Emerging drugs for postmenopausal osteoporosis

Postmenopausal osteoporosis (PMO) is a common skeletal disease with serious consequences due to fractures, including increased risk of disability and death. The risk of fractures can be reduced with medications that are currently available; however, these drugs are frequently not prescribed due to failure to recognize that a patient is at high risk for fracture; fear of adverse drug effects; or, sometimes, high cost. When these drugs are prescribed, long-term adherence to therapy is poor. Efforts to improve the clinical effectiveness of pharmacological therapies have included lengthening the interval between doses, simplifying drug administration, and manipulating the molecular structure of drugs in existing therapeutic classes. Recent improvement in understanding the pathophysiology of PMO at the molecular level has fostered the development of new therapeutic agents with novel mechanisms of action. This is a review of the data on the efficacy and safety of emerging drugs for the treatment of PMO, including agents with novel mechanisms of action (denosumab, odanacatib, antibody to sclerostin), new estrogen agonists/antagonists (lasofoxifene, bazedoxifene, arzoxifene), new delivery systems for existing drugs (salmon calcitonin, teriparatide), and drug combinations given concurrently, sequentially, or cyclically. These new therapeutic agents, new delivery systems, and new methods of combining drugs may ultimately reduce the great personal and economic burden of osteoporotic fractures.     

Novel therapies for osteoporosis

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason research continues in search of more effective and more tolerable agents. Anabolic agents offer a unique mechanism of action. The anabolic agents parathyroid hormone and strontium will be discussed. The investigational bisphosphonates ibandronate, minodronate and zoledronic acid may offer the advantage of less frequent dosing. Arzoxifene, bazedoxifene, lasofoxifene, MDL-103,323 and ospemifene are investigational selective oestrogen receptor modulators shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. While studies of the effect of isoflavones on bone mineral density have been encouraging, a large, multi-centre study in Europe showed no effect of isoflavones on fractures. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Other agents with unique mechanisms of action in early development include cathepsin K inhibitors, integrin receptor inhibitors, nitrosylated non-steroidal anti-inflammatory agents and Src inhibitors. The efficacy of statins in bone continues to be debated with no prospective, randomised studies yet to confirm the suggestion of benefit seen in epidemiological studies.     

Emerging drugs for the treatment of transplant rejection

Introduction: Kidney allograft rejection is an important cause of early and late allograft failure. The importance of antibody-mediated rejection especially in the context of late allograft failure has only recently been acknowledged.

Areas covered: This review summarizes new developments in the treatment of cellular and antibody-mediated kidney allograft rejection. Drugs presented here include monoclonal antibodies and novel innovative approaches such as proteasome and complement inhibition. In addition, other options for the treatment of allograft rejection such as the administration of intravenous immune globulins or the use of plasmapheresis and immunoadsorption are discussed.

Expert opinion: Especially the treatment of chronic antibody-mediated rejection represents a challenge and new therapeutic options are needed.     

Emerging drugs for respiratory syncytial virus infection

Although respiratory syncytial virus (RSV) was discovered > 40 years ago, treatment remains largely supportive. There are no safe and effective vaccines or specific treatments other than prophylaxis with passive antibody therapy (palivizumab). However, there are good reasons to think that the scene may soon change. As the pace of development of anti-viral drugs accelerates and optimism over vaccines increases, novel therapies are set to make a major impact in the management of this very common infection. The use and effect of such interventions are not easy to anticipate, but could ultimately include the interruption of RSV's transmission resulting in profound changes to the impact ozf RSV on human health.     

Emerging drugs for perennial allergic rhinitis

Introduction: Allergic rhinitis (AR) is a high-prevalence disease, sustained by an IgE-triggered reaction with histamine release, followed by an inflammatory response which involves cells, mediators, cytokines and adhesion molecules. According to its duration, AR can be either intermittent or persistent. In the persistent form, the inflammatory component usually predominates.

