Investigational drugs for the treatment of osteoarthritis

Introduction: Osteoarthritis (OA) is a common joint disease with multiple pathophysiological processes, affecting the whole joint. Current therapeutic options such as NSAIDs can provide a palliative effect on symptoms but have limited effect on disease progression. New drugs targeting OA structures may retard disease progression at an earlier stage and delay the need for joint replacement.

Areas covered: Some drugs have entered into clinical trials and a few, such as strontium ranelate, do have improvements in both pain and structure changes. However, most of them have failed in clinical trials largely due to increased side effects or the failure to identify the right OA phenotype for the right drug in clinical design. This review describes various investigational drugs developed for the treatment of OA covering those at stages from preclinical experiments to early phase clinical trials. They include drugs for slowing cartilage degradation, regulating cartilage metabolism, targeting subchondral bone, controlling inflammation and relieving pain.

Expert opinion: Treatment options for OA remain limited. However, with the emergence of sensitive tools to detect early disease progression and identification of different OA phenotypes, disease-modifying anti-OA drugs with increased benefit and reduced risks will become available for OA treatment in the near future.     

Green-lipped (greenshell™) mussel (Perna canaliculus) extract supplementation in treatment of osteoarthritis: a systematic review

Objectives

Intervention studies using New Zealand green-lipped or greenshell? mussel (GSM) (Perna canaliculus) extract in osteoarthritis (OA) patients have shown effective pain relief. This systematic review summarises the efficacy of GSM extracts in the treatment of OA.

Methods

A literature search of the three databases EMBASE, MEDLINE, and Scopus was performed to identify relevant articles published up to March 2020. Inclusion criteria were clinical trials published in English measuring the effect of supplementation of whole or a lipid extract from GSM on pain and mobility outcomes in OA patients.

Results

A total of nine clinical trials were included in systematic review, from which five studies were considered appropriate for inclusion in a forest plot. Pooled results showed that GSM extracts (lipid extract or whole powder) provide moderate and clinically significant treatment effects on a visual analogue scale (VAS) pain score (effect size: ? 0.46; 95% CI ? 0.82 to ? 0.10; p?=?0.01). The whole GSM extract improved gastrointestinal symptoms in OA patients taking anti-inflammatory medications. The GSM extract was considered to be generally well tolerated in most of the studies.

Conclusion

The overall analysis showed that GSM provided moderate and clinically meaningful treatment effects on OA pain. However, the current evidence is limited by the number and quality of studies, and further larger and high-quality studies are needed to confirm the effectiveness and to identify the optimal GSM format. Nevertheless, it is worth considering using GSM extracts especially for patients seeking alternative pain relief treatments with fewer side effects compared to conventional treatment.

     

New and emerging treatments for osteoarthritis management: will the dream come true with personalized medicine?

Introduction: Osteoarthritis (OA) is a dynamic process involving the main tissues of the joint for which a global approach should be considered. No disease-modifying OA drug (DMOAD) has yet been approved. New therapeutic strategies are needed that would be cost effective by reducing the need for pharmacological interventions and surgical management while targeting specific pathways leading to OA. The treatment landscape of OA is about to change based on new agents having shown some structural effects and emerging therapies with DMOAD effects.

Areas covered: In this review based on a Medline (via PubMed) search, promising new and emerging therapies with a potential structural effect (DMOAD) will be discussed including growth factors, platelet-rich plasma, autologous stem cells, bone remodeling modulators, cytokine inhibition, gene therapy, and RNA interference.

Expert opinion: DMOAD development should focus on targeting some phenotypes of OA patients evidenced with sensitive techniques such as magnetic resonance imaging, as a single treatment will unlikely be appropriate for all OA patients. This will allow the development of DMOADs based on personalized medicine. An exciting new era in DMOAD development is within reach, provided future clinical trials are sufficiently powered, systematically designed, use the appropriate evaluation tools, and target the appropriate categories of OA patients.     

