, MRCPath, Senior Lecturer in the Haematology Department Academic Haematology, Royal Free & University College Medical School, London, UK, stated, "The data with migalastat continue to be encouraging. I believe migalastat has the potential to be an important new treatment option for Fabry patients."
John F. Crowley, President and CEO of Amicus Therapeutics, added, "We are very pleased with this additional set of Phase 2 data and are very confident we have a solid basis for a successful Phase 3 program. We continue to work in collaboration with the FDA and remain on track to finalize our protocol and initiate the Phase 3 program in the second quarter of this year."
In January 2009, Amicus announced that the FDA supports a Phase 3 clinical trial comparing Amigal to placebo based on a surrogate primary endpoint of the change in the amount of kidney GL-3, the substrate that accumulates in the cells of Fabry patients. The Company expects to finalize the protocol and initiate Phase 3 development in the second quarter of this year. Amicus is developing Amigal as part of a strategic collaboration with Shire Human Genetic Therapies (HGT), a business unit of Shire plc, to develop and commercialize Amicus' three lead pharmacological chaperone compounds for lysosomal storage disorders. Under the agreement, Shire received commercial rights outside of the United States. Amicus retains all U.S. rights.
About Fabry Disease Fabry disease is a lysosomal storage disorder caused by inherited genetic mutations in the GLA gene, which result in deficient activity of the enzyme alpha-galactosidase A (a-Gal A). Deficient a-Gal A activity leads to lysosomal accumulation of globotriaosylceramide (GL-3), which is believed to cause the various symptoms of Fabry disease, including pain, kidney failure and increased risk of heart attack and stroke. Amigal is designed to selectively bind to and stabilize a-Gal A, which facilitates proper trafficking of the enzyme to the lysosomes, where it is needed to break down GL-3.
Fabry disease is estimated to affect approximately 5,000 to 10,000 people in the developed world, but recent evidence suggests that the disease may be significantly under-diagnosed. The U.S. Food and Drug Administration's Office of Orphan Products Development has granted orphan designation for Amigal in the United States, and the European Commission has designated Amigal as an orphan medicinal product in the European Union. About 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) and gastrointestinal (GI) diseases as well as opportunities in other therapeutic areas to the extent they arise through acquisitions. Shire's in-licensing, merger and acquisition efforts are focused on products in specialist markets with strong intellectual property protection and global rights. Shire believes that a carefully selected and balanced portfolio of products with strategically aligned and relatively small-scale sales forces will deliver strong results. For further information on Shire, please visit the Company's website: www.shire.com.
About Amicus Therapeutics Amicus Therapeutics is a biopharmaceutical company developing novel, oral therapeutics known as pharmacological chaperones for the treatment of a range of human genetic diseases. Pharmacological chaperone technology involves the use of small molecules that selectively bind to and stabilize proteins in cells, leading to improved protein folding and trafficking, and increased activity. Amicus is initially targeting lysosomal storage disorders, which are severe, chronic genetic diseases with unmet medical needs.
Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as, but not limited to, "look forward to," "believe," "expect," "anticipate," "estimate," "intend," "plan," "targets," "likely," "will," "would," "should" and "could," and similar expressions or words identify forward-looking statements. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. The inclusion of forward-looking statements should not be regarded as a representation by Amicus that any of its plans will be achieved. Any or all of the forward-looking statements in this press release may turn out to be wrong. They can be affected by inaccurate assumptions Amicus might make or by known or unknown risks and uncertainties. For example, with respect to statements regarding the goals, progress, timing and outcomes of ongoing discussions with regulatory authorities and the potential goals, progress, timing and results of clinical trials, actual results may differ materially from those set forth in this release due to the risks and uncertainties inherent in the business of Amicus, including, without limitation: the potential inability to reach final agreement with regulatory agencies on the use of a surrogate endpoint and phase 3 trial design for Amigal, the potential that the interim results of the phase 2 extension study may not be predictive of the final results of the study, the potential that results of clinical or pre-clinical studies indicate that the product candidates are unsafe or ineffective; and, our dependence on third parties in the conduct of our clinical studies. Further, the results of earlier clinical trials may not be predictive of future results. Additionally, all forward looking statements are subject to other risks detailed in our Annual Report on Form 10-K for the year ended December 31, 2008, and our other public filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, and Amicus undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. This caution is made under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995. FOLD-G SOURCE Amicus Therapeutics http://www.amicustherapeutics.com/
BioMarin's Clinical Trial Application for GALNS for Morquio A Syndrome Accepted by the MHRA
NOVATO, Calif., March 18 /PRNewswire-FirstCall/ -- BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) announced today that its application for clinical trial authorization (CTA) for BMN 110 or N-acetylgalactosamine 6-sulfatase (GALNS), intended for the treatment of the lysosomal storage disorder Mucopolysaccharidosis Type IVA (MPS IVA), or Morquio A Syndrome, has been accepted by the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA). BioMarin expects to initiate a Phase 1/2 clinical trial in the next few weeks.
