FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy. Approval was based on Study FRESCO-2, a globally conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival. A total of 691 patients were randomly assigned (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 [95% confidence interval (CI), 0.55, 0.80; P < 0.001]. The median OS was 7.4 months (95% CI, 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI, 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with the inhibition of VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single-country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI, 0.51, 0.83; P < 0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, an anti-EGFR therapy.

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma.

In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee-assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% [95% confidence interval (CI), 41-59], and the complete response rate was 13% (95% CI, 7-20), with an estimated median duration of response of 8.3 months. The most common nonhematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.

FDA Approval Summary: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%-37%] with a median duration of response of 17.5 months (95% CI, 7.4-20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC.

FDA Approval Summary: Belumosudil for Adult and Pediatric Patients 12 Years and Older with Chronic GvHD after Two or More Prior Lines of Systemic Therapy.

On July 16, 2021, the FDA approved belumosudil, a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic GvHD (cGvHD) after failure of at least two prior lines of systemic therapy. Approval was based on the results of Study KD025-213, which included 65 patients with cGvHD treated with belumosudil 200 mg daily in an open-label, single-arm cohort. Efficacy was determined by the overall response rate (ORR) through Cycle 7 Day 1, which included complete response (CR) or partial response (PR) according to the 2014 NIH consensus criteria, and durability of response. The ORR through Cycle 7 Day 1 was 75% [95% confidence interval (CI), 63-85]; 6% of patients achieved a CR, and 69% achieved a PR. The median duration of response was 1.9 months (95% CI, 1.2-2.9), and 62% (95% CI, 46-74) of responding patients remained alive without new systemic therapy for at least 12 months from response. The common adverse reactions were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma-glutamyl transferase increased, lymphocytes decreased, and hypertension. Additional study is warranted to confirm safety with long-term use.

Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction.

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID-19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS-443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS-443902 in tissues. A whole body physiologically-based pharmacokinetic (PBPK) modeling and simulation approach was utilized to elucidate the disposition mechanism of RDV and its metabolites in the lungs and liver and explore the relationship between plasma and tissue pharmacokinetics (PK) of RDV and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of RDV and its metabolites in patients with organ dysfunction was explored. Our simulation results indicated that intracellular exposure of GS-443902 was decreased in the liver and increased in the lungs in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS-443902 in the liver was slightly increased, whereas the lung exposure of GS-443902 was not impacted. These predictions along with the organ impairment study results may be used to support decision making regarding the RDV dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole body PBPK modeling to aid in decision making for nucleotide analogue prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

Numerical analysis of local non-equilibrium heat transfer in layered spherical tissue during magnetic hyperthermia.

A solid multi-layered concentric sphere with Gaussian space source is considered as the tissue model for magnetic hyperthermia treatment. The generalized dual-phase-lag model of bioheat transfer is used to describe the behavior of heat transport in tissue in the hyperthermia treatment process for accounting the local non-equilibrium effect. The effects of blood perfusion with the transient temperature are included in the tissue model. The hybrid numerical scheme based on Laplace transform, change of variables, and the modified discretization technique is extended to solve the present problem. The analytical solution for constant heat generation in the inner sphere is presented and evidences the accuracy and rationality of the present numerical results. In an ideal hyperthermia treatment, all the diseased tissues should be selectively heated without affecting any healthy tissue. Attempting to achieve the ideal temperature distribution, the thermal dose is estimated at the specified condition. The corresponding thermal efficacy of tumor damage has also been assessed based on the Arrenius equation.

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis.

In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Approval was based on results from CPKC412D2201, a single-arm trial of midostaurin (100 mg orally twice daily) in previously treated or untreated patients. For the patients with ASM and SM-AHN, efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria with six cycles of midostaurin. There were no CRs reported; ICR was achieved by 6 of 16 patients (38%; 95% confidence interval [CI]: 15%-65%) with ASM and by 9 of 57 patients (16%; 95% CI: 7%-28%) with SM-AHN. Within the follow-up period, the median duration of response was not reached for the patients with ASM (range, 12.1+ to 36.8+ months) or with SM-AHN (range, 6.6+ to 52.1+ months). For the patients with MCL, efficacy was established on the basis of confirmed CR using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis criteria. Of 21 patients with MCL, 1 (5%) achieved a CR. Of 142 patients with SM evaluated for safety, 56% had dose modifications for toxicity, and 21% discontinued treatment due to a toxicity. Over 50% reported nausea, vomiting, or diarrhea, and ≥30% reported edema, musculoskeletal pain, fatigue, abdominal pain, or upper respiratory tract infection. New or worsening grade ≥3 lymphopenia, anemia, thrombocytopenia, or neutropenia developed in ≥20%. Although midostaurin is an active drug for treatment of advanced SM, it is not clear that the optimal dose has been identified. IMPLICATIONS FOR PRACTICE: Midostaurin is the only U.S. Food and Drug Administration-approved therapy for patients with systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and is the only therapy approved for patients with aggressive systemic mastocytosis regardless of KIT D816V mutation status. Based on response rate and duration, midostaurin has meaningful clinical activity in these rare, life-threatening diseases.

