Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.

BACKGROUND: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. METHODS: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS). RESULTS: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib. CONCLUSIONS: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

CBX Chromodomain Inhibition Enhances Chemotherapy Response in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) lacks effective therapeutic options leaving patients with a survival time of approximately one year. Recently, the alteration of chromatin modulators has been implicated in the pathogenesis and chemoresistance of numerous cancers; in particular, the Polycomb Group Proteins have been shown to play a role in glioblastoma progression and maintenance [1-5]. In this study, we aimed to identify drug combinations that decrease GBM cell viability by combining small molecule inhibitors against the Polycomb family with two standard chemotherapies. We identified dual inhibition of the CBX chromodomain with doxorubicin as a novel therapeutic strategy. While treatment with chromodomain inhibitor is non-toxic to cells alone, it dramatically increased the toxicity of standard chemotherapy drugs. We further validated an increase in DNA damage resulting in a G2/M block and subsequent apoptosis using the dual inhibitor treatment.

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). METHODS: In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm3) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]). RESULTS: The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (-474.5 mm3 [-1,098.0 to -3.0], p = 0.047) and vs DMF (-711.6 [-1,290.0 to -149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups. DISCUSSION: Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.

Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials.

BACKGROUND: Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR). METHODS: A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V [subtype 1a only], R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants. RESULTS: Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval [CI], 9.47-12.20) in subtype 1a and 0.9 months (95% CI, 0.00-2.07) in subtype 1b infections. CONCLUSIONS: After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time.

Retreatment with telaprevir combination therapy in hepatitis C patients with well-characterized prior treatment response.

UNLABELLED: Retreatment with peginterferon alpha and ribavirin (PR) offers a limited chance of sustained virologic response (SVR) in patients who did not achieve SVR with prior PR treatment. This study evaluated the safety and efficacy of telaprevir-based treatment in combination with PR in well-characterized patients who did not achieve SVR in the control arms of three Phase II clinical trials. Patients eligible to enroll in this open-label nonrandomized study either met on-treatment criteria for nonresponse or relapsed after 48 weeks of treatment in the control arm of the three Phase II PROVE studies. The initial protocol was a 24-week regimen: 12 weeks of telaprevir and PR followed by an additional 12 weeks of PR. During the study the protocol was amended to extend PR to 48 weeks for patients with previous null response. All other patients with undetectable hepatitis C virus (HCV) RNA at weeks 4 and 12 received 24 weeks of therapy. Those with detectable HCV RNA at weeks 4 or 12 received a total of 48 weeks of therapy. The overall SVR rate was 59% (69/117). SVR rates with T12PR were 37% (19/51) in prior null responders, 55% (16/29) in prior partial responders, 75% (6/8) in prior breakthroughs, and 97% (28/29) in prior relapsers. The overall relapse rate was 16% (13/83). Adverse events were similar to those in previous trials with telaprevir, with 9% of patients discontinuing due to an adverse event (most commonly rash and anemia). CONCLUSION: This study demonstrated the benefit of retreatment with a telaprevir-based regimen for patients with well-characterized nonresponse (null and partial) or relapse to a prior course of PR treatment.

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration-QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers.

Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling, and a rational therapeutic target for autoimmune diseases. This first-in-human phase I, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics (PK), target occupancy, and effects on QT interval of evobrutinib, a highly selective, oral inhibitor of BTK, in healthy subjects. This dose escalation trial consisted of two parts. Part 1 included 48 subjects in 6 ascending dose cohorts (25, 50, 100, 200, 350, and 500 mg) randomized to a single dose of evobrutinib or placebo. Part 2 included 36 subjects in 3 ascending dose cohorts (25, 75, and 200 mg/day) randomized to evobrutinib or placebo once daily for 14 days. Safety and tolerability, as well as PK and target occupancy (total and free BTK in peripheral blood mononuclear cells), were assessed following single and multiple dosing. PK parameters were determined by noncompartmental methods. QT interval was obtained from 12-lead electrocardiogram recordings and corrected for heart rate by Fridericia's method (QTcF). Treatment-emergent adverse events (TEAEs) were mostly mild, occurring in 25% of subjects after single dosing, and 48.1% after multiple dosing. There was no apparent dose relationship regarding frequency or type of TEAE among evobrutinib-treated subjects. Absorption was rapid (time to reach maximum plasma concentration (Tmax ) ~ 0.5 hour), half-life short (~ 2 hours), and PK dose-proportional, with no accumulation or time dependency on repeat dosing. BTK occupancy was dose-dependent, reaching maximum occupancy of > 90% within ~ 4 hours after single doses ≥ 200 mg; the effect was long-lasting (> 50% occupancy at 96 hours with ≥ 100 mg). After multiple dosing, full BTK occupancy was achieved with 25 mg, indicating slow turnover of BTK protein in vivo. Concentration-QTcF analyses did not show any impact of evobrutinib concentration on corrected QT (QTc). In summary, evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was associated with no prolongation of QT/QTc interval in healthy subjects. Evobrutinib is, therefore, suitable for investigation in autoimmune diseases.

Searching for Exoplanets Using a Microresonator Astrocomb.

Orbiting planets induce a weak radial velocity (RV) shift in the host star that provides a powerful method of planet detection. Importantly, the RV technique provides information about the exoplanet mass, which is unavailable with the complementary technique of transit photometry. However, RV detection of an Earth-like planet in the 'habitable zone'1 requires extreme spectroscopic precision that is only possible using a laser frequency comb (LFC)2. Conventional LFCs require complex filtering steps to be compatible with astronomical spectrographs, but a new chip-based microresonator device, the Kerr soliton microcomb3-8, is an ideal match for astronomical spectrograph resolution and can eliminate these filtering steps. Here, we demonstrate an atomic/molecular line-referenced soliton microcomb as a first in-the-field demonstration of microcombs for calibration of astronomical spectrographs. These devices can ultimately provide LFC systems that would occupy only a few cubic centimetres9,10, thereby greatly expanding implementation of these technologies into remote and mobile environments beyond the research lab.

Neuropsychological measures in normal individuals that predict subsequent cognitive decline.

OBJECTIVE: To examine neuropsychological measures among normal individuals that predict time to subsequent cognitive decline. DESIGN: Cognitive performance, as measured by 6 neuropsychological tests, was examined at baseline. Participants were followed up for approximately 5 years. Cox proportional hazards models were used to evaluate the neuropsychological measures at baseline that predicted time to progression from normal cognition to mild impairment. Comparable data also examined time to progression from mild impairment to a diagnosis of Alzheimer disease. SETTING: Community volunteer-based sample examined at a medical institution. PARTICIPANTS: One hundred and seven individuals who were cognitively normal and 235 individuals with mild cognitive impairment at baseline. MAIN OUTCOME MEASURES: Time to progression from normal cognition to mild impairment and time to progression from mild impairment to a diagnosis of Alzheimer disease. RESULTS: The risk of progressing from normal to mild impairment was considerably greater among those with lower scores on tests of episodic memory (eg, hazard ratio for a 1-SD decrease in the California Verbal Learning Test, 0.55; P<.001). Normal individuals who carried at least 1 copy of the apolipoprotein E epsilon2 allele were less likely to develop cognitive impairments over time than individuals with no epsilon2 allele (hazard ratio for presence of allele, 0.13; P = .006). Measures of both episodic memory and executive function were significant predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease (eg, hazard ratio for a 1-SD decrease in California Verbal Learning Test score, 0.67; P = .005; hazard ratio for a 1-SD increase in the time to complete part B of the Trail Making test, 1.40; P = .007). Among individuals with mild impairments, the apolipoprotein E epsilon4 allele increased risk for Alzheimer disease in a dose-dependent manner; however, this effect was not significant within the context of multivariable models. CONCLUSIONS: Episodic memory performance among normal individuals predicts time to progression to mild impairment while apolipoprotein E epsilon2 status is associated with lower risk of cognitive decline among normal individuals. Tests of both episodic memory and executive function are predictors of time to progression from mild impairment to a clinical diagnosis of Alzheimer disease.

Effectiveness of Splanchnic Nerve Neurolysis for Targeting Location of Cancer Pain: Using the Pain Drawing as an Outcome Variable.

