Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.

While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.

Ulotaront: A TAAR1 Agonist for the Treatment of Schizophrenia.

Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure-activity relationships.

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action.

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.

Clinical Outcome of Carotid Artery Stenting According to Provider Specialty and Volume.

BACKGROUND: Several studies have demonstrated better outcomes for carotid endarterectomy with high-volume hospitals and providers. However, only a few studies have reported on the impact of operator specialty/volume on the perioperative outcome of carotid artery stenting (CAS). This study will analyze the correlation of CAS outcomes and provider specialty and volume. METHODS: Prospectively collected data of CAS procedures done at our institution during a 10-year period were analyzed. Major adverse events (MAEs; 30-day stroke, myocardial infarction, and death) were compared according to provider specialty (vascular surgeons [VSs], interventional cardiologists [ICs], interventional radiologists [IRs], interventional vascular medicine [IVM]), and volume (≥5 CAS/year vs. <5 CAS/year). RESULTS: Four hundred fourteen CAS procedures (44% for symptomatic indications) were analyzed. Demographics/clinical characteristics were somewhat similar between specialties. MAE rates were not significantly different between various specialties: 3.1% for IC, 6.3% for VS, 7.1% for IR, 6.7% for IVM (P = 0.3121; 6.3% for VS and 3.8% for others combined, P = 0.2469). When physicians with <5 CAS/year were excluded: the MAE rates were 3.1% for IC, 4.7% for VS, and 6.7% for IVM (P = 0.5633). When VS alone were compared with others, and physicians with <5 CAS/year were excluded, the MAE rates were 4.7% for VS vs. 3.6% for non-VS (P = 0.5958). The MAE rates for low-volume providers, regardless of their specialty, were 9.5% vs. 4% for high-volume providers (P = 0.1002). Logistic regression analysis showed that the odds ratio of MAE was 0.4 (0.15-1.1, P = 0.0674) for high-volume providers, while the odds ratio for VS was 1.3 (0.45-3.954, P = 0.5969). CONCLUSIONS: Perioperative MAE rates for CAS were similar between various providers, regardless of specialties, particularly for vascular surgeons with similar volume to nonvascular surgeons. Low-volume providers had higher MAE rates.

Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.

The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat.

Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.

Ten-Year Experience of Vascular Surgeon Management of Iatrogenic Pseudoaneurysms: Do Anticoagulant and/or Antiplatelet Medications Matter?

BACKGROUND: Previous studies examining the natural history of femoral pseudoaneurysms (PSAs) were performed before the current era of anticoagulant and/or antiplatelet therapy. The purpose of our study was to elucidate in a vascular surgeon directed approach to PSAs, the association between medication use and the failure of conservative, observation-only management. METHODS: We retrospectively examined 308 femoral iatrogenic PSAs diagnosed via duplex imaging at our institution during a 10-year time period (2004-2013). Information on PSA characteristics, treatment, and antiplatelet and/or anticoagulant medication usage was obtained. We identified patients who failed observation-only conservation management, with failure defined as the need for delayed treatment because of PSAs triggered by either expansion (≥ 1 cm increase or size enlarging to ≥ 3 cm) and/or persistence (≥ 15 days). RESULTS: Immediate and/or acute treatments of PSAs included 1 ultrasound-guided compression, 14 surgical repairs, and 126 thrombin injections. Of the 167 PSAs initially managed by observation only, 70 (42%) were found by ultrasound imaging to thrombosis spontaneously. An additional 70 (42%) patients had the diagnosis of PSA <3 cm and were managed conservatively with only clinical follow-up. Twenty-seven PSAs (16%) originally managed conservatively required additional treatment because of expansion and/or persistence. Patients receiving dual-antiplatelet therapy had higher rates of failed conservative management (44%) than patients not on dual therapy (9%, P < 0.01). The number of antiplatelet and/or anticoagulant medications used during observation was larger in patients failing conservative management (2.0 ± 0.7) versus patients not requiring additional intervention (1.5 ± 0.7, P < 0.01). CONCLUSIONS: Most of the PSAs initially managed with observation-only did not require additional intervention. However, anticoagulant and/or antiplatelet agents use associated with PSAs required further intervention after failing observation-only management. When observation is the chosen strategy for PSA management, especially in the setting of aggressive antithrombotic and dual-antiplatelet therapy, surveillance is required to ensure proper resolution.

