Biogen Idec (MA, USA) and Abbott (IL, USA) have announced the enrollment of the first patient to the DECIDE study, a global Phase III clinical trial evaluating the efficacy and safety of daclizumab compared with IFN-β1a (Avonex®; one of the most common treatments for multiple sclerosis [MS]) in patients with relapsing–remitting MS (RRMS).
Multiple sclerosis is a neurological disorder in which the myelin sheath surrounding nerve fibers is destroyed by the body‘s own immune system. This destruction can lead to cognitive impairment, physical disability and fatigue. MS affects more than 2.5 million people worldwide. RRMS accounts for approximately 85% of all newly diagnosed MS, and is characterized by periods of recovery (remission) following MS flares (relapse).
“Despite significant advances in MS therapy, many patients continue to experience disease activity. The MS community is eager for new treatment approaches,” said Ludwig Kappos, Head, MS-Research Group, University Hospital Basel, Switzerland, and lead investigator for the study. “As shown in previous studies, daclizumab appears to selectively target immune cells that are thought to become activated in MS and cause damage to the central nervous system.”
Daclizumab is a humanized monoclonal antibody that binds to CD25, a receptor expressed at low levels on resting T cells but high levels on T cells that are thought to cause the autoimmune response observed in MS. Through the binding of daclizumab, these activated T cells can be inhibited, while resting T cells are generally not affected.
The previous Phase II trial (CHOICE) has demonstrated that daclizumab 2 mg/kg administered subcutaneously every 2 weeks in combination with IFN-β therapy resulted in a 72% reduction in the number of new or enlarged MS lesions when compared with IFN-β therapy alone in patients with active RRMS. Daclizumab increased the number of CD56bright NK cells, which help regulate the immune system.
“The DECIDE study builds on the positive results we saw in the CHOICE trial, which showed that daclizumab, when added to IFN-β, significantly reduced MS lesions compared to IFN-β therapy alone,” said Alfred Sandrock, Senior Vice President of Neurology Research and Development at Biogen Idec. “Initiating this trial demonstrates our commitment to developing new treatment options for patients who suffer from this terrible disease.”
The new DECIDE study is a randomized, double-blind Phase III clinical trial that is expected to enroll 1500 RRMS patients between the ages of 18 and 55 years in 28 countries. Patients will receive either a subcutaneous injection of daclizumab 150 mg once every 4 weeks or weekly injections of IFN-β1a. Treatment will continue for 96–144 weeks, and the primary end point is the safety and efficacy of daclizumab compared with IFN-β1a in reducing the MS relapse rate.
“Initiating the Phase III DECIDE trial is a tremendous milestone for the collaboration as it brings daclizumab one step closer to becoming a potential new treatment option for patients with MS,” said Eugene Sun, Vice President, Global Pharmaceutical Clinical Development, Abbott. “Extensive preclinical and clinical experience with daclizumab suggest this drug holds promise as a new approach for the treatment of MS, and we look forward to expanding our knowledge further with the DECIDE trial.”
Source: Biogen Idec, MA, USA: www.biogenidec.com
A Phase III clinical trial, led by Michael Rafii (Assistant Professor of Neurosciences, University California San Diego School of Medicine, CA, USA, and Associate Medical Director of the Alzheimer‘s Disease Cooperative Study [ADCS]), aims to investigate a novel approach to slow Alzheimer‘s disease (AD) progression using intravenous immune globulin (IVIg).
IVIg, also known as gammaglobulin, has not been approved for the treatment of Alzheimer‘s at present, but has been a tool used for over 20 years in treating immunodeficiency disorders. A previous Phase II trial demonstrated promising results, and this study hopes to build on these results, before regulatory approval is sought.
It is not yet fully understood whether β-amyloid plaques, protein deposits found in the brain of AD patients, are a cause or result of the disease, and researchers are keen to discover methods of reducing “the toxic effects of β-amyloid in the brain”.