The effectiveness of splanchnic nerve neurolysis (SNN) for cancer-related abdominal pain has been investigated using numeric pain intensity rating as an outcome variable. The outcome variable in this study used the grid method for obtaining a targeted pain drawing score on 60 patients with pain from pancreatic or gastro-intestinal primary cancers or metastatic disease to the abdominal region. Results demonstrate excellent inter-rater agreement (intra-class correlation [ICC] coefficient at pre-SNN = 0.97 and ICC at within one month post-SNN = 0.98) for the grid method of scoring the pain drawing and demonstrate psychometric generalizability among patients with cancer-related pain. Using the Wilcoxon signed rank test and associated effect sizes, results show significant improvement in dispersion of pain following SNN. Effect sizes for the difference in pre-SNN to 2 post-SNN time points were higher for the pain drawing than for pain intensity rating. Specifically, the effect size difference from pre- to within one month post-SNN was r = 0.42 for pain drawing versus r = 0.23 for pain intensity rating. Based on a smaller subset of patients who were seen within 1 - 6 months following SNN, the effect size difference from pre-SNN was r = 0.46 for pain drawing versus r = 0.00 for pain intensity rating. Collectively, these data support the use of the pain drawing as a reliable outcome measure among patients with cancer pain for procedures such as SNN that target specific location and dispersion of pain.

Interest in Health Behavior Intervention Delivery Modalities Among Cancer Survivors: A Cross-Sectional Study.

BACKGROUND: Effective, broad-reaching channels are important for the delivery of health behavior interventions in order to meet the needs of the growing population of cancer survivors in the United States. New technology presents opportunities to increase the reach of health behavior change interventions and therefore their overall impact. However, evidence suggests that older adults may be slower in their adoption of these technologies than the general population. Survivors' interest for more traditional channels of delivery (eg, clinic) versus new technology-based channels (eg, smartphones) may depend on a variety of factors, including demographics, current health status, and the behavior requiring intervention. OBJECTIVE: The aim of this study was to determine the factors that predict cancer survivors' interest in new technology-based health behavior intervention modalities versus traditional modalities. METHODS: Surveys were mailed to 1871 survivors of breast, prostate, and colorectal cancer. Participants' demographics, diet and physical activity behaviors, interest in health behavior interventions, and interest in intervention delivery modalities were collected. Using path analysis, we explored the relationship between four intervention modality variables (ie, clinic, telephone, computer, and smartphone) and potential predictors of modality interest. RESULTS: In total, 1053 respondents to the survey (56.3% response rate); 847 provided complete data for this analysis. Delivery channel interest was highest for computer-based interventions (236/847, 27.9% very/extremely interested) and lowest for smartphone-based interventions (73/847, 8.6%), with interest in clinic-based (147/847, 17.3%) and telephone-delivered (143/847, 16.9%) falling in between. Use of other technology platforms, such as Web cameras and social networking sites, was positively predictive of interest in technology-based delivery channels. Older survivors were less likely to report interest in smartphone-based diet interventions. Physical activity, fruit and vegetable consumption, weight status, and age moderated relationships between interest in targeted intervention behavior and modality. CONCLUSIONS: This study identified several predictors of survivor interest in various health behavior intervention delivery modalities. Overall, computer-based interventions were found to be most acceptable, while smartphones were the least. Factors related to survivors' current technology use and health status play a role in their interest for technology-based intervention versus more traditional delivery channels. Future health behavior change research in this population should consider participants' demographic, clinical, and lifestyle characteristics when selecting a delivery channel. Furthermore, current health behavior interventions for older cancer survivors may be best delivered over the Internet. Smartphone interventions may be feasible in the future following further adoption and familiarization by this particular population.

Impact of a Yoga Intervention on Physical Activity, Self-Efficacy, and Motivation in Women with PTSD Symptoms.

BACKGROUND: Studies using yoga have demonstrated initial efficacy for treating symptoms across anxiety disorders, including posttraumatic stress disorder. OBJECTIVE: Understanding how interventions influence participants' physical activity and what determinants affect continued physical activity behavior change is important because maintenance of the behavior may be critical to continued mental health gains and symptom reduction. METHODS: This study investigated change in physical activity and possible psychological mechanisms of physical activity behavior change, including self-efficacy and regulatory motivation, in a randomized controlled trial of yoga for women with post-traumatic stress disorder symptoms (n=38). RESULTS: Growth curve modeling results showed no significant changes in physical activity or self-efficacy for either group, whereas external motivation decreased significantly in the yoga group but not in the control group. CONCLUSIONS: Investigators of future yoga interventions may want to focus on increasing self-efficacy and internal regulatory motivation, so that physical activity and resultant symptom relief can be maintained.

Neurolymphomatosis.

