Emerging drugs for the treatment of gastrointestinal stromal tumour

Introduction: Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for patients with gastrointestinal stromal tumors (GIST). Unfortunately, resistance to the currently approved TKIs poses a huge challenge, and patients are in need of additional therapeutic options. Fortunately, many novel therapeutic approaches are being tested in treatment of GIST to overcome resistance to the approved TKIs

Areas covered: We performed an extensive literature (PUBMED) search to identify emerging drugs being tested in treatment of GIST in early phase clinical trials. We discuss recent ongoing research and emerging novel inhibitors of KIT and PDGFRA receptors, inhibitors in downstream signaling pathways (mTOR and PIK3 inhibitors), inhibitors of other potential targets including ETV1/MEK, MET, FGFR, IGF1R, histone deacetylase inhibitors, heat shock protein 90 inhibitors, cyclin-dependent kinase inhibitors and immune checkpoint inhibitors in treatment of GIST

Expert opinion: Multiple agents are under evaluation; those that benefit GIST patients with imatinib resistant mutations, or those with benefit in patients refractory to approved agents are most likely to be developed in this disease. The role of immunotherapy for GIST is still investigational.     

Autotaxin inhibitors: a patent review (2012-2016)

Introduction: Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA) and choline. The ATX/LPA axis has received increasing interest in recent years because both the enzyme ATX and the bioactive lipid LPA are involved in various pathological conditions such as tumor progression and metastasis, fibrotic diseases, autoimmune diseases, arthritis, chronic hepatitis, obesity and impaired glucose homeostasis. Thus, a great effort has been devotd in developing synthetic ATX inhibitors as new agents to treat various diseases including cancer and fibrotic diseases.

Areas covered: This review article summarizes the autotaxin inhibitors presented in patent literature from October 2012 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo.

Expert opinion: During the recent years, there has been an intensive effort on the discovery of potent and selective ATX inhibitors. Although various synthetic inhibitors have been developed, only limited studies for their in vivo activity have been reported so far. A decade after the first claim of synthetic ATX inhibitors in 2006, one inhibitor has been in clinical trials for idiopapthic pulmonary fibrosis. The use of ATX inhibitors seems an attractive strategy to produce novel medicinal agents, for example anticancer agents.     

Promising therapies for the treatment of chronic lymphocytic leukemia

Introduction: The combination schedule of fludarabine, cyclophosphamide and rituximab is the gold standard of therapy for younger, physically fit chronic lymphocytic leukemia (CLL) patients; it allows achieving high and durable complete response rates. Although treatment outcome has considerably improved with chemo-immunotherapy, most patients eventually relapse and CLL is still incurable. Thus, newer and more rationally developed drugs are needed to improve CLL therapy, particularly in cases of relapsed/refractory disease.

Areas covered: The authors review preclinical and clinical data regarding newer CLL agents, currently undergoing examination, such as: signal transduction and cyclin-dependent kinase inhibitors, immunomodulatory agents, B-cell lymphoma 2 inhibitors, next generation mAbs, heat shock protein 90 and histone deacetylase inhibitors, and chimeric antigen receptor T-cell therapy.

Expert opinion: Newer compounds with different mechanisms of action, such as B-cell receptor signal transduction inhibitors, lenalidomide, next generation mAbs and several pro-apoptotic molecules, have shown efficacy in relapsed or refractory CLL patients. Several studies are under way to investigate the efficacy of combinations of these novel drugs. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will change the therapeutic approach in the near future and will pave the way for a long-term control of CLL.     

A synopsis of drugs currently in preclinical and early clinical development for the treatment of benign prostatic hyperplasia

Introduction: Benign prostatic hyperplasia (BPH) is a common disease among men and significantly impacts quality of life by causing lower urinary tract symptoms (LUTS). Current medical therapies are not always adequate in controlling LUTS or slowing disease progression, and there is unmet need for new effective therapeutic options.

Areas covered: The authors review the standard current medical therapies for BPH which include the use of α-1 blockers, 5-α reductase inhibitors, combination therapy and PDE inhibitors. Following this, the authors then discuss new therapies that are currently undergoing preclinical and clinical investigation.