"There are a significant number of untreated Morquio patients in clinics around the world who are very anxious to receive a new treatment option. We are moving forward expeditiously with our GALNS program in the hope of bringing those patients the much-needed treatment they deserve. BioMarin has successfully advanced two enzyme replacement therapies from IND filing to FDA approval in approximately five years each and we plan to leverage our clinical, manufacturing and regulatory expertise to develop this treatment for Morquio A syndrome," said Jean-Jacques Bienaime, Chief Executive Officer of BioMarin. "Enrollment in the MorCAP study initiated last November is continuing and we continue to add additional sites. We expect that this survey study will yield valuable information on Morquio patients and will aid in our scientific understanding of the disorder as we further pursue this program."
The Phase 1/2 study is designed as an open-label, within-patient dose escalation trial in approximately 20 patients followed by a treatment continuation phase. During the dose escalation phase of the study, subjects will receive weekly intravenous infusions of BMN 110 in 3 consecutive 12-week dosing intervals. The objectives of the Phase 1/2 study will be to evaluate safety, pharmacokinetics, pharacodynamics and to identify the optimal dose of GALNS for future studies.
BioMarin has developed and manufactures two FDA-approved enzyme replacement therapies, one for the treatment of MPS I and one for the treatment of MPS VI. Naglazyme(R) (galsulfase) for MPS VI is wholly developed and commercialized by BioMarin. Aldurazyme(R) (laronidase) for MPS I is manufactured by BioMarin and marketed by Genzyme Corporation.
About MPS IVA Mucopolysaccharidosis IVA (MPS IVA, also known as Morquio A Syndrome) is a disorder characterized by deficient activity of N-acetylgalactosamine 6-sulfatase (GALNS) causing excessive lysosomal storage of keratan sulfate (KS). This excessive storage causes a systemic skeletal dysplasia, short stature, and joint abnormalities, which limit mobility and endurance. Malformation of the thorax as well as macrophage dysfunction in the lung likely impairs respiratory function and contributes to sinopulmonary infections. Odontoid dysplasia and ligamentous laxity can commonly cause cervical spinal instability and potentially spinal cord compression. Other symptoms may include recurrent infections, hearing loss, corneal clouding, and heart valvular disease. Initial symptoms often become evident in the first five years of life. Depending on severity of the disorder, age of diagnosis will vary. Many patients become wheelchair dependent in their second decade of life and undergo numerous surgeries to alleviate life-threatening conditions caused by the underlying enzyme deficiency.
The incidence estimates for MPS IVA vary widely, between 1 in 200,000 live births to 1 in 300,000 live births. Approximately 400 patients worldwide have been identified and tracked through an independent registry. Based on the number of identified patients to date, the prevalence of patients with MPS IVA appears similar to that with MPS I.
About BioMarin BioMarin develops and commercializes innovative biopharmaceuticals for serious diseases and medical conditions. The company's product portfolio comprises three approved products and multiple clinical and preclinical product candidates. Approved products include Naglazyme(R) (galsulfase) for mucopolysaccharidosis VI (MPS VI), a product wholly developed and commercialized by BioMarin; Aldurazyme(R) (laronidase) for mucopolysaccharidosis I (MPS I), a product which was developed through a 50/50 joint venture with Genzyme Corporation; and Kuvan(R) (sapropterin dihydrochloride) Tablets, a product for the treatment of phenylketonuria (PKU), developed in partnership with Merck Serono, a division of Merck KGaA of Darmstadt, Germany. Other product candidates include PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase), which is currently in Phase 1 clinical development for the treatment of PKU. For additional information, please visit www.BMRN.com. Information on BioMarin's website is not incorporated by reference into this press release.
