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2.
Expert Opin Investig Drugs ; 29(2): 125-133, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31899984

RESUMO

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is strongly associated with obesity and insulin resistance. NAFLD refers to a spectrum of disorders ranging from asymptomatic hepatic steatosis (nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), which increases the risk of developing more severe forms of liver disease such as progressive fibrosis, cirrhosis, and liver cancer. Currently, there are no food and drug administration (FDA) approved drugs to treat NASH. Pegbelfermin (BMS-986036) is a PEGylated fibroblast growth factor 21 (FGF21) analogue that is under investigation for the treatment of NASH.Areas covered: We reviewed the (pre)clinical pegbelfermin studies and compared these with other studies that assessed FGF21 and FGF21 analogues in the treatment of NASH.Expert opinion: With no FDA approved treatments available for NASH, there is an urgent need for novel therapies. Pegbelfermin is a systemic treatment with pleiotropic effects on various tissues. Short-term adverse effects are limited, but more research is required to study potential long-term safety issues. In a phase 2a trial, pegbelfermin has shown promising improvements in several NASH related outcomes. However, clinical trials demonstrating long-term benefits on hard outcomes such as liver histology, cirrhosis development, or survival are required for further validation.


Assuntos
Fatores de Crescimento de Fibroblastos/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Animais , Progressão da Doença , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Fatores de Crescimento de Fibroblastos/efeitos adversos , Fatores de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/complicações , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacologia
3.
Expert Opin Investig Drugs ; 29(2): 135-141, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31519114

RESUMO

Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Isobutiratos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Acetil-CoA Carboxilase/antagonistas & inibidores , Animais , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Humanos , Isobutiratos/efeitos adversos , Isobutiratos/farmacologia , Lipogênese/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxazóis/efeitos adversos , Oxazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Triglicerídeos/sangue
4.
Expert Opin Investig Drugs ; 29(1): 33-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31869253

RESUMO

Introduction: Despite current guideline-based, secondary prevention strategies in patients with the acute coronary syndrome, the residual ischemic risk is still at an unacceptable rate, and there is a concomitant high bleeding event rate. These observations mandate investigations of novel treatment strategies to meet the unmet need to improve outcomes in patients with ACS.Areas covered: In this review, the author(s) focus on new agents with ongoing or recently completed phase II trials for the treatment of ACS. We searched MEDLINE and clinicaltrials.org for Phase II trials in ACS patients, and important original investigations are reviewed.Expert opinion: Some of the novel drugs evaluated in the Phase II trials hold promise for future therapies such as AZD5718, anakinra, tocilizumab, CSL112, MEDI 6102, inclisiran, PZ128, selatogrel, and RVX-208. Their efficacy and safety should be evaluated in large scale Phase III trials. The higher cost of the drug will be a major limitation for wide-spread use of novel agents in general practice in future.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/prevenção & controle , Animais , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/efeitos adversos , Humanos , Guias de Prática Clínica como Assunto , Prevenção Secundária/métodos
5.
Expert Opin Investig Drugs ; 28(12): 1095-1100, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31783714

RESUMO

Introduction: Checkpoint kinase 1 (CHK1) inhibitors have been in development for two decades. The initial CHK1 inhibitor staurosporine analog, UCN01, entered clinical trials whilst it was still considered to act via PKC inhibition; only later were trials performed in a more focused fashion to determine whether CHK1 inhibition could dysregulate cell cycle checkpoints. Many of the subsequently synthesized more specific CHK1 inhibitors have failed because of poor PK/PD or cumulative normal tissue toxicities in patients. CHK1 inhibitor monotherapy often demonstrates limited efficacy and in general, must be combined with other agents. The combination of CHK1 inhibitors with modern signaling regulators may be a better therapeutic strategy.Areas covered: This review discusses the history of, and translational use of CHK1 inhibitors; the latest generation of CHK1 inhibitors to enter clinic development are also examined.Expert opinion: Some CHK1 inhibitors can be administered safely, but that when they are combined with traditional cytotoxic DNA damaging agents, the normal tissue toxicities outweigh the very modest gains in therapeutic efficacy. Researchers need to think outside of the box and consider how CHK1 inhibitors can be combined with other signal transduction modulators such as MEK1/2 and PARP1 inhibitors to kill tumor cells.


Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quinase 1 do Ponto de Checagem/metabolismo , Desenvolvimento de Medicamentos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos
6.
Expert Opin Investig Drugs ; 28(12): 1081-1094, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31714807

RESUMO

Introduction: Binge eating disorder (BED) is the most common eating disorder and is frequently associated with psychiatric and medical comorbidities and functional impairment. Although psychological treatments have been the cornerstones of BED treatment, pharmacologic interventions also play an important part of the multimodal management of this condition.Areas covered: This review examines investigational, approved and other pharmacological agents for the treatment of BED. We searched PubMed and clinicaltrials.gov to identify pharmacological interventions for the management of this condition.Expert opinion: BED pharmacological studies have incorporated new drug targets based on our enhanced understanding of the pathophysiology of BED. Neurobiological dysregulation in the reward center and impulse control circuitry and related disturbances in dopamine neurotransmission are among the neurobiological explanations that have been suggested for BED. These mechanisms serve as a pharmacodynamic foundation for the development of new compounds such as lisdexamfetamine (LDX) and dasotraline. Despite these advances, pharmacological trials in BED have numerous challenges that must be overcome. For most compounds studied, larger and more definitive trials is a high priority.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Desenvolvimento de Medicamentos , Drogas em Investigação/administração & dosagem , Animais , Transtorno da Compulsão Alimentar/fisiopatologia , Transtorno da Compulsão Alimentar/psicologia , Dopamina/metabolismo , Drogas em Investigação/farmacologia , Humanos , Recompensa
7.
Expert Opin Investig Drugs ; 28(12): 1101-1112, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31731883

RESUMO

Introduction: The insulin-like growth factors (IGFs) are a family of secreted peptide hormones with important roles in different cellular and organism functions. The biological activities of the IGFs are mediated by the IGF1 receptor (IGF1R), a cell surface, tyrosine kinase-containing heterotetramer that is linked to numerous cytoplasmic signaling cascades. The IGF1R displays potent antiapoptotic, pro-survival capacities and plays a key role in malignant transformation. Research has identified the IGF1R as a candidate therapeutic target in cancer.Areas covered: We offer a synopsis of ongoing efforts to target the IGF axis for therapeutic purposes. Our review includes a digest of early experimental work that led to the identification of IGF1R as a candidate therapeutic target in oncology.Expert opinion: Targeting of the IGF axis has yielded disappointing results in phase III trials, but it is important to learn from this to improve future trials in a rational manner. The potential of anti-IGF1R antibodies and small molecular weight inhibitors, alone or in combination with chemotherapy or other biological agents, should be investigated further in randomized studies. Moreover, the implementation of predictive biomarkers for patient selection will improve the outcome of future trials. Emerging personalized medicine could have a major impact on IGF1R targeting.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Seleção de Pacientes , Receptor IGF Tipo 1/metabolismo
8.
Expert Opin Investig Drugs ; 28(12): 1059-1079, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752565

RESUMO

Introduction: Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering.Areas covered: We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed.Expert opinion: We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being 'optimally' treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/farmacologia , Animais , Doenças Cardiovasculares/etiologia , Desenvolvimento de Medicamentos , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Humanos , Hipertrigliceridemia/complicações , Hipolipemiantes/administração & dosagem , Índice de Gravidade de Doença , Triglicerídeos/sangue
9.
Expert Opin Investig Drugs ; 28(11): 967-975, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31661331

RESUMO

Introduction: The amyloid hypothesis of Alzheimer's disease (AD) states that brain accumulation of amyloid-ß (Aß) oligomers and soluble aggregates represents the major causal event of the disease. Several small organic molecules have been synthesized and developed to inhibit the enzyme (ß-site amyloid precursor protein cleaving enzyme-1 or BACE1) whose action represents the rate-limiting step in Aß production.Areas covered: We reviewed the pharmacology and clinical trials of major BACE1 inhibitors.Expert opinion: In transgenic mouse models of AD, BACE1 inhibitors dose-dependently lower Aß levels in brain and cerebrospinal fluid (CSF) but the evidence for attenuation or reversal cognitive or behavioral deficits is very scanty. In AD patients, BACE1 inhibitors robustly lower plasma and CSF Aß levels and reduce brain plaques but without cognitive, clinical, or functional benefit. To date, seventeen BACE1 inhibitors have failed in double-blind, placebo-controlled clinical trials in patients with mild-to-moderate or prodromal AD, or in cognitively normal subjects at risk of developing AD. Several of these studies were prematurely interrupted due to toxicity or cognitive and behavioral worsening compared to placebo-treated patients. Elenbecestat, the last BACE1 inhibitor remaining in late clinical testing for AD, was recently discontinued due to safety concerns.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Drogas em Investigação/administração & dosagem , Doença de Alzheimer/fisiopatologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Camundongos , Camundongos Transgênicos
10.
Dis Markers ; 2019: 2304931, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583026

RESUMO

Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Cirrose Hepática/diagnóstico , Fígado/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transdução de Sinais/genética , c-Mer Tirosina Quinase/genética , Biomarcadores/sangue , Progressão da Doença , Drogas em Investigação/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Expressão Gênica , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas/sangue , Receptores Proteína Tirosina Quinases/sangue , Transdução de Sinais/efeitos dos fármacos , c-Mer Tirosina Quinase/sangue
11.
Expert Opin Investig Drugs ; 28(11): 941-949, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31590579