Loss of BAP1 function leads to EZH2-dependent transformation.

The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

Pharmacological evaluation of a novel phosphodiesterase 10A inhibitor in models of antipsychotic activity and cognition.

In this study, we report the pharmacological effects of a novel PDE10A inhibitor, SEP-39. SEP-39 is a potent (1.0nM) inhibitor of human PDE10A in vitro, with good selectivity (>16000-fold) against other PDEs. In an in vivo occupancy study, the RO50 value was determined to be 0.7mg/kg (p.o.), corresponding to plasma and brain exposures of 28ng/mL and 43ng/g, respectively. Using microdialysis, we show that 3mg/kg (p.o.) SEP-39 significantly increased rat striatal cGMP concentrations. Furthermore, SEP-39 inhibits PCP-induced hyperlocomotion at doses of 1 and 3mg/kg (p.o.) corresponding to 59-86% occupancy. At similar doses in a catalepsy study, the time on the bar was increased but the maximal effect was less than that seen with haloperidol. In an EEG study, 3 and 10mg/kg (p.o.) SEP-39 suppressed REM intensity and increased the latency to REM sleep. We also demonstrate the procognitive effects of SEP-39 in the rat novel object recognition assay. These effects appear to require less PDE10A inhibition than the reversal of PCP-induced hyperlocomotion or EEG effects, as improvements in recognition index were seen at doses of 0.3mg/kg and above. Our data demonstrate that SEP-39 is a potent, orally active PDE10A inhibitor with therapeutic potential in a number of psychiatric indications.

EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in Vivo Activity.

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.

Evolution and synthesis of novel orally bioavailable inhibitors of PDE10A.

The design and synthesis of highly potent, selective orally bioavailable inhibitors of PDE10A is reported. Starting with an active compound of modest potency from a small focused screen, we were able to evolve this series to a lead molecule with high potency and selectivity versus other PDEs using structure-based design. A systematic refinement of ADME properties during lead optimization led to a lead compound with good half-life that was brain penetrant. Compound 39 was highly potent versus PDE10A (IC50=1.0 nM), demonstrated high selectivity (>1000-fold) against other PDEs and was efficacious when dosed orally in a rat model of psychosis, PCP-induced hyperlocomotion with an EC50 of 1 mg/kg.

A High-Throughput Mass Spectrometry Assay Coupled with Redox Activity Testing Reduces Artifacts and False Positives in Lysine Demethylase Screening.

Demethylation of histones by lysine demethylases (KDMs) plays a critical role in controlling gene transcription. Aberrant demethylation may play a causal role in diseases such as cancer. Despite the biological significance of these enzymes, there are limited assay technologies for study of KDMs and few quality chemical probes available to interrogate their biology. In this report, we demonstrate the utility of self-assembled monolayer desorption/ionization (SAMDI) mass spectrometry for the investigation of quantitative KDM enzyme kinetics and for high-throughput screening for KDM inhibitors. SAMDI can be performed in 384-well format and rapidly allows reaction components to be purified prior to injection into a mass spectrometer, without a throughput-limiting liquid chromatography step. We developed sensitive and robust assays for KDM1A (LSD1, AOF2) and KDM4C (JMJD2C, GASC1) and screened 13,824 compounds against each enzyme. Hits were rapidly triaged using a redox assay to identify compounds that interfered with the catalytic oxidation chemistry used by the KDMs for the demethylation reaction. We find that overall this high-throughput mass spectrometry platform coupled with the elimination of redox active compounds leads to a hit rate that is manageable for follow-up work.

Current Treatment Strategies for Acute Type B Aortic Dissection.