The term "neurolymphomatosis" (NL) has included infiltration of the peripheral nervous system by lymphoma and nontumor lymphocytes. We describe NL as a lymphoma entity that affects cranial and peripheral nerves and roots. We reviewed the medical records of patients at the Massachusetts General Hospital (MGH) who registered between 1972 and 2000, as well as cases published in the English-language literature. Inclusion criteria were (A) histopathologic demonstration of lymphoma within peripheral nerve, nerve root/plexus, or cranial nerve or (B) CT/MRI or intraoperative evidence of nerve enlargement and/or enhancement beyond the dural sleeve in the setting of prior or concurrent lymphoma in systemic or CNS sites. We identified 25 patients with NL in addition to 47 reported by others. Four clinical presentations were (1) painful involvement of nerves or roots, (2) cranial neuropathy with or without pain, (3) painless involvement of peripheral nerves, (4) painful or painless involvement of a single peripheral nerve. Twenty of our patients and 44 of those reported had histopathologic confirmation of lymphoma infiltrating root or nerve. In the remainder, diagnosis was based upon clinical presentation, nodular nerve enlargement or enhancement, and lymphoma cells in spinal fluid or extraneural sites. For antemortem diagnosis, imaging studies were of greatest utility, followed by biopsy. Thirty-three patients of the combined series were not correctly diagnosed until postmortem examination. Systemic chemotherapy was used to address the multiple potential sites of involvement. When properly treated, NL carries a prognosis similar to primary CNS lymphoma in the modern era.

DASH to wellness: emphasizing self-regulation through e-health in adults with prehypertension.

OBJECTIVE: High prevalence rates of prehypertension require nonpharmaceutical lifestyle interventions. The objective of this study was to assess the feasibility and initial efficacy of a primarily electronically delivered intervention for prehypertension. METHODS: Twenty-three adults with prehypertension (M age of 54.3; systolic blood pressure [BP], 126.3 mmHg; weight, 87.8 kg; body mass index, 31.5; 6514 steps/day) were randomized to DASH 2 wellness only standard of care or to DASH 2 wellness plus. Both groups received instruction on the DASH eating plan, instructions to increase steps per day and use of a weight scale and pedometer, and information about social-cognitive theory-based self-regulation strategies. D2W plus also involved home blood pressure monitoring and monitoring steps per day, nutrition, and body weight. Through weekly newsletters, participants engaged in electronic reporting and goal setting and received feedback on progress. RESULTS: D2W plus showed a larger increase in daily steps (M = 2,900) than D2W only (M = 636); a larger decrease in systolic BP (mmHg), M = 15.1 versus M = 4.6, and a larger decrease in weight (in kg), M = 4.8 versus M = 1.5. CONCLUSIONS: Concentrating efforts not only toward adoption and initiation of innovative risk-reduction strategies but also toward the provision for long-term maintenance of a healthy lifestyle once initial changes have been accomplished is paramount. The D2W plus program could be adapted for such use in health care and other settings for treating prehypertension.

Telaprevir-related dermatitis.

OBJECTIVE: To evaluate the incidence, type, and severity of telaprevir-associated skin reactions. DESIGN: Three dermatologists assessed available information including photographs, biopsy results, and clinical summaries of all cases with skin eruptions reported as moderate or severe during the telaprevir clinical development program. For cases from placebo-controlled trials, they were masked to exposure. SETTINGS: Phase 1 to 3 studies of telaprevir combination therapy for hepatitis C. PATIENTS: All patients with skin eruptions enrolled in telaprevir clinical trials prior to 2011 MAIN OUTCOME MEASURES: Incidence, diagnosis, morphologic features, extent, and severity of skin eruption. RESULTS: Skin eruptions were more frequent in patients who received telaprevir as part of hepatitis C treatment compared with pegylated interferon (peginterferon) and ribavirin alone (56% vs 34% overall; 3.7% vs 0.4% severe). Occurring at any time during the 12 weeks of telaprevir combination regimen, in more than 90% of cases, this eruption is pruritic eczematous dermatitis. None of the clinical or genetic factors examined were substantial risk factors for dermatitis. Three cases of Stevens-Johnson Syndrome (SJS), and 11 cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were suspected, with 2 SJS and 3 DRESS cases considered likely. CONCLUSIONS: Telaprevir-related dermatitis occurs in a majority of telaprevir-treated patients. It is an eczematous dermatitis that differs in timing and appearance from the eruptions usually associated with drug reactions. The strong signal for an increased risk of DRESS or SJS requires particular vigilance in telaprevir-treated patients.