Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients Coinfected With Hepatitis C Virus and Human Immunodeficiency Virus Type 1: The EXPEDITION-2 Study.

Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.

Depatuxizumab mafodotin in EGFR-amplified newly diagnosed glioblastoma: A phase III randomized clinical trial.

BACKGROUND: Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. METHODS: In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. RESULTS: There were 639 randomized patients (median age 60, range 22-84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82-1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70-1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56-0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61-0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3-4), causing 12% to discontinue. CONCLUSIONS: Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Drawing inferences about the coancestry coefficient.

The coancestry coefficient, also known as the population structure parameter, is of great interest in population genetics. It can be thought of as the intraclass correlation of pairs of alleles within populations and it can serve as a measure of genetic distance between populations. For a general class of evolutionary models it determines the distribution of allele frequencies among populations. Under more restrictive models it can be regarded as the probability of identity by descent of any pair of alleles at a locus within a random mating population. In this paper we review estimation procedures that use the method of moments or are maximum likelihood under the assumption of normally distributed allele frequencies. We then consider the problem of testing hypotheses about this parameter. In addition to parametric and non-parametric bootstrap tests we present an asymptotically-distributed chi-square test. This test reduces to the contingency-table test for equal sample sizes across populations. Our new test appears to be more powerful than previous tests, especially for loci with multiple alleles. We apply our methods to HapMap SNP data to confirm that the coancestry coefficient for humans is strictly positive.

Vibegron (RVT-901/MK-4618/KRP-114V) Administered Once Daily as Monotherapy or Concomitantly with Tolterodine in Patients with an Overactive Bladder: A Multicenter, Phase IIb, Randomized, Double-blind, Controlled Trial.

BACKGROUND: Antimuscarinics have shown modest efficacy with unwanted side effects in patients with overactive bladder (OAB). Efficacy of vibegron, a new ß3-adrenergic receptor agonist, for OAB is unknown. OBJECTIVE: To evaluate the efficacy of once-daily oral vibegron in OAB patients (primary), and its safety, tolerability, and efficacy when administered alone or concomitantly with tolterodine (secondary). DESIGN, SETTING, AND PARTICIPANTS: International, phase IIb, randomized, double-blind, placebo- and active comparator-controlled, two-part superiority trial (2011-2013) in OAB-wet or OAB-dry patients aged 18-75 yr (NCT01314872). INTERVENTIONS: Part 1: once-daily oral vibegron monotherapy (3 [V3], 15 [V15], 50 [V50], or 100 [V100] mg), tolterodine extended release 4mg (TER4), or placebo for 8 wk, or combination V50/TER4 for 4 wk and then V50 for 4 wk; part 2: V100/TER4, V100, TER4, or placebo for 4 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Average daily micturitions at week 8 of part 1 (primary); urge incontinence episodes, total incontinence episodes, and urgency episodes (secondary). RESULTS AND LIMITATIONS: Overall, 1395 patients were randomized. From baseline to week 8, V50 and V100 significantly decreased average daily micturitions (least square mean difference [95% confidence interval], -0.64 [-1.11, -0.18]; p=0.007 and -0.91 [-1.37, -0.44]; p<0.001, respectively) and the number of urge incontinence episodes (-0.72 [-1.11, -0.33] and -0.71 [-1.10, -0.32], respectively; both p<0.001) versus placebo. All vibegron doses were well tolerated. The incidence of dry mouth was higher with TER4 than with vibegron monotherapy. Results are limited by the relatively short treatment duration. CONCLUSIONS: Once-daily V50 and V100 improved OAB symptoms; vibegron was well tolerated as monotherapy and concomitantly with tolterodine. Further development is warranted. PATIENT SUMMARY: Antimuscarinics, commonly used to treat overactive bladder, produce modest efficacy and unwanted side effects. In this study, a different type of drug (vibegron) was efficacious and safe, alone or with an antimuscarinic (tolterodine).

A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis.

