Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer.

BACKGROUND: In a previous phase 3 trial, treatment with trifluridine-tipiracil (FTD-TPI) prolonged overall survival among patients with metastatic colorectal cancer. Preliminary data from single-group and randomized phase 2 trials suggest that treatment with FTD-TPI in addition to bevacizumab has the potential to extend survival. METHODS: We randomly assigned, in a 1:1 ratio, adult patients who had received no more than two previous chemotherapy regimens for the treatment of advanced colorectal cancer to receive FTD-TPI plus bevacizumab (combination group) or FTD-TPI alone (FTD-TPI group). The primary end point was overall survival. Secondary end points were progression-free survival and safety, including the time to worsening of the Eastern Cooperative Oncology Group (ECOG) performance-status score from 0 or 1 to 2 or more (on a scale from 0 to 5, with higher scores indicating greater disability). RESULTS: A total of 246 patients were assigned to each group. The median overall survival was 10.8 months in the combination group and 7.5 months in the FTD-TPI group (hazard ratio for death, 0.61; 95% confidence interval [CI], 0.49 to 0.77; P<0.001). The median progression-free survival was 5.6 months in the combination group and 2.4 months in the FTD-TPI group (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.54; P<0.001). The most common adverse events in both groups were neutropenia, nausea, and anemia. No treatment-related deaths were reported. The median time to worsening of the ECOG performance-status score from 0 or 1 to 2 or more was 9.3 months in the combination group and 6.3 months in the FTD-TPI group (hazard ratio, 0.54; 95% CI, 0.43 to 0.67). CONCLUSIONS: Among patients with refractory metastatic colorectal cancer, treatment with FTD-TPI plus bevacizumab resulted in longer overall survival than FTD-TPI alone. (Funded by Servier and Taiho Oncology; SUNLIGHT ClinicalTrials.gov number, NCT04737187; EudraCT number, 2020-001976-14.).

Efficacy and Safety of Trifluridine/Tipiracil-Containing Combinations in Colorectal Cancer and Other Advanced Solid Tumors: A Systematic Review.

We performed a systematic literature review to identify and summarize data from studies reporting clinical efficacy and safety outcomes for trifluridine/tipiracil (FTD/TPI) combined with other antineoplastic agents in advanced cancers, including metastatic colorectal cancer (mCRC). We conducted a systematic search on May 29, 2021, for studies reporting one or more efficacy or safety outcome with FTD/TPI-containing combinations. Our search yielded 1378 publications, with 38 records meeting selection criteria: 35 studies of FTD/TPI-containing combinations in mCRC (31 studies second line or later) and 3 studies in other tumor types. FTD/TPI plus bevacizumab was extensively studied, including 19 studies in chemorefractory mCRC. Median overall survival ranged 8.6-14.4 months and median progression-free survival 3.7-6.8 months with FTD/TPI plus bevacizumab in refractory mCRC. Based on one randomized and several retrospective studies, FTD/TPI plus bevacizumab was associated with improved outcomes compared with FTD/TPI monotherapy. FTD/TPI combinations with chemotherapy or other targeted agents were reported in small early-phase studies; preliminary data indicated higher antitumor activity for certain combinations. Overall, no safety concerns existed with FTD/TPI combinations; most common grade ≥ 3 adverse event was neutropenia, ranging 5%-100% across all studies. In studies comparing FTD/TPI combinations with monotherapy, grade ≥ 3 neutropenia appeared more frequently with combinations (29%-67%) vs. monotherapy (5%-41%). Discontinuation rates due to adverse events ranged 0%-11% for FTD/TPI plus bevacizumab and 0%-17% with other combinations. This systematic review supports feasibility and safety of FTD/TPI plus bevacizumab in refractory mCRC. Data on non-bevacizumab FTD/TPI combinations remain preliminary and need further validation.

Phase 1 study of safety and tolerability of an oral contraceptive containing low-dose ethinyl oestradiol combined with glecaprevir/pibrentasvir treatment in healthy premenopausal women.

Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.