Areas covered: The current therapeutic strategy is based on antihistamines, antileukotrienes and on corticosteroids (which broadly act on inflammation). Allergen-specific immunotherapy is a biological response modifier that affects the immune response to allergens in a broad sense. The available pharmacotherapy is overall effective in controlling symptoms and inflammation, but safety concerns may be present (especially for prolonged treatments), and a proportion of patients remain uncontrolled. The available therapeutic innovations, as derived from the most recent literature are reviewed herein.

Expert opinion: In the last years there have been very few innovative approaches to optimize the management of AR. These include new histamine receptor antagonists, combination therapy and strategies to selectively block relevant signaling pathways of the allergic reaction. Some more promising advances have been shown for allergen immunotherapy, where a number of new strategies are currently under development.     

Emerging angiogenesis inhibitors for non-small cell lung cancer

Introduction: Angiogenesis represents a complex process crucial during embryo development, wound healing, and collateral formation for improved organ perfusion. Numerous stimulatory and inhibitory pathways through their balance regulate angiogenesis and vascular homeostasis. Targeting the pathways implicated in the regulation of angiogenesis and neo-angiogenesis plays an important role in cancer research, treatment, and patients’ outcome. Antiangiogenic strategies, including monoclonal antibodies binding vascular endothelial growth factor (VEGF) or the corresponding receptor and small molecules which inhibit the function of different angio–related tyrosine kinase, produced interesting results in cancer treatments including non-small-cell lung cancer (NSCLC).

Areas covered: The current state-of-the-art of anti-angiogenesis treatment in the management of NSCLC patients is reviewed and discussed. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken in order to discuss about emerging angiogenesis inhibitors in NSCLC.

Expert opinion: Targeting angiogenesis remains an important therapeutic strategy in the management of NSCLC. Moreover, VEGF has been recognized having also an immunosuppressive action leading to investigate the potential activity of angiogenic inhibitors in restoring the antitumor immunity by targeting VEGF/VEGF-Receptor. Furthermore, new anti-angiogenic drugs for which there is also the availability of predictive biomarkers are welcome.     

Emerging drugs for the management of cancer treatment induced bone loss

Areas covered in this review: We focus our attention on data on the efficacy of currently available and emerging drugs for the management of cancer treatment induced bone loss (CTIBL) found in a PubMed research from 1997 till today.

Importance of the field: One of the most common and severe safety issues of the antihormonal therapy in both sexes is the CTIBL and the related fragility fractures. In postmenopausal women with estrogenic receptor positive breast cancer, the third-generation aromatase inhibitors (AIs) are the standard therapy. Observational retrospective studies have found that AIs treated patients had a high rate of bone loss and fracture risk (RR 1.3). Also in men with prostate cancer receiving androgen deprivation therapy, the increase in bone turnover and the consequent bone loss are very rapid and sustained significantly increasing the fracture risk.

What the reader will gain: The aim of our review is to provide the current evidences for the management of bone loss and fracture risk in this subpopulation.

Take home message: The very high rate of bone loss and the high incidence of fractures indicate that cancer patients at risk of CTIBL need to be carefully monitored and stratified for fracture risk. Although there is a strong evidence of efficacy in prevention of bone loss and reduction of fracture risk for many drugs approved for postmenopausal osteoporosis (PMO) and male osteoporosis, for CTIBL there are actually no drugs approved for this indication.     

Risedronate for prevention and treatment of osteoporosis in postmenopausal women

Risedronate sodium is an N-containing bisphosphonate that has been approved for the prevention and treatment of osteoporosis in postmenopausal women. An increase in the rate of bone remodelling is a regular feature of oestrogen withdrawal during the menopausal transition, but excessive remodelling leads to bone fragility. Risedronate and similar compounds reduce the rate of bone remodelling by suppressing the action of osteoclasts. The antifracture efficacy of risedronate is impressive. In large clinical trials of postmenopausal women with osteoporosis-related fracture(s) at entry, the risk of incident vertebral and non-vertebral fractures was reduced by ~ 40%. In older women at risk for hip fracture, incident hip fractures were also reduced by ~ 40%. Antifracture efficacy develops within the first 6months, and treatment has been followed for as long as 5 years without deleterious effects on bone. We await reports of experience with risedronate in ‘real-world’ cases of greater complexity (i.e., in patients with co-morbidities and medications that would have excluded them from published clinical trials).     