A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial.

CONTEXT: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. OBJECTIVE: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). DESIGN: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. SETTING: This was a multicenter study conducted in North America and Europe. PARTICIPANTS: A total of 228 men entered the open-label phase and 219 completed the study. INTERVENTION: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. MAIN OUTCOME MEASURES: BMD, serum collagen type I C-telopeptide, and safety were measured. RESULTS: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. CONCLUSIONS: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.

Cross-species transcriptomic analysis of mouse and rat lung exposed to chloroprene.

ß-Chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of neoprene elastomers, is of regulatory interest due to the production of multiorgan tumors in mouse and rat cancer bioassays. A significant increase in female mouse lung tumors was observed at the lowest exposure concentration of 12.8 ppm, whereas a small, but not statistically significant increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of chloroprene results in the generation of reactive epoxides, and the rate of overall chloroprene metabolism is highly species dependent. To identify potential key events in the mode of action of chloroprene lung tumorigenesis, dose-response and time-course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional ANOVA approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in tumor incidence. Transcriptional BMD values for the pathway were more similar to differences in tumor response than were estimated target tissue dose surrogates based on the total amount of chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the tumor response is likely due to their reflection of the overall balance between metabolic activation and detoxication reactions, whereas the current tissue dose surrogate reflects only oxidative metabolism.

Kinetic modeling of ß-chloroprene metabolism: Probabilistic in vitro-in vivo extrapolation of metabolism in the lung, liver and kidneys of mice, rats and humans.

ß-Chloroprene (chloroprene) is carcinogenic in inhalation bioassays with B6C3F1 mice and Fischer rats, but the potential effects in humans have not been adequately characterized. In order to provide a better basis for evaluating chloroprene exposures and potential effects in humans, we have explored species and tissue differences in chloroprene metabolism. This study implemented an in vitro-in vivo extrapolation (IVIVE) approach to parameterize a physiologically based pharmacokinetic (PBPK) model for chloroprene and evaluate the influence of species and gender differences in metabolism on target tissue dosimetry. Chloroprene metabolism was determined in vitro using liver, lung and kidney microsomes from male or female mice, rats, and humans. A two compartment PK model was used to estimate metabolism parameters for chloroprene in an in vitro closed vial system, which were then extrapolated to the whole body PBPK model. Two different strategies were used to estimate parameters for the oxidative metabolism of chloroprene: a deterministic point-estimation using the Nelder-Mead nonlinear optimization algorithm and probabilistic Bayesian analysis using the Markov Chain Monte Carlo technique. Target tissue dosimetry (average amount of chloroprene metabolized in lung per day) was simulated with the PBPK model using the in vitro-based metabolism parameters. The model-predicted target tissue dosimetry, as a surrogate for a risk estimate, was similar between the two approaches; however, the latter approach provided a measure of uncertainty in the metabolism parameters and the opportunity to evaluate the impact of that uncertainty on predicted risk estimates.

An analysis of N-acetylcysteine treatment for acetaminophen overdose using a systems model of drug-induced liver injury.

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V(max) for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

Reproducibility of myocardial perfusion reserve - variations in measurements from post processing using commercially available software.