Acute type B aortic dissection (ATBAD) is a medical emergency that is a common occurrence in patients with atherosclerotic disease. The presentation is usually severe, with tearing pain that radiates to the back, and various levels of end-organ ischemia and malperfusion, even rupture, may occur. Everyone agrees that prompt and aggressive blood pressure control with ß-blockers and nitroprusside is imperative, but when to surgically intervene is still not well characterized. However, the advent of minimally invasive stent graft placement has reshaped our thoughts regarding therapeutic intervention for ATBAD. This review is an attempt to define the current surgical indications for treating ATBAD.

Early results with LifeStent implantation in RESILIENT and non-RESILIENT inclusion criteria patients.

The purpose of our study was to determine outcomes of patients receiving the LifeStent (Bard Peripheral Vascular, Tempe, AZ) for femoropopliteal peripheral arterial disease in real-world academic practice outside the limitations of an industry supported trial. All patients from 2009 to 2012 at our institution who received a LifeStent during endovascular interventions and had follow-up were included. Outcomes evaluated included patency and freedom from limb loss. A total of 166 limbs in 151 patients had the LifeStent implanted in de novo vessels (54% male; 68 ± 12 years). Eighty-percent of limbs did not meet RESILIENT criteria due to Rutherford category >3 (51%), TransAtlantic Inter-Society Consensus II classifications C/ D (51%), zero runoff vessels (6%), or stent location (17%). Primary patency rates were 81% at 6 months and 58% at 12 months with predictors for primary patency loss at 1 year including Rutherford category >3 (HR: 1.8 (95% CI: 1.0-3.1), p = 0.04), tobacco use (HR: 1.8 (95% CI: 1.0-3.3), p = 0.04), and no clopidogrel at discharge (HR: 3.2 (95% CI: 1.6-6.7), p < 0.01). A preintervention Rutherford category >3 predicted 24-month limb loss (HR, 16.0 (95% CI: 2.0-122.0), p < 0.01). The LifeStent is a viable option regardless of the TransAtlantic Inter-Society Consensus II classification; however, critical limb ischemia, current tobacco use, and absence of clopidogrel on discharge predict decreased patency on follow-up.

Femoral pseudoaneurysms after percutaneous access.

The femoral artery has been the primary percutaneous-based arterial access site for coronary artery catheterizations for more than three decades. Noncardiac percutaneous-based procedures have also been performed primarily with femoral access and have increased in number exponentially by vascular specialists in past decades. Groin complications are infrequent in incidence after femoral arterial access for cardiac and peripheral diagnostic and interventional cases, with groin hematomas and pseudoaneurysms being the most common. Until ultrasound-based treatment modalities became the mainstay of treatment, vascular surgeons were the primary specialty managing pseudoaneurysms, but now other specialties also manage these cases. This review outlines the clinical implications and current issues relevant to understanding the ideal treatment strategy for this common complication.

C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) and brain natriuretic peptide (BNP) have been shown to be independent predictors of adverse cardiovascular outcomes and increased risk of secondary interventions or limb loss in patients with peripheral arterial disease (PAD). To assist clinicians in decision-making about treatment approaches and predicting postprocedure mortality and morbidity, we retrospectively examined patients with preprocedure hsCRP and BNP levels who underwent elective angioplasty or stent placement for lower extremity PAD. METHODS: The study period was from January 1, 2007, to December 31, 2012, and patients were included who had angioplasty or stenting for PAD. Minimal required follow-up for study inclusion was at least one postoperative ankle-brachial index, contrast angiography, or duplex imaging of the treated limb. Events of interest included major adverse limb events (MALE), defined as target vessel revascularization, amputation, or disease progression by 1 year, and major adverse cardiovascular events (MACE; stroke, myocardial infarction, or death) by 2 years. Elevated/abnormal values for our biomarkers of interest were established by the upper limits of our institution's clinical laboratory reference range (hsCRP, >0.80 mg/dL; BNP, >100 pg/mL). RESULTS: A total of 159 limbs in 118 patients were included in analysis (42% men; median age [range], 64 [42-87] years). All limbs were symptomatic (Rutherford classification: 1-6). Iliac artery revascularization without other adjunct lower extremity intervention was performed in 60% of the limbs. High hsCRP levels (>0.80 mg/dL) were present in 32 patients (27%) and high BNP values (>100 pg/mL) in 24 patients (20%). Kaplan-Meier analysis with log-rank comparison demonstrated that elevated hsCRP levels were associated with MALE but only in limbs receiving interventions distal to the iliac arteries (P = .005). High BNP levels did not affect MALE rates (P = .821). Conversely, both elevated BNP levels (hazard ratio, 5.6; 95% confidence interval [CI], 2.0-5.8; P = .001) and hsCRP levels (hazard ratio, 2.9; 95% CI, 1.1-7.6; P = .034) predicted MACE at 2 years in the presence of confounders in Cox proportional hazards multivariate analysis. Patients with high preintervention values of hsCRP and BNP were 10.6 times (95% CI, 2.6-42.9; P = .001) more likely to experience MACE than were patients with normal hsCRP and BNP values. CONCLUSIONS: After lower extremity endovascular interventions, elevated preprocedural hsCRP levels are associated with MALE (femoral-popliteal interventions), and elevated levels of hsCRP and BNP are associated with late cardiovascular events.

