Aurora kinase inhibitor patents and agents in clinical testing: an update (2011 – 2013)

Introduction: Aurora kinase A, B and C, members of serine/threonine kinase family, are key regulators of mitosis. As Aurora kinases are overexpressed in many of the human cancers, small-molecule inhibitors of Aurora kinase have emerged as a possible treatment option for cancer.

Areas covered: In 2009 and 2011, the literature pertaining to Aurora kinase inhibitors and their patents was reviewed. Here, the aim is to update the information for Aurora kinase inhibitors in clinical trials and the patents filed between the years 2011 and 2013. Pubmed, Scopus®, Scifinder®, USPTO, EPO and www.clinicaltrials.gov databases were used for searching the literature and patents for Aurora kinase inhibitors.

Expert opinion: Even though both Aurora sub-type selective as well as pan-selective inhibitors show preclinical and clinical efficacy, so far no Aurora kinase inhibitor has been approved for clinical use. Particularly, dose-limiting toxicity (neutropenia) is a key issue that needs to be addressed. Preliminary evidence suggests that the use of selective Aurora A inhibitors could avoid Aurora B-mediated neutropenia in clinical settings. Also, use of adjunctive agents such as granulocyte stimulating factor to overcome neutropenia associated with Aurora B inhibition could be an answer to overcome the toxicity and bring Aurora inhibitors to market in the future.     

Aurora kinase inhibitor patents and agents in clinical testing: an update (2009 – 10)

Introduction: Mitosis is a key step in the cell cycle and is controlled by several cell cycle regulators, including aurora kinases. Aurora family members A, B and C are essential for spindle assembly, centrosome maturation, chromosomal segregation and cytokinesis. Overexpression/amplification of aurora kinases has been implicated in oncogenic transformation, including the development of chromosomal instability in cancer cells. Hence, the use of aurora kinase small molecule inhibitors as a potential molecular-targeted therapeutic intervention for cancer is being pursued by various researchers.

Area covered: This review provides an update on aurora kinase inhibitors based on developments from 2009 to 2010. The medicinal chemistry aspects of aurora kinase inhibitors, with a particular emphasis on the patent literature, are reviewed. Databases such as PubMed, SCOPUS, Scifinder and www.clinicaltrials.gov database were used to search for literature in the preparation of this review.

Expert opinion: Around a dozen aurora kinase inhibitors are currently undergoing various Phase I – II evaluations for different human cancers. Instead of being applied as a monotherapy, combinations of aurora kinase inhibitors and existing chemotherapeutic compounds seem to give better therapeutic outcomes and are, therefore, a promising future cancer therapy.     

An update on PTEN modulators – a patent review

ABSTRACT

Introduction: A multitude of cellular and physiological functions have been attributed to the biological activity of PTEN (Phosphatase and tensin homolog) such as inhibiting angiogenesis, promoting apoptosis, preventing cell proliferation, and maintaining cellular homeostasis. Based on whether cell growth is needed to be initiated or to be inhibited, enhancing PTEN expression or seeking to inhibit it was pursued.

Areas covered: Here the authors provide recent updates to their previous publication on ‘PTEN modulators: A patent review’, and discuss on new specificities that affirm the therapeutic potential of PTEN in promoting neuro-regeneration, stem cell regeneration, autophagy, bone and cartilage regeneration. Also, targeting PTEN appears to be effective in developing new treatment strategies for Parkinson’s disease, Alzheimer’s disease, macular degeneration, immune disorders, asthma, arthritis, lupus, Crohn’s disease, and several cancer types.

Expert opinion: PTEN mainly inhibits the PI3k/Akt pathway. However, the PI3k/Akt pathway can be activated by other signaling proteins. Thus, novel treatment strategies that can regulate PTEN alone, or combinational treatment approaches that can induce PTEN and simultaneously affect downstream mediators in the PI3K/Akt pathway, are needed, which were not investigated in detail. Commercial interests associated with molecules that regulate PTEN are discussed here, along with limitations and new possibilities to improve them.     

An update on emerging drugs in osteosarcoma: towards tailored therapies?

ABSTRACT

Introduction: Current treatment of conventional and non-conventional high-grade osteosarcoma (HGOS) is based on the surgical removal of primary tumor and, when possible, of metastases and local reccurrence, together with systemic pre- and post-operative chemotherapy with drugs that have been used since decades.

