Current opinion in investigational drugs最新文献

In asthma, airway inflammation is driven by Th2-related cytokines, such as IL-4, IL-5 and IL-13. IL-4 and IL-13, in particular, have a major role in the development of airway hyperresponsiveness, allergen-specific IgE synthesis and airway remodeling because of their synergistic effects induced by binding to the IL-4Rα subunit. Pitrakinra (AER-001, BAY-16-9996), being developed by Aerovance, under license from Bayer, for the potential treatment of asthma and eczema, is an IL-4 mutein, which binds to the IL-4Rα subunit and prevents the inflammation induced by IL-4 and IL-13. Pitrakinra demonstrated a potent inhibitory activity on IL-4/IL-13-mediated proliferative effects in vitro and reduced allergen-induced inflammation in animal models of asthma and skin inflammation. In phase I and II clinical trials in patients with asthma, subcutaneous and inhaled (as dry powder or nebulized) formulations of pitrakinra reduced airway inflammation, with superior effects observed with inhaled formulations. At the time of publication, a phase II clinical trial with the dry powder formulation of pitrakinra was ongoing in patients with asthma. Subcutaneous pitrakinra demonstrated preliminary efficacy results in patients with atopic eczema in a phase II clinical trial and a PEGylated variant of subcutaneous pitrakinra is being investigated for this indication. Further studies are warranted to allow a better therapeutic positioning and a more detailed characterization of the efficacy and safety of pitrakinra in asthma and atopic eczema.

Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases. There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Oligonucleotides may be divided in two groups based on their main mechanism of action: (i) RNA-targeting; and (ii) protein-targeting. Antisense oligonucleotides and siRNAs, both of which belong to the RNA-targeting group, and the immunostimulatory sequence-based drugs, which are members of the protein-targeting group, are progressing through clinical trials. In principle, the development of these agents is facilitated by a series of significant advantages, such as those associated with delivery to the lung via inhalation, and targeting to the site of action, resulting in reduced levels of systemic exposure. Although no oligonucleotide-based drug has been approved for the treatment of asthma or COPD, this class of compounds holds significant promise in the treatment of these two diseases. Several oligonucleotide drug candidates have been evaluated in the clinic with no significant adverse safety findings, while clinical proof of concept based on short-term inhalation protocols in challenge models in humans has also been established.

Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation. Therapeutic efficacy of teriflunomide has been demonstrated in vivo in an experimental autoimmune encephalomyelitis model of MS using Dark Agouti rats. In a phase II, randomized, double-blind, placebo-controlled clinical trial of patients with relapsing-remitting MS, treatment with teriflunomide reduced the number of active lesions in the brain and preliminary evidence indicated a slowing in the development of disability. Recently reported data from the phase III TEMSO clinical trial support these initial findings. Compared with current therapies, teriflunomide has the advantage of oral administration. Thus, if good efficacy is demonstrated, teriflunomide may have a role to play in the future treatment of MS.

The IL-1 family of cytokines comprises 11 proteins with pro- and anti-inflammatory functions that are mediated through an equally large group of receptors and coreceptors. Dysregulation of the IL-1 system may lead to diseases such as psoriasis, atopic dermatitis, contact dermatitis and cutaneous lupus erythematosus. These inflammatory skin conditions greatly affect quality of life and life expectancy, and their frequencies are increasing. However, treatment options for these diseases are unsatisfactory. This review briefly summarizes new findings, reported in the past 2 years, implicating IL-1 family members in skin inflammation. Furthermore, how the biological activities of the IL-1 family members may be inhibited is discussed.

Brain and spinal cord injuries result in cognitive and/or sensorimotor impairments that can significantly diminish the quality of life for the patient and their carers, and result in healthcare system costs totaling in the billions. The current gold-standard of acute care for spinal cord injury is to administer high doses of glucocorticoids within 8 h of injury; administration after 8 h may be without effect or detrimental to the outcome of the patient. Therefore, improved pharmacological approaches for limiting the extent of tissue damage and neurological dysfunction in the acute injury setting are urgently needed. Early intervention in CNS injury by antagonizing or controlling the post-injury inflammatory process with pharmaceutical agents is a major focus of current clinical and preclinical investigations. In this editorial overview, recent clinical trials and preclinical studies of brain and spinal cord injuries are discussed, including studies focusing on the use of broad-spectrum immunosuppressive drugs (eg, minocycline); growth factors (eg, erythropoietin); dual anti-inflammatory and anti-vasospasm drugs, such as Rho and ROCK kinase inhibitors; and broad-spectrum anti-inflammatory drugs, such as PDE4 inhibitors. These new approaches hold great promise to improve outcomes for patients with brain and spinal injuries.