Rafii stated: “Initial research in experimental models and patients suggest that IVIg, which contains naturally occurring human antiamyloid antibodies, will defend the brain of Alzheimer‘s patients against the damaging effects of β-amyloid. If it does, administering IVIg to patients with mild-to-moderate Alzhiemer‘s may potentially slow the rate of progression of the disease.”
The double-blind, placebo-controlled, study, will continue for up to 82 weeks, and aims to investigate how effective and safe it is to use IVIg to neutralize or eliminate toxic forms of β-amyloid.
Norman Relkin (Weill Cornell Alzheimer‘s Disease and Memory Disorders Program, NY, USA) explained: “In our initial studies in AD patients, IVIg provided significant cognitive benefits, improved brain metabolism and reduced β-amyloid levels in the spinal fluid.” He described an improvement in the daily activities of participants of a Phase II trial at Weill Cornell undergoing continuous IVIg therapy. Relkin stated: “These findings, as well as IVIg‘s long-established record of safe use for treating other diseases, provide a strong rationale for further study in AD patients on a larger scale.”
Source: UC San Diego News Center, CA, USA: http://ucsdnews.ucsd.edu
Amgen‘s Prolia® (denosumab) has been granted marketing authorization by the EMA for the treatment of postmenopausal osteoporosis in women at increased risk of fractures. It has already been approved for the treatment of bone loss owing to hormone ablation in prostate cancer patients at increased risk of fractures. In addition to the 27 EU member states, denosumab has also been approved in Iceland, Lichtenstein and Norway.
The marketing authorization was based on six Phase III trials and results from the two pivotal studies demonstrated that denosumab reduced the incidence of fractures when administered as a 60-mg subcutaneous injection every 6 months. The trials involved 7808 women with postmenopausal osteoporosis and showed a 68% decrease in the relative risk of suffering a new vertebral fracture, a 40% decrease in the relative risk of suffering a hip fracture and a 20% decrease in the relative risk of suffering a nonvertebral fracture at 36 months, compared with placebo. Bone mineral density was also seen to increase in all six Phase III studies, at all skeletal sites tested.
Socrates Papapoulos, Leiden University Medical Center, The Netherlands, comments: “Osteoporosis is a serious, chronic disease that can significantly impact the lives of millions of affected women. Despite widely available treatments, new options are still needed to help protect against fractures. By targeting RANK ligand, Prolia offers an innovative new approach that helps reduce fracture risk.”
Approximately 30% of all postmenopausal women in Europe suffer from osteoporosis and of those, more than 40% will suffer osteoporotic fractures. The marketing authorization of denosumab is a significant breakthrough in the treatment of this silent epidemic.
Source: Amgen Inc., CA, USA: http://wwwext.amgen.com
4SC AG (Germany), a drug discovery and development company focusing on autoimmune and cancer drugs, has announced the publication of preclinical data on vidofludimus (4SC-101), 4SC‘s lead autoimmune small-molecule drug. The data were published in two journals, Inflammatory Bowel Diseases and the American Journal of Pathology.
Vidofludimus is a novel, orally administered small molecule that aims to slow the disease progression in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE) and inflammatory skin conditions. Vidofludimus inhibits dihydroorotate dehydrogenase, a key enzyme for pyrimidine biosynthesis, thereby inhibiting the proliferation of activated T and B cells involved in the pathology of autoimmune disorders. Vidofludimus also inhibits the expression of IL-17, a proinflammatory cytokine that has a pathogenic role in autoimmune diseases. The combination of two mechanisms of action provides an innovative therapeutic approach with broad clinical potential in various autoimmune diseases. Vidofludimus is currently in a randomized, placebo-controlled Phase IIb study in rheumatoid arthritis where it is tested on the background therapy with methotrexate, the current gold standard of rheumatoid arthritis treatment, and in a Phase IIa study in IBD, which analyses the option to utilize vidofludimus in patients with Crohn‘s disase or colitis ulcerosa.