Areas covered: This review is intended to summarize the new agents and therapeutic strategies that are under clinical evaluation in HGOS, with the aim to increase the cure probability of this highly malignant bone tumor, which has not significantly improved during the last 30–40 years. The list of drugs, compounds and treatment modalities presented and discussed here has been generated by considering only those that are included in presently ongoing and recruiting clinical trials, or which have been completed in the last 2 years with reported results, on the basis of the information obtained from different and continuously updated databases.

Expert opinion: Despite HGOS is a rare tumor, several clinical trials are presently evaluating different treatment strategies, which may hopefully positively impact on the outcome of patients who experience unfavorable prognosis when treated with conventional therapies.

Trial registration: ClinicalTrials.gov identifier: NCT01459484.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT00134030.

Trial registration: ClinicalTrials.gov identifier: NCT00180908.

Trial registration: ClinicalTrials.gov identifier: NCT00470223.

Trial registration: ClinicalTrials.gov identifier: NCT01532687.

Trial registration: ClinicalTrials.gov identifier: NCT02357810.

Trial registration: ClinicalTrials.gov identifier: NCT03163381.

Trial registration: ClinicalTrials.gov identifier: NCT02432274.

Trial registration: ClinicalTrials.gov identifier: NCT02048371.

Trial registration: ClinicalTrials.gov identifier: NCT02389244.

Trial registration: ClinicalTrials.gov identifier: NCT02243605.

Trial registration: ClinicalTrials.gov identifier: NCT02867592.

Trial registration: ClinicalTrials.gov identifier: NCT03210714.

Trial registration: ClinicalTrials.gov identifier: NCT03526250.

Trial registration: ClinicalTrials.gov identifier: NCT03213678.

Trial registration: ClinicalTrials.gov identifier: NCT03718091.

Trial registration: ClinicalTrials.gov identifier: NCT03233204.

Trial registration: ClinicalTrials.gov identifier: NCT03698994.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT02689336.

Trial registration: ClinicalTrials.gov identifier: NCT03678883.

Trial registration: ClinicalTrials.gov identifier: NCT01962103.

Trial registration: ClinicalTrials.gov identifier: NCT02945800.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT03598595.

Trial registration: ClinicalTrials.gov identifier: NCT02644460.

Trial registration: ClinicalTrials.gov identifier: NCT02517918.

Trial registration: ClinicalTrials.gov identifier: NCT03002805.

Trial registration: ClinicalTrials.gov identifier: NCT02013336.

Trial registration: ClinicalTrials.gov identifier: NCT02536183.

Trial registration: ClinicalTrials.gov identifier: NCT02557854.

Trial registration: ClinicalTrials.gov identifier: NCT02390843.

Trial registration: ClinicalTrials.gov identifier: NCT03643133.

Trial registration: ClinicalTrials.gov identifier: NCT03006848.

Trial registration: ClinicalTrials.gov identifier: NCT03676985.

Trial registration: ClinicalTrials.gov identifier: NCT03277924.

Trial registration: ClinicalTrials.gov identifier: NCT03190174.

Trial registration: ClinicalTrials.gov identifier: NCT02304458.

Trial registration: ClinicalTrials.gov identifier: NCT02406781.

Trial registration: ClinicalTrials.gov identifier: NCT02502786.

Trial registration: ClinicalTrials.gov identifier: NCT03860207.

Trial registration: ClinicalTrials.gov identifier: NCT03320330.

Trial registration: ClinicalTrials.gov identifier: NCT03610490.

Trial registration: ClinicalTrials.gov identifier: NCT02100891.

Trial registration: ClinicalTrials.gov identifier: NCT02508038.

Trial registration: ClinicalTrials.gov identifier: NCT03356782.

Trial registration: ClinicalTrials.gov identifier: NCT01953900.

Trial registration: ClinicalTrials.gov identifier: NCT03618381.

Trial registration: ClinicalTrials.gov identifier: NCT03462316.

Trial registration: ClinicalTrials.gov identifier: NCT02487979.     

Radiation countermeasure agents: an update (2011 – 2014)

Introduction: Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government.

Area covered: This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period.

Expert opinion: A number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future.     

