Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue.

Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life.

Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.     

Novel investigational drugs mimicking exercise for the treatment of cachexia

Introduction: Cachexia is a syndrome characterized by body weight loss, muscle wasting and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, which is able to both induce anabolism and inhibit catabolism.

Areas covered: This review focuses on exercise mimetics and their potential inclusion in combined protocols to treat cachexia. The authors pay with particular reference to the cancer-associated cachexia.

Expert opinion: Even though exercise improves muscle phenotype, most patients retain sedentary habits which are quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and comorbidities that reduce exercise tolerance. For these reasons, drugs mimicking exercise could be beneficial to those who are unable to comply with the practice of physical activity. Since some exercise mimetics may exert serious side effects, further investigations should focus on treatments which maintain their effectiveness on muscle phenotype while remaining tolerable at the same time.     

Developing models for cachexia and their implications in drug discovery

Introduction: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. Systemic inflammation plays a central role in its pathophysiology. As millions of patients are in a cachectic state of chronic disease, cachexia is one of the major causes of death worldwide. Difficulties in the recruitment and follow-up of clinical trials mean that well-characterized animal models are of great importance in developing cachexia therapies. However, some of the widely used animal models have limitations in procedural reproducibility or in recapitulating in the cachectic phenotype, which has warranted the development of novel models for cachexia.

Areas covered: This review focuses on some of the currently developing rodent models designed to mimic each co-morbidity in cachexia.

Expert opinion: Through developing cancer models, researchers have been seeking more targets for intervention. In cardiac cachexia, technical issues have been overcome by transgenic models. Furthermore, the development of new animal models has enabled the elucidation of the roles of inflammation, anabolism/catabolism in muscle/fat tissue and anorexia on cachexia. As metabolic and inflammatory pathways in cachexia may compromise cardiac muscle, the analysis of cardiac function/tissue in non-cardiac cachexia may be a useful component of cachexia assessment common to different underlying diseases and pave the way for novel drug discovery.     

Current pharmacotherapy options for cancer anorexia and cachexia

Introduction: Anorexia and cachexia syndrome represents a complex clinical picture that occurs in the late stage of several chronic inflammatory diseases, including cancer. Unless counteracted cancer-related anorexia and cachexia syndrome affects quality of life (QL) and survival. However, to date a standard effective treatment is lacking.

Areas covered: The aim of this review is to describe the current pharmacological approaches for anorexia and cachexia syndrome, focusing on cancer-related syndrome. The several pharmacological agents tested so far are discussed, distinguishing them in unproven drugs, effective drugs, and drugs under investigation. Moreover, a section is devoted to the promising use of nutritional supplements and nutraceuticals. The emerging role of a multitargeted combined treatment approach is exhaustively reviewed.

Expert opinion: Considering the complex clinical picture and the multifactorial pathogenesis of anorexia and cachexia syndrome, we believe that its clinical management requires a multidisciplinary and multipharmacological approach. In our opinion the anorexia and cachexia syndrome treatment should include drugs that target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, anemia, immunosuppression, and fatigue. The multidimensional therapies for anorexia and cachexia syndrome should ideally be introduced within a context of the “best supportive care,” which includes optimal symptom management and careful psychosocial counseling.     

Inhibiting PAR-1 in the prevention and treatment of atherothrombotic events

Importance of the field: Aspirin, an irreversible inhibitor of thromboxane A₂ production, in combination with clopidogrel, an inhibitor of PY₁₂ ADP platelet receptors, represents the current standard-of-care of antiplatelet therapy for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Although these agents have demonstrated significant clinical benefit, the increased risk of bleeding and the recurrence of thrombotic events represent substantial limitations.

Areas covered in this review: The inhibition of protease-activated receptors (PAR)-1, is the target for novel antiplatelet drugs, which showed a good safety profile in preclinical studies. The drugs most developed are vorapaxar (SCH530348) and atopaxar (E5555), which will be further evaluated in ongoing Phase III and II clinical trials respectively.

What the reader will gain: This review is focused on the current knowledge of PAR-1 antagonists, analyzing the pharmacological and early phase clinical investigation findings on these new drugs.

Take home message: The PAR-1 receptor offers a new target for the inhibition of platelet activation and aggregation. Preliminary results showed the good safety profile of these new agents. The results of the Phase III ongoing trials will provide important clinical insight into the blockade of thrombin-induced platelet activation.     