An overview of early investigational therapies for chemoresistant ovarian cancer

Introduction: Epithelial ovarian cancer (EOC) is the fourth commonest cause of female cancer death in the developed world. Although progress in treatment has improved survival, ～ 80% of patients with advanced EOC will experience a recurrence and eventually will become resistant to chemotherapy. The aim of treatment for chemoresistant EOC has traditionally been limited to palliation of symptoms but the recent introduction of new therapies targeting molecular pathways is beginning to demonstrate improvements in disease control.

Areas covered: This review provides an overview of early investigational drugs for the treatment of ‘platinum-resistant’ EOC. The article is based on English peer-reviewed articles located on MEDLINE and related abstracts presented at major international meetings.

Expert opinion: Drugs targeting several pathways are increasingly used to treat ‘platinum-resistant’ EOC. Currently, drugs targeting the angiogenesis pathway have been shown to significantly improve patient outcome. Studies are also being undertaken with inhibitors of poly(ADP-ribose) polymerase (PARP), targeting the DNA repair pathway as it is possible that the benefits seen with these agents in ‘platinum-sensitive’ disease will apply to those with ‘platinum-resistant’ disease. The discovery of predictive biomarkers that identify patients which benefit from these targeted therapies is paramount to the success of these treatments in the future.     

Current and emerging treatment options for endometriosis

Introduction: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors including age and patient preference, reproductive plans, intensity of pain, severity of disease and incidence of adverse effects.

Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that are currently available or are under investigation for the treatment of endometriosis highlighting on-going clinical trials.

Expert opinion: Almost all of the available treatment options for endometriosis suppress ovarian function and are not curative. Combined oral contraceptives and progestins are commonly administered to these patients in order to ameliorate pain symptoms. Gonadotropin-releasing hormone-agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary.     

Emerging drugs for Hodgkin's lymphoma

Importance of the field: Although to date most patients with Hodgkin's lymphoma (HL) can be cured, the current treatment is associated with acute and long-term complications such as infertility, cardiovascular damage and secondary malignancies. Moreover, novel effective therapies are urgently needed for elderly patients and for patients relapsing after high-dose chemotherapy.

Areas covered in this review: Currently emerging promising approaches include drugs targeting cell surface structures by mAbs and immunotoxins, as well as small molecules targeting intracellular proteins. This article includes clinical trials published within the past 3 decades and early results reported in international conferences.

What the reader will gain: This article summarizes the biological basis and early clinical data on emerging drugs for HL.

Take home message: To date, several new drugs are being tested for HL that are expected to change the approach in both first-line and relapsed patients.     

GP and Patient Perspectives on Treatment with Non-steroidal Anti-inflammatory Drugs for the Treatment of Pain in Osteoarthritis

Summary

Two nationwide surveys were carried out using an electronic poll of 2000 GPs and postal questionnaires were sent to 30000 patients with osteoarthritis (OA).

Both surveys found a high level of gastrointestinal (GI) side-effects in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs). Almost every GP (97%) reported experience of patients suffering GI symptoms while on an NSAID, 38% reported patients who had been hospitalised and 4% reported patients who had died owing to NSAID-induced side-effects. Most GPs (92%) said they were concerned about GI safety when prescribing an NSAID and almost a third (32%) said they were concerned about litigation from patients who had experienced a bleed.

Use of NSAIDs in OA remained high, with 44% of GPs prescribing conventional NSAIDs to at least three quarters of their patients, 57% of GPs using simple analgesia and just 12% using a cyclo-oxygenase-2 (COX-2) selective inhibitor in over 74% of patients.

Some 45% of patients reported receiving NSAIDs compared with 43% on simple analgesia and 4% on COX-2 selective inhibitors.

Most GPs (69%) stated that their main therapeutic objective in using an NSAID to treat OA was to control pain without GI side-effects. Almost a quarter (24%) said they used low-dose NSAIDs in the hope that this would control pain without GI side-effects.