Tropomyosin receptor kinase inhibitors: a patent update 2009 – 2013

Introduction: Tropomyosin receptor kinases (Trks) are a family of three similar tyrosine kinases activated by peptide hormones of the neurotrophin family. The nerve growth factor antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA pathway in pain. As an alternative modality, small-molecule inhibitors of the Trks have been pursued in recent years to probe the role of these neurotrophin pathways in pain, cancer and other indications.

Areas covered: This paper reviews the patent literature between mid-2009 and 2013, claiming inhibitors of Trk family members as the primary biological targets. Additional patents have been reviewed where Trk is not the main kinase of interest but in which high Trk potency is observed and the chemical matter is particularly noteworthy. Patents pre-dating this period have been reviewed previously. Scifinder and Google were used to find relevant patents and clinical information using Trk or Tropomyosin as the search term.

Expert opinion: Considerable recent progress has been made in the identification of selective pan Trk inhibitors with pharmacodynamic and pharmacokinetic properties appropriate for clinical evaluation. Inhibitors of both active and inactive conformations of the Trks as well as peripherally restricted molecules have been identified. Furthermore, TrkA-selective allosteric inhibitors have recently been disclosed, which enables the biology of this isoform to be probed. The recent identification of a TrkA gene fusion in a subset of lung cancer patients will increase further the attraction of Trk inhibition to the pharmaceutical industry.     

An update on medical management on Crohn’s disease

Introduction: The management of Crohn’s disease (CD) is continuously evolving. New issues emerging from more recent studies could influence the decision-making process in clinical practice.

Areas covered: The aim of this review article is to highlight critical issues on the management of CD, new evidence from clinical trials, long-term prospective studies and real life experience, beyond the current guidelines.

Expert opinion: The role of mucosal healing in clinical practice is uncertain, clinical remission remains the primary end point. The timing for the definition of steroid-resistant CD should be considered between 2 and 4 weeks. Early treatment strategy with immunomodulators is effective for inducing remission but no controlled data are available regarding long-term outcome. Combination therapy (anti-TNFs agents and immunosuppressors) is more effective than single therapy but there is a lack of long-term data and an increased risk of malignancy. The effect of mesalazine, metronidazole and azathioprine in reducing postoperative recurrence is not clinically relevant; biologics are effective, but the duration of treatment is unknown. New drugs are under investigation in order to find exit strategy for patients who no longer respond to biologics. Combination therapy set on anti-TNF-α is until now the best option both to achieve fistula healing and avoid recurrence     

An update on the advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren’t effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn’t necessarily outweigh associated risks.

Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation.

Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.     

Thyromimetics: a review of recent reports and patents (2004 – 2009)

Importance of the field: Thyroid hormones are produced by the thyroid gland and peripheral tissues, and control metabolic rate, including oxygen consumption, lipid metabolism and the cardiovascular system, mainly through binding to and activating thyroid hormone receptors (TRs). Abnormal elevation or lowering of circulating thyroid hormone induces various physiological disorders. As candidates for the treatment of such diseases, various thyromimetics, such as subtype- or tissue-selective TR agonists and antagonists, have been developed.

Areas covered in this review: This review focuses on recent reports and patents covering thyromimetics, especially those published in the last 6 years.

What the reader will gain: In this review, we classify thyromimetics based on structure. The structures of most thyromimetic compounds are based on those of endogenous thyroid hormones, which consist of a biaryl ether skeleton substituted with iodine, α-alanine moiety and hydroxyl group at two benzene rings. Many thyromimetics have been developed by replacement of the polar group, changing the bridging oxygen, or introduction of heterocycles. This review provides an overview of the structure–activity relationship.

Take home message: Some thyromimetics are subtype- or tissue-selective TR agonists and antagonists, and such compounds have the potential to become novel therapeutic agents, especially in the field of metabolic diseases.     

Antibiotic and non-antibiotic tetracycline patents: 2002 – 2007

Background: Infectious diseases in all populations are increasing in frequency and severity as the problem of antibiotic resistance continues to emerge. As other antibiotics become ineffective, it is up to researchers worldwide to create new and more potent compounds to thwart such diseases. Objective: This review presents the recent efforts and patent portfolios of those groups actively engaged in tetracycline research. Methods: The tetracyclines, once studied thoroughly shortly after their discovery > 50 years ago, have been neglected as new sources of scaffolds suitable for producing more potent compounds until recently, where several companies and research institutions have described newer and more potent analogs via semisynthesis or by total synthesis. Furthermore, other useful therapeutic properties of the tetracyclines have also been discovered, primarily as observations from their use as clinical antibiotic agents, in the areas of inflammation, neurodegeneration and diseases characterized by tissue degradation. Results and conclusions: The recent patents pertaining to the synthesis and biological properties indicate that the tetracyclines are undergoing a renaissance as their activities are being revised against prokaryotic organisms and against mammalian disease states related to inflammation.     

An overview on in situ micronization technique – An emerging novel concept in advanced drug delivery

The use of drug powders containing micronized drug particles has been increasing in several pharmaceutical dosage forms to overcome the dissolution and bioavailability problems. Most of the newly developed drugs are poorly water soluble which limits dissolution rate and bioavailability. The dissolution rate can be enhanced by micronization of the drug particles. The properties of the micronized drug substance such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used. Mechanical communition, spray drying and supercritical fluid (SCF) technology are the most commonly employed techniques for production of micronized drug particles but the characteristics of the resulting drug product cannot be controlled using these techniques. Hence, a newer technique called in situ micronization is developed in order to overcome the limitations associated with the other techniques. This review summarizes the existing knowledge on in situ micronization techniques. The properties of the resulting drug substance obtained by in situ micronization were also compared.     

Secretases as therapeutic targets in Alzheimer’s disease: patents 2000 – 2004

This article briefly reviews the biology of the secretase enzymes (α, β and γ) that metabolise the amyloid precursor protein, pathways that are believed to be central to the pathogenesis of Alzheimer’s disease. Therapeutic patents claiming secretase inhibitors or modulators for the treatment of Alzheimer’s disease published over the last 4 years are then considered. Although there are many claims, no agent has yet reached the clinical arena, and the paucity of data provided in the patents makes it difficult to predict which, if any, might do so.     

An update on the safety of long-acting β-agonists in asthma patients using inhaled corticosteroids

Importance of the field: Pooled trial data have shown that long-acting β-agonists increase the risk for asthma hospitalizations and deaths by two to fourfold compared with placebo. Until recently, it was unclear whether concomitant inhaled corticosteroids (ICSs) could eliminate this risk.

Areas covered in this review: This review summarizes the available data on the safety of long-acting β-agonist use in asthma, with and without concomitant ICSs. The results from an updated meta-analysis are presented, with data through December 2008.

What the reader will gain: In pooled trial data, catastrophic asthma events (defined as asthma-related intubation or death) were increased fourfold for concomitant treatment with long-acting β-agonists and ICSs compared with corticosteroids alone (odds ratio 3.7; 95% CI 1.4 – 9.6). It is estimated that the addition of long-acting β-agonists to ICS therapy is associated with an absolute increase of one catastrophic event per 1500 patient-years.

Take home message: When the available trial data are pooled together, it is clear that long-acting β-agonists significantly increase the risk for asthma-related intubations and deaths, even when used in a controlled fashion with concomitant ICSs. Clinical guidelines should readdress the role long-acting β-agonists have in the management of asthma.     

Drugs in the medical treatment of Cushing's syndrome – an update on mifepristone and pasireotide

Introduction: The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing along with the worldwide epidemic of obesity and their strong association with metabolic syndrome. Currently existing pharmacological therapies include anti-oxidants, insulin-sensitizing agents, lipid-lowering drugs and cytoprotective agents, but there is a lack of consensus regarding the most effective and appropriate pharmacologic therapies for NASH. Clinical trials examining new therapeutic drugs for NASH that act via various mechanisms are being performed in several countries, and these drugs may strongly influence current NASH treatment.

Areas covered: This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of NASH.

Expert opinion: Ideally, treatment for NASH should not only improve liver disease, but also reduce the risks of adverse cardiovascular outcomes and the development of diabetes and cancers. However, this goal is likely to be too high in the context of clinical trials designed to obtain approval for the treatment of liver disease. The only way to achieve the goal is to accumulate the results of these relatively short-term clinical trials.     

An update on adverse drug reactions related to β-lactam antibiotics

Introduction: β-lactams have been consistently associated with the majority of drug-related adverse events. Generally, these are mild under proper dosing and judicious selection.

