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Microtubule-dependent movement is crucial for the spatial organization of endosomes in most eukaryotes, but as yet there has been no systematic analysis of how a particular microtubule motor contributes to early endosome dynamics. Here we tracked early endosomes labeled with GFP-Rab5 on the nanometer scale, and combined this with global, first passage probability (FPP) analysis to provide an unbiased description of how the minus-end microtubule motor, cytoplasmic dynein, supports endosome motility. Dynein contributes to short-range endosome movement, but in particular drives 85-98% of long, inward translocations. For these, it requires an intact dynactin complex to allow membrane-bound p150(Glued) to activate dynein, since p50 over-expression, which disrupts the dynactin complex, inhibits inward movement even though dynein and p150(Glued) remain membrane-bound. Long dynein-dependent movements occur via bursts at up to ∼8 µms(-1) that are linked by changes in rate or pauses. These peak speeds during rapid inward endosome movement are still seen when cellular dynein levels are 50-fold reduced by RNAi knock-down of dynein heavy chain, while the number of movements is reduced 5-fold. Altogether, these findings identify how dynein helps define the dynamics of early endosomes.

Summary Long-term bone mineral density (BMD) gains, bone marker levels, and safety of 3 mg quarterly intravenous (IV) ibandronate were studied in this 3-year extension to the Dosing IntraVenous Administration (DIVA) trial. Quarterly IV ibandronate consistently increased lumbar spine bone mineral density measured with dual-energy X-ray absorptiometry (DXA-BMD) over 5 years (8.1%) and was well tolerated in women with postmenopausal osteoporosis. Introduction Treatment with IV ibandronate regimens, 2 mg bimonthly and 3 mg quarterly, has been studied for up to 5 years in a long-term extension (LTE) to the 2-year DIVA trial. Methods DIVA LTE is an open-label extension to a 2-year randomized, double-blind, double-dummy, noninferiority, phase III study (DIVA core). DIVA LTE involved postmenopausal women who had completed 2 years of DIVA core, comparing daily oral and IV ibandronate (≥75% adherence with IV ibandronate in year 2 of DIVA). Patients previously treated with 2 mg bimonthly or 3 mg quarterly IV ibandronate continued on the same regimen; patients who had received 2.5 mg daily oral ibandronate and placebo IV in DIVA core were switched to IV ibandronate. Results Pooled analysis of 497 intent-to-treat (ITT) patients receiving IV ibandronate from DIVA core baseline showed consistent increases over 5 years in lumbar spine DXA-BMD (8.4% [95% confidence interval (CI) = 7.5, 9.3] with 2 mg bimonthly and 8.1% [95% CI = 7.2, 8.9] with 3 mg quarterly). Three-year data relative to DIVA LTE baseline in the full ITT population (756 patients randomized or reallocated from DIVA, including those previously on daily treatment) showed maintenance of DXA-BMD gains from DIVA core with further gains in lumbar spine DXA-BMD. These benefits are supported by sustained reductions in markers of bone metabolism. No tolerability concerns or new safety signals were observed. Conclusions Treatment with IV ibandronate 2 mg bimonthly or 3 mg quarterly is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

Summary The long-term efficacy and safety of once-monthly ibandronate were studied in this extension to the 2-year Monthly Oral Ibandronate in Ladies (MOBILE) trial. Over 5 years, lumbar spine bone mineral density (BMD) increased from baseline with monthly ibandronate 150 mg (8.4%). Long-term monthly ibandronate is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis. Introduction Once-monthly therapy with ibandronate has been studied for up to 5 years in a long-term extension (LTE) to the 2 year MOBILE trial. Methods This multicenter, double-blind extension study of monthly ibandronate involved postmenopausal women who had completed 2 years of the MOBILE core study, with ≥75% adherence. Patients were reallocated, or were randomized from daily therapy, to ibandronate 100 mg monthly or 150 mg monthly for a further 3 years. Results A pooled intent-to-treat (ITT) analysis of 344 patients receiving monthly ibandronate from the core MOBILE baseline showed increases over 5 years in lumbar spine BMD (8.2% with 100 mg and 8.4% with 150 mg). Three-year data relative to MOBILE LTE baseline in the full ITT population of all 698 patients randomized or reallocated from MOBILE (including those previously on daily treatment) showed, on average, maintenance of proximal femur BMD gains achieved in the core 2-year study, with further small gains in lumbar spine BMD. In general, maintenance of efficacy was also indicated by markers of bone metabolism. Conclusions There were no tolerability concerns or new safety signals. Monthly treatment with ibandronate 100 and 150 mg is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting the joints. A heterogeneous response to available therapies demonstrates the need to identify those patients likely to benefit from a particular therapy. Our objective was to identify genetic factors associated with response to tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor, recently approved for treating RA. We report the first genome-wide association study on the response to tocilizumab in 1683 subjects with RA from six clinical studies. Putative associations were identified with eight loci, previously unrecognized as linked to the IL-6 pathway or associated with RA risk. This study suggests that it is unlikely that a major genetic determinant of response exists, and it illustrates the complexity of performing genome-wide association scans in clinical trials.

Background RA characterized by poly-articular and synovial inflammation, cartilage loss and erosion of subchondral bone. It is critical to diagnose and effectively treat the disease early to suppress inflammation and prevent destruction of the joint. Thus, identification of the patients most likely to respond to a given intervention may be pursued for optimal benefits for both patients and payers. Objectives To investigate early changes in biomarkers of bone, cartilage, synovium and inflammation as an effect of tocilizumab (TCZ) treatment, and to identify profiles associated with responders and non-responders. Methods The LITHE study (Roche WA17823) is a 2-year phase III, 3-arm randomized, double-blind, placebo-controlled, parallel group, with moderate/severe active RA, inadequate response to MTX. 1196 patients were randomized to the 3 treatment groups: TCZ8mg/kg (TCZ8), TCZ4mg/kg or placebo. Every 4 weeks, patients received an infusion of TCZ8 mg/kg or 4mg/kg placebo for a total of up to 13 infusions in 52 weeks. Escape patients was defined as those who experienced <20% improvement in both swollen (SJC) and tender joint counts (TJC) at week 16. These patients were designated non-responders in current sub-study. The sub-study only the TCZ8 group was investigate and fasted serum was analyzed baseline and week 4weeks. Following biomarkers were measured: C2M (cartilage degradation), C3M (synovial inflammation), MMP3, total CRP, CRPM (MMP-degraded CRP), VICM (Citrullinated and MMP degraded Vimentin), ICTP (MMP destroyed type I collagen), osteocalcin (bone formation) and CTX-I (Bone resorption). The sub-study consisted of 102 responders and 33 non-responders. Data is shown as percentage change from baseline (Mann-Whitney test). Results Cartilage degradation - C2M - was reduced to 90.4% of baseline levels upon treatment with TCZ8 in the responder group, whereas the level of C2M was increased to 111% of baseline level in the non-responder group (p=0.0031). Synovial tissue turnover, C3M, was decreased to 77.3% of baseline in the responder group, compared to 90.5% in the non-responder group (p=0.0034). MMP-3, ICTP and Citrullinated vimentin decreased to approx. 85% of baseline and there were no difference between the groups. The general inflammatory marker hsCRP was decreased in both responders and non-responders to approx. 35%, with no significant ability to separate these groups. In contrast, there was a significant difference between the level of MMP cleaved CRP, CRPM (p=0.031). The level of CRPM was decreased to 75.9% in the responder group and only to 85.9% in non-responder group. There were only minimal significant differences in the bone resorption and bone formation markers. Conclusions The novel biomarkers of cartilage and synovial turnover were able to discriminate between responders and non-responders to IL-6 intervention, in contrast to traditional CRP and bone markers. Whether the markers may reflect the same response and power for prediction to other biological interventions need to be investigated. TCZ strongly inhibited cartilage degradation and inflammation mediated tissue turnover which may explain the clinical benefits of this biological intervention. Disclosure of Interest None Declared

In a randomized trial involving children with severe systemic juvenile idiopathic arthritis, the anti–interleukin-6 receptor antibody tocilizumab was effective (response rate, 85% with tocilizumab vs. 24% with placebo). Adverse events included serious infections and neutropenia. Systemic juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis, systemic manifestations (spiking fever, rash, hepatosplenomegaly, lymphadenopathy, and serositis), and substantially elevated inflammatory markers. 1 It is the most severe subtype of JIA; approximately half the patients have an unremitting course of chronic polyarthritis (with or without persistent systemic features). Substantial joint damage and disability often develop in these patients. 2 , 3 Treatment remains challenging because of the limited efficacy of methotrexate 4 and tumor necrosis factor inhibitors 5 , 6 and because of the major toxicity of high-dose glucocorticoids. Efficacy of the interleukin-1 inhibitor anakinra has been reported in a subset of patients. 7 – . . .

Background The IL-6 receptor inhibitor TCZ was investigated for the treatment of sJIA patients (pts) in the ongoing 3-part, 5-y, phase 3 TENDER study. Objectives Long-term efficacy and safety are presented. Methods 112 pts 2-17 y with active sJIA for ≥6 mo were randomised 2:1 to TCZ (8 mg/kg if body weight ≥30 kg; 12 mg/kg if <30 kg, n=75) or placebo (n=37) every 2 wks for 12 wks in part 1; all pts received open-label TCZ in part 2 (to 104 wks). Oral corticosteroid (CS) tapering was permitted according to pre-defined criteria. Data were cut for each ongoing pt 104 wks from randomisation, with first dose of TCZ as baseline (BL) in the extension. At the data cut, 61 pts received ≥104 wks of TCZ, 32 pts were ongoing and 20 withdrew, including 1 at wk 104 (safety, 9; insufficient therapeutic response, 5; other non-safety, 6). Results BL characteristics included mean disease duration of 5.2 y, mean active joint count of 19.8 and presence of fever in 43% of pts. At 2 y, 88% and 71% of pts on TCZ achieved JIA ACR70 and 90 responses (Table 1). In pts on oral CS at BL, 60% stopped by wk 104, and mean dose decreased from 0.30 mg/kg/d at BL to 0.04 at wk 104. 47 serious adverse events (SAEs), 15 considered TCZ-related, occurred in 35 pts (Table 2). Of 22 serious infections (8 considered TCZ-related) in 20 pts, all but 1 resolved (pt death). 3 pts died (1, suspected tension pneumothorax; 1 traffic accident [both unrelated]; 1 suspected streptococcal sepsis; possibly related]). 3 additional pts died 6, 12 and 13 mos after leaving the study. Table 1. Efficacy Endpoints (ITT Population) Wk 12aWk 52bWk 104b Placebo (N=37)TCZ (N=75)TCZ (N=106)TCZ (N=65) JIA ACR70/90, n (%)3 (8)/2 (5)c53 (71)/28 (37)c92 (87)/67 (63)e57 (88)/46 (71)e Active joints, mean (SD)9.5 (9.0)d7.3 (11.9)d2.8 (6.4)f1.9 (3.6)f Absence of active joints, n (%)2 (5)12 (16)50 (47)e36 (55)e aBL was date of randomisation. bBL was first dose of TCZ. c% is based on all pts; those who withdrew or escaped were assumed non-responders. dPts who withdrew or escaped were excluded. e% is based on number of pts who reached time point + pts who withdrew because of insufficient therapeutic response and are assumed to have been non-responders. fPts who withdrew have been excluded at post-withdrawal visits. Table 2. Cumulative Safety (Safety Population, N=112) Prior Safety UpdateaWk 104b Exposure to TCZ, y157.46202.03 SAEs/100PY (n)24.8 (39)23.3 (47) Serious infection AEs/100PY (n)11.4 (18)10.9 (22) SAEs related (remotely, possibly, probably) to TCZ/100PY (n)8.3 (13)7.4 (15) AEs leading to withdrawal/100PY (n)3.8 (6)c3.0 (6)c Deaths/100PY (n)0.6 (1)1.5 (3) PY, pt-years. aIncludes all safety data up to 10 Aug 2010. bAll safety data up to wk 104 infusion for each pt. Last date for this was 31 May 2011. cIncludes 2 withdrawals (protocol mandated) for transaminase increases. Conclusions TENDER 2-y results demonstrated continued maintenance of efficacy and no change in the safety profile with long-term TCZ treatment. Disclosure of Interest F. De Benedetti Grant/Research support from: Abbott, BMS, Pfizer, SOBI, Novimmune, Roche, Novartis, Consultant for: BMS, Pfizer, Roche, H. Brunner Consultant for: Genentech, Novartis, UCB, Jansen, Medimmune, GSK, BMS, PFizer, Employee of: Cincinnati Children’s Hospital Medical Center, N. Ruperto Grant/Research support from: Abbott, Astrazeneca, BMS, Centocor Research and Development, Eli Lilly and Company, “Francesco Angelini” s.p.a., GSK, Italfarmaco, Merk Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speakers Bureau: Astrazeneca, BMS, Jansen Biologics BV, Novartis, Roche, A. Kenwright Employee of: Roche, C. Devlin Shareholder of: Roche, Employee of: Roche, I. Calvo: None Declared, R. Cuttica Grant/Research support from: Novartis, Hoffmann-La Roche, Consultant for: Hoffmann-La Roche, Speakers Bureau: Hoffmann-La Roche, A. Ravelli: None Declared, R. Schneider: None Declared, D. Eleftheriou: None Declared, C. Wouters: None Declared, R. Xavier Consultant for: Pfizer, Roche, Speakers Bureau: Pfizer, Roche, Abbott, L. Zemel: None Declared, E. Baildam: None Declared, R. Burgos-Vargas Grant/Research support from: Abbott, Consultant for: Abbott, BMS, Jannsen, Pfizer, Roche, Speakers Bureau: Abbott, BMS, Jannsen, Pfizer, Roche, P. Dolezalova Grant/Research support from: Novatis, Speakers Bureau: BMS, Novartis, S. M. Garay: None Declared, R. Joos: None Declared, A. Grom Consultant for: Novartis, Merck, N. Wulffraat: None Declared, Z. Zuber: None Declared, F. Zulian: None Declared, D. Lovell Grant/Research support from: BMS, Abbott, Consultant for: Astrazeneca, Wyeth, Amgen, Pfizer, Regeneron, Roche, Novartis, UMC, Xoma, A. Martini Grant/Research support from: Abbott, Astrazeneca, BMS, Centocor Research and Development, Eli Lilly and Company, “Francesco Angelini” s.p.a., GSK, Italfarmaco, Merk Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speakers Bureau: Astrazeneca, Novartis, BMS, GSK

Background Elevated IL-6 levels are associated with disease activity in patients (pts) with juvenile idiopathic arthritis (JIA).1 Tocilizumab (TCZ), an IL-6 receptor inhibitor, was evaluated for the treatment of polyarticular-course JIA (pcJIA; RF+ and RF– poly- and extended oligoarticular JIA) in the CHERISH study. Methods CHERISH is a 104-wk study in pts age 2-17 y with active pcJIA for ≥6 mo who failed MTX. Prior to wk 16, all pts received open-label (OL) TCZ every 4 wks (if body weight [BW] ≥30 kg, 8 mg/kg [n=119]; if BW <30 kg, pts randomly assigned to 8 mg/kg [n=34] or 10 mg/kg [n=35]). At wk 16, eligible pts (with ≥JIA ACR30 response) entered a 24-wk randomised (pts assigned [1:1] to placebo [PBO] or to continue TCZ at the same dose), double-blind (DB) withdrawal period for evaluation of the primary endpoint (JIA ACR30 flare relative to wk 16). Pts who flared or completed the DB period entered an OL extension and received the same TCZ dose as in the lead-in period. Efficacy data (until wk 40) are presented for the ITT population; safety data based on 184.4 pt-y (PY) of exposure are presented. Results 188 pts entered the OL lead-in period (77% female; 79%/46% receiving concurrent MTX/oral corticosteroids [CS], respectively). 22 (12%) pts withdrew from the OL extension (15 pts [8%] insufficient response; 3 [2%] adverse events [AEs]; 4 [2%] other reasons), and 166 pts entered the DB period. Efficacy responses at the end of the OL extension at wk 16 are shown (Table). At wk 40, the primary endpoint was met (48.1% PBO pts vs 25.6% TCZ pts), and JIA ACR30/50/70 responses were significantly higher with TCZ than PBO (Table). The degree of improvement at wk 16 was lower for these endpoints in the TCZ 8 mg/kg <30 kg BW group than in the other 2 TCZ groups (Table). At the safety data cut, 184 PY of follow-up had occurred in the 188 pts enrolled. Rates/100PY of AEs and SAEs were 480 and 12.5, respectively; infection was the most common AE (164/100PY) and SAE (4.9/100PY). ALT/AST elevations ≥3× ULN occurred in 3.7%/<1% of pts, neutropenia (<1000 cells/mm3) in 3.7% of pts, thrombocytopenia (<50,000 cells/mm3) in 1.1% of pts and LDL-cholesterol ≥110 mg/dl in 11.4% of pts. Image/graph Conclusions The CHERISH trial supports that TCZ treatment in pcJIA is efficacious and leads to a sustained clinically meaningful improvement with a monthly regimen at doses of 8 mg/kg if BW ≥30 kg and 10 mg/kg if BW <30 kg. The safety profile is consistent with that in other TCZ-treated pts.2 References Clin Exp Rheumatol. 