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Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.

Summary Objective Since 2014, cannabidiol (CBD) has been administered to patients with treatment‐resistant epilepsies (TREs) in an ongoing expanded‐access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. Methods Twenty‐five US‐based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4‐week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2‐10 mg/kg/d, titrated to a maximum dose of 25‐50 mg/kg/d. Patient visits were every 2‐4 weeks through 16 weeks and every 2‐12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last‐observation‐carried‐forward method to account for missing data. Adverse events (AEs) were documented at each visit. Results Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4‐62). Median number of concomitant AEDs was 3 (range, 0‐10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add‐on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). Significance Results from this ongoing EAP support previous observational and clinical trial data showing that add‐on CBD may be an efficacious long‐term treatment option for TRE.

ObjectiveTo determine long term safety and efficacy of endovascular treatment of spinal cord arteriovenous malformations (AVMs), with calibrated particle embolization as a firstline approach.MethodsWe reviewed clinical and imaging data of consecutive patients who underwent endovascular treatment for both nidal and fistulous type spinal cord AVMs in our center, from 1990 to 2015. Outcome at the last follow-up was assessed by an independent observer.ResultsEmbolization of spinal cord AVMs was performed in 61 patients, including 46 (75%) with particles (exclusively in 29 patients), 30 (49%) with cyanoacrylate, and 6 (10%) with combined surgical treatments. Particle embolizations were iterative in 33 patients (median number of sessions 5 (range 3–6)). Neurological deterioration after treatment occurred in 5 patients (cyanoacrylate=4, surgery=1, particles=0; PConclusionOur study suggests that particle embolization as a firstline therapy to treat spinal cord AVMs is safe and offers long term efficacy, especially for those with small, distal, and multiple shunts. Partial occlusion of the AVM may be sufficient to prevent rebleeding, without the potential risks of complete occlusion. Particle calibration and injection technique, ‘one by one’, are critical to safety. Cyanoacrylate embolization or surgery remains necessary if particle embolization fails to occlude large shunts.

Purpose To report the safety and efficacy of single-port pars plana anterior vitrectomy. Setting Cincinnati Eye Institute, Cincinnati, Ohio, USA. Design Retrospective case series. Methods Eyes that had anterior vitrectomy from September 2010 to June 2016 were electronically identified. Charts were reviewed for demographics, history of ocular trauma, underlying ocular or systemic comorbidity, surgical indications, outcomes, and postoperative complications. Results The mean postoperative follow-up was 10.9 months with a mean patient age of 62.4 years. Three hundred thirty-five eyes (97.7%) were scheduled as planned anterior vitrectomies, whereas 8 eyes (2.3%) were operated on unexpectedly after posterior capsule ruptures. Eighty-two eyes (23.9%) had a history of trauma. Twenty-five eyes (7.3%) had documented postoperative cystoid macular edema (CME), whereas 7 (2.0%) of these eyes had known preoperative CME. There were 3 eyes (0.9%) with retinal detachments and 1 eye (0.3%) with a retinal tear without detachment. There were no cases of endophthalmitis and no evidence of residual vitreous prolapse in the anterior chamber in any eye postoperatively. Conclusions The safety and efficacy profile of a pars plana technique compared favorably against historical data for both coaxial and bimanual limbal clear corneal infusion and cutting. Sutureless pars plana anterior vitrectomy might be considered a safe and reliable solution for the anterior segment surgeon in managing vitreous prolapse during anterior segment surgeries.

Drug Development Tools are methods, materials, or measures that have the potential to facilitate drug development. USFDA has specified three major drug development tools and has also given the guidelines recommending their qualification which would expedite the drug development process. This qualification would ensure better understanding of drug targets and long term safety outcomes. Regulatory authorities of Europe, Japan & India have also focused on developing a formal qualification process of drug development tools though most of it follows USFDA.

Oral supplementation with l-carnitine is a common therapeutic modality for mitochondrial disorders despite limited evidence of efficacy. Recently, a number of studies have demonstrated that a gut microbiota-dependent metabolite of l-carnitine, trimethylamine oxide (TMAO), is an independent and dose-dependent risk factor for cardiovascular disease (CVD). Given the limited data demonstrating efficacy with oral l-carnitine therapy and the newly raised questions of potential harm, we assessed plasma TMAO levels in patients with mitochondrial disease with and without oral l-carnitine supplementation. Nine subjects were recruited and completed the study. Eight out of 9 subjects at baseline had plasma TMAO concentrations