Expert opinion: Existing preclinical and clinical trials have highlighted many promising therapies to treat BPH. Further investigation with larger clinical trials is needed to establish these drugs as standard therapies. As the number of drugs in the arsenal against BPH continues to grow, providers and patients will have to engage in a discussion that weighs the risks and benefits of each therapy.     

HIV integrase inhibitors: a new era in the treatment of HIV

Introduction: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming ‘standard’ drugs in the treatment of both naïve as well as heavily pretreated individuals with HIV.

Areas covered: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.

Expert opinion: Due to their outstanding data of efficacy, tolerability, safety – shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals – INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.     

PARP inhibitors as antitumor agents: a patent update (2013-2015)

Introduction: PARP inhibitors have been extensively explored as antitumor agents and have shown potent efficacy both in vitro and in vivo. They can be used in monotherapy under the synthetic lethality concept or in combination with radiotherapy or chemotherapy, inducing a synergistic effect.

Areas covered: This review covers relevant efforts in the development of PARP inhibitors with a particular focus on recently patented PARP inhibitors, combination therapy involving PARP inhibitors, tumor responsiveness to PARP inhibitors as detailed in reports made from 2013 – 2015, and PARP drugs in clinical trials and other novel inhibitors that emerged in 2013 – 2015.

Expert opinion: Clinical studies and applications of PARP inhibitors as antitumor agents have gained considerable recognition in the last few years. In addition to FDA-approved olaparib, an increasing number of new inhibitors have been designed and synthesized, some of which are under preclinical or clinical evaluation. Novel inhibitors are still required, especially new scaffold compounds or drugs with improved properties, such as higher selectivity, higher potency and lower toxicity. The development of combination therapies involving PARP inhibitors and the exploration of biomarkers to predict outcomes with PARP inhibitors would expand the applications of these inhibitors, allowing more patients to benefit from this promising class of drugs in the future.     

Cathepsin B and L inhibitors: a patent review (2010 - present)

Introduction: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad-spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L.

Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present.

Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents.     

New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors,stromal modifiers and conjugated therapies

Introduction: Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options.

Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future.

Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.     

An update in treatment options for multiple myeloma in nontransplant eligible patients

Introduction: Despite the fact that multiple myeloma (MM) is still an incurable disease, the outcome of patients who are eligible and ineligible for high-dose therapy has dramatically improved with the introduction of novel agents, that is proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). However, this improvement is often not seen in elderly patients (above 75 years).

Areas covered: This review will focus on the impact of known prognostic factors in elderly MM patients, and risk factors to identify frail elderly patients. Furthermore, data on known and novel PIs and IMiDs, as well as data on other promising novel treatment strategies, chosen based on current practice and anticipated timely approval, will be discussed. Novel treatment strategies include the use of monoclonal antibodies, such as elotuzumab, daratumumab, SAR650984 and more targeted therapies, such as histone deacetylase inhibitors, kinesin spindle protein inhibitors, and selective inhibitors of nuclear export.

Expert opinion: Besides efficacy of treatment, toxicity and quality of life play an important role in treatment choice. Treatment and treatment dosing for the frail elderly as well as risk factors to identify the frail elderly require further consideration, as these patients frequently do not benefit from these novel agents due to early discontinuation of treatment due to toxicity.     

Class act: safety comparison of approved tyrosine kinase inhibitors for non-small-cell lung carcinoma

Introduction: The past decade has seen the development and widespread use of tyrosine kinase inhibitors (TKIs) targeting a mutated EGFR (mEGFR) for the treatment of metastatic NSCLC. We discuss the main properties of the TKIs currently recommended for the treatment of mEGFR NSCLC: gefitinib, erlotinib and afatinib.

Areas covered: The mechanism of action, pharmacodynamics and pharmacokinetics of these drugs, with emphasis on the historical context of their preclinical and clinical development, will be covered, including potential resistance mechanisms to these first-generation TKIs that has driven the trial design for second and third generations of EGFR inhibitors. Six Phase III clinical trials comparing these three TKIs with cisplatin-based chemotherapy upfront for mEGFR NSCLC provide the basis for the comparative safety and toxicity analysis between these agents. Class-related toxicity of these EGFR inhibitors, including life-threatening effects, will be discussed.

Expert opinion: Toxicity and safety analysis from the Phase III trials of these agents in mEGFR populations suggests that afatinib has more frequent and severe side effects. Given that an efficacy advantage has not yet been demonstrated for afatinib over erlotinib and gefitinib, the consistent class toxicity profile of these agents means that gefitinib and erlotinib are a safer first-line treatment recommendation.     