1992;493; Ann Rheum Dis 2011;70(S3):67 Disclosure of Interest F. De Benedetti Grant/research support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, N. Ruperto Grant/research support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (fees received by organization) Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, Z. Zuber: None Declared, C. Keane Employee of: Roche, O. Harari Employee of: Roche, A. Kenwright Employee of: Roche, R. Cuttica Grant/research support from: Roche, Novartis, Lilly, Centocor, Consultant for: Roche, Novartis, Centocor, Pfizer, Speakers bureau: Roche, Pfizer, BMS, Novartis, V. Keltsev: None Declared, R. Xavier: None Declared, I. Calvo: None Declared, I. Nikishina: None Declared, N. Rubio-Pérez: None Declared, E. Alekseeva: None Declared, V. Chasnyk: None Declared, J. Chavez: None Declared, G. Horneff Grant/research support from: Abbott, Pfizer, Speakers bureau: Abbott, Pfizer, Novartis, Roche, Chugai, V. Opoka-Winiarska: None Declared, P. Quartier Grant/research support from: Abbott, Novartis, Pfizer, Consultant for: Novartis, Abbott, Pfizer, BMS, Roche, C. Silva Grant/research support from: Roche, E. Silverman: None Declared, A. Spindler: None Declared, A. Martini Grant/research support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (fees received by organization) Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, BMS, Astellas, Boehringer, Italfarmaco, MedImmune, Novartis, Pfizer, D. Lovell Grant/research support from: National Institutes of Health, Consultant for: AstraZeneca, Centocor, Wyeth, Amgen, BMS, Abbott, Pfizer, Hoffmann-La Roche Novartis, UCB, Forest Research, H. Brunner Shareholder of: PRCSG, Grant/research support from: National Institutes of Health, Lupus Foundation, Cincinnati Center for Clinical and Translational Research, Consultant for: Roche, Novartis, GSK, Medimmune, Pfizer, BMS

IntroductionImmunocompromised patients infected with influenza exhibit prolonged viral shedding and higher risk of resistance. Optimized treatment strategies are needed to reduce the risk of antiviral resistance. This phase IIIb, randomized, double-blind study (NCT00545532) evaluated conventional-dose or double-dose oseltamivir for the treatment of influenza in immunocompromised patients.MethodsPatients with primary or secondary immunodeficiency and influenza infection were randomized 1:1 to receive conventional-dose oseltamivir (75 mg adolescents/adults [≥ 13 years]; 30–75 mg by body weight in children [1–12 years]) or double-dose oseltamivir (150 or 60–150 mg, respectively), twice daily for an extended period of 10 days. Nasal/throat swabs were taken for virology assessments at all study visits. Co-primary endpoints were safety/tolerability and viral resistance. Secondary endpoints included time to symptom alleviation (TTSA) and time to cessation of viral shedding (TTCVS).ResultsOf 228 patients enrolled between February 2008 and May 2017, 215 (199 adults) were evaluable for safety, 167 (151 adults) for efficacy, and 152 (138 adults) for resistance. Fewer patients experienced an adverse event (AE) in the conventional-dose group (50.5%) versus the double-dose group (59.1%). The most frequently reported AEs were nausea, diarrhea, vomiting, and headache. Fifteen patients had post-baseline resistance, more commonly in the conventional-dose group (n  = 12) than in the double-dose group (n  = 3). In adults, median TTSA was similar between arms, while median TTCVS was longer with conventional dosing.ConclusionsOseltamivir was well tolerated, with a trend toward better safety/tolerability for conventional dosing versus double dosing. Resistance rates were higher with conventional dosing in this immunocompromised patient population.Trial RegistrationClinicalTrials.gov identifier: NCT00545532.FundingF. Hoffmann-La Roche Ltd.

15 serious infections occurred; 6 (gastroenteritis, varicella, septic arthritis, otitis media, pharyngotonsillitis, upper respiratory tract infection) were considered related to TCZ; all resolved and none led to discontinuation. 12 pts withdrew (4, AEs; 4, insufficient response).