RESUMO

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the burden of disease is increasing globally. Until recently, systemic therapies for HCC were limited and prognosis for advanced disease generally poor.Area covered: This article describes some recent phase I and II clinical trials for the treatment of HCC. We performed a search on Pubmed with keywords hepatocellular carcinoma, phase I clinical trial, phase II clinical trial, and immunotherapy. We also searched https://clinicaltrials.gov and identified relevant trials listed as active. Studies in progress or recently reported were conducted using novel therapies based on targets identified through molecular profiling of tumors or based on insights into immune system dysregulation in HCC. We also identified studies using drugs targeting recently discovered biomarkers such as endoglin or aldo-keto reductase 1c3. The major outcomes were safety and efficacy as measured by response rate, progression-free survival or overall survival.Expert opinion: HCC is a heterogeneous disease resulting from aberrations in intracellular signaling and immune system dysregulation. Thus, a multisystem approach will be required to deliver personalized therapy. Combination therapies are likely to be future options; it is also possible that modulation of the microbiome might form part of future treatment paradigms.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Imunoterapia , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Sobrevida
12.
Expert Opin Investig Drugs ; 28(11): 1003-1012, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31607187

RESUMO

Introduction: Generalized anxiety disorder (GAD) is a common and disabling psychiatric condition that affects 3% of the population and exacts significant costs to society if untreated. There are numerous treatment options available, but all have side effects, and none are reliably effective; hence, there is a significant need for new medications.Areas covered: The authors reviewed clinical Phase II and III studies listed on the clinicaltrials.gov and clinicaltrialsregister.eu websites, 2007-present. Additional information was gathered from the study sponsor websites and Pubmed. The categories of mechanisms investigated include: modulators of GABAergic or glutamatergic activity; modulators of monoaminergic systems including serotonin, norepinephrine, and dopamine; and modulators of neuropeptide corticotropin release factor.Expert opinion: There are few investigational drugs in the later stages of clinical development. Challenges include high placebo response rates, enrollment of symptomatic volunteers with minimal depressive and anxiety comorbidity, and the lack of a unifying pathophysiological model. Drug developers should consider implementing trial designs such as sequential parallel comparison design to enhance signal detection. Inclusion of depressive comorbidity may also enhance signal detection by reducing placebo-responsivity. More studies examining glutamate-mediated neuroplasticity in GAD are needed.


Assuntos
Ansiolíticos/administração & dosagem , Transtornos de Ansiedade/tratamento farmacológico , Drogas em Investigação/administração & dosagem , Animais , Ansiolíticos/farmacologia , Transtornos de Ansiedade/fisiopatologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Projetos de Pesquisa
13.
Expert Opin Investig Drugs ; 28(12): 1031-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31623469

RESUMO

Introduction: Brain swelling due to edema formation is a major cause of neurological deterioration and death in patients with large hemispheric infarction (LHI) and severe traumatic brain injury (TBI), especially contusion-TBI. Preclinical studies have shown that SUR1-TRPM4 channels play a critical role in edema formation and brain swelling in LHI and TBI. Glibenclamide, a sulfonylurea drug and potent inhibitor of SUR1-TRPM4, was reformulated for intravenous injection, known as BIIB093.Areas covered: We discuss the findings from Phase 2 clinical trials of BIIB093 in patients with LHI (GAMES-Pilot and GAMES-RP) and from a small Phase 2 clinical trial in patients with TBI. For the GAMES trials, we review data on objective biological variables, adjudicated edema-related endpoints, functional outcomes, and mortality which, despite missing the primary endpoint, supported the initiation of a Phase 3 trial in LHI (CHARM). For the TBI trial, we review data on MRI measures of edema and the initiation of a Phase 2 trial in contusion-TBI (ASTRAL).Expert opinion: Emerging clinical data show that BIIB093 has the potential to transform our management of patients with LHI, contusion-TBI and other conditions in which swelling leads to neurological deterioration and death.


Assuntos
Edema Encefálico/prevenção & controle , Glibureto/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Administração Intravenosa , Animais , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacologia , Glibureto/farmacologia , Humanos , Fármacos Neuroprotetores/farmacologia , Índice de Gravidade de Doença
14.
Expert Opin Investig Drugs ; 28(10): 891-902, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31550938

RESUMO

Introduction: Alpha-1 antitrypsin deficiency (AATD) is most often associated with chronic lung disease, early onset emphysema, and liver disease. The standard of care in lung disease due to AATD is alpha-1 antitrypsin augmentation but there are several new and emerging treatment options under investigation for both lung and liver manifestations. Areas covered: We review therapeutic approaches to lung and liver disease in alpha-1 antitrypsin deficiency (AATD) and the agents in clinical development according to their mode of action. The focus is on products in clinical trials, but data from pre-clinical studies are described where relevant, particularly where progression to trials appears likely. Expert opinion: Clinical trials directed at lung and liver disease separately are now taking place. Multimodality treatment may be the future, but this could be limited by treatment costs. The next 5-10 years may reveal new guidance on when to use therapeutics for slowing disease progression with personalized treatment regimes coming to the forefront.