Daridorexant treatment for chronic insomnia: a real-world retrospective single-center study.

INTRODUCTION: Chronic insomnia disorder (CID) significantly impacts well-being and daily functioning. Daridorexant, a double orexin receptor blocker, has shown efficacy in randomized clinical trials and has been recently approved for the treatment of CID in adult patients. This retrospective observational study aimed to describe real-world data on daridorexant effectiveness and safety in adult patients with CID. METHODS: Consecutive patients initiating on-label daridorexant at the Sleep Medicine Centre, University Hospital of Rome Tor Vergata were enrolled. Baseline and 30-day follow-up (FU) evaluations included patients' and CID characteristics, comorbidities, and clinicians' and patients' subjective ratings of changes with the Clinical and Patient Global Impression-Improvement scores (CGI-Is and PGI-Is), as well as Insomnia Severity Index (ISI) scores in a subgroup of patients. RESULTS: Sixty-nine patients initiated 50-mg daily dosage. At FU, 58% of both patients and clinicians rated CID as improved on CGI-Is and PGI-Is, with no differences based on comorbidities, sex, or number of previous medications. No significant predictors of CGI-Is and PGI-Is improvement were identified. At FU, ISI scores (n = 24) significantly decreased from 18.25 ± 3.21 to 12.08 ± 6.12 (Z = 8.000; p < 0.001). Of these, eight patients (33.3%) had absence of insomnia symptoms, and no patients reported a worsening in ISI score categories. CONCLUSIONS: This study suggests daridorexant to be effective and safe in real-world CID treatment whether used as a first-ever treatment, switch, or add-on, as reflected by subjective and objective measures and the absence of serious treatment-related adverse events. Future research on larger cohorts should explore daridorexant potential across diverse patient characteristics.

Usage of vildagliptin among patients with type 2 diabetes mellitus attending a public primary healthcare clinics in Kuala Selangor District, Selangor.

INTRODUCTION: Studies showed that vildagliptin can lower HbA1c levels by 0.8%-1%. However, there is limited data looking at vildagliptin use among suburban populations. The efficacy of vildagliptin use may differ among different populations, especially those with low socio-economic status. Thus, this study aimed to assess the HbA1c reduction after vildagliptin initiation, treatment patterns and the reason for its initiation among patients with type 2 diabetes mellitus attending outpatient clinics in Kuala Selangor District, Selangor. MATERIALS AND METHODS: This is a cross-sectional, retrospective study design. All patients who received vildagliptin in the Pharmacy Integrated Health System (PHIS) registry database from 2016 to 2021 were included as study samples. The exclusion criteria were being less than 18 years old and having type 1 diabetes mellitus. Patients' medical records were retrieved after sampling, and data were collected. One medical record was missing, thus SPSS analysis were performed on 144 vildagliptin users. RESULTS: In total, 84 females (58.3%) and 60 males (41.7%) with a mean age of 62.1 (±10.1) years were analysed in this study. Mean HbA1c pre-therapy was 8.5 ± 2.1%; while posttherapy 6 months demonstrated a mean HbA1c of 7.9 ± 1.8%. Use of vildagliptin alone or as an adjunct was associated with a mean reduction of 0.6% in HbA1c (p = 0.01). Factors influencing this HbA1c reduction were advancing age, specifically individuals aged 62 years and older (p = 0.02), patients who are already receiving insulin therapy (p=0.00) and those who express a willingness to commence insulin treatment during the counselling session prior to initiating the treatment plan (p = 0.00). Reasons for vildagliptin initiation documented by prescribers were non-insulin acceptance (n = 59, 40.97%), frequent hypoglycaemia (n = 6, 4.1%) and non-compliance with medications (n = 23, 15.9%). There was no association between demographic, medical background and reason for starting vildagliptin variables and HbA1c reduction (p < 0.001). CONCLUSION: This study showed that initiating vildagliptin alone or as an adjunct therapy significantly reduced HbA1c and is beneficial for uncontrolled diabetes patients. While advancing age, concurrent administration of insulin and the patients' willingness to accept insulin treatment prior to the commencement of therapy were the factors that influenced HbA1c reduction among patients receiving vildagliptin therapy, we recommend primary care providers prioritise all of the significant variables discovered before initiating vildagliptin for their patients.