PURPOSE: Adenosine stress first pass cardiac magnetic resonance imaging (CMRI) is a rapidly evolving tool in the diagnosis of ischemic heart disease (IHD). The rest and stress first pass myocardial perfusion data may be interpreted using commercially available software for calculation of time intensity curves in order to generate a numeric value of the segmental or whole heart myocardial perfusion reserve index (MPRI). The objective of this study was to determine the inter- and intra-observer reliability of the data generated by standard commercially available software. METHODS: Data from 20 adenosine stress CMRI (1.5 T) studies were analyzed using commercially available CAAS MRV 3.3 software (Pie Medical Imaging B.V., Netherlands) for calculation of the MPRI. The stress CMRI was performed using a standardized protocol in 20 women including 10 women with angina and the absence of obstructive CAD and 10 healthy volunteers. MPRI calculation was made in a standardized manner on separate occasions by two independent observers. A single observer repeated the calculation of MPRI three months later, without reference to the prior data. Basal, mid, and apical segments, for the whole myocardium, sub-endocardium, and sub-epicardium were analyzed. Intra-class correlation coefficients (ICC), repeatability coefficients (RC), and coefficients of variation (CoV) were determined. RESULTS: The MPRI results by repeated software measurements were highly correlated, with potentially important variations in measurement observed. The myocardial inter-observer ICC was 0.80 (95% CI, 0.57, 0.92) with a CoV of 7.5%, and intra-observer ICC was 0.89 (95% CI, 0.77, 0.95) with a CoV of 3.6%. The mid-ventricular level MPRI was most reproducible, with intra-observer ICC at 0.91 (95% CI, 0.77, 0.97); intra-observer measurement was more reproducible than inter-observer measurement. CONCLUSIONS: There is variation in measurement of MPRI observed in post processing of perfusion data when using a standardized approach and commercially available software. This has implications in the interpretation of data obtained for clinical and research purposes.

Red versus white wine as a nutritional aromatase inhibitor in premenopausal women: a pilot study.

BACKGROUND: An increased risk of breast cancer is associated with alcohol consumption; however, it is controversial whether red wine increases this risk. Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogen and occur naturally in grapes, grape juice, and red, but not white wine. We tested whether red wine is a nutritional AI in premenopausal women. METHODS: In a cross-over design, 36 women (mean age [SD], 36 [8] years) were assigned to 8 ounces (237 mL) of red wine daily then white wine for 1 month each, or the reverse. Blood was collected twice during the menstrual cycle for measurement of estradiol (E2), estrone (E1), androstenedione (A), total and free testosterone (T), sex hormone binding globulin (SHBG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). RESULTS: Red wine demonstrated higher free T vs. white wine (mean difference 0.64 pg/mL [0.2 SE], p=0.009) and lower SHBG (mean difference -5.0 nmol/L [1.9 SE], p=0.007). E2 levels were lower in red vs. white wine but not statistically significant. LH was significantly higher in red vs. white wine (mean difference 2.3 mIU/mL [1.3 SE], p=0.027); however, FSH was not. CONCLUSION: Red wine is associated with significantly higher free T and lower SHBG levels, as well as a significant higher LH level vs. white wine in healthy premenopausal women. These data suggest that red wine is a nutritional AI and may explain the observation that red wine does not appear to increase breast cancer risk.

Do patients gain weight after thyroidectomy for thyroid cancer?

BACKGROUND: Patients who undergo thyroidectomy often complain of weight gain, which they frequently attribute to inadequate thyroid hormone replacement. To assess the weight changes associated with thyroid hormone replacement or suppressive therapy after thyroidectomy, we measured the weights of patients before and after thyroidectomy and compared them to the weights of euthyroid patients with thyroid nodules who were being followed for many years. METHODS: The weights and heights of 67 women and 35 men who underwent total thyroidectomy for thyroid cancer were recorded before and for a mean of 8.3 years after thyroidectomy. All patients received either suppressive or replacement doses of levothyroxine. As a comparison group, 70 women and 22 men with goiter or thyroid nodules and were euthyroid had serial measurements of height and weight. They were followed for a mean of 7.6 years. The body mass index (BMI) and age-adjusted BMI percentiles were calculated. The weight, BMI, and BMI percentile changes were compared both unadjusted and adjusted for age, gender, thyrotropin (TSH) level, and duration between measurements. RESULTS: At baseline, patients with thyroid nodules were older (mean 50.4 years) than those with thyroid cancer (mean 45.8 years). There were no significant differences in baseline weight, BMI, or BMI percentile. The baseline TSH levels were lower for patients with thyroid cancer (mean 0.8 mIU/L) than for those with nodules (mean 1.8 mIU/L) (p=0.002). There were no significant differences between the changes in weight, BMI, or BMI percentile from the start to the completion of the study whether unadjusted or after adjustment for age, gender, TSH, and duration of follow-up. CONCLUSIONS: Despite the perception of many patients that their thyroidectomy and thyroid hormone replacement or suppressive therapy is responsible for their subsequent weight gain, there were no significant differences in weight gain over time in comparison to a control group of euthyroid patients with thyroid nodules or goiter.