CONTEXT: MK-5442 is an orally bioavailable calcium-sensing receptor antagonist that is hypothesized to stimulate bone formation by stimulating endogenous secretion of a pulse of PTH. Earlier clinical and preclinical studies demonstrated increased bone mineral density (BMD) after treatment. OBJECTIVE: Our objective was to identify a dose of MK-5442 that produces osteoanabolic effects without excessive hypercalcemia. DESIGN AND SETTING: This was a randomized, double-blind, placebo-controlled, parallel-group trial of private or institutional practice. PARTICIPANTS AND INTERVENTION: In total, 383 postmenopausal women with osteoporosis were administered daily oral MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo. MAIN OUTCOME MEASURES: Serum PTH and calcium, bone turnover markers, areal BMD, and safety were evaluated. RESULTS: A dose-dependent transient increase in PTH occurred after an MK-5442 dose and lasted more than 3.5 hours. Compared with placebo, significant increases in bone formation markers (serum procollagen 1 N-terminal peptide and bone-specific alkaline phosphatase) were observed by 6 months, whereas bone resorption markers (serum C-telopeptide of type 1 collagen, urine N-telopeptides of type 1 collagen) initially decreased but were also significantly increased by 6 months. Despite the biochemical marker changes suggestive of an anabolic response, there were no statistically significant differences between any dose of MK-5442 and placebo in percent change from baseline at month 6 in any of the BMD endpoints. The frequency of hypercalcemia (trough serum calcium ≥ 10.8 mg/dL) was greater with higher MK-5442 doses. CONCLUSION: In postmenopausal women with low bone mass, treatment with MK-5442 resulted in transient pulses of PTH. Bone formation markers increased quickly and bone resorption markers decreased temporarily, suggestive of an anabolic window. However, there were no increases in BMD versus placebo.

Once-weekly dose of 8400 IU vitamin D(3) compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency.

BACKGROUND: Vitamin D insufficiency, which is prevalent in older individuals, is associated with bone and muscle weakness and falls. OBJECTIVE: We examined the effects of a weekly dose of 8400 IU vitamin D(3) on postural stability, muscle strength, and safety. DESIGN: In this double-blind trial, subjects aged > or =70 y with serum 25-hydroxyvitamin D [25(OH)D] concentrations < or =20 but > or =6 ng/mL were randomly assigned to receive a weekly dose of 8400 IU vitamin D(3) (n = 114) or a placebo (n = 112). Mediolateral body sway with eyes open (assessed with the AccuSway(PLUS) platform; Advanced Medical Technology Inc, Watertown, MA) was the primary endpoint. Secondary endpoints included the short physical performance battery (SPPB) and serum 25(OH)D concentrations. An analysis of covariance model was used for treatment comparisons. Safety and tolerability were monitored. RESULTS: Serum 25(OH)D concentrations rose significantly (from 13.9 to 26.2 ng/mL, P < 0.001) in patients treated with 8400 IU vitamin D(3) but not in patients treated with the placebo. After 16 wk, neither mediolateral sway nor SPPB differed significantly between treatment groups. However, in the post hoc analysis of patients subgrouped by baseline sway (> or = 0.46 compared with <0.46 cm), treatment with 8400 IU vitamin D(3) significantly reduced sway compared with treatment with placebo (P = 0.047) in patients with elevated baseline sway but not in patients with normal baseline sway. Adverse experiences and incidences of hypercalcemia, hypercalciuria, and elevated creatinine were similar with both treatments. In patients treated with 8400 IU vitamin D(3), but not in placebo-treated patients, parathyroid hormone decreased significantly. CONCLUSIONS: Weekly treatment with 8400 IU vitamin D(3) raised 25(OH)D concentrations in elderly, vitamin D-insufficient individuals. Treatment with 8400 IU vitamin D(3) did not reduce mediolateral sway significantly compared with treatment with placebo in this population, although in post hoc analysis, treatment with 8400 IU vitamin D(3) reduced sway in the subgroup of patients who had elevated sway at baseline. Weekly treatment with 8400 IU vitamin D(3) was well tolerated. This trial was registered at clinicaltrials.gov as NCT00242476.