Areas covered: Immediate hypersensitivity reactions are the most feared adverse events encountered after β-lactam administration. Emerging evidence shows that immediate reactions are not as common as previously thought. Specialist consultation and testing seems prudent before a patient is officially declared allergic to β-lactams. The risk of cross-reactions between not only members of the β-lactam super-family but also between specific classes is also lower than previously thought. Newer studies have shown that cross-reactions are not universal and pertain to specific agents with similar side chains or metabolites of the β-lactam core. The frequency of severe kidney or liver toxicity, neurotoxicity, cytopenias and Clostiridium difficile infection following β-lactam administration seem to be agent-specific.

Expert opinion: The currently available data denote that in addition to age, gender, co-morbidity, renal or liver function, and co-administered agents, the antibiotic levels rather than the dose itself seem to be associated with the emergence of adverse events. Most of them subside with time after withdrawal of the offending agent, but the number of cases resulting in chronic disabilities or even deaths in not negligible.     

Pharmacotherapy of alcoholism – an update on approved and off-label medications

Introduction: Only a few medications are available for the treatment of alcohol use disorders (AUDs).

Areas covered: This paper discusses approved AUD medications, including the opioid antagonists naltrexone and nalmefene (the latter is licensed for reduction of alcohol consumption only), the putative glutamate receptor antagonist acamprosate and the aldehyde dehydrogenase inhibitor disulfiram. It also covers off-label medications of interest, including topiramate, gabapentin, ondansetron, varenicline, baclofen, sodium oxybate and antidepressants. Clinical implications, benefits and risks of treatment are discussed.

Expert opinion: Acamprosate, naltrexone, nalmefene and disulfiram are the only approved ‘alcohol-specific’ drugs. Acamprosate and naltrexone have been evaluated in numerous clinical trials and represent evidence-based treatments in AUDs. Nalmefene use, however, is controversial. Supervised disulfiram is a second-line treatment approach. Compounds developed and licensed for different neuropsychiatric disorders are potential alternatives. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence. The GABA (γ-aminobutyric acid)-B receptor agonist baclofen has shown mixed results; it is currently licensed for the treatment of AUDs in France only. Gabapentin may be close to approval in the USA. Further studies of these novel treatment approaches in AUDs are needed.     

Novel 8-heterocyclyl xanthine derivatives in drug development – an update

Naturally occurring methyl xanthines, especially caffeine and theophylline, have been widely investigated for their pharmacological properties as cognition enhancers, bronchodilator agents and mild diuretics. The xanthine core (3,7-dihydro-1H-purine-2,6-dione) has been largely manipulated in the search for selective ligands for different pharmacological targets, proving to be a versatile scaffold for the development of lead compounds in multiple therapeutic areas. The introduction of a heterocycle at the 8-position of some xanthine derivatives demonstrated to be a successful strategy for the identification of potent and selective A₁ or A_2B adenosine receptors antagonists as potential agents for the treatment of Alzheimer's disease and asthma, respectively. Interesting examples of 8-heterocyclyl-xanthines as dipeptidyl peptidase IV inhibitors and liver X receptor agonists have been claimed for their possible therapeutic use in the treatment of Type 2 diabetes and atherosclerosis.     

Pharmacotherapy of bone metastases in breast cancer patients – an update

Introduction: Bone metastases in breast cancer patients are a common clinical problem and pose a threat to the quality of life of such patients. Multiple randomized trials have demonstrated the benefit of both bisphosphonates and denosumab in reducing the incidence and delaying the onset of skeletal related events (SREs) in breast cancer patients with bone metastases.

Areas covered: We review the current literature on the use of bisphosphonates and denosumab along with strategies to maximize benefit and minimize risk of these agents. We also review potential future targets.

Expert opinion: Despite the potent osteoclast inhibiting effects of the bone-targeted agents in current clinical use, we have likely maximized their ability to inhibit SREs and must in turn focus on minimizing their potential toxicity. The future will likely involve more novel treatment strategies as well as the development of new agents. The current ‘one size fits all’ approach for the management of breast cancer bone metastases will be replaced by ‘tailored’ treatment for each individual patient as we usher in the era of ‘personalized medicine.’ In addition, new bone-targeted agents (e.g., sclerostin inhibitors) and combinations will continue to be explored, as will the evaluation of the bone-targeting properties of more conventional non-osteoclast targeting therapies.