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February 11th, 2009 Press release - Octapharma starts phase II clinical study in Alzheimer's disease with octagam®10% Lachen, Switzerland, 11 February 2009 Octapharma AG announces the start of a phase II clinical trial following U.S. Food and Drug Administration (FDA) review of its investigational new drug application for octagam®10%, (human normal intravenous immunoglobulin, liquid), in mild-to-moderate Alzheimer’s disease. After the publication of promising results from a pilot study with octagam® (Dodel et al., 2004), this trial is expected to be the first of a series of trials required to support filing for regulatory approval for octagam®10% as a treatment for the disease. This prospective, double-blind, randomized, multicenter, placebo-controlled phase II trial (ISRCTN64846759, NCT 00812565) in subjects of both genders, aged 50 to 85 years old with mild to moderate Alzheimer’s disease will document parameters of safety, tolerability and specific surrogate parameters of efficacy of different doses of octagam®10%. Changes in an Alzheimer’s disease related serum biomarker in each treatment arm will be documented as primary outcome measure. Secondary outcome measures include cognitive, functional and global clinical outcome measures as well as several additional plasma and cerebrospinal fluid (CSF) biomarkers. Furthermore, morphological and functional brain imaging markers will be used to assess disease progression and response to therapy. Octapharma AG, the sole sponsor of the trial, will carry out the study in eight study centers in Germany and the U.S.A.. The principal investigator is Professor Richard Dodel, MD, Department of Neurology, Philipps-University, Marburg, Germany. About Alzheimer's disease. Alzheimer’s disease (AD), the most common form of dementia among elderly population (prevalence: approx. 1,000 per 100,000), represents the fourth leading cause of death in the developed world (Berr et al., 2005). In the US alone, there are as many as 5 million people affected by Alzheimer’s disease. Cortical atrophy, neuronal loss, region-specific amyloid deposition, neuritic plaques, and neurofibrillary tangles are key neuropathological features in brains of AD patients. These alterations are thought to be linked to cognitive decline, which clinically defines AD (Selkoe, 1999). To date, there is no disease modifying therapy available. In studies it was tested whether there is a difference of CSF anti-Aβ autoantibody concentration in patients with Alzheimer’s disease compared to controls. A significant difference was found between the two groups resulting in a decreased titer of autoantibodies against Aβ in patients with Alzheimer’s disease. These results have been confirmed later (Weksler et al., 2002). This adds more evidence to the hypothesis that reduced levels of autoantibodies against Aβ may be involved in the pathogenesis of Alzheimer’s disease. An increase in these autoantibodies against Aβ may reduce amyloid plaque load or deposition, and reverse symptoms of cognitive decline in patients with Alzheimer’s disease. These observations led to the question whether these anti-Aβ autoantibodies are detectable in human commercially available IVIG preparations. Using an ELISA those autoantibodies against Aβ were detected in IVIG (Dodel et al., 2002). Results from a pilot trial with IVIG (octagam®) in five patients with AD, who were treated with 0.4 g/kg for three consecutive days every four weeks for a duration of six months showed that concentration of total Aβ was reduced in the CSF and increased in the serum compared to baseline (Dodel et al., 2004). Furthermore, in the five investigated patients no cognitive deterioration was observed during the six months observation period. These results were reproduced in a small clinical trial using IVIG in eight AD patients using different doses for a duration of six months (Adamiak et al., 2006). This biomarker shift could be seen already after the first IVIG treatment (Relkin et al., 2006). Clinically, these findings were corroborated in a 24-patient phase II trial presented at the ICAD 2008 conference in Chicago (poster 3147 by Tsakanikas D et al.): subjects with Alzheimer’s who get uninterrupted IVIG treatment for nine months had statistically significant and clinically relevant improvements on both cognitive and global clinical measures compared to placebo. About octagam®10% octagam®10% is a 10% (100 mg/mL) immune globulin (human) solution for intravenous administration (IVIG) developed as a new strength of the essentially similar octagam®. octagam®10% has recently been approved in European countries and will become available in the U.S.A. later. About octagam® octagam® is a 5% (50 mg/mL) immune globulin (human) solution for intravenous administration (IVIG) which is currently registered in about 60 countries, including the U.S.A. and the EU. In the U.S.A. it is indicated for treatment of primary humoral immunodeficiency (PI), such as congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome and severe combined immunodeficiencies. In EU countries, octagam® is approved for the following indications:
Warning statements: octagam® is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to Immune Globulin (Human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IVIG products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIG products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. octagam® does not contain sucrose. Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose contained in octagam® as glucose. This has resulted in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering octagam® or other parenteral maltose- containing products, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products. octagam® is made from human plasma. It may carry a risk of transmitting infectious agents, viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Components used in the packaging of this product are latex-free. Thrombotic events have been reported in association with IVIG. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoagulable disorders, and prolonged periods of immobilization. IVIG products can contain blood group antibodies that may cause a positive direct antiglobulin reaction and, rarely, hemolysis. Various mild and moderate reactions, such as headache, fever, fatigue, chills, flushing, dizziness, urticaria, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, muscle cramps, and changes in blood pressure may occur with infusions of Immune Globulin Intravenous (Human). For full country specific prescribing information, please visit www.octapharma.com. |