Emerging drugs for alopecia areata: JAK inhibitors

Introduction: Alopecia Areata is a common form of non-scarring hair loss that usually starts abruptly with a very high psychological impact. Due to the still not completely understood etiopathogenesis, at present there is no treatment that can induce a permanent remission and there is no drug approved for the treatment of this disorder.

Areas covered: Leading existing treatment are briefly overviewed and then ongoing research on Janus Kinases Inhibitors is discussed, reviewing trials with oral and topical formulations so as new opportunities for other forms of alopecia, such as cicatricial alopecia.

Expert opinion: JAK inhibitors represent a promise among alopecia treatments, but further studies are needed on long term safety. There is still no validated dosage for alopecia areata and the vehicles used for topical formulations seem not yet ideal in terms of skin penetration and reduced systemic absorption. Hopefully several studies are ongoing and we hope, in the near future, that JAK inhibitors will become part of the armamentarium to treat alopecia areata patients in terms of safety and costs.     

Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings

Introduction: There are considerable interests in the development of novel small-molecule CD73 inhibitors for the treatment of cancers, autoimmune diseases, precancerous syndromes, and other diseases associated with CD73 activity.

Areas covered: The application claims novel substituted benzothiadiazine derivatives as CD73 inhibitors for the treatment of cancer, precancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Many of the exemplified compounds have pIC50 values between 5 to 8.4 against CD73.

Expert Opinion: These benzothiadiazine derivatives provide good leads for the discovery of potent CD73 inhibitors for the treatment of cancer and other diseases mediated by adenosine and its action on adenosine receptors.     

Pharmacotherapy for treating metastatic clear cell renal cell carcinoma

Introduction: Over the past decade metastatic renal cell carcinoma (RCC) treatment landscape has dramatically evolved from the era of cytokines-based immunotherapy (which benefited very few patients, at the expenses of high toxicities) to the present era of targeted agents and novel immunotherapeutics, greatly improving the prognosis of our patients.

Areas covered: Here we have reviewed the present status of the medical treatment of metastatic RCC. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for the relevant trials coducted so far.

Expert opinion: Despite all the advances made in these relatively few years, further improvements are needed, since none of the available agents proved able to cure even a sigle metastatic RCC patient. In particular, advances are awaited from the results of ongoing trial of combinations of different immune checkpoint inhibitors and of immune checkpoint inhibitors with anti-VEGF/VEGFRs agents. Furthermore, a better understanding of the molecular escape pathways used by the tumor to overcome VEGFR blockade or immune activation will hopefully bring soon to the clinic more active, tailored treatments, to be used in second line and beyond.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.     

Can binimetinib,encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Introduction: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations.

Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT.

Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.     

A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017

Introduction: Butyrylcholinesterase (BuChE) has obtained a renewed interest as therapeutic target in Alzheimer’s disease (AD), when changes in BuChE activity and expression along disease progression were highlighted as well as correlation between BuChE levels and cognitive function.

Areas covered: During the last eight years, fourteen patents on BuChE inhibitors (BuChEI) have been submitted. Only three of them relate to BuChE selective inhibitors, while four of them focus on multitarget inhibitors which address different key pathological factors other than BuChE. Two patents report on non-selective acetylcholinesterase (AChE)/BuChE inhibitors, while four patents deal with natural compounds and their derivatives. One patent relates to antitoxic agents to treat exposure to ChEI pesticides and nerve agents.

Expert opinion: Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well-known AChE. However, hitting a single pathological target is likely not sufficient to halt the disease progression. Therefore, patented BuChE inhibitors with a multifunctional profile may open new therapeutic avenues, since the additional activities could reinforce the therapeutic effects. Unfortunately, in vivo studies are limited and key parameters, such as ADMET data, are missing. This lack of information makes difficult to forecast the development of patented BuChEIs into effective drug candidates.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

Infection risk associated with anti-TNF-α agents: a review

Introduction: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases.

Areas covered: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events.

Expert opinion: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitor treatment. Finally, patients who are at high risk of herpes zoster (HZ) reactivation would benefit from a second vaccination in adulthood when receiving TNF-α inhibitors.