Forward-Looking Statement This press release contains forward-looking statements about the business prospects of BioMarin Pharmaceutical Inc., including, without limitation, statements about: the development of its program for MPS IVA, and particularly the timing and conuct of clinical trials related thereto, and expectations regarding filings with regulatory agencies. These forward-looking statements are predictions and involve risks and uncertainties such that actual results may differ materially from these statements. These risks and uncertainties include, among others: the results of current and planned pre-clinical trials related to the enzyme replacement therapy for MPS IVA; the content and timing of decisions by the U.S. Food and Drug Administration, EMEA and other regulatory agencies, particularly with respect to the enzyme replacement therapy for MPS IVA, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission, including, without limitation, the factors contained under the caption "Risk Factors" in BioMarin's 2008 Annual Report on Form 10-K. Stockholders are urged not to place undue reliance on forward-looking statements, which speak only as of the date hereof. BioMarin is under no obligation, and expressly disclaims any obligation to update or alter any forward-looking statement, whether as a result of new information, future events or otherwise. BioMarin(R), Naglazyme(R) and Kuvan(R) are registered trademarks of BioMarin Pharmaceutical Inc.
Aldurazyme(R) is a registered trademark of BioMarin/Genzyme LLC.
SOURCE BioMarin Pharmaceutical Inc. -0- 03/18/2009
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FDA Grants Priority Review of a Supplemental Biologics License Application for Cinryze(TM) C1 Inhibitor (Human) as Treatment for Acute Attacks of Hereditary Angioedema (HAE)
- PDUFA Date for Cinryze for Acute HAE Indication is June 3, 2009 - EXTON, Pa., Feb. 3 /PRNewswire-FirstCall/ -- ViroPharma Incorporated (Nasdaq: VPHM) today announced that the U.S. Food and Drug Administration (FDA) has granted priority review for Cinryze C1 Inhibitor (human) as a treatment for acute attacks of Hereditary Angioedema (HAE). The supplemental Biologics License Application (sBLA), submitted to the FDA on December 1, 2008, was based on a re-analysis and resubmission of data from a pivotal Phase 3 acute treatment study of Cinryze and interim data from an ongoing open label acute study of the drug.
Cinryze was approved on October 10, 2008 for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE.
Priority review is granted by the FDA for a treatment that addresses an unmet medical need and demonstrates improvement over existing therapies. The FDA expedites the approval process for applications granted priority review from ten to six months. The PDUFA date for the sBLA is June 3, 2009.
"The priority review designation marks a positive step in bringing another use of Cinryze closer to the patients who suffer acute attacks of hereditary angioedema," commented Vincent Milano, ViroPharma's president and chief executive officer. "We look forward to working with the FDA on approval so that we can help this additional group of patients." The administration of Cinryze produced beneficial effects in treating acute HAE attacks in these studies. The safety profile was similar to that observed with the use of Cinryze for routine prophylaxis of angioedema attacks in patients with HAE, the currently approved indication. Overall, more than 9,000 doses of Cinryze have been administered to over 180 patients in all controlled and open label clinical studies of Cinryze for both acute treatment and routine prophylaxis against angioedema attacks.
The Phase 3 acute treatment study was a randomized, double blind, placebo controlled multi-center trial in 71 patients evaluating the safety and efficacy profile of Cinryze for treatment of HAE attacks. The primary efficacy measure in the pivotal Phase 3 acute treatment study was the time from initial treatment to the start of unequivocal relief of the defining symptom. Based on the primary efficacy variable, in the All Randomized (ITT) Dataset, the likelihood of a patient having the start of unequivocal relief of the defining symptom was 2.048 times greater in the Cinryze treatment group than in the placebo treatment group (p=0.048). The median time to the start of unequivocal relief of the defining symptom was shorter in subjects in the Cinryze treatment group (two hours) than in subjects in the placebo treatment group (greater than four hours).
In the open label study of Cinryze as treatment for acute attacks of HAE, no patients who had acute laryngeal edema attacks required hospitalization or intubation. Cinryze was generally well tolerated. There were no deaths or serious adverse reactions related to Cinryze administration, or discontinuations due to treatment-emergent adverse events. In the analysis of 447 acute attacks in 82 patients, open label Cinryze administration provided substantial relief of the defining symptom in 93.4 percent of the attacks within four hours of injection, with a median time to onset of relief of 30 minutes. There was no observed loss of effectiveness over multiple administrations of Cinryze for subsequent HAE attacks.
About Cinryze C1 Inhibitor (human) Cinryze is a highly purified, pasteurized and nanofiltered plasma-derived C1 inhibitor product that has been approved by FDA for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE. C1 inhibitor therapy has been used acutely for more than 35 years in Europe to treat patients with C1 inhibitor deficiency. Cinryze has not been approved for acute treatment in the United States or any other jurisdiction.
Cinryze has been generally well tolerated. The most common adverse reactions observed have been upper respiratory infection, sinusitis, rash and headache. No drug-related serious adverse events (SAEs) have been observed in clinical trials. Severe hypersensitivity reactions may occur. Thrombotic events have occurred in patients receiving high dose off-label C1 inhibitor therapy well above the approved treatment dosage regimen. With any blood or plasma derived product, there may be a risk of transmission of infectious agents, e.g. viruses and, theoretically, the CJD agent. The risk has been reduced by screening patients for prior exposure to certain virus infections and by manufacturing steps to reduce the risk of viral transmission including pasteurization and nanofiltration.
Cinryze is for intravenous use only. A dose of 1000 Units of Cinryze can be administered every 3 or 4 days for routine prophylaxis against angioedema attacks in HAE patients. Cinryze is administered at an injection rate of 1 mL per minute. About Hereditary Angioedema
HAE is a rare, severely debilitating, life-threatening genetic disorder caused by a deficiency of C1 inhibitor, a human plasma protein. This condition is the result of a defect in the gene controlling the synthesis of C1 inhibitor. C1 inhibitor maintains the natural regulation of the contact, complement, and fibrinolytic systems, that when left unrestricted, can initiate or perpetuate an attack by consuming the already low levels of endogenous C1 inhibitor in HAE patients. Patients with C1 inhibitor deficiency experience recurrent, unpredictable, debilitating, and potentially life threatening attacks of inflammation affecting the larynx, abdomen, face, extremities and urogenital tract. Patients with HAE experience approximately 20 to 100 days of incapacitation per year. There are estimated to be at least 4600 people with HAE in the United States.
For more information on HAE, visit the U.S. HAE Association's website at: www.haea.org.
About ViroPharma Incorporated ViroPharma Incorporated is a biopharmaceutical company dedicated to the development and commercialization of products that address serious diseases treated by physician specialists and in hospital settings. ViroPharma commercializes Vancocin(R) (vancomycin hydrochloride capsules, USP), approved for oral administration for treatment of antibiotic-associated pseudomembranous colitis caused by Clostridium difficile and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains, and Cinryze(TM) (C1 inhibitor (human)) for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE), also known as C1 inhibitor deficiency (for prescribing information on ViroPharma's commercial products, please download the package inserts at http://www.viropharma.com/Products.aspx). ViroPharma currently focuses its drug development activities in diseases including cytomegalovirus (CMV), HAE and C. difficile. ViroPharma routinely posts information, including press releases, which may be important to investors in the investor relations and media sections of our company's web site, www.viropharma.com. The company encourages investors to consult these sections for more information on ViroPharma and our business.
Forward-Looking Statements Certain statements in this press release contain forward-looking statements that involve a number of risks and uncertainties. Forward-looking statements provide the Company's current expectations or forecasts of future events. Forward-looking statements in this press release include statements regarding ViroPharma's clinical development programs. Our actual results could differ materially from those results expressed in, or implied by, these forward-looking statements. The development and commercialization of pharmaceutical products is subject to risks and uncertainties. The data that were submitted to the U.S. Food and Drug Administration includes data from two separate studies including the pivotal Phase 3 study of Cinryze in acute HAE attacks and the ongoing open-label study of Cinryze for acute treatment of HAE, which includes partial data from an ongoing open label study. There can be no assurance that the complete data from the open label study will demonstrate that Cinryze successfully treats all types of acute hereditary angioedema (HAE) attacks and may not be predictive of the results of any future testing. The FDA may view the data regarding the use of Cinryze for acute treatment of HAE we have submitted as a supplemental BLA as insufficient or inconclusive, not accept our submission, request additional data, require additional clinical studies, delay any decision past the time frames anticipated by us, limit any approved indications, deny the approval of Cinryze for acute treatment of HAE or approve a competing product which has been granted orphan drug designation thereby preventing Cinryze from reaching the market for acute treatment of HAE. These factors, and other factors, including, but not limited to those described in ViroPharma's annual report on Form 10-K and quarterly reports on Form 10-Q filed with the Securities and Exchange Commission during 2008, could cause future results to differ materially from the expectations expressed in this press release. The forward-looking statements contained in this press release may become outdated over time. ViroPharma does not assume any responsibility for updating any forward-looking statements.
SOURCE ViroPharma Incorporated - 02/03/2009
Hyperion Therapeutics Announces Results for Phase II Study in Urea Cycle Disorders Company preparing to initiate phase III trial South San Francisco, California - March 30, 2009 Hyperion Therapeutics, Inc. today announced top-line results from their phase II study of HPN-100 for the treatment of urea cycle disorders. The data was presented on March 27th at the 16th Annual Clinical Genetics Meeting of the American College of Medical Genetics by Brendan Lee, M.D., Ph.D., Howard Hughes Medical Institute Investigator and Professor Department of Molecular and Human Genetics Baylor College of Medicine. The abstract is entitled “Phase 2 Study of A Novel Ammonia Scavenging Agent In Adults With Urea Cycle Disorders (UCDs).” The phase II study was an open-label, fixed sequence, switch-over study [BUPHENYL® (sodium phenylbutyrate) to HPN-100] of ten adult subjects with UCDs. The primary endpoint was safety; secondary outcome measures included pharmacokinetics (PK), pharmacodynamics (PD), and exploratory efficacy as measured by time-normalized area under the curve (TNAUC) for ammonia. Patients were enrolled on their stable dose of BUPHENYL and 24-hour PK, ammonia measurements, amino acids, and urine collections were completed in a study unit after seven days of on-study treatment. Each patient was then switched to HPN-100 at a dose providing the same amount of the active ingredient (PBA). After seven days of HPN-100 dosing, patients were re-admitted for the same battery of assessments that were completed at day seven. Both BUPHENYL and HPN-100 were administered TID with meals.
Twenty-one adverse events (AEs) occurred in seven subjects during BUPHENYL treatment and fifteen AEs occurred in five subjects with HPN-100. There were two SAEs related to hyperammonemia; both occurred during 100% BUPHENYL treatment. No SAEs occurred during 100% HPN-100 treatment. Ammonia values were ~30% lower on HPN-100 assessed as TNAUC over 24 hours [mean (SD) = 38.4 (19.6) versus 26.1 (10.3) umol/L), Cmax = 79.1 (40.1) versus 56.3 (27.9) umol/L, or the percentage of normal values: 58% vs. 72%]. Differences in ammonia values were not statistically significant.
"We are very pleased with the study results and our recent end of phase II meeting with the Food and Drug Administration,” said Don Santel, Chief Executive Officer of Hyperion Therapeutics. “We are currently finalizing our phase III study protocol in consultation with the Agency and are eager to further explore the potential of HPN-100 for the treatment of urea cycle disorders."
About Urea Cycle Disorders Urea cycle disorders are inherited, inborn errors of metabolism present in an estimated 1 in 10,000 births in the United States. Patients with urea cycle disorders are deficient in one of the key enzymes that comprise the urea cycle, the body’s primary vehicle for removing ammonia, a potent neurotoxin, from the bloodstream. Onset may occur at any age depending on the severity of the disorder. Left untreated, urea cycle disorders can cause dangerously heightened levels of ammonia in the bloodstream (hyperammonemia) resulting in brain damage, coma, and/or death.
About HPN-100 HPN-100 is a pro-drug of phenylbutyrate and a pre-pro-drug of phenylacetic acid, the active moiety of BUPHENYL®, the only therapy currently FDA-approved as adjunctive therapy for the chronic management of patients with the most prevalent urea cycle deficiencies including those related to carbamylphosphate synthetase, ornithine transcarbamylase and argininosuccinic acid synthetase. HPN-100, which is dosed orally in liquid form, provides an alternative pathway to the urea cycle for the disposal of waste nitrogen through the renal excretion of phenylacetylglutamine, which is formed from phenylacetic acid and glutamine.
Hyperion and Ucyclyd Pharma, Inc., a subsidiary of Medicis Pharmaceutical Corporation, entered into a collaboration agreement for HPN-100 in August 2007. Under the terms of the agreement, Hyperion is conducting ongoing research and development of HPN-100 for urea cycle disorders, hepatic encephalopathy, and other forms of hyperammonemia.