Advances in pharmacologic strategies for cancer cachexia

Introduction: Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with body weight loss is the main feature of this syndrome.

Areas covered: The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes.

Expert opinion: Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.     

Emerging neuroprotective drugs for the treatment of acute ischaemic stroke

Introduction: Neuroprotection aims to restrict the ischaemic damage following stroke by preventing salvageable neurons from dying. Despite successes in experimental stroke studies, neuroprotective strategies have failed in clinical trials so far. Nevertheless, promising neuroprotective drugs are currently being investigated in clinical trials.

Areas covered: This review provides an overview of the existing treatment of acute ischaemic stroke, discusses current research goals and puts special emphasis on emerging neuroprotective drugs. The authors systematically searched the database Clinicaltrials.gov for ongoing Phase II and Phase III clinical trials of neuroprotective drugs for acute ischaemic stroke. Mechanisms of action of these candidate neuroprotectants and the results of preceding preclinical studies and clinical pilot trials are described.

Expert opinion: In order to facilitate a successful translation from bench to bedside, future experimental studies should follow rigorous quality standards. Recent concepts to overcome the translation roadblock include the implementation of multicentre preclinical Phase III studies, the use of stroke models in non-human primates and the introduction of a preclinical trial registration.     

Update on emerging drugs for cancer cachexia

Cancer cachexia is a complex syndrome that describes the progressive muscle wasting and weakness in many cancer patients. Muscle wasting reduces the ability of affected patients to perform the tasks of daily living and causes severe fatigue, leading to a reduction in quality of life. Cancer cachexia reduces patient response to anti-neoplastic treatments, increases the risk of postoperative complications and accounts for > 20% of cancer-related deaths. The pathogenesis of cancer cachexia is multifactorial and includes anorexia, inflammation, metabolic disturbances and enhanced muscle proteolysis, and each of these presents as a potential therapeutic target for ameliorating cancer cachexia. Objective: This review provides an update on some of the emerging drugs for cancer cachexia. Methods: This is a review of the current status of emerging therapies for cancer cachexia. Results: An increasing number of studies are focused on the development of novel therapies for cancer cachexia. Initial studies concentrated on the treatment of anorexia, but now aim to attenuate inflammation or muscle proteolysis, or to use different drugs in combination so as to treat several aspects of cachexia simultaneously. Conclusions: There are several existing and emerging drugs with the potential to ameliorate cancer cachexia, but the most efficacious treatment will probably come from combined drug therapies.     

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

Introduction: Cachexia is a frequent feature of chronic diseases. This syndrome includes loss of body weight, depletion of skeletal muscle mass and altered metabolic homeostasis. Acceleration of protein and energy metabolism, impaired myogenesis, and systemic inflammation contribute to cachexia. Its occurrence impinges on treatment tolerance and on the quality of life of the patient, however, no effective therapy is available yet.

Areas covered: This review focuses on the use of histone deacetylase inhibitors as pharmacological tools to prevent or delay cachexia, with reference to muscle wasting.

Expert opinion: Novel histone deacetylase inhibitors could be considered as exercise mimetics and this supports their use as a treatment for muscle-wasting associated diseases, such as cachexia. The ability of some of these inhibitors to modulate the release of extracellular vesicles from tumor cells is a potential tool for restricting the development of cancer-induced muscle protein depletion. There are few clinical trials that are testing histone deacetylase inhibitors as a treatment for cachexia; this reflects the lack of robust experimental evidence of effectiveness. The determination of the pathogenic mechanisms of muscle wasting and the identification of suitable histone deacetylase inhibitors that target such mechanisms are necessary.     

Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

ABSTRACT

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis.

Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies.

Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.

Trial registration: ClinicalTrials.gov identifier: NCT03937479.     

An update on bronchodilators in Phase I and II clinical trials

Introduction: Inhaled bronchodilators are the mainstay of the current management of COPD at all stages of the disease, and are critical in the symptomatic management of asthma. Therefore, there is still considerable interest in finding novel classes of broncholytic drugs or, at least, in improving the existing classes of bronchodilator.

Areas covered: This review paper mainly focuses on bronchodilators that are in Phase I and II clinical trials.