A retrospective study to investigate racial and ethnic variations in the treatment of psoriasis with etanercept.

OBJECTIVES: Psoriasis is a chronic inflammatory condition that occurs worldwide; however, few studies have examined this condition in non-Caucasian populations. The purpose of this study was to investigate racial/ethnic differences in demographics, psoriasis severity, efficacy, safety, and health-related quality of life in patients treated with etanercept using data from the Etanercept Assessment of Safety and Effectiveness (EASE) in Psoriasis trial. PATIENTS AND METHODS: This is an investigator-initiated evaluation of data from the EASE study. RESULTS: The study included 2511 patients (Caucasian n=2164; Hispanic/Latino n=173; African American n=98; Asian n=76). Although baseline Physicians' Global Assessment (PGA) scores were similar, we found significant baseline differences in patient characteristics, prior therapy, percentage of body surface area (%BSA) affected and Dermatology Life Quality Index (DLQI) scores between the groups. At baseline, the Caucasian group had the longest disease duration (19 years), but the lowest percentage of BSA involvement (28%). The Asian group had the highest percentage of BSA involvement (41%). Baseline DLQI score was lowest for Caucasians (12.0) and highest for Hispanic/Latinos (14.6). At week 12, response to therapy was similar in all ethnic/racial groups. The BSA involvement was reduced by more than 50 percent for all groups, but remained significantly higher for the Asian group (17%) than for the Caucasian (13%; P=0.0105) and African American groups (13%; P=0.0461). At week 12, the mean Asian DLQI score of 5.2 was significantly higher (worse) than scores for the Caucasian (3.5; P=0.0001) and Hispanic/Latino groups (3.8; P=0.028). For both percentage of BSA and DLQI, differences among racial/ethnic groups in the percentage improvement from baseline were not statistically significant. Adverse event rates were similar for the groups. CONCLUSIONS: Patient characteristics at enrollment differed among ethnic groups, but no significant racial/ethnic differences were found in safety or efficacy of etanercept. However, racial/ethnic differences in the impact of psoriasis on quality of life were observed.

Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease.

OBJECTIVES: We conducted a pilot study for a large definitive clinical trial evaluating the impact of ranolazine in women with angina, evidence of myocardial ischemia, and no obstructive coronary artery disease (CAD). BACKGROUND: Women with angina, evidence of myocardial ischemia, but no obstructive CAD frequently have microvascular coronary dysfunction. The impact of ranolazine in this patient group is unknown. METHODS: A pilot randomized, double-blind, placebo-controlled, crossover trial was conducted in 20 women with angina, no obstructive CAD, and ≥ 10% ischemic myocardium on adenosine stress cardiac magnetic resonance (CMR) imaging. Participants were assigned to ranolazine or placebo for 4 weeks separated by a 2-week washout. The Seattle Angina Questionnaire and CMR were evaluated after each treatment. Invasive coronary flow reserve (CFR) was available in patients who underwent clinically indicated coronary reactivity testing. CMR data analysis included the percentage of ischemic myocardium and quantitative myocardial perfusion reserve index (MPRI). RESULTS: The mean age of subjects was 57 ± 11 years. Compared with placebo, patients on ranolazine had significantly higher (better) Seattle Angina Questionnaire scores, including physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). There was a trend toward a higher (better) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074) on ranolazine. Among women with coronary reactivity testing (n = 13), those with CFR ≤ 3.0 had a significantly improved MPRI on ranolazine versus placebo compared to women with CFR > 3.0 (Δ in MPRI 0.48 vs. -0.82, p = 0.04). CONCLUSIONS: In women with angina, evidence of ischemia, and no obstructive CAD, this pilot randomized, controlled trial revealed that ranolazine improves angina. Myocardial ischemia may also improve, particularly among women with low CFR. These data document approach feasibility and provide outcome variability estimates for planning a definitive large clinical trial to evaluate the role of ranolazine in women with microvascular coronary dysfunction. (Microvascular Coronary Disease In Women: Impact Of Ranolazine; NCT00570089).

Effects of denosumab on fracture and bone mineral density by level of kidney function.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass.

CONTEXT: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. OBJECTIVE: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. DESIGN: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. PARTICIPANTS: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. INTERVENTIONS: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. MAIN OUTCOME MEASURES: We measured the percentage changes in BMD and BTM, and evaluated safety. RESULTS: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. CONCLUSIONS: In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.