About BUPHENYL®
About Hyperion Therapeutics Hyperion Therapeutics is a privately held specialty therapeutics company focused on the development of therapies that address critical unmet needs and underserved patient populations in the areas of gastroenterology and hepatology. Hyperion is headquartered in South San Francisco, CA. For additional information, visit www.hyperiontx.com. BUPHENYL® is exclusively licensed from Ucyclyd Pharma, Inc. BUPHENYL® is a registered trademark of Ucyclyd Pharma, Inc. Full Prescribing Information for BUPHENYL® is available at www.Buphenyl.com or by contacting Ucyclyd Pharma, Inc. Press contact:
Christine Nash
Zavesca® (miglustat) receives EU approval for the treatment of progressive neurological manifestations in patients with Niemann-Pick type C diseaseALLSCHWIL/BASEL, SWITZERLAND - 29 January 2009 - Actelion Ltd (SIX: ATLN) announced today that Zavesca® (miglustat) has been approved in the European Union for the treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann-Pick type C disease (NPC). Zavesca® is the first treatment to be approved for patients with Niemann-Pick type C disease, a very rare, invariably progressive and eventually fatal neurodegenerative genetic disorder affecting both children and adults.
Zavesca® (100 mg miglustat) is already indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Zavesca® may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "I am very proud that Actelion - together with the scientific community - has been able to demonstrate the role of Zavesca® in reducing the progression of clinically relevant neurological symptoms in patients with NPC. I would like to thank both the patients and their families who, over the years, have been involved in our clinical program with so much dedication, as well as all the clinical experts for their continuous support. Actelion will continue to support the rare disease community in its efforts to advance science and medicine for the patient".
Ed Wraith, M.D., Royal Manchester Children's Hospital, commented: "For the first time we have an approved therapy for NPC. The data on the effects of treatment with Zavesca® obtained in a clinical trial and in a retrospective cohort study consistently showed a favorable clinical response. As a treating physician I am acutely aware of the importance of reducing progression of neurological symptoms."
Regulatory proceedings to extend the use of miglustat in patients with NPC are ongoing in other territories worldwide.
About Niemann-Pick type C disease NPC is a very rare, fatal, neurodegenerative, genetic condition, primarily affecting children and teenagers but which can strike at any age. The symptoms are caused by the storage of some glycosphingolipids within certain cells in the body, including the brain. It is invariably progressive and most patients die within five to ten years of diagnosis; for the majority the disease is fatal during childhood. Neurological deterioration is the key feature of the disease, and can manifest itself as clumsy body movements, balance problems, slow and slurred speech, difficulty in swallowing, problems with eye movements and seizures. Intellectual decline is also common. In the final stages of the disease the child or young adult is frequently bedridden, has little muscle control and is intellectually impaired. Diagnosis of the disease can be difficult and lengthy due to its rarity and heterogeneity. There is currently no treatment option approved for this condition.
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Notes to the editor
About Zavesca® and Niemann-Pick type C disease Zavesca® is indicated for the treatment of progressive neurological manifestations in adult patients and pediatric patients with Niemann-Pick type C disease.
In order to gain approval for Zavesca® in Niemann-Pick type C disease, a set of clinical data were obtained from one clinical trial OGT918-007 and two multicenter retrospective cohort studies in patients with NPC.
The usual dose of Zavesca® in adult NPC patients was 200 mg miglustat three times a day, and was adjusted according to body surface area in pediatric NPC patients.
In the clinical trial OGT918-007, adult and juvenile patients with NPC (n=29, age >=12 years) were randomized to either miglustat 200 mg t.i.d. (n=20) or standard of care (n=9) for 12 months [1]. In addition, 12 children aged 4-12 years received miglustat at a dose adjusted for body surface area. All patients were then given miglustat for another 12 months. Horizontal saccadic eye movement (HSEM) velocity was the primary endpoint. Other endpoints included swallowing, ambulation, neurological examination, neuropsychological assessment, tremor and quality of life. At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028) [1]. Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years [1].
In an uncontrolled extension phase of the OGT918-007 trial, data indicated that treatment with miglustat can provide disease stabilization for important markers of neurological dysfunction in NPC disease, both in the juvenile/adult and pediatric cohorts, further strengthening the interpretation of a treatment effect of miglustat observed at 12 months in the controlled phase of the trial [2,3].