Viral mediated gene therapy has progressed after overcoming early failures, and gene therapy has now been approved for several conditions in Europe and the USA. Glycogen storage disease (GSD) type Ia, caused by a deficiency of glucose-6-phosphatase-α, has been viewed as an outstanding candidate for gene therapy. This follow-up report describes the long-term outcome for the naturally occurring GSD-Ia dogs treated with rAAV-GPE-hG6PC-mediated gene therapy. A total of seven dogs were treated with rAAV-GPE-hG6PC-mediated gene therapy. The first four dogs were treated at birth, and three dogs were treated between 2 and 6 months of age to assess the efficacy and safety in animals with mature livers. Blood and urine samples, radiographic studies, histological evaluation, and biodistribution were assessed. Gene therapy improved survival in the GSD-Ia dogs. With treatment, the biochemical studies normalized for the duration of the study (up to 7 years). None of the rAAV-GPE-hG6PC-treated dogs had focal hepatic lesions or renal abnormalities. Dogs treated at birth required a second dose of rAAV after 2–4 months; gene therapy after hepatic maturation resulted in improved efficacy after a single dose. rAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders.

Objectives To evaluate the long-term safety and efficacy of vibegron 50 mg and 100 mg, a novel β3 -adrenoreceptor agonist, in Japanese patients with overactive bladder. Methods This was a 1-year, multicenter, open-label, non-controlled study. After a 1-week observation phase, patients were treated with vibegron for 52 weeks. When the efficacy was insufficient after an 8-week treatment with 50 mg, the dose was increased to 100 mg and maintained for an additional 44 weeks. Results Among a total of 169 patients receiving one or more doses of vibegron, 118 (69.8%) received vibegron 50 mg for 52 weeks, and the dose was increased to 100 mg in 51 (30.2%) patients. The incidence of drug-related adverse events was 18.1% (21/116) in the vibegron 50 mg group and 11.8% (6/51) in the vibegron 100 mg group. Most frequent drug-related adverse events were dry mouth (3.0%), residual urine volume increased (3.0%), constipation (2.4%) and cystitis (1.8%). Statistically significant changes in overactive bladder symptom variables (daily means of micturitions, urgency episodes, urgency incontinence episodes, incontinence episodes and night-time frequency) from baseline were observed at week 4 and maintained until week 52. The condition of patients who did not respond well to vibegron 50 mg was much improved by increasing the dose to 100 mg. Vibegron improved the quality of life, and the proportion of patients' satisfaction after the treatment with vibegron was high. Conclusions Long-term (52-week) treatment with vibegron is safe, well-tolerated and effective in patients with overactive bladder.

Die Einfuhrung der Biologika hat die Therapie der mittelschweren bis schweren Plaquepsoriasis bahnbrechend verandert. Indem die biologischen Therapien der Psoriasis kontinuierlich erweitert werden, ist es besonders wichtig, die Wirksamkeit und Sicherheit der Substanzen nicht nur in klinischen Studien, sondern auch in langfristigen Anwendungsbeobachtungen im Rahmen von Registern zu ermitteln. Es erfolgt die Darstellung typischer Nebenwirkungen und signifikanter Risiken der Biologikatherapien im Rahmen der Psoriasis unter der Berucksichtigung psoriatischer Kontrollpopulationen. Es wurde eine selektive Literatursuche in PubMed durchgefuhrt, und Studien zur Langzeitsicherheit im Rahmen der Psoriasisregister PsoBest, PSOLAR und BADBIR wurden ausgewertet. Zur Beurteilung der langfristigen Sicherheit der Biologika ist es von besonderer medizinischer Bedeutung, die Verlaufe an moglichst vielen Patienten in Langzeitregistern zu beobachten. Eine Tendenz zu verbesserten Nebenwirkungs- und Sicherheitsprofilen der neueren biologischen Medikamente scheint sich abzuzeichnen.

Development of an iodine immobilization technique that can fix radioactive iodine in waste form for a long period and constrain its leaching into pore water is necessary in order to secure the long-term safety of geological disposal of transuranic (TRU) waste.Lead borate glass vitrified at a low temperature is regarded as one of the promising immobilization materials of Iodine-129 which will be removed from spent AgI filters generated from reprocessing plants and may have a significant effect on long term safety of geological disposal.Leaching experiments in bentonite-equilibrium water have been conducted to understand the lead borate glass dissolution behaviors in possible geological disposal conditions. Boron dissolved with the highest rate in all types of the solutions and was regarded as an index element to represent the glass dissolution rate. On the other hand, lead dissolved with a far slower rