Current Opinion in Molecular Therapeutics最新文献

The inflammatory cytokine IL-1β has an essential role in the innate immune response. High levels of IL-1β have been implicated in the development of many diseases, including type 1 and 2 diabetes (T1D and T2D), rheumatoid arthritis (RA) and cardiovascular disease. XOMA is developing gevokizumab (XOMA-052), an IgG2 humanized mAb against human IL-1β, for the potential treatment of these diseases. Gevokizumab has a high affinity for IL-1β and a long t1/2, which would allow for once-monthly dosing and offer a considerable advantage for patients over agents requiring more frequent dosing. Data from preclinical studies and clinical trials suggest that gevokizumab is a potentially effective and well-tolerated treatment for the indicated diseases. At the time of publication, phase II clinical trials were ongoing in patients with T1D, T2D and RA, with the T2D trials assessing key cardiovascular markers. Following promising data from a recent pilot trial, XOMA was also planning a phase I/II trial of gevokizumab for the potential treatment of uveitis in patients with the vasculitic inflammatory disorder Behçet's disease and the autoinflammatory conditions familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

Corticorelin is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Peritumoral brain edema (PBE), caused by an intracerebral tumor, manifests several features of vasogenic edema, which is a type of edema characterized by disruption of the blood-brain barrier. Traditionally, PBE has been treated using corticosteroids, primarily dexamethasone. Introduced more than four decades ago, dexamethasone revolutionized the treatment of PBE, but the side effects and withdrawal symptoms associated with corticosteroids propelled the investigation of other drugs. Clinical trials with the synthetic human CRF (hCRF) corticorelin (Xerecept, NEU-3002; Celtic Pharmaceutical Holdings) have indicated that this drug has a distinct advantage over classical corticosteroids in the treatment of PBE. Fewer and/or milder side effects have been reported for corticorelin compared with dexamethasone, although at higher doses of corticorelin several side effects, including hypotension and transient flushing, have been reported. Nevertheless, corticorelin was reasonably well tolerated in patients and healthy volunteers, and may be a good candidate for reducing PBE and associated neural damage, as well as improving neurological symptoms.

Dulaglutide (LY-2189265) is a novel, long-acting glucagon-like peptide 1 (GLP-1) analog being developed by Eli Lilly for the treatment of type 2 diabetes mellitus (T2DM). Dulaglutide consists of GLP-1(7-37) covalently linked to an Fc fragment of human IgG4, thereby protecting the GLP-1 moiety from inactivation by dipeptidyl peptidase 4. In vitro and in vivo studies on T2DM models demonstrated glucose-dependent insulin secretion stimulation. Pharmacokinetic studies demonstrated a t1/2 in humans of up to 90 h, making dulaglutide an ideal candidate for once-weekly dosing. Clinical trials suggest that dulaglutide reduces plasma glucose, and has an insulinotropic effect increasing insulin and C-peptide levels. Two phase II clinical trials demonstrated a dose-dependent reduction in glycated hemoglobin (HbA1c) of up to 1.52% compared with placebo. Side effects associated with dulaglutide administration were mainly gastrointestinal. To date, there have been no reports on the formation of antibodies against dulaglutide, but, clearly, long-term data will be needed to asses this and other possible side effects. The results of several phase III clinical trials are awaited for clarification of the expected effects on HbA1c and body weight. If dulaglutide possesses similar efficacy to other GLP-1 analogs, the once-weekly treatment will most likely be welcomed by patients with T2DM.

Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage.

The list of potential cardiovascular biomarkers has expanded dramatically in recent years; however, the number of regulatory agency-approved diagnostic tests that guide treatment has been relatively unchanged compared with this growth in the discovery of putative biomarkers. Surrogate biochemical endpoints such as LDL and HDL are included in the current guidelines of various regulatory agencies for the management of cardiovascular diseases, as a result of many years of research. Inclusion of tests for these markers, as well as any future tests, in treatment guidelines requires data obtained from large-scale clinical trials comparing these endpoints with 'hard' clinical endpoints, such as morbidity and mortality. Consequently, current guidelines are limited to conventional in vitro tests and incorporate few novel tests for guiding or modifying treatment. Despite the failure to include newer in vitro tests in cardiovascular treatment and prevention paradigms, ongoing biomarker discovery and assay optimization has provided many improvements in drug discovery and development, and has afforded opportunities for the optimized medical treatment of patients with cardiovascular disease.

