Current opinion in investigational drugs最新文献

Parkinson's disease (PD) is a neurodegenerative disease affecting nigrostriatal dopaminergic neurons. Dopamine depletion in the striatum leads to functional changes in several deep brain nuclei, including the subthalamic nucleus (STN), which becomes disinhibited and perturbs the control of body movement. Although there is no cure for PD, some pharmacological and surgical treatments can significantly improve the functional ability of patients, particularly in the early stages of the disease. Among neurodegenerative diseases, PD is a particularly suitable target for gene therapy because the neuropathology is largely confined to a relatively small region of the brain. Neurologix Inc is developing NLX-P101 (AAV2-GAD), an adeno-associated viral vector encoding glutamic acid decarboxylase (GAD), for the potential therapy of PD. As GAD potentiates inhibitory neurotransmission from the STN, sustained expression of GAD in the STN by direct delivery of NLX-P101 decreases STN overactivation. This procedure was demonstrated to be a safe and efficient method of reducing motor deficits in animal models of PD. A phase I clinical trial has demonstrated that NLX-P101 was safe and indicated the efficacy of this approach in patients with PD. Results from an ongoing phase II clinical trial of NLX-P101 are awaited to establish the clinical efficacy of this gene therapy.

The limited effect of AChE inhibitors and NMDA receptor antagonists for the treatment of the cognitive symptoms of Alzheimer's disease has prompted the search for new drugs that are capable not only of treating behavioral symptoms, but also of modifying the disease process. Considerable research efforts have been focused on orthosteric muscarinic M1 functional agonists during the past decade to address both these strategies. Part of this research has included the use of non-human primates as models of cognitive impairment to demonstrate preclinical efficacy. No M1 functional agonist has been successfully registered for the treatment of Alzheimer's disease, mostly because of mechanism-related adverse side effects and marginal cognitive effects. However, the M1 agonist xanomeline exhibited preclinical and clinical efficacy for the treatment of the negative and cognitive symptoms of schizophrenia. These results prompted renewed interest in repositioning compounds such as sabcomeline (Proximagen Group plc) for this indication, as well as developing allosteric muscarinic M1 ligands to improve efficacy while reducing side-effect-related attrition. This review discusses preclinical and clinical data from orthosteric M1 functional agonists, focusing on target validation in primate cognition studies, and provides recommendations for testing a new generation of M1 ligands and compounds with novel mechanisms of action.

Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which was discovered by Genentech Inc under a collaboration with Curis Inc. Vismodegib inhibits the Hedgehog (Hh) pathway, which is involved in tumorigenesis, thus providing a strong rationale for its use in the treatment of a variety of cancers. Vismodegib suppresses Hh signaling by binding to and interfering with smoothened, a membrane protein that provides positive signals to the Hh signaling pathway. Preclinical studies demonstrated the antitumor activity of vismodegib in mouse models of medulloblastoma (MB) and in xenograft models of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted an objective response to vismodegib. Reported side effects were minor, with only one grade 4 adverse event. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and other solid tumors. Because of its low toxicity and specificity for the Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.

PI3K pathway signaling is the focus of intensive oncology drug-development programs at several academic institutions and pharmaceutical companies. With several drugs that target different parts of the pathway in early clinical trials, this review presents evidence demonstrating that the PI3K pathway represents a suitable target for cancer drug development, discusses therapeuticstrategies for targeting the pathway, and highlights the status of drugs currently in development.

Cancer chemotherapy has evolved from the use of cytotoxic drugs that are accompanied by highly deleterious and often life-threatening side effects, to the application of hormone antagonists that are more specific for hormone-mediated tumor growth and that are generally substantially less toxic and, most recently, to the use of targeted therapies including humanized mAbs and drugs such as imatinib (Gleevec) that have been developed for the treatment of malignancies induced by a unique chromosomal rearrangement. While these newer agents should theoretically prove to be more efficacious than the conventional drugs that have been the foundation of cancer treatment for decades, such improvement has not always been demonstrated either with the use of single agents or when these agents are combined with established therapies. Furthermore, neither cell culture nor animal model systems have provided reliable predictions of drug efficacy or toxicity. Consequently, despite advancing knowledge relating to signaling pathways and potential druggable targets involved in cancer, the use of newer agents will ultimately be dependent on empirical clinical trials, many of which will likely fail to demonstrate efficacy because of pharmacokinetic limitations or undesirable and limiting patient toxicities.