The safety and tolerability of miglustat 200 mg three times a day in clinical trial participants was consistent with previous trials in type 1 Gaucher disease, where half this dose was used [1, 2, 3].
A first retrospective cohort study was performed in 25 centers in 12 countries to assess data on changes of neurological status and overall utility of treatment with miglustat in 66 NPC patients receiving miglustat outside of the clinical trial OGT918-007 for a mean duration of 1.5 years. A disease-specific disability scale was used to evaluate the severity of dysphagia (swallowing), dystonia (manipulation), ataxia (ambulation) and dysarthria (language articulation) at diagnosis, treatment initiation and last visit [4]. A majority of patients remained at least stable after treatment with regard to the four parameters, indicating that miglustat provides clinically relevant benefits on neurological disease progression in patients with NPC [4].
A second retrospective cohort study was performed in 7 centers in 6 countries to assess data on changes in neurological status in 57 patients not treated with miglustat during the natural course of the disease for a mean duration of 5.5 years. The same disease-specific disability scale was used to evaluate the severity of dysphagia, dystonia, ataxia and dysarthria at the time of diagnosis until the last visit. The results will be presented in the first half of 2009.
The benefit of treatment with Zavesca® for neurological manifestations in patients with Niemann-Pick type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re-appraised after at least 1 year of treatment with Zavesca®.
About Zavesca® and type 1 Gaucher disease Zavesca® (100 mg miglustat capsule) is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Zavesca® may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable. It is approved in the European Union, the United States, Canada, Switzerland, Brazil, Australia, Turkey and Israel.
Zavesca® safety information Gastrointestinal events, mainly diarrhea, have been observed in more than 80% of patients treated with Zavesca®, either at the onset of treatment or intermittently during treatment. The majority of cases are mild and are expected to resolve after the first weeks on therapy. In clinical practice, diarrhea has been observed to respond to diet modification (reduction of lactose and other carbohydrate intake), to taking Zavesca® away from meals, and/or to antidiarrheal medicinal products such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Zavesca® has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease.
Cases of peripheral neuropathy have been reported in patients treated with Zavesca®. Peripheral neuropathy seems to be more common in patients with type 1 Gaucher disease compared to the general population. All patients should undergo baseline and repeat neurological evaluation. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of risk benefit.
Zavesca® may cause fetal harm if administered to a pregnant woman and is contraindicated in women who are or who may become pregnant; patients should be informed of the potential hazard to the fetus. There is a risk of impaired fertility in men. Men should maintain reliable contraceptive methods and not plan to conceive while taking Zavesca® and for three months thereafter.
Reduced growth has been reported in some pediatric patients with Niemann-Pick type C disease in the early phase of treatment with Zavesca® where the initial reduced weight gain may be accompanied or followed by reduced height gain. Growth should be monitored in pediatric and adolescent patients during treatment with Zavesca®; the benefit/risk balance should be re-assessed on an individual basis for continuation of therapy.
Mild reductions in platelet counts without association to bleeding were observed in some patients with Niemann-Pick type C disease treated with Zavesca®. In patients included in the clinical trial, 40%-50% of patients had platelet counts below the lower limit of normal at baseline. Monitoring of platelet counts is recommended in these patients.
References 1. Patterson MC, Vecchio D, Prady H, Abel L and Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 2007; 6:765-772. 2. Patterson MC, Vecchio D, Prady H, Abel L and Wraith JE. Miglustat for treatment of Niemann-Pick C disease: results of 24 month's treatment. Proceedings of 57th Annual meeting of the American Society of Human Genetics, 2007; abstract # 2253. 3. Patterson MC, Vecchio D, Jacklin E and Wraith JE. Miglustat in Niemann-Pick disease Type C (NPC): long-term data from a clinical trial. Proceedings of 58th Annual meeting of the American Society of Human Genetics, 2008; abstract # 766. 4. Pineda M, Wraith JE, Sedel F, et al. Miglustat in patients with Niemann-Pick type C disease (NPC): a multicentre retrospective survey. Journal of Inherited Metabolic Disease 2008; 31(Suppl 1) 98. Note: this abstract describes the results of the survey with the first 44 cases collected.
Actelion Ltd Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer® through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 1900 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI® )
For further information please contact: Roland Haefeli Vice President, Head of Investor Relations & Public Affairs Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil +41 61 565 62 62 +1 650 624 69 36
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