Dissatisfaction with treatment was the most common reason reported by GPs for patients on an NSAID to re-present, with 73% citing either breakthrough pain or incomplete pain relief as the most common reason for patient dissatisfaction. This mirrored the patients' perception, with 63% citing inadequate pain relief as their main reason for dissatisfaction with current painkillers compared to 17% who cited stomach upsets or irritation.

Patient and GP appear to be united in their concern at the GI risks of NSAID treatment. In the light of this and recent data on the efficacy, safety profile and cost-effectiveness of COX-2 selective inhibitors, GPs should re-examine their medical management of OA.     

Advancing synthetic therapies for the treatment of restless legs syndrome

ABSTRACT

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory.

Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED.

Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.     

Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development

Introduction: Pain is a major burden for affected individuals and society, and controlling neuropathic pain is especially challenging. The number of drugs available is limited and treatments are often marginally effective and burdened by side effects. Voltage-gated calcium channels (VGCC) play a major role in the development and maintenance of neuropathic pain and are thus prime targets for its treatment.

Areas covered: Currently available drugs that target the calcium channel include ziconotide, gabapentin and pregabalin. While there are no VGCC blockers currently in clinical trials, there are many in development. Recently, orally available, use-dependent compounds have been reported. We will review, in detail, compounds currently in development and include a brief review of VGCC and the drugs currently in use.

Expert opinion: There is real hope that new drugs targeting calcium channels will soon be available. This hope is based on advancing technologies for peptide synthesis, more efficient drug screening and orally available, use-dependent compounds. Some form of direct VGCC blockade or modulation will always have a place in the treatment of neuropathic pain, but given the complexity and neuroplasticity of pain transmission, polypharmacy will likely be required for many chronic pain sufferers for the foreseeable future.     

Disease-modifying drugs in osteoarthritis: current understanding and future therapeutics

ABSTRACT

Introduction: Osteoarthritis (OA) is a leading cause of pain and disability among adults with a current prevalence of around 15% and a predicted prevalence of 35% in 2030 for symptomatic OA. It is increasingly recognized as a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity. Current therapeutic regimens for OA are only partially effective and often have significant associated toxicities. There are no disease-modifying drugs approved by the regulatory bodies.

Areas covered: We reviewed the opportunities within key OA pathogenetic mechanism: cartilage catabolism/anabolism, pathological remodeling of subchondral bone and synovial inflammation to identify targeted disease-modifying osteoarthritis drugs, based on compounds currently in Phase II and III stages of clinical development in which x-ray and/or MRI was used as the structural outcome with/without symptomatic outcomes according to regulatory requirements.

Expert opinion: Given the heterogeneity of the OA disease process and complex overlapping among these phenotypes, a ‘one size fits all’ approach used in most clinical trials would unlikely be practical and equally effective in all patients, as well as in all anatomical OA sites. On the other hand, it is a challenge to develop a targeted drug with high activity, specificity, potency, and bioavailability in the absence of toxicity for long-term use in this chronic disease of predominantly older adults. Further research and insight into evaluation methods for drug-targeted identification of early OA and specific characterization of phenotypes, improvement of methodological designs, and development/refinement of sensitive imaging and biomarkers will help pave the way to the successful discovery of disease-modifying drugs and the optimal administration strategies in clinical practice.     

Tyrosine kinase inhibitors to treat liver cancer

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern.

Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways.

What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC.

Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies.     

Investigational approaches to therapies for restless legs syndrome

Introduction: Restless Legs Syndrome (RLS) is a common neurological disorder that impairs nocturnal rest, causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by severe RLS, pharmacological treatment is mandatory.

Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 – 2014. It focuses on drugs currently in development for the treatment of RLS.

Expert opinion: The drugs currently available for treating RLS do not always allow the patient to obtain a dose capable of controlling the symptoms, particularly in the long term. There is still the need for effective and well-tolerated new drugs. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone has demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled with first-line drugs; it could be used as a long-term treatment option in severe cases of RLS for which alternative satisfactory drug regimens are unavailable. There is a paucity of data comparing medications in head-to-head trials to determine their relative effectiveness and adverse event profiles. Furthermore, there is also a need for further studies that evaluate nondopaminergic agonists and combination therapies for treating RLS.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Current perspectives on pharmacotherapy of Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials .

Areas covered: This review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years.

Expert opinion: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

An update on the utility and safety of cholinesterase inhibitors for the treatment of Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer’s disease (AD) is the most common cause of major neurocognitive disorders with a prevalence in the US of about 5.7 million in 2018. With the disease burden projected to increase dramatically in the coming years, it is imperative to review the current available treatment regimens for their safety and utility. The cholinesterase inhibitors (ChEIs) have continued to play a pivotal role in managing the symptoms and possibly slowing the rate of progression of AD since 1993. Owing to their being a mainstay in the treatment of AD, the safety and efficacy of prescribing these drugs needs to be reviewed often, especially with the approval of new formulations and doses.

Areas covered: The three ChEIs currently approved by the FDA are donepezil, rivastigmine and galantamine. This article will review the safety and tolerability of these ChEIs and analyze the potential disease modifying properties of these drugs. The authors have reviewed all recent literature including review articles, meta-analyzes, clinical trials and more.

Expert opinion: These ChEIs differ subtly in their mechanisms of action, in their tolerability and safety and FDA-approved indications. All are considered first-line, symptomatic treatments of the various phases of AD and may even have potentially disease-modifying effects.     

Investigational MET inhibitors to treat Renal cell carcinoma

ABSTRACT

Introduction: Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC.

Areas covered: The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway.

Expert opinion: MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.     

Drug treatment of chronic subdural hematoma

ABSTRACT

Introduction: Chronic subdural hematoma (CSDH) is a common neurosurgical disease, whose incidence has been steadily increasing with our aging population. While not common, CSDH can also occur in children. CSDH is often associated with traumatic head injury, but its underlying mechanism remains poorly understood. The first line treatment for CSDH is surgery. However, surgery is contraindicated in some patients and has a high rate of recurrence. Effective non-surgical treatment is therefore highly desirable.

Areas covered: This review discusses the pathogenesis of CSDH and drugs that have been used to treat CSDH either as monotherapy or an adjuvant to surgery, including controlled clinical trials.

Expert opinion: The pathophysiology of CSDH remains poorly understood. Developing effective drug treatments is therefore challenging. Most drugs discussed in this review are evaluated in small clinical studies without sufficient sample size and controls for confounding variables. More controlled clinical trials are therefore needed to carefully evaluate drugs for the non-surgical treatment of CSDH, especially for drugs targeting specific pathogenic pathways of CSDH.     

Noradrenergic reuptake inhibition in the treatment of pain

Introduction: Noradrenergic reuptake inhibitors can be effective analgesics, finding application in a wide variety of clinical pain settings. Due to a shift toward noradrenergic-mediated pain pathways following nerve injury, they are particularly well suited to the treatment of neuropathic pain. This phenotypic shift makes neuropathic pain difficult to control with opioids alone; some noradrenergic reuptake inhibitors have demonstrated synergy with opioids. Agents currently in early clinical trials are discussed and include both novel delivery of old drugs and the development of new drugs.

Areas covered: This review was limited to noradrenergic reuptake inhibitors and analgesia. Literature search included the terms adrenergic, noradrenergic, reuptake, inhibitors, analgesia, NET, norepinephrine transporter, and pain using Medline, Google scholar, Web of Knowledge, www.clinicaltrials.gov, and Pharmaprojects (Informa UK Ltd. 2012).

Expert opinion: Topical drug delivery and the use of combinations of agents both topically and systemically are under active investigation. The intrathecal delivery of noradrenergic reuptake inhibitors, allowing delivery directly to the central nervous system thus limiting systemic exposure, represents an exciting avenue of investigation. Gaps in current knowledge have complicated the development of prophylactic therapies for susceptible individuals or preemptive intervention. Disease-modifying agents and selective inhibitors would facilitate these treatment strategies.