Efficacy and Safety of Sarecycline, a Novel, Once-Daily, Narrow Spectrum Antibiotic for the Treatment of Moderate to Severe Facial Acne Vulgaris: Results of a Phase 2, Dose-Ranging Study.

BACKGROUND: There is a need for new oral antibiotics for acne with improved safety profiles and targeted antibacterial spectra. Sarecycline is a novel, tetracycline-class antibiotic specifically designed for acne, offering a narrow spectrum of activity compared with currently available tetracyclines, including less activity against enteric Gram-negative bacteria. This phase 2 study evaluated the efficacy and safety of three doses of sarecycline for moderate to severe facial acne vulgaris. METHODS: In this multicenter, double-blind, placebo-controlled study, patients aged 12 to 45 years were randomized to once-daily sarecycline 0.75 mg/kg, 1.5 mg/kg, 3.0 mg/kg, or placebo. Efficacy analyses included change from baseline in inflammatory and noninflammatory lesion counts at week 12, with between-group comparisons using analysis of covariance. Safety assessments included adverse events (AEs), clinical laboratories, vital signs, electrocardiograms, and physical examinations. RESULTS: Overall, 285 randomized patients received at least one dose of study drug. At week 12, sarecycline 1.5 mg/kg and 3.0 mg/kg groups demonstrated significantly reduced inflammatory lesions from baseline (52.7% and 51.8%, respectively) versus placebo (38.3%; P=0.02 and P=0.03, respectively). Sarecycline was safe and well tolerated, with similar gastrointestinal AE rates in sarecycline and placebo groups. Vertigo and photosensitivity AEs occurred in less than 1% of patients when pooling sarecycline groups; no vulvovaginal candidiasis AEs occurred. Discontinuation rates due to AEs were low. No serious AEs occurred. CONCLUSION: Once-daily sarecycline 1.5 mg/kg significantly reduced inflammatory lesions versus placebo and was safe and well tolerated with low rates of AEs, including gastrointestinal AEs. Sarecycline 3.0 mg/kg did not result in additional efficacy versus 1.5 mg/kg. Sarecycline may represent a novel, once-daily treatment for patients with moderate to severe acne. It offers a narrow antibacterial spectrum relative to other tetracycline options, which may lead to less selective pressure on enteric Gram-negative bacteria, resulting in less disruption of commensal organisms and less potential for antibiotic resistance.

J Drugs Dermatol. 2018;17(3):333-338.

Boceprevir for untreated chronic HCV genotype 1 infection.

BACKGROUND: Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. METHODS: We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. RESULTS: A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. CONCLUSIONS: The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).

Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial.

UNLABELLED: Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response-guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had ≥1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. CONCLUSION: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation.

Factors that predict response of patients with hepatitis C virus infection to boceprevir.

BACKGROUND & AIMS: Little is known about factors associated with a sustained virologic response (SVR) among patients with hepatitis C virus (HCV) infection to treatment with protease inhibitors. METHODS: Previously untreated patients (from the Serine Protease Inhibitor Therapy 2 [SPRINT-2] trial) and those who did not respond to prior therapy (from the Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 [RESPOND-2] trial) received either a combination of peginterferon and ribavirin for 48 weeks or boceprevir, peginterferon, and ribavirin (triple therapy) after 4 weeks of peginterferon and ribavirin (total treatment duration, 28-48 wk). A good response to interferon was defined as a ≥ 1 log(10) decrease in HCV RNA at week 4; a poor response was defined as a <1 log(10) decrease. We used multivariate regression analyses to identify baseline factors of the host (including the polymorphism interleukin [IL]-28B rs12979860) associated with response. The polymorphism IL-28B rs8099917 also was assessed. RESULTS: In the SPRINT-2 trial, factors that predicted a SVR to triple therapy included low viral load (odds ratio [OR], 11.6), IL-28B genotype (rs 12979860 CC vs TT and CT; ORs, 2.6 and 2.1, respectively), absence of cirrhosis (OR, 4.3), HCV subtype 1b (OR, 2.0), and non-black race (OR, 2.0). In the RESPOND-2 trial, the only factor significantly associated with a SVR was previous relapse, compared with previous nonresponse (OR, 2.6). Most patients with rs12979860 CC who received triple therapy had undetectable levels of HCV RNA by week 8 (76%-89%), and were eligible for shortened therapy. In both studies, IL-28B rs12979860 CC was associated more strongly with a good response to interferon than other baseline factors; however, a ≥ 1 log(10) decrease in HCV-RNA level at week 4 was associated more strongly with SVR than IL-28B rs12979860. Combining the rs8099917 and rs12979860 genotypes does not increase the association with SVR. CONCLUSIONS: The CC polymorphism at IL-28B rs12979860 is associated with response to triple therapy and can identify candidates for shorter treatment durations. A ≥ 1 log(10) decrease in HCV RNA at week 4 of therapy is the strongest predictor of a SVR, regardless of polymorphisms in IL-28B.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin.

