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Galcanezumab; Chronic migraine; Preventive treatment Galcanezumab; Migraña crónica; Tratamiento preventivo Galcanezumab; Migranya crònica; Tractament preventiu Background Galcanezumab, a monoclonal antibody to calcitonin gene-related peptide, was found to be safe and efficacious for the preventive treatment of chronic migraine based on the randomized, placebo-controlled double-blind period of the REGAIN study. Long-term safety and efficacy were assessed in an open-label extension. Methods Patients 18–65 years old with chronic migraine completing the 3-month double-blind period of REGAIN could enter a 9-month open-label extension (OLE; months 4–12). Upon entering the OLE, patients received a 240-mg galcanezumab loading dose, then 120 mg at the next month, with flexible dosing thereafter (120 or 240 mg/month). The primary efficacy measure was the mean change in the number of monthly migraine headache days from double-blind baseline to month 12. Other endpoints included response rates (based on percent reduction in monthly migraine headache days from double-blind baseline to month 12), safety and tolerability. Results Of patients who completed double-blind treatment, 1022 (99%) entered the OLE, with 81% completing month 12. From a baseline of 19.4 monthly migraine headache days at the beginning of the double-blind period, patients at month 12 in the previous placebo, 120-mg, and 240-mg galcanezumab groups had a mean change of −8.5, −9.0, and −8.0, respectively (SE = 0.43 to 0.55, within-group p’s < .001). At month 12, the percentage of patients with ≥50% response was 57%, 57%, and 53%, respectively. Percentage with ≥75% response was 32%, 31%, and 30%, respectively. Percentage with 100% response was 8%, 6%, and 6%, respectively. There were no significant new safety findings during the open-label period. The incidence of discontinuation from the OLE due to adverse events was 5%. Conclusion Galcanezumab was effective, safe, and well-tolerated, with high adherence, for up to 12 months of treatment in patients with chronic migraine.

SummaryPurpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.

Medullary thyroid cancer; Tyrosine kinase inhibitor Cáncer medular de tiroides; Inhibidor de la tirosina cinasa Càncer medul·lar de tiroide; Inhibidor de la tirosina cinasa The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by off-target toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naïve patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach. This manuscript was funded by Eli Lilly and Company. The funder reviewed the manuscript and was involved in the decision to submit it for publication.

Introduction: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. Methods: Endpoints at week 16 included proportions of responders (C 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, IntroductionCombining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo.MethodsEndpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders.ResultsPooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints.ConclusionResponders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

Diabetic cardiomyopathy (CM), occurring in the absence of hypertension, coronary artery disease, and valvular or congenital heart disease, is now recognized as a distinct, multifactorial disease leading to ventricular hypertrophy and abnormal myocardial contractility that correlates with an array of complex molecular and cellular changes. Animal models provide the unique opportunity to investigate mechanistic aspects of diabetic CM, but important caveats exist when extrapolating findings obtained from preclinical models of diabetes to humans. Indeed, animal models do not recapitulate the complexity of environmental factors, most notably the duration of the exposure to insulin resistance that may play a crucial role in the development of diabetic CM. Moreover, most preclinical studies are performed in animals with uncontrolled or poorly controlled diabetes, whereas patients tend to undergo therapeutic intervention. Finally, whilst type 2 diabetes mellitus prevalence trajectory mainly increases at 40- < 75 years (with a currently alarming increase at younger ages, however), it is a legitimate concern how closely rodent models employing young animals recapitulate the disease developing in old people. The aim of this review is to identify the current limitations of rodent models and to discuss how future mechanistic and preclinical studies should integrate key confounding factors to better mimic the diabetic CM phenotype.

International audience; Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management. Copyright

International audience

International audience; AimTo assess impact of pre-specified patient characteristics on efficacy and safety of subcutaneous tanezumab in patients with osteoarthritis (OA).MethodsData were pooled from two (efficacy; N = 1545) or three (safety; N = 1754) phase 3 placebo-controlled trials. Change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and patient global assessment of OA (PGA-OA) scores was compared between tanezumab (2.5 and 5 mg) and placebo groups via analysis of covariance. Treatment-emergent adverse events (TEAEs) were summarized descriptively. Analyses were done in patient subgroups (male or female; age

Introduction Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points• Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease.• A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis.• Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

Targeting various disease pathways using monoclonal antibodies (mAbs) has transformed the treatment paradigm for inflammatory bowel disease (IBD), with these agents exhibiting improved efficacy over corticosteroids or immunosuppressive therapies. Antibodies targeting tumor necrosis factor α (TNF-α) were the first approved biologics for IBD, followed by the more recent approval of antibodies targeting the α4β7 integrin heterodimer and ustekinumab, which targets the p40 subunit of interleukin-23. Current efforts are focused on the development of additional biologics targeting these known and other newly discovered pathways. Still significant unmet needs remain, as a large proportion of patients either fail to achieve remission or fail to respond altogether. Both Crohn's disease and ulcerative colitis are complex and heterogeneous diseases with several molecular pathways involved in disease pathophysiology. We propose an additional therapeutic approach to the treatment of IBD, bispecific antibodies (BsAbs), which combine two distinct binding specificities within a single biologic to allow the simultaneous targeting of multiple disease-causing cytokines or pathways. Although primarily used in oncology thus far, the unique combinatorial mechanism of action of BsAbs may provide new therapeutic options for a broad range of clinical applications, including autoimmune and inflammatory diseases. This review will discuss the current status of BsAb development in general and potentially therapeutic application in IBD.

Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA).These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study.Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes.Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points.High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity. Trial registration NCT03151551 Key Points • Treatment goals for patients with psoriatic arthritis emphasise the importance of improving both musculoskeletal and non-musculoskeletal manifestations of the disease. • A combined endpoint considering both these manifestations, achievement of at least 50% improvement in American College of Rheumatology criteria and 100% improvement in Psoriasis Area Severity Index, was linked with achievement of a number of other endpoints relevant to psoriatic arthritis, including health-related quality of life that are important to patients with psoriatic arthritis. • Patients meeting the combined endpoint were more likely to achieve a disease state of remission, which is the stated aim of treatment for psoriasis.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

Purpose Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A. The objective of this study was to assess the long-term efficacy and safety (to week 156) of ixekizumab in patients with active psoriatic arthritis and inadequate response or intolerance to one or two tumor necrosis factor inhibitors. Methods In the SPIRIT-P2 study (ClinicalTrials.gov ID: NCT02349295), patients were randomized to placebo or ixekizumab 80 mg every 4 weeks (IXE Q4W) or every 2 weeks (IXE Q2W) following a 160-mg starting dose. During the extension period (weeks 24–156), patients maintained their original ixekizumab dose, and placebo patients received IXE Q4W or IXE Q2W (1:1). Exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are presented. Results Of 363 patients enrolled in the study, 310 entered the extension period. In all patients treated with IXE Q4W and IXE Q2W at week 0, responses persisted to week 156. At week 156, clinical responses (observed) in patients treated with IXE Q4W and IXE Q2W were assessed [American College of Rheumatology (ACR) response criteria and minimal disease activity (MDA) criteria]: 84 and 85% showed 20% improvement (ACR20); 60 and 58% showed 50% improvement (ACR50); 35 and 47% showed 70% improvement (ACR70), respectively; and 48 and 54% showed MDA. Placebo patients re-randomized to ixekizumab also demonstrated sustained efficacy, as measured by ACR and MDA responses. In the All Ixekizumab Exposure Safety Population (n = 337), with 644 PY of ixekizumab exposure, treatment-emergent adverse events (TEAEs) were reported by 286 patients (44.4 IR). The most common TEAEs were upper respiratory tract infection (9.80 IR), nasopharyngitis (8.2 IR), sinusitis (6.2 IR), and bronchitis (4.5 IR). Serious adverse events were reported by 42 (6.5 IR) patients (included 3 deaths and 10 infections). Conclusion In this 156-week study of ixekizumab, improvements in signs and symptoms of psoriatic arthritis and the safety profile remained consistent with those in previous reports. Trial registration ClinicalTrials.gov identifier: NCT02349295. Electronic supplementary material The online version of this article (10.1007/s40744-020-00261-0) contains supplementary material, which is available to authorized users.