Acute myelogenous leukemia (AML) is a disease more common in older patients than in the young. It is increasingly recognized that conventional cytotoxic chemotherapies used in children and young adults may not be appropriate in older adults because of diverse host- and disease-biology factors. This review highlights some of the most promising new treatment options that are being evaluated for older patients with AML. These options include CPX-351 (Celator Pharmaceuticals Inc), a unique liposomal formulation of a fixed ratio of cytarabine and daunorubicin; timed sequential therapy with the CDK inhibitor alvocidib (flavopiridol; sanofi-aventis/NCI); the second-generation purine nucleoside analog clofarabine; the farnesyltransferase inhibitor tipifarnib (Johnson & Johnson Pharmaceutical Research and Development LLC); and the DNA methyltransferase inhibitors decitabine and azacitidine.

PLX-4032 is a small-molecule, orally available B-Raf kinase inhibitor being developed by Plexxikon Inc and Hoffman-La Roche Ltd for the treatment of cancers harboring activating BRAF mutations. The primary focus of development is in melanoma (> 50% harbor activating BRAF mutations) with other solid tumors, such as colorectal carcinoma (> 10% harbor BRAF mutations), also under investigation. Purified kinase assays have demonstrated that PLX-4032 and its related analogs are highly potent inhibitors of B-Raf activity, with 3-fold selectivity for the V600E mutation over the wild-type kinase. In preclinical models, PLX-4032 and its analogs inhibited the growth of BRAFV600E-positive melanoma cell lines both in vitro and in vivo. In phase I clinical trials, PLX-4032 was well tolerated and objective responses were observed in several patients with BRAFV600E-positive tumors. Responses correlated well with inhibition of intratumoral phospho-ERK and cell proliferation, and reductions in fluorodeoxyglucose uptake on PET scanning. A preliminary analysis of this phase I data suggested that progression-free survival was approximately 7 months, and phase II and III clinical trials are now underway. These studies provide the proof-of-concept for B-Raf as a therapeutic target in melanoma.

Tumor progression and metastasis depend on signals in the tumor microenvironment acting on both the malignant cells and benign stroma to create an environment favorable to tumor expansion. A factor of emerging importance that acts in the tumor microenvironment is lysophosphatidic acid (LPA), a small signaling molecule that not only induces the transformation of benign cells into malignant invasive tumors, but also increases tumor growth, invasion, metastasis and angiogenesis. This review examines the LPA signaling pathway, its role in selected human malignancies, and the current state of development of inhibitors targeting molecules in this pathway.

The treatment of thyroid cancer is evolving. The molecular mechanisms of carcinogenesis for many thyroid cancers have been investigated, and have yielded targets for potential therapies. These targets include VEGFR in the treatment of all thyroid cancers, BRAF in the treatment of papillary thyroid cancer, and RET in the treatment of medullary thyroid cancer (MTC). Many promising drugs that target one or more of these proteins are currently being evaluated, including sorafenib and sunitinib, both of which are still under development for the treatment of thyroid cancer but which have been approved for use in other malignancies. In addition, compounds such as vandetanib (AstraZeneca plc) and XL-184 (Bristol-Myers Squibb Co/Exelixis Inc) have demonstrated activity in early-phase clinical trials of MTC and are being tested further in randomized trials.

Conatumumab (AMG-655), under development by Amgen Inc and Japanese licensee Takeda Bio Development Center Ltd, is a fully human IgG1 mAb that binds to the extracellular domain of death receptor 5 (DR5) for the potential intravenous treatment of cancer. In vitro and in vivo studies have demonstrated that conatumumab induces apoptosis in cell lines derived from colon and pancreatic cancers, as well as in mice bearing xenograft tumors. Preclinical studies also indicated that conatumumab enhances the antitumor activity of agents, such as irinotecan and gemcitabine. The results of phase I clinical trials have demonstrated the safety of conatumumab as a monotherapy, as well as in combination with other antibody therapies or standard chemotherapeutic regimes. In addition, anti-conatumumab antibody responses have not been observed in the trials conducted to date. At the time of publication, initial results from phase I/II trials suggest a possible therapeutic role for conatumumab in patients with tumors expressing DR5.