Emerging drugs targeting human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer

Introduction: Human epidermal growth factor 2 (HER2) overexpression is present in 20% of breast cancer patients. It is associated with more aggressive disease and worse clinical outcome. New drugs are thus needed. Approved and future treatments will be discussed in this review.

Areas covered: The monoclonal antibodies trastuzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib and the antibody-drug conjugate trastuzmab emtansine are approved for HER2 positive breast cancer. The combination of trastuzumab, pertuzumab and docetaxel is currently the first-line treatment in the metastatic setting. New therapies are still needed due to frequent relapse and resistance. These include mammalian target of rapamycin inhibitors, heat shock protein 90 inhibitors, pan-HER2 tyrosine kinase inhibitors, antibody-drug conjugates, immunotherapy agents (antibodies and vaccines), radioimmunotherapy and HER2 specific affinity proteins. Possible developmental issues are the complexity of the molecular biology of the HER2 positive cancer cell, the occurrence of resistance, toxicity and the high cost.

Expert opinion: The determination of the right sequence of use of old and new therapies remains a challenging issue. The selection of patients who do or don’t benefit from potentially toxic chemotherapy is also difficult. Central nervous system metastases are a common problem in HER2 positive breast cancer that needs to be addressed in future trials.     

Emerging lipid-lowering drugs: squalene synthase inhibitors

Background: Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism. Objective: The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors. Methods: A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms “squalene synthase inhibitors” or “lapaquistat”. All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis. Results/conclusion: Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug–drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.     

Novel investigational drugs for gastric cancer

Background: Gastric cancer still represents a leading cause of death worldwide. Several cytotoxic agents have demonstrated activity and combination regimens improve progression-free survival, overall survival and quality of life. Nevertheless, now there is no standard therapy for advanced gastric cancer patients. Objective: To evaluate the role of new investigational agents. Methods: We analysed Phase I, II and III studies that evaluated tailored drugs directed against the epidermal growth factor receptor (EGFR), the c-erbB2, the vascular endothelial growth factor (VEGF), the vascular endothelial growth factor receptor (VEGFR), the matrix metalloproteinases (MMP) and the mammalian target of rapamycin (mTOR). Conclusion: Data from Phase II trials indicate the potential of improved efficacy of chemotherapy when administered in combination with bevacizumab and cetuximab. Trastuzumab results are ongoing, while marimastat has not obtained clinical developments even if it has demonstrated to be an active drug in this setting of patients.     

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC)

Introduction: Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015. Current efforts with anti-PD1-based therapy include combinations with ipilimumab and with VEGF pathway blockers in the hopes on building on the activity of single agent therapy.

Areas covered: We describe our current understanding of tumor immunology including the basis of the tumor-specific immune response and the adaptive mechanisms used by the tumor for immune escape. We describe the mechanisms of action as well as the therapeutic application of the antibodies, ipilimumab, nivolumab and atezolizumab in patients with RCC. We identify key areas of active research in biomarker development and combination therapies.

Expert opinion: Clinical trials and the field of RCC therapeutics are expected to move in the direction of combination therapies using immune checkpoint inhibitors, extending overall survival as a benchmark for new drug approvals, and biomarker validation for improved selection of patients for specific therapies.     

An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs

Introduction: Antiepileptic drugs (AEDs) have been associated with a negative impact on bone health. Comorbid disorders in patients with epilepsy may require drugs exerting a pro-osteoporotic effect, so a possibility of untoward interactions with AEDs is probable.

Areas covered: This review discusses evidence related to the deteriorating influence of AEDs on bone, demonstrating generally stronger negative effects of conventional AEDs. Lamotrigine seems to be a safer AED in this regard. Further, literature data indicate that generally AEDs can lower the serum concentration of vitamin D. Importantly, pediatric patients are of greater risk of bone problems during therapy with AEDs, which is probably due to their effects on bone-forming processes.