Introduction Patients with ankylosing spondylitis (AS) are burdened with symptoms impacting work productivity measured by presenteeism, absenteeism, overall work impairment, and activity impairment. Ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been demonstrated to improve disease signs and symptoms in two phase 3 trials of AS. This study investigated for 52 weeks the effect of ixekizumab treatment on work productivity in patients with active AS. Methods COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, controlled trials investigating the efficacy of ixekizumab 80 mg every 4 weeks (Q4W) and every 2 weeks (Q2W) in patients with AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) or who were inadequate responders or intolerant to tumor necrosis factor inhibitors (TNFi; COAST-W). Work productivity was measured with the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis at weeks 16 and 52. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work. Activity impairment was assessed regardless of work status. Results At baseline, 66.2% (434/656) of patients reported paid work. At week 16, bDMARD-naïve patients treated with both ixekizumab dose regimens and TNFi-experienced patients treated with ixekizumab Q2W reported significant improvements in activity impairment (p

OBJECTIVE: This study examines European decision makers' consideration and use of quantitative preference data.; METHODS: The study reviewed quantitative preference data usage in 31 European countries to support marketing authorization, reimbursement, or pricing decisions. Use was defined as: agency guidance on preference data use, sponsor submission of preference data, or decision-maker collection of preference data. The data could be collected from any stakeholder using any method that generated quantitative estimates of preferences. Data were collected through: (1) documentary evidence identified through a literature and regulatory websites review, and via key opinion leader outreach; and (2) a survey of staff working for agencies that support or make healthcare technology decisions.; RESULTS: Preference data utilization was identified in 22 countries and at a European level. The most prevalent use (19 countries) was citizen preferences, collected using time-trade off or standard gamble methods to inform health state utility estimation. Preference data was also used to: (1) value other impact on patients, (2) incorporate non-health factors into reimbursement decisions, and (3) estimate opportunity cost. Pilot projects were identified (6 countries and at a European level), with a focus on multi-criteria decision analysis methods and choice-based methods to elicit patient preferences.; CONCLUSION: While quantitative preference data support reimbursement and pricing decisions in most European countries, there was no utilization evidence in European-level marketing authorization decisions. While there are commonalities, a diversity of usage was identified between jurisdictions. Pilots suggest the potential for greater use of preference data, and for alignment between decision makers. Copyright © 2020 ISPOR-The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.

ObjectiveTo compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic (bDMARD)-naïve RA patients using matching-adjusted indirect comparisons (MAICs).MethodsData were from Phase III trials on patients receiving monotherapy baricitinib, tocilizumab, adalimumab, tofacitinib or MTX. Pain was assessed using a visual analogue scale (0–100 mm) and physical function using the Health Assessment Questionnaire-Disability Index (HAQ-DI). An MAIC based on treatment-arm matching, an MAIC with study-level matching and Bucher’s method without matching compared change in outcomes between therapies. Matching variables included age, gender, baseline disease activity and baseline value of outcome measure.ResultsWith all methods, greater improvements were observed in pain and HAQ-DI at 6 months for baricitinib compared with adalimumab and tocilizumab (pConclusionsResults suggest greater pain reduction and improved physical function for baricitinib monotherapy compared with tocilizumab and adalimumab monotherapy. No statistically significant differences in pain reduction and improved physical function were observed between baricitinib and tofacitinib with the MAIC analyses.

Background The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3). Methods Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events. Results Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6). Conclusions The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis. Trial registration SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

ObjectiveTanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.MethodsThis double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study.ResultsFrom March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, pConclusionTanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups.Trial registration numberNCT02709486.

Background & Aims: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP≥400ng/mL by three prespecified age subgroups (

International audience; No abstract available

Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p &lt, 0.001 and p &lt, 0.01, respectively) and adalimumab (p &lt, 0.05 for both). For both outcomes, differences between adalimumab and placebo were not significant. The proportions of patients in remission or low disease activity with minimal or no pain and with normalised physical function were numerically greater with baricitinib than placebo. Baricitinib 4 mg once daily provided enhanced improvement in pain and physical function in patients with well-controlled RA, suggesting it may produce effects beyond immunomodulation.

Patients with rheumatoid arthritis (RA) have a high prevalence of comorbidities.1 This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of baricitinib 4 mg once daily in patients with moderate-to-severe active RA and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Data from the placebo-controlled periods of five baricitinib studies2–6 were pooled for baricitinib 4 mg; data for baricitinib 2 mg were not analysed due to low (n=302) patient numbers. Additional data for all baricitinib-treated patients with a median exposure of 2 years were derived from an ongoing open-label, long-term extension (LTE) study that included patients from phase II and III studies (RA-BEYOND; NCT01885078).7 Efficacy outcomes were evaluated at week 12 (vs placebo). Interaction of comorbidity-by-treatment was analysed using logistic regression or analysis of covariance. Safety observations up to week 16 (vs placebo) and during the LTE were summarised by the Medical Dictionary for Regulatory Activities preferred term. Data from 1684 patients (803, baricitinib 4 mg; 881, placebo) from the placebo-controlled periods were analysed. The mean (SD) age was 52.7 (12.1) years, with only 38 (2.3%) patients aged ≥75 years; most patients (1506, 89.4%) were receiving background methotrexate, alone or in combination with another csDMARD. The numbers of patients receiving placebo and baricitinib 4 mg combined (with or without each comorbidity, respectively) were 133/1551 for depression, 247/1437 for osteoporosis, 424/1260 for hepatic disorders, 731/953 for cardiovascular disorders, and 166/1518 for pulmonary disorders. Demographic and clinical characteristics within each comorbidity subgroup were similar between patients randomised to baricitinib or placebo. Higher …

ObjectiveWe aimed to study the epidemiology of the prodromal and mild stages of Alzheimer’s disease (AD) patients who are eligible for clinical trials with disease-modifying therapies.SettingsWe analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed.ParticipantsPatients, 50–85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders.Primary outcome measureDescriptive statistics of the population of interest was the primary measure.ResultsIn the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients.ConclusionsAD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.

International audience; BACKGROUND:In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial, the prasugrel pre-treatment strategy versus placebo was associated with excess bleeding complications and no improved ischemic outcome in non-ST-segment elevation myocardial infarction (MI). Whether patients with the longest pre-treatment duration had an ischemic benefit is unknown.OBJECTIVES:This pre-specified analysis of the ACCOAST trial aimed to assess the effect of pre-treatment duration with prasugrel (time from randomization to angiography) on outcomes.METHODS:Within the 4,033 patients randomized in the ACCOAST trial, pre-treatment duration was available in 4,001 patients (99.2%). The population of the trial was divided into quartiles of pre-treatment duration (0.1 to 2.5 h, 2.5 to 3.9 h, 3.9 to 13.6 h, and >13.6 h) with an evaluation of the primary efficacy endpoint of cardiovascular death, MI, stroke, urgent revascularization or glycoprotein IIb/IIIa inhibitor bailout use. Secondary efficacy outcomes including cardiovascular death, MI, or stroke; all-cause death; stent thrombosis and safety outcomes (all coronary artery bypass graft [CABG] or non-CABG TIMI [Thrombolysis In Myocardial Infarction] major bleeding) were also evaluated at 7 days.RESULTS:The primary efficacy outcome of cardiovascular death, MI, stroke, urgent revascularization or glycoprotein IIb/IIIa inhibitor bailout use did not differ between the quartiles of pre-treatment duration in the trial population (p = 0.17 for interaction). None of the secondary efficacy outcomes were found to be dependent on pre-treatment duration. The safety outcome of all CABG or non-CABG TIMI major bleeding did not differ between the quartiles of pre-treatment duration (p = 0.37 for interaction).CONCLUSIONS:In non-ST-segment elevation MI patients, the excess risk of bleeding and the absence of ischemic benefit were consistent across the quartiles of increasing duration of prasugrel pre-treatment. (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction [ACCOAST]; NCT01015287).

Background: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. Methods: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. Findings: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0–12·5), median overall survival (8·5 months [95% CI 7·0–10·6] vs 7·3 months [5·4–9·1]; hazard ratio [HR] 0·710 [95% CI 0·531–0·949]; p=0·0199) and progression-free survival (2·8 months [2·8–4·1] vs 1·6 months [1·5–2·7]; 0·452 [0·339–0·603]; p

International audience; OBJECTIVE:To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).METHODS:In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed.RESULTS:A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging-evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group).CONCLUSION:Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo.

Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods:The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3- 6µg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean±SD 3.4±1.4) was greater than in non-carriers (2.0±1.4; P

The REVEL study demonstrated improved efficacy with ramucirumab plus docetaxel versus placebo plus docetaxel for previously treated advanced/metastatic non-small-cell lung cancer (NSCLC) without further detriment to patient quality of life, symptoms, or functioning. This post hoc analysis explored the association between baseline Lung Cancer Symptom Scale (LCSS) Average Symptom Burden Index (ASBI) and efficacy.Baseline ASBI scores were the average of the 6 LCSS symptom components. Low and high symptom burden (LSB ≤ median, HSB median) were analyzed across and by treatment arms for effects on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) using the Kaplan-Meier method and Cox proportional hazards model.Baseline LCSS compliance was approximately 78% in both REVEL treatment arms. Patients with LSB versus HSB had fewer poor prognostic factors. The HSB patient population significantly overlapped with previously identified aggressive disease subgroups (rapidly progressing disease or refractory to first-line treatment). Patients with LSB versus HSB had significantly improved OS (P 0.0001), PFS (P 0.0001), and ORR (P = 0.0003) regardless of treatment, with superior ORR and PFS but not OS in the ramucirumab plus docetaxel arm. Patients with HSB treated with ramucirumab plus docetaxel versus docetaxel had improved OS (median, 7.39 vs. 5.95 months; HR 0.749 [95% CI 0.610-0.920]; P = 0.0308), PFS (median, 4.01 vs. 2.63 months; HR 0.749 [0.619-0.907]; P = 0.0202), and ORR (18% vs. 11%; P = 0.0458). Of patients with rapidly progressing disease, 57% (92/162) also had HSB.Baseline ASBI may be an independent prognostic factor in this large second-line cohort of patients with advanced NSCLC. The preservation of improved PFS and OS in the HSB cohort suggests that the addition of ramucirumab to docetaxel provides benefit in patients with greater symptom burden, consistent with previous data on REVEL patients with aggressive disease.

International audience; OBJECTIVES:To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function.METHODS:In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function.RESULTS:Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p

INTRODUCTION: Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

International audience; To explore the variability in biosensor studies, 150 participants from 20 countries were given the same protein samples and asked to determine kinetic rate constants for the interaction. We chose a protein system that was amenable to analysis using different biosensor platforms as well as by users of different expertise levels. The two proteins (a 50-kDa Fab and a 60-kDa glutathione S-transferase [GST] antigen) form a relatively high-affinity complex, so participants needed to optimize several experimental parameters, including ligand immobilization and regeneration conditions as well as analyte concentrations and injection/dissociation times. Although most participants collected binding responses that could be fit to yield kinetic parameters, the quality of a few data sets could have been improved by optimizing the assay design. Once these outliers were removed, the average reported affinity across the remaining panel of participants was 620 pM with a standard deviation of 980 pM. These results demonstrate that when this biosensor assay was designed and executed appropriately, the reported rate constants were consistent, and independent of which protein was immobilized and which biosensor was used. (C) 2008 Elsevier Inc. All rights reserved.

The pathophysiology of depression remains enigmatic, although abnormalities in serotonin signaling have been implicated. We have found that the serotonin 1B receptor [5-hydroxytryptamine (5-HT 1B ) receptor] interacts with p11. p11 increases localization of 5-HT 1B receptors at the cell surface. p11 is increased in rodent brains by antidepressants or electroconvulsive therapy, but decreased in an animal model of depression and in brain tissue from depressed patients. Overexpression of p11 increases 5-HT 1B receptor function in cells and recapitulates certain behaviors seen after antidepressant treatment in mice. p11 knockout mice exhibit a depression-like phenotype and have reduced responsiveness to 5-HT 1B receptor agonists and reduced behavioral reactions to an antidepressant.