Assuntos
Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/administração & dosagem , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Animais , Progressão da Doença , Drogas em Investigação/farmacologia , Humanos , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Medicina de Precisão/métodos , Deficiência de alfa 1-Antitripsina/fisiopatologia
15.
Expert Opin Investig Drugs ; 28(10): 835-849, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31510809

RESUMO

Introduction: The incidence of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is increasing with the aging population. Prognosis and overall survival (OS) remain poor in elderly patients and in those not eligible for intensive treatment. Hypomethylating agents (HMAs) have played an important role in this group of patients but their efficacy is limited. Areas covered: This article reviews the mechanism of action, pharmacology, safety profile and clinical efficacy of subcutaneous guadecitabine, a second-generation DNA methylation inhibitor in development for the treatment of AML and MDS. Expert opinion: Although guadecitabine did not yield improved complete remission (CR) rates and OS compared to the control arm in patients with treatment-naïve AML who were ineligible for intensive chemotherapy, subgroup analysis in patients who received ≥4 cycles of therapy demonstrated superior outcomes in favor of guadecitabine. Given its stability, ease of administration, safety profile and prolonged exposure time, guadecitabine would be the more appropriate HMA, replacing azacitidine and decitabine, to be used combination treatment regimens in patients with myeloid malignancies.


Assuntos
Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Prognóstico , Taxa de Sobrevida , Fatores de Tempo
16.
Expert Opin Investig Drugs ; 28(10): 851-860, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31554440

RESUMO

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.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Drogas em Investigação/farmacologia , Humanos , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
17.
Expert Opin Investig Drugs ; 28(9): 799-809, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398295

RESUMO

Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms, which represent approximately 75% of all primary cutaneous lymphomas. Mycosis fungoides and Sézary syndrome are the most common CTCL. Early stage disease follows a protracted course, carries a 5-year disease specific survival of 97% and can be treated with skin-directed therapies. Widespread, advanced disease has a 5-year OS of less than 25% and necessitates systemic treatment. Allogeneic stem cell transplantation is a potentially curative treatment option for advanced CTCL, however, transplant-related morbidity and mortality must be considered and a risk-benefit assessment performed on individual basis. Areas covered: Herein, we provide a review of investigative drugs in early-stage trials for the treatment of cutaneous CTCL, including topically applied immunomodulators such as replicating herpes virus or toll-like receptor 7/8 agonist resiquimod and systemic therapies with monoclonal antibodies, such as anti-CD47, recombinant cytotoxic interleukin 2 fusion protein anti-KIR3DL2 antibody and anti-miR-155 antibody. Expert Opinion: Among the reviewed drugs, resiquimod shows promising clinical efficacy with good tolerability in early CTCL. In refractory or relapsed disease, intratumoral anti-CD47-, anti-CCR4- and anti-KIR3DL2-antibodies show high response rates, however, latter two also show considerable toxicity. Larger trials are needed to better evaluate the discussed therapies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Animais , Antineoplásicos Imunológicos/efeitos adversos , Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Estadiamento de Neoplasias , Síndrome de Sézary/tratamento farmacológico , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Taxa de Sobrevida
18.
Expert Opin Investig Drugs ; 28(9): 757-770, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31412742

RESUMO

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.


Assuntos
Antineoplásicos/farmacologia , Drogas em Investigação/farmacologia , Neoplasias da Bexiga Urinária/terapia , Animais , Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Biomarcadores Tumorais/metabolismo , Cistectomia/métodos , Sistemas de Liberação de Medicamentos , Drogas em Investigação/administração & dosagem , Humanos , Imunoterapia/métodos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/patologia
19.
Expert Opin Investig Drugs ; 28(9): 771-785, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449760

RESUMO

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.


Assuntos
Antineoplásicos/farmacologia , Terapia de Alvo Molecular , Neoplasias Ovarianas/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Drogas em Investigação/farmacologia , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
20.
Expert Opin Investig Drugs ; 28(8): 733-740, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347405

RESUMO

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.


Assuntos
Caquexia/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Neoplasias/complicações , Apetite/efeitos dos fármacos , Caquexia/etiologia , Caquexia/fisiopatologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Apoio Nutricional/métodos , Qualidade de Vida , Projetos de Pesquisa
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