Biopharmaceutical approaches have been used to target key elements in the processes controlling airway inflammation in asthma and COPD. There is compelling evidence that IL-13 is a key mediator in the inflammatory processes in the asthmatic lung. Tralokinumab (CAT-354), under development by MedImmune, is an injectable, anti-IL-13 humanized mAb for the potential treatment of asthma and COPD. In a study in mice, tralokinumab prevented the development of the asthmatic phenotype, including eosinophil recruitment and airway hyperresponsiveness. In clinical trials, tralokinumab demonstrated favorable safety and pharmacokinetic profiles, both in healthy volunteers and in patients with asthma. This review summarizes the problems and successes regarding recent developments in mAb-based strategies targeted against IL-13 in asthma and COPD, with an emphasis on tralokinumab.

Abnormal wound healing is a major problem in healthcare today, with both scarring and chronic wounds affecting large numbers of individuals worldwide. Wound healing is a complex process involving several variables, including growth factors and their receptors. Chronic wounds fail to complete the wound healing process, while scarring is considered to be an overzealous wound healing process. Growth factor receptors and their ligands are being investigated to assess their potential in the development of therapeutic strategies to improve wound healing. This review discusses potential therapeutics for manipulating growth factors and their corresponding receptors for the treatment of abnormal wound healing.

Fibrosis is characterized by the excessive accumulation of extracellular matrix components, leading to tissue scarring. Fibrosis can occur in various tissue and organ systems, and is considered a leading cause of morbidity and mortality. Because of unsatisfactory results with currently available therapies for fibrotic diseases, the development of new therapies that target fibrosis directly is warranted. This review focuses on the importance of an imbalance in T-helper type 1 (Th1)/Th2 cell responses in fibroproliferation in several major fibrotic diseases, and discusses the prospects of novel therapeutic options targeting the Th2-type inflammatory response and cytokines. With the aim of shifting the immune response toward Th1 and IFNγ responses, antagonists of IL-4, IL-5 and IL-13 have been investigated as candidate therapies for fibrogenic conditions. Several clinical trials with such cytokine antagonists are underway, but have yet to demonstrate improvements in therapeutic outcomes compared with existing therapies; however, based on the evidence available, cytokine therapies should remain the focus in fibrotic diseases, with the aim of improving the outcomes of patients.

The concept of thyroid hormone (TH) analogs that retain the beneficial effects of TH excess on lipid lowering and fat metabolism, while avoiding any harmful effects on the heart, muscle, bone and other tissues, has interested scientists and physicians for several decades. While there have been many attempts to develop selective TH receptor (TR) modulators (STRMs) for safe lipid lowering, these approaches have failed consistently. This review details recent advances in the development of TRβ subtype- and liver-selective STRM analogs, and presents the results of preliminary clinical trials with one of these compounds, eprotirome (KB-2115; Karo Bio AB).

HIV-associated lipodystrophy characterized by body composition changes and associated metabolic abnormalities, including dyslipidemia and insulin resistance, is a major challenge in the treatment of HIV infection. Growth hormone-releasing factor (GRF) analogs with greater stability than the natural hormone can induce growth hormone secretion in a physiological manner, and appear to be promising candidate therapies for these conditions. The most promising GRF agonist in development is tesamorelin (EMD Serono/Theratechnologies), which has exhibited efficacy for the treatment of excess visceral adipose tissue in patients with HIV infection in two recent phase III, randomized, placebo-controlled clinical trials. Additional long-term outcome trials are required to determine the long-term safety of tesamorelin and to evaluate whether this agent, or other GRF agonists, could reduce the cardiovascular risk associated with lipodystrophy-related metabolic complications and help to maintain a more normal distribution of body fat.