Ras proteins are key elements in the regulation of cellular proliferation, differentiation and survival. Mutational activation of Ras or of components of its effector pathways are detected in one-third of human cancers and are essential for the genesis and maintenance of the tumoral phenotype. Research efforts have been dedicated to the development of therapeutic agents that inhibit aberrant Ras signals and, subsequently, tumor progression. However, many of these initiatives have proven less successful than expected. This review summarizes the current status of developments in Ras research, the challenges that have arisen during preclinical and clinical stages, and how novel approaches to targeting Ras pathways have introduced new strategies toward the development of antitumoral agents that are alternative or complementary to those currently in use. These new approaches would be aimed at disrupting key protein-protein interactions that are essential for the conveyance of Ras aberrant signals or would be directed against new proteins recently demonstrated to be critical participants in Ras-regulated pathways.

Mogamulizumab (KW-0761; AMG-761), under development by Kyowa Hakko Kirin and Amgen, is a defucosylated humanized IgG1 mAb against C-C chemokine receptor 4 (CCR4) for the potential intravenous treatment of T-cell lymphomas and asthma. Chemokines and their receptors are signaling molecules constitutively responsible for lymphocyte and neutrophil chemotaxis, which can also be involved in pathogenic mechanisms of various diseases. In particular, CCR4 has been demonstrated to play a major role in adult T-cell leukemia/lymphoma (ATL), in which it is a marker of poor prognosis. Consequently, CCR4 blockade might have therapeutic potential in treating ATL, a disease that is most often aggressive in course, and for which existing therapies are not always effective. Mogamulizumab reduced tumor load via enhanced antibody-dependent cell cytotoxicity in preclinical studies and demonstrated promising efficacy in early clinical trials in patients with ATL. In addition, CCR4 also has a role in maintaining T-helper cell type 2 airways inflammation in asthma, and Amgen have acquired the rights to develop mogamulizumab for this indication and other non-oncology indications; however, at the time of publication, no data were available from Amgen's investigations. This is a review on the potential use of mogamulizumab for the treatment of T-cell lymphomas and asthma, with specific emphasis on the treatment of ATL.

Convection-enhanced delivery (CED) has been introduced to overcome the inability of many pharmacological agents to cross the blood-brain barrier, making these agents potentially effective in situ and suitable for the treatment of brain disorders. To achieve CED, drugs are pumped continuously through stereotactically placed catheters directly into the brain, or into or within the vicinity of a tumor mass. This medical technology has been applied to the local delivery of small-molecule drugs, including standard chemotherapeutics, and novel experimental targeted drugs, including targeted cytotoxins. When administered by an experienced clinician, the CED of a molecularly targeted cytotoxin has resulted in a significantly better outcome in patients with recurrent glioblastoma multiforme (GBM). More recent gene therapy clinical trials have also demonstrated that such treatments impact on the course of the disease when administered using CED. The use of CED to administer gene therapy for brain neoplasms may improve the efficacy of this treatment. However, CED is under development, and issues such as the type of catheters to use and their placement, as well as the pharmacological formulation and stability of drugs or vectors, are being studied to achieve efficacious delivery into the desired regions of the diseased brain. This review discusses the use of CED to deliver gene therapy for brain tumors, particularly gliomas, such as GBM.

Cancer stem cells (CSCs) form a highly tumorigenic core in most human tumors. Although there is no consensus regarding CSC phenotype from different tumor types, CSCs from different cancers share a primitive undifferentiated nature, including a capacity to expand and differentiate, albeit aberrantly, into the major cell types observed in the corresponding tumor. This review focuses on the development of therapeutics targeting CSCs, for which new assays that replace those reporting the inhibition of cell division and rapid tumor shrinkage will be required to account for the quiescent nature and properties of CSCs. The inhibition of signaling pathways related to the stem cell nature of the CSCs may appear an attractive target for novel therapeutics, but these targets could result in significant unwanted off-target effects against essential healthy tissue stem cells. Instead, the ideal therapies targeting CSCs will be directed against functions that contribute to the oncogenic nature of CSCs relative to healthy stem cells, an altogether more challenging task.

Peripheral arterial disease remains an often devastating condition, particularly in patients with diabetes, because of the high rate of functional disability, amputation and death. For those patients for whom conventional endovascular or surgical revascularization procedures have been unsuccessful, new options are eagerly awaited, among which cell therapy has gained increasing interest. Most clinical trials of cell therapy have used multiple intramuscular injections of bone marrow-derived mononuclear cells that have yielded encouraging suggestions of efficacy. The prevailing opinion is that the benefits of cell therapy are not a result of the structural integration of grafted cells within new vessels, but of the paracrine activation of angiogenesis, arteriogenesis and vasculogenesis pathways by the cytokines, chemokines and growth factors released from such cells. An analysis of cell therapy clinical trial outcomes has also identified several key issues that need to be addressed, including the optimal cell type, source and dosing, the most effective route for cell transfer, and methods for enhancing survival of the cellular graft. Finally, because of the strong placebo effect that may confound interpretation of outcome measures, rigorously randomized controlled trials are mandatory in order to assess more thoroughly whether cell therapy will be beneficial for patients with peripheral arterial disease.