Effectiveness, safety and quality of life of trifluridine/tipiracil in pretreated patients with metastatic colorectal cancer: Real-world data from the noninterventional TACTIC study in Germany.

The prospective, multicenter, noninterventional TACTIC study assessed effectiveness and safety of trifluridine/tipiracil (FTD/TPI) in patients with metastatic colorectal cancer (mCRC) in a real-world setting in Germany, thus evaluating the external validity of the findings from the pivotal RECOURSE trial. Primary endpoint was overall survival (OS). Secondary objectives included progression-free survival (PFS), safety, and quality of life (QoL). Subgroups comprised patients with good (<3 metastatic sites at inclusion, ≥18 months from diagnosis of first metastasis to inclusion) or poor (remaining patients) prognostic characteristics (GPC/PPC). GPC without liver metastases was considered best prognostic characteristics (BPC). In total, 307 eligible patients (pretreated or not suitable for other available therapies) were treated with FTD/TPI. Overall, median [95%-CI] OS was 7.4 months [6.4-8.6], median PFS was 2.9 months [2.8-3.3]. In BPC (n = 65) and GPC (n = 176) compared to PPC (n = 124) subgroup, median OS (13.3 [9.1-17.6] vs 8.9 [7.6-9.8] vs 5.1 [4.4-7.0] months) and median PFS (4.0 [3.3-5.3] vs 3.4 [3.0-3.7] vs 2.6 [2.4-2.8] months) were longer. Patient-reported QoL, assessed by validated questionnaires (EQ-5D-5L, PRO-CTCAE), was stable throughout FTD/TPI treatment. Predominant FTD/TPI-related adverse events of grades 3 or 4 were neutropenia (13.0%), leukopenia (7.5%), and anemia (5.2%). Altogether, palliative FTD/TPI therapy in patients with pretreated mCRC was associated with prolonged survival, delayed progression, maintained health-related QoL, and manageable toxicity. Low metastatic burden and indolent disease were favorable prognostic factors for survival. TACTIC confirms the effectiveness and safety of FTD/TPI, highlighting its value in routine clinical practice.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1.

PURPOSE: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1. METHODS: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT). RESULTS: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naïve patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naïve patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naïve patients and remained moderate in ERT-switch patients. MIP-1ß (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naïve patients and remained in the healthy reference range among ERT-switch patients. CONCLUSION: These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naïve and ERT-switch patients.

Analysis of neutropenia as a predictive factor of the efficacy of trifluridine-tipiracil treatment.

OBJECTIVES: Trifluridine-tipiracil (TAS-102), an oral cytotoxic agent used in adult patients with refractory metastatic colorectal cancer (mCRC), has been associated with neutropenia (chemotherapy-induced neutropenia) (CIN)). MATERIALS AND METHODS: We evaluated the efficacy and safety of TAS-102 in a group of 45 mCRC patients (median age 66 years) in Huelva province, Spain, in a retrospective, multicenter observational study. RESULTS: We showed that the association between TAS-102 and CIN can be used as a predictor of efficacy. 20% (9/45) of patients with an Eastern Cooperative Oncology Group (ECOG) score of 2 had received at least one previous chemotherapy treatment. Overall, 75.5% (34/45) and 28.9% (13/45) had received anti-VEGF and anti-EGFR monoclonal antibodies, respectively. Additionally, 80% (36/45) of patients had received third-line treatment. The mean treatment period, duration of overall survival (OS), and duration of progression-free survival (PFS) were 3.4, 12, and 4 months, respectively. A partial response was seen in 2 patients (4.3%), and disease stabilization was observed in 10 patients (21.3%). Neutropenia was the most frequent grade 3 - 4 toxicity (46.7%; 21/45). Other findings were anemia (77.8%; 35/45), all grades of neutropenia (73.3%; 33/45), and gastrointestinal toxicity (53.3%; 24/45). The dose of TAS-102 needed to be reduced in 68.9% (31/45) of patients, whereas treatment needed to be interrupted in 80% (36/45) of patients. Grade 3 - 4 neutropenia was a positive prognostic factor for OS (p = 0.023). CONCLUSION: A retrospective evaluation shows that grade 3 - 4 neutropenia is an independent predictor of treatment response and survival in patients undergoing routine treatment for mCRC, but this finding needs confirmation in a prospective study.