Expert opinion: To date, finding new classes of bronchodilators has proved difficult. Consequently, many research groups have sought to improve the existing classes of bronchodytic drugs. The majority of programs in development for novel bronchodilators are focused on developing new ligands that interact with β₂-adrenoceptors and/or muscarinic acetylcholine receptors in a manner that enhances their bronchodilator effectiveness and duration of action, which allows only one administration per day, although the twice-daily dosing of bronchodilators is still considered a useful approach to the symptomatic treatment of COPD, and improving their safety profiles. Moreover, the current opinion is that it is advantageous to develop inhalers containing combinations of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Another goal is to develop novel combinations of one or two classes of long-acting bronchodilators along with inhaled corticosteroids.     

Beyond bevacizumab: new anti-VEGF strategies in colorectal cancer

Introduction: Treatment of colorectal cancer (CRC) has changed dramatically over the past decade, mainly due to the advent of molecularly targeted agents. In particular, an improved understanding of the role of the angiogenesis pathway in CRC has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic CRC (mCRC) and at present is the only antiangiogenesis agent approved for the treatment of this cancer.

Areas covered: In this review, the authors outline the most recent data on the VEGF signaling pathway and on new therapeutic reagents that target it, provide insight into their mechanisms, and describe results from recent clinical trials.

Expert opinion: In the new decade of ‘modern therapy', an increasing number of antiangiogenic agents for the treatment of mCRC are being tested in preclinical models, and dozens of studies on these drugs are ongoing. Presently, eight novel antiangiogenic agents are in Phase III trials and a wide range of other candidates are being tested in Phase I/II trials. Given the preliminary positive results of two recent Phase III trials, aflibercept and regorafenib, probably, will be new-targeted agents approved for the treatment of mCRC. Furthermore, the list of potentially approved agents seems to increase in the next years and to maximize their potential clinical impact, is critically important to introduce efficient molecular diagnostic methodologies into the drug development process to indentify the subset of patients who would benefit most from their use.     

Dimethyl fumarate for multiple sclerosis

Importance of the field: One of the disadvantages of currently available disease-modifying drugs (DMDs) for multiple sclerosis (MS) is their parenteral administration. Moreover, efficacy is only partial. Most patients treated with first-line DMDs do not remain relapse-free. There is a need for new oral drugs that are more effective than currently available compounds. Innovative oral drugs with new mechanisms of action showed promising results in clinical trials. One of these emerging drugs is BG00012 (BG-12), a fumaric acid ester (FAE). Its active agent, dimethyl fumarate had first been included in FAE treatments for psoriasis.

Areas covered in this review: Results that highlight the potential role of BG-12 in MS treatment. We focus on findings of experimental studies and current results of clinical studies with FAE in MS.

What the reader will gain: An overview of the immunomodulatory and neuroprotective effects of FAE, their effect in animal models of MS and their short-term efficacy and safety profile in a Phase IIb clinical trial.

Take home message: BG-12 is a promising emerging treatment for relapsing–remitting MS, combining anti-inflammatory and possibly clinically relevant neuroprotective effects with the convenience of oral administration. However, the future role of BG-12 in treatment of MS will have to be determined after the completion of ongoing Phase III studies.     

Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review

Introduction: Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development.

Areas covered: The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists.

Expert opinion: To enter the market, a newly-developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted.     

New investigational drugs for the treatment of neuropathic pain

Introduction: Neuropathic pain (NP) is a chronic condition that arises from a lesion or dysfunction of the somatosensory nervous system. However, there are several new targets and novel technologies in the pipeline to address this unmet medical need.

Areas covered: In this review, the authors briefly discuss a direction of the development of agents that could be potentially used in NP treatment. Special attention is paid to 1.7-selective voltage-gated sodium channels, N-type voltage-gated calcium channels, angiotensin II (Ang II) AT₂ receptors and nerve growth factor (NGF) as promising targets for new drugs. Furthermore, the article also presents and discusses, in detail, the results of Phase II clinical studies with the AT₂ receptor antagonist ? EMA401 in NP (the results of Phase II clinical trials of other described compounds are not available, yet).

Expert opinion: There is a real hope that new drugs for NP may be available soon. This hope is based on advancing methods of genomics, developing new targets and more efficient drug screening. Some forms of direct influence on voltage-gated ion channels have a place in the treatment of NP, while the development of entirely novel Ang II AT₂ receptor antagonists or NGF inhibitors may be available for many chronic pain sufferers in the foreseeable future.     

Development of novel therapy of schizophrenia in children and adolescents

Introduction: Typical and atypical antipsychotics are efficacious treatments for early-onset schizophrenia (EOS) with very subtle differences in their efficacy. Therefore, when choosing an antipsychotic, the side-effect profile of the individual antipsychotic needs to be taken into account. There is a growing body of neurobiological and genetic evidence for early-onset patients, but these findings have not yet translated into the clinic.