The publication in Inflammatory Bowel Diseases is the result of collaboration with Leo Fitzpatrick, Professor at Department of Pharmacology, Penn State College of Medicine (PA, USA). Vidofludimus was demonstrated to effectively improve both chronic and acute IBD in mice and to significantly inhibit IL-17 production both in vitro and in vivo. Since IL-17 inhibition is independent from lymphocyte proliferation, and other signaling molecules such as TNF, IL-1 and IL-6 are not affected, vidofludimus is thought to block IL-17 production by a highly specific mechanism, which will be evaluated further in this collaboration.
In the American Journal of Pathology article, vidofludimus was demonstrated to be as effective as the standard therapy high-dose cyclophosphamide (CYC) in controlling SLE without causing myelosuppression, which is frequently seen with CYC. Vidofludimus could deplete spleen autoreactive T cells, B cells and plasma cells. This was associated with a comparable amelioration of renal, dermal and pulmonary SLE manifestations in MRL(Fas)lpr mice. On the other hand, even at the highest dose tested, vidofludimus had no effect on bone marrow neutrophil counts that were significantly reduced in CYC-treated mice. The findings were the result of collaboration with Hans-Joachim Anders, Professor at Medizinische Poliklinik-Innenstadt, University of Munich, Germany.
Bernd Hentsch, Chief Development Officer of 4SC, commented: “We are very excited about the progress we have made in our academic collaborations, which we pursue in parallel to our current clinical development program for vidofludimus in rheumatoid arthritis and inflammatory bowel disease. These excellent scientific results substantiate the positioning of vidofludimus as a novel and broadly applicable anti-inflammatory drug which through its dual mechanism of action inhibits cell proliferation and the cytokine IL-17. Based on these findings, vidofludimus may be suitable for the treatment of a range of autimmune disorders.”
Sources: Fitzpatrick LR, Deml L, Hofmann C et al.: 4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease. Inflamm. Bowel Dis. DOI: 10.1002/ibd.21264 (2010); Kulkarni OP, Sayyed SG, Kantner C et al.: 4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice. Am. J. Pathol. 176(6), 2840–2847 (2010); 4SC AG, Germany: www.4sc.de/en
In a recent article published in the May issue of the journal Cell Host & Microbe, researchers from Mount Sinai School of Medicine (NY, USA) have demonstrated a new role of bone marrow cells in fighting viral infections in the lungs of infected mice.
It is well established that upon respiratory viral infections (e.g., with influenza or Sendai viruses), a robust immune response is triggered in the lungs, with the production of various cytokines and growth factors, promoting the infiltration of leukocytes from blood to the lungs to fight against infections. However, the effect of these lung cytokines on distal lymphoid tissues, such as bone marrow, remains unclear.
In their article, the research team led by Carolina Lopez, Assistant Professor of Microbiology at Mount Sinai School of Medicine, demonstrated that “during infection with influenza or Sendai virus, the lung communicates with the sterile bone marrow, the primary site of hematopoiesis, through type I interferons. While in the bone marrow, leukocytes exposed to type I interferons activate an antiviral transcriptional program and become resistant to infection with different viruses. The protected bone marrow leukocytes are capable of migrating to the infected lung and contribute to virus clearance.”
“Our research shows that in addition to the regulation of the development of cells, the immune response is regulated at a much earlier stage by influencing cells in the distal bone marrow and that this regulation of what is known as the innate immune response is important for the efficient clearance of the infection,” said Lopez. “Very limited research has been done to evaluate bone marrow‘s response to a virus infection. Our study is the first to determine the pivotal role bone marrow cells play in fighting a respiratory infection. This discovery has broad-reaching implications in boosting protection against viruses.”
According to the authors, it is type I interferons from the lungs of infected animals that strengthen bone marrow‘s leukocytes and prepare them for the battle against the viruses. These cells then migrate to the lungs and help fight the infection.
The authors concluded that “appropriate instruction of cells during their development in the bone marrow is needed for effective control of infection.” “The findings may be especially significant for people with compromised immune systems, including transplant and HIV patients,” said Lopez. This new discovery may open new avenues for prevention and treatment of lethal infections.”
Sources: Hermesh T, Moltedo B, Moran TM, López CB: Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe 7(5), 343–353 (2010); Mount Sinai Medical Center, NY, USA: www.mountsinai.org