Effects of short-term treatment with vibegron for refractory nocturnal enuresis.

BACKGROUND: Long-term nocturnal enuresis treatment leads to stress and lowered self-esteem for children and their parents. This study evaluated the short-term effectiveness and safety of vibegron (50 mg) for children with refractory nocturnal enuresis. METHODS: A retrospective cohort study of children with therapy-resistant enuresis was conducted using data for July to December 2019. Enuresis frequency was recorded during 30 days before and after additional vibegron administration with prior treatment. We assessed the treatment effectiveness based on enuresis frequencies between before and after treatment with vibegron 50 mg. Statistical evaluation was performed using a paired t-test. RESULTS: Among 29 children receiving vibegron, 14 (48.3%) exhibited a partial or complete response to the drug. Enuresis frequencies (mean ± standard deviation [SD]) were, respectively, 15.8 ± 9.2 and 9.5 ± 9.6 before and after treatment with vibegron during the observed 30 days. A statistically significant reduction in enuresis frequency was found (p < 0.001). Moreover, maximum mean±SD morning urine of 200 ± 62.9 mL before treatment with vibegron changed to 232 ± 76.6 mL after treatment. A significant increase in voiding volume in the early morning was found (p < 0.05). No drug-related severe adverse event was found. CONCLUSION: Short-term treatment with vibegron is safe and effective for children with refractory enuresis.

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study.

BACKGROUND AND AIMS: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years. APPROACH AND RESULTS: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults. CONCLUSIONS: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP ("flakka") Derivatives.

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

Monitoring FTD in the peripheral blood mononuclear cells of elderly patients with metastatic colorectal cancer administered FTD plus bevacizumab as first-line treatment.

Trifluridine/tipiracil (FTD/TPI) is an orally administrated anticancer drug with efficacy validated for patients with metastatic colorectal cancer (mCRC) or gastric cancer. FTD, a key component of FTD/TPI, exerts antitumor effects via its incorporation into DNA. Using specific antibodies against bromodeoxyuridine, FTD incorporation into DNA is detected in tumors and peripheral blood mononuclear cells (PBMC) of patients with mCRC who are administered FTD/TPI. The proportion of FTD-positive PBMC fluctuates according to the schedule of treatment, although the association between the proportion of FTD-positive PBMC and the clinical outcomes of patients is unknown. To answer this question, here we monitored the FTD-positive PBMC of 39 elderly patients with mCRC enrolled in KSCC1602, a single-arm phase 2 trial of FTD/TPI plus bevacizumab as a first-line treatment, for 1 month, during the first cycle of treatment. The median values and interquartile ranges of the percentage of FTD-positive PBMC on days 8, 15, and 29 were 39.3% (30.7%-52.2%), 66.9% (40.0%-75.3%), and 13.5% (5.7%-26.0%), respectively. Receiver operating characteristic analysis revealed that the percentage of FTD-positive PBMC on day 8 (the end of the first week of treatment) had moderate ability to accurately diagnose the occurrence of severe neutropenia and leukopenia within 1 month (area under the curve = 0.778 [95% confidence interval, 0.554-0.993]). This result suggests that excess FTD incorporation into PBMC at the initial phase of FTD/TPI plus bevacizumab treatment is a risk factor for early onset of severe hematological adverse events.

Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study.

Milademetan (DS-3032, RAIN-32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2-p53 interaction. This phase I, dose-escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle. Dose-limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once-daily 21/28-day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI-142693.

A phase 1b expansion study of TAS-102 with oxaliplatin for refractory metastatic colorectal cancer.