BACKGROUND & AIMS: Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS: Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS: SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION: Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Health-Related Quality of Life With Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To investigate effects of ulipristal acetate on health-related quality of life (QOL) and symptom severity in women with symptomatic uterine leiomyomas and abnormal uterine bleeding. METHODS: Women were randomized to ulipristal (5 mg, 10 mg) or placebo in two phase 3, multicenter, double-blind, placebo-controlled trials (VENUS I and II). Health-related QOL and symptom severity were assessed at baseline, and over one (VENUS I and II) and two (VENUS II) 12-week treatment courses using the Uterine Fibroid Symptom Health-Related Quality of Life questionnaire. In pooled VENUS I and II data, change from baseline to the end of the first course for each Uterine Fibroid Symptom Health-Related Quality of Life scale was analyzed, including a Revised Activities subscale that measured physical and social activities. The proportion of women achieving meaningful change in the Symptom Severity (20 or more points), Health-Related QOL Total (20 or more points), and Revised Activities (30 or more points) scales was calculated. In VENUS II data, change from baseline to the end of each course in each scale was analyzed for each treatment arm. RESULTS: In pooled analyses, the intent-to-treat population included 589 patients (placebo, n=169; ulipristal 5 mg, n=215; ulipristal 10 mg, n=205). Significantly greater improvements from baseline in all Uterine Fibroid Symptom Health-Related Quality of Life scales were observed with both ulipristal doses compared with placebo (P<.001). A meaningful change in Revised Activities was achieved by 51 patients receiving placebo (34.9%), compared with 144 (73.5%; OR 5.0 [97.5% CI 2.9-8.6]) and 141 (80.6%; OR 7.9 [97.5% CI 4.3-14.6]) patients receiving ulipristal 5 mg, and 10 mg, respectively. In VENUS II, at end of courses 1 and 2, both ulipristal doses demonstrated significant improvements from baseline compared with placebo for all Uterine Fibroid Symptom Health-Related Quality of Life scales (P<.01). Mean Revised Activities scores showed that beneficial ulipristal effects were maintained in course 2, and improvements occurred on switching to ulipristal; results for other scales were similar. CONCLUSION: Ulipristal was associated with significant improvements in health-related QOL and symptom severity compared with placebo for women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147197 and NCT02147158. FUNDING SOURCE: Allergan plc, Dublin, Ireland.

A randomized, multicenter, double-blind study to evaluate the safety and efficacy of estradiol vaginal cream 0.003% in postmenopausal women with dyspareunia as the most bothersome symptom.

OBJECTIVE: Vulvovaginal atrophy (VVA) is characterized by vaginal changes, dyspareunia, and itching/irritation. Efficacy and safety of a lower-dose estradiol vaginal cream (0.003%) were evaluated in postmenopausal women with VVA-related dyspareunia. METHODS: This was a phase 3, randomized, double-blind, placebo-controlled study. Sexually active postmenopausal women with moderate-severe dyspareunia as the most bothersome symptom, ≤5% vaginal superficial cells, and vaginal pH >5.0 were randomized (1:1) to 0.003% estradiol vaginal cream (15 µg estradiol; 0.5 g cream) or placebo (0.5 g cream) applied daily for 2 weeks followed by three applications/week for 10 weeks. Coprimary outcomes were changes in dyspareunia severity, vaginal cytology, and vaginal pH from baseline to final assessment. Additional efficacy outcomes and safety were assessed. RESULTS: A total of 550 participants (average age, 58 y) were randomized. Compared with placebo, estradiol reduced dyspareunia severity (mean change from baseline ±â€ŠSD: -1.5 ±â€Š1.0 estradiol vs -1.2 ±â€Š0.9 placebo), decreased vaginal pH (-1.36 ±â€Š0.89 vs -0.53 ±â€Š0.92), and improved vaginal cytology (percentage superficial and parabasal cells 10.1 ±â€Š16.7 vs 1.4 ±â€Š6.1 and -48.5 ±â€Š45.1 vs -14.6 ±â€Š39.6; P < 0.001, all) at the final assessment. In addition, estradiol decreased dyspareunia severity at weeks 8 and 12, vaginal/vulvar irritation/itching at weeks 4 and 12, and dryness at week 12 versus placebo (P < 0.01, all). VVA severity, pH, and cytology improved at week 12 with estradiol versus placebo (P < 0.001, all). Vulvovaginal mycotic infections were more frequent with estradiol. One serious event leading to discontinuation occurred with estradiol. No deaths occurred. CONCLUSIONS: Lower-dose estradiol vaginal cream (0.003%) dosed three applications/week is an effective and well-tolerated treatment for VVA-related dyspareunia.

A Randomized, Multicenter, Double-Blind, Study to Evaluate the Safety and Efficacy of Estradiol Vaginal Cream 0.003% in Postmenopausal Women with Vaginal Dryness as the Most Bothersome Symptom.

BACKGROUND: Vulvovaginal atrophy (VVA) is characterized by vaginal/vulvar dryness, irritation, dyspareunia, or dysuria. The objective of this study was to examine the efficacy and safety of a very low-dose estradiol vaginal cream (0.003%) applied twice per week in postmenopausal women with VVA-related vaginal dryness. MATERIALS AND METHODS: In this phase 3, randomized, double-blind, placebo-controlled, multicenter study, postmenopausal women with moderate-severe vaginal dryness as the most bothersome VVA symptom were randomized (1:1) to estradiol cream 0.003% (15 µg estradiol; 0.5 g cream) or placebo (0.5 g cream). Treatments were applied vaginally once daily for 2 weeks followed by two applications/week for 10 weeks. Coprimary outcomes were changes in severity of vaginal dryness, percentage of vaginal superficial and parabasal cells, and vaginal pH at final assessment. Additional outcomes comprised changes in severity of other VVA signs and symptoms. Adverse events (AEs) were assessed. RESULTS: Of the 576 randomized participants, most were white and had an average age of 59 years. At final assessment, estradiol reduced vaginal dryness severity, decreased vaginal pH, increased superficial cell percentage, and decreased parabasal cell percentage versus placebo (p ≤ 0.05, all). Estradiol also reduced vaginal dryness severity at Weeks 4-12 and dyspareunia at Week 8 versus placebo (p ≤ 0.05, all). Improvements in vaginal/vulvar irritation/itching severity and dysuria were similar between estradiol and placebo. Estradiol had comparable rates of treatment-emergent AEs to placebo. No deaths occurred. CONCLUSIONS: Very low-dose estradiol vaginal cream (0.003%) dosed twice weekly is an effective and well-tolerated treatment for VVA symptoms and dryness associated with menopause.

Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To assess efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, placebo-controlled study enrolled premenopausal women (aged 18-50 years) with abnormal uterine bleeding, one or more discrete leiomyomas, and uterine size 20 weeks of gestation or less. Patients were randomized 1:1:1 to 5 mg ulipristal, 10 mg ulipristal, or placebo once daily for 12 weeks followed by 12-week drug-free follow-up. Coprimary endpoints were rate of and time to amenorrhea, defined as no bleeding for the last 35 consecutive days of treatment. Secondary endpoints included rates of amenorrhea from day 11 and change from baseline to endpoint in the Revised Activities subscale of the Uterine Fibroid Symptom and Quality of Life questionnaire, which includes questions pertaining to physical and social activities. Safety assessments included adverse event monitoring and endometrial biopsies. A sample size of 150 was planned to compare separately each dose of ulipristal with placebo. RESULTS: From March 2014 to March 2016, 157 patients were randomized. Demographics were similar across treatment groups. Amenorrhea was achieved by 25 of 53 (47.2% [97.5% CI 31.6-63.2]) and 28 of 48 (58.3% [97.5% CI 41.2-74.1]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 1 of 56 (1.8% [97.5% CI 0.0-10.9]) placebo-treated patients (both P<.001). Time to amenorrhea was shorter for both ulipristal doses compared with placebo (P<.001), and both doses of ulipristal resulted in improved quality of life compared with placebo (P<.001). Common adverse events (5% or greater in either ulipristal group during treatment) were hypertension, elevated blood creatinine phosphokinase, and hot flushes. Serious adverse events occurred in four patients, but none was considered related to treatment. Endometrial biopsies were benign. CONCLUSION: Ulipristal at 5 mg and 10 mg were well tolerated and superior to placebo in rate of and time to amenorrhea in women with symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov number, NCT02147197.

Ulipristal Acetate for Treatment of Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and tolerability of ulipristal acetate, a selective progesterone receptor modulator, for treatment of symptomatic uterine leiomyomas. METHODS: This phase 3, double-blind, double-dummy, placebo-controlled trial randomized premenopausal women (18-50 years) with uterine leiomyomas and abnormal uterine bleeding to once-daily 5 mg ulipristal, 10 mg ulipristal, or placebo in two 12-week treatment courses separated by a drug-free interval of two menses. Coprimary end points were rates of and time to amenorrhea during course 1. Change from baseline to end of course 1 in the Revised Activities subscale of the Uterine Fibroid Symptom and Health-Related Quality of Life questionnaire was a secondary end point. A sample size of 400 was planned to compare separately each ulipristal dose with placebo. RESULTS: From January 2014 through November 2016, 432 women were randomized. Demographic characteristics were similar across treatment groups. In course 1, 68 of 162 (42.0% [97.5% CI 33.3-51.1]) and 86 of 157 (54.8% [97.5% CI 45.5-63.8]) patients treated with 5 mg and 10 mg ulipristal, respectively, compared with 0 of 113 (0.0% [97.5% CI 0.0-3.8]) patients treated with placebo achieved amenorrhea (P<.001 for each dose); most women who achieved amenorrhea did so within 10 days (time to amenorrhea, P<.001 for each dose). Significantly greater improvements in Uterine Fibroid Symptom and Health-Related Quality of Life Revised Activities subscale scores were reported with 5 mg and 10 mg ulipristal compared with placebo (least squares mean change from baseline: 48.3, 56.7, and 13.0, respectively; P<.001 for each dose). Both ulipristal doses were well tolerated; in course 1, hot flush occurred in 7.5%, 11.6%, and 1.7% of patients treated with 5 mg ulipristal, 10 mg ulipristal, and placebo, respectively. CONCLUSION: Treatment with 5 mg or 10 mg ulipristal was superior to placebo in achieving amenorrhea and generally well tolerated for the medical management of symptomatic uterine leiomyomas. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02147158.

Analysis of boceprevir resistance associated amino acid variants (RAVs) in two phase 3 boceprevir clinical studies.

BACKGROUND: We investigated the frequency of RAVs among patients failing to achieve SVR in two clinical trials. We also investigated the impact of interferon responsiveness on RAVs and specific baseline RAVs relationship with boceprevir treatment failure. METHODS: Data are from 1020 patients enrolled into either SPRINT-2 or RESPOND-2; patients received a 4-week PR lead-in prior to receiving boceprevir or placebo. RAVs were analyzed via population-based sequence analysis of the NS3 protease gene (success rate of >90% at a virus level of ≥ 10,000IU/mL) RESULTS: The high SVR rate in patients who received boceprevir resulted in a low rate of RAVs; 7% was detected at baseline in all patients, which rose to 15% after treatment. However, RAVs were detected in 53% of patients that failed to achieve SVR, which declined to 22.8% 6-14 months following cessation of boceprevir therapy. Baseline RAVs alone were not predictive of virologic outcome; poor interferon responsiveness was highly predictive of non-SVR. RAVs were more frequently detected in poor interferon responders. CONCLUSIONS: We detected no association between the presence of baseline amino acid variants at boceprevir resistance-associated loci and outcome in the context of good IFN response.