Expert opinion: Supplementation with vitamin D and calcium is frequently recommended in patients taking AEDs chronically. Whether to add a bisphosphonate remains an open question due to the limited data on this issue. A possibility of negative interactions exists between AEDs and other pro-osteoporotic drugs: glucocorticoids, proton pump inhibitors and aromatase inhibitors. Depression is a frequent comorbidity in patients with epilepsy. Clinical data indicate that antidepressant drugs may also increase the risk of fractures. Again, patients with epilepsy and depression may be exposed to a greater risk of osteoporosis.     

Emerging drugs for the treatment of myelofibrosis

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant disease burden composed of splenomegaly, constitutional symptoms and a reduced life expectancy. The advent of targeted treatments has provided new means by which to improve MF associated splenomegaly, symptoms, health-related quality of life and even mortality.

Areas covered: We discuss the spectrum of targeted treatments currently under investigation for MF. We furthermore compare their effects on improving anemia, reducing fibrosis and splenomegaly and enhancing symptom control.

Expert opinion: MF is a complex disorder, partly attributable to its heterogeneity. Although the severity of patient symptoms correlates with risk category, high symptom burden may also be observed in low-risk patients. Serial use of PRO tools allows clinicians to objectively evaluate the MF symptom burden, compare efficacy of therapies and adjust medications to improve symptom control. Novel targeted agents have proven superior to historic treatment regimens for symptom management. Promising treatment categories include JAK2 inhibitors, histone deacetylase inhibitors, hypomethylating agents, heat shock protein-90 inhibitors, hedgehog inhibitors, PI3-AKT-mTOR inhibitors, antifibrosing agents and telomerase inhibitors. The majority of therapies remain under investigation, either alone or in combination with other treatments. It is anticipated that these agents will be increasingly integrated into standard treatment algorithms for MF symptom management.     

Effect of a sequential treatment combining abaloparatide and alendronate for the management of postmenopausal osteoporosis

The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 µg/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non-vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis.     

Emerging drugs for psoriatic arthritis

Importance of the field: The socioeconomic burden of psoriatic arthritis (PsA) is considerable and not different from that of rheumatoid arthritis. Current treatment options do not always allow reaching the therapeutic objectives consisting of the remission of symptoms and prevention of the appearance of damage in the early stage of PsA or the blocking of PsA progression in the established cases.

Areas covered in this review: After reviewing the current treatment choices, we examine the new drugs in clinical Phase II and III trials for PsA up to January 2010. Information was mainly obtained from the network of international clinical trial registries.

What the reader will gain: The current management of PsA includes NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α blocking agents. These last drugs are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life and function and can inhibit the progression of the structural joint damage. Recent advancement in the knowledge of the immunopathogenesis of PsA has permitted the development of novel drugs including new TNF-α blockers, IL-1, -6, -12, -23 and -17 inhibitors, co-stimulator modulation inhibitors, B-cell depleting agents, small molecules and receptor activator of NF-κB/receptor activator of NF-κB ligand inhibitors.

Take home message: The currently available anti-TNF-α blocking agents have revolutionized the management of PsA. However, there is a need for more effective and safer drugs.     

Emerging drugs for malignant glioma

Background: Malignant gliomas are amongst the most devastating and intractable of all cancers. The most common malignant glioma, glioblastoma multiforme (GBM), is associated with a median survival in the range of 12 – 15 months. Survival for patients with GBM has improved with the addition of temozolomide chemotherapy to post-operative radiotherapy. Further advances in the treatment of malignant glioma will hinge on the discovery of novel and likely targeted therapies with activity against these diseases. Objective: Review recent published experience using targeted therapeutics for malignant glioma. Methods: Key studies from a Medline review of targeted therapies for malignant glioma performed between 2000 and the present are summarised in this review. Conclusions: Experience with targeted therapeutics for malignant glioma has been to date disappointing. These agents are generally well tolerated, but activity is limited. Novel therapeutics with activity against malignant gliomas must be identified to improve prognosis for patients with these diseases.