BACKGROUND: TAS-102, a novel antimetabolite, is approved for treatment of refractory metastatic colorectal cancer (CRC). This study sought to determine whether the addition of TAS-102 to oxaliplatin (TAS-OX) was safe and effective in metastatic CRC previously treated with oxaliplatin. METHODS: This investigator-initiated, open-label, single-arm phase 1b study enrolled patients with metastatic CRC previously treated with 5-fluorouracil, irinotecan, and oxaliplatin. In dose escalation, TAS-102 was given at 3 dose levels: 25, 30, and 35 mg/m2 twice daily on day 1 to day 5 with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. The primary endpoint of dose escalation was the recommended dose for expansion, and in dose expansion, the primary endpoint was overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Forty-one patients were treated with TAS-OX. No dose-limiting toxicities were observed in the 11 patients treated in escalation. The recommended dose for expansion was 35 mg/m2 TAS-102 twice daily on day 1 to day 5 in combination with 85 mg/m2 oxaliplatin on day 1 in 14-day cycles. In the intention-to-treat population, the ORR was 2.4% (95% CI, 0%-12.9%) with 1 of 41 patients having a partial response, although 12 (29%) had tumor shrinkage. The median progression-free survival was 2.7 months (95% CI, 2.4-4.8 months) and median overall survival was 6.8 months (95% CI, 5.7-10 months). CONCLUSIONS: TAS-OX is safe with no unexpected toxicities at standard doses of each agent. The combination did not result in a clinically meaningful ORR, although progression-free survival and overall survival were encouraging in this heavily pretreated population. LAY SUMMARY: For metastatic colorectal cancer, the treatment combination of TAS-102 and oxaliplatin was found to be well-tolerated and revealed no unexpected side effects. Twelve of 41 patients had reductions in the size of their tumor, and the study treatment delayed the time to tumor growth as opposed to what would be expected.

Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.

VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.

BACKGROUND: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. METHODS: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). RESULTS: VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations. CONCLUSIONS: Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).

Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR).

PURPOSE: The long-term safety, tolerability and efficacy of vibegron in adults with overactive bladder were evaluated in the 40-week phase 3 EMPOWUR extension study. MATERIALS AND METHODS: Patients who completed 12 weeks of once-daily vibegron 75 mg or tolterodine 4 mg extended release in EMPOWUR continued double-blind treatment; patients who completed 12 weeks of placebo were randomly assigned 1:1 to receive double-blind vibegron or tolterodine. The primary outcome was safety, measured by incidence of adverse events. Secondary outcomes included change from baseline at week 52 in average daily number of micturitions and urgency episodes (all patients), and urge and total urinary incontinence episodes (patients with overactive bladder wet) based on 7-day diary data. RESULTS: Of 506 patients randomized 505 received ≥1 dose of medication, and 430 (85%) completed the study. A total of 12 patients (2.4%) discontinued owing to adverse events. The most common adverse events with vibegron/tolterodine (>5% in either group) were hypertension (8.8%/8.6%), urinary tract infection (6.6%/7.3%), headache (5.5%/3.9%), nasopharyngitis (4.8%/5.2%) and dry mouth (1.8%/5.2%). Improvements in efficacy end points were maintained for patients receiving vibegron for 52 weeks; least squares mean change from baseline to week 52 in micturitions was ‒2.4 for vibegron vs ‒2.0 for tolterodine; in urge urinary incontinence episodes ‒2.2 vs ‒1.7 (p <0.05); in urgency episodes ‒3.4 vs ‒3.2; and in total incontinence episodes ‒2.5 vs ‒1.9 (p <0.05). Among patients with overactive bladder wet 61.0% receiving vibegron experienced ≥75% reduction in urge urinary incontinence episodes after 52 weeks of treatment vs 54.4% with tolterodine, while 40.8% vs 34.2% experienced a 100% reduction. CONCLUSIONS: Vibegron demonstrated favorable long-term safety, tolerability and efficacy in patients with overactive bladder, consistent with results of the 12-week study.