Expert opinion on investigational drugs
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Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 ( ixazomib ) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss. ⋯ Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.
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Expert Opin Investig Drugs · Jan 2015
ReviewTherapies in early development for the treatment of opiate addiction.
Opiate drugs are psychoactive substances used to manage severe pain. However, their chronic use is associated with the development of addiction. Opiate addiction represents a significant public health concern. ⋯ Among the currently available agonist therapies, new dosage forms of buprenorphine can increase patient acceptability and compliance. New extended-release forms of naltrexone are building hope of retaining opiate-dependent subjects in a drug-free state. Unfortunately, the review of the literature shows that successful preclinical studies are often followed by discouraging results in human clinical trials. Nevertheless, all targets of potential interest should be tested exhaustively. Indeed, a number of new targets and research lines (genetics and neuroinflammation approaches) may lead to breakthroughs in the future.
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Expert Opin Investig Drugs · Jan 2015
ReviewAn overview of experimental and investigational multikinase inhibitors for the treatment of metastatic colorectal cancer.
The era of molecular-targeted agents, particularly bevacizumab and cetuximab, has revolutionized the treatment paradigm for metastatic colorectal cancer (mCRC). Amongst the multikinase inhibitors (MKIs) examined, regorafenib was the first to establish its role in mCRC. Despite its modest efficacy, this finding had reignited interest in exploring MKIs with the hope of maximizing their therapeutic potential in mCRC. ⋯ Clinical progress using MKIs in mCRC has been disappointing due to their limited efficacy. The exact role of regorafenib, apart from in chemo-refractory disease setting, requires further delineation. The role of MKIs in combination with other targeted agents or chemotherapy and in the maintenance setting is still considered experimental and warrants further investigation. The broader role of the current generation of MKIs will depend upon the accurate identification of patients with specific molecular phenotypes and better pharmacodynamic understanding of these agents to minimize toxicity.
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Expert Opin Investig Drugs · Jan 2015
ReviewPhosphodiesterase 4 inhibitors for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs.
Phosphodiesterase (PDE) inhibitors modulate lung inflammation and cause bronchodilation by increasing intracellular cyclic adenosine 3', 5'-monophosphate in airway smooth muscle and inflammatory cells. Roflumilast is the only approved PDE-4 inhibitor (PDE4I) for use in chronic obstructive pulmonary disease (COPD). Its beneficial clinical effects occur preferentially in patients with chronic bronchitis and frequent COPD exacerbations. Use of roflumilast as adjunctive or alternate therapy to other COPD medications reduces exacerbations and modestly improves lung function. ⋯ After decades of research in drug development, PDE4Is are a welcomed addition to the COPD therapeutic armamentarium. In its current clinical role, the salubrious clinical effects of PDE4I in reducing exacerbations and stabilizing the frequent exacerbator phenotype have to be cautiously balanced with numerous adverse effects. Developing drugs may provide similar or better clinical benefits while minimizing adverse effects by changing the mode of drug delivery to inhaled formulations, combining dual PDE isoenzyme inhibitors (PDE1/4I and PDE3/4I) and by forming hybrid molecules with other bronchodilators (muscarinic receptor antagonist/PDE4I and β2-agonist/PDE4I).
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Expert Opin Investig Drugs · Jan 2015
ReviewFocus on ceftazidime-avibactam for optimizing outcomes in complicated intra-abdominal and urinary tract infections.
Complicated intra-abdominal infections and urinary tract infections are frequently associated with Gram-negative bacteria and treatment can be hampered by the involvement of resistant organisms. A common resistance mechanism is β-lactamase production which confers resistance to β-lactam antibiotics. ⋯ The increasing problem and complexity of β-lactamase resistance has been met by resurgence in the development of β-lactamase inhibitor combinations. These show promise in the treatment of resistant infections. One β-lactamase inhibitor in advanced development with a broad spectrum of activity is avibactam, covering class A, class C and some class D enzymes. Importantly, the activity of avibactam also includes carbapenemases such as the KPC and OXA-48. The combination of avibactam with the cephalosporin ceftazidime is attractive, given the spectrum of antimicrobial activity and the low toxicity of the cephalosporin class.