Areas covered: The authors summarize the current treatment options for EOS and discuss the novel treatment options that are under evaluation. The authors focus specifically on Phase II and Phase III clinical trials.

Expert opinion: Currently, there are no truly groundbreaking pharmacological treatment options emerging in EOS. There are several newer antipsychotic agents (iloperidone, lurasidone, asenapine, blonanserin) that are currently in clinical trials. It is unclear whether therapeutic efficacy of any of these agents will be superior or even similar to the existing treatment and the main differentiating factor between individual drugs remains to be their side-effect profile. Beyond these antipsychotics, oxytocin and N-acetylcysteine are the only new pharmacological treatment options that are being evaluated in EOS. Therefore, a major change in the treatment development paradigm is necessary to identify novel and efficacious drugs.     

Emerging drugs for osteoporosis

Introduction: Osteoporotic fracture is a cause of pain, loss of autonomy and excess mortality. Current drugs however, do not allow for a satisfactory non vertebral fracture risk reduction and the compliance is suboptimal.

Areas covered: Current treatments consist of mainly bisphosphonates, denosumabs, selective estrogen receptor modulators and teriparatides. All drugs currently in development will target some aspect of bone remodeling by using the recent advances in our knowledge of bone biology: cathepsin-K inhibitors (odanacatib) are antiresorptive, antisclerostin monoclonal antibodies (romosozumab and blosozumab) are anabolic agents and PTHrp 1-34 (abaloparatide) is an anabolic agent.

Expert opinion: New drugs with better tolerance and ideally with intermittent administration may improve their compliance. New drugs will have to provide higher efficiency levels with regards to reducing the risk of fractures. They may be second-line options, targeted at patients who are poor responders, or those who display contraindications to the older drugs, as a result of cost issues. In addition, some of these new drugs with potent anabolic effect may be confined to niches, for those patients at high risk of refracture after an initial severe fracture such as a hip fracture or a clinical vertebral fracture.     

Epigenetic drug discovery for Alzheimer’s disease

Introduction: It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer’s disease (AD).

Areas covered: This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs.

Expert opinion: Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.     

Investigational drugs for treating anal cancer and future perspectives

Introduction: Anal cancer is a relatively rare malignancy which comprises about 2.5% of all digestive system malignancies in the United States. The majority of cases are squamous cell carcinoma which is closely related to human papilloma virus (HPV) infection. Despite high cure rates with chemoradiation alone, 10 – 20% of patients do develop metastatic disease with little data to guide their treatment.

Areas covered: In this review article, the authors describe the current standard treatment of early and advanced squamous cell carcinoma of the anal canal based on published data. The authors then describe the new approaches to the disease, focusing on new radio sensitizing agents, systemic targeted drugs and immunotherapy.

Expert opinion: The authors believe that current standard treatment options for squamous cell carcinoma of the anal canal are well defined with acceptable results. However the major challenge in the treatment of anal cancer is the lack of randomized or even large single arm Phase II trials due to rarity of the disease, especially in the metastatic disease. But we are slowly making progress. Currently, the most promising areas of research are immunotherapy, targeted therapy and even HPV prevention. We are eagerly anticipating the results of these studies in order to expand the treatment armamentarium.     

The current state of pemetrexed in ovarian cancer

Introduction: The development of preventive treatments for migraine has lagged behind, in part because of limited knowledge about the primum movens of attacks.

Areas covered: We aimed to make a status report about newer preventive drugs for migraine, mainly by reviewing ongoing studies and their potential mechanism of action. An overview of published and unpublished trials was obtained from electronic databases focusing on randomized controlled trials (RCTs) published or initiated during the last 3 years. Drugs inhibiting cortical spreading depression and calcitonin gene-related peptide antagonist, which mainly acts vasoconstrictive, seem promising, but need further exploration. The use of nitric oxide blockers and drugs modifying excitatory brain activity such as glutamate antagonists and newer antiepileptics have so far not been successful. Drugs such as melatonin, vitamin E and botulinum toxins aiming for other targets seem to have no or marginal effect.

Expert opinion: The results from Phase II studies with newer prophylactic drugs for migraine targeting binding sites in the brain are conflicting, but they may have potential for clinical use. No major breakthrough in migraine prevention can be expected from the ongoing trials, but further insight into the effect on migraine subtypes is anticipated.