Splenic artery embolization for the treatment of bleeding gastric varices secondary to splenic vein thrombosis.

Splenic vein thrombosis can lead to gastric varices. Subsequent upper gastrointestinal bleeding may ensue related to the change in venous outflow to the portal system. Vascular surgeons are infrequently asked to assist in the management of this entity. However, with many vascular surgeons providing diverse endovascular-based interventions, understanding catheter-based solutions is imperative. This report presents a case in which arterial embolization was used to treat gastric variceal bleeding.

Predictors of percutaneous access failure requiring open femoral surgical conversion during endovascular aortic aneurysm repair.

OBJECTIVE: To determine predictors of percutaneous (PEVAR) access failure requiring conversion to an open approach (OEVAR) during endovascular aortic aneurysm repair (EVAR). METHODS: A single-center retrospective review of all EVAR patients from January 2009 through June 2011 with multivariate analysis of clinical and anatomic variables that could impact access outcome was conducted. Target vessel calcification was categorized as mild, moderate, or severe based on circumferential calcium arc (<⅓, ⅓ to ½, and >½ respectively), dyslipidemia (defined as low-density lipoprotein >130 mg/dL or receiving lipid lowering medication), and obesity (defined as body mass index [BMI] >30). RESULTS: We investigated 400 access sites for 200 patients who underwent EVAR. The study cohort's characteristics included an average age of 72.8 ± 9.0 years, vessel size of 9.6 ± 1.8 mm, sheath size of 17.1 ± 3.0 Fr, BMI of 27.6 ± 5.3, and estimated glomular filtration rate of 68.5 ± 24.2 mL/min. Comorbidities included dyslipidemia in 129 patients (64.5%) and diabetes in 54 patients (27%). There were 132 OEVAR (66 patients), two mixed OEVAR with contralateral PEVAR (one patient), and 266 (133 patients) PEVAR approaches. Use of PEVAR increased over time (45.5% [2009], 77.8% [2010], and up to 88.5% [2011]; P = .001) while conversions decreased (24.3% [2009], 8.7% [2010], and 4.3% [2011]; P = .001]. More OEVAR patients (35.8%) stayed longer than 3 days compared with 21.1% for PEVAR (P = .028). For the 266 PEVAR approaches, 32 access sites (12.0%) had to be converted. Severely calcified arteries were most predictive of conversion (odds ratio [OR], 36.4; P < .001). Year of procedure (2010; OR, 0.17; P = .001; 2011, OR, 0.20; P = .049), female gender (OR, 3.1; P = .017), moderately calcified arteries (OR, 2.5; P = .085), and age (OR, 2.3 [per decade]; P = .002) were all also significant. Vessel size, sheath size, and BMI were found to be nonsignificant predictors of conversion. CONCLUSIONS: PEVAR was found to be safe, reliable, and feasible. Several factors, including learning curve, vessel calcification, age, and female gender predicted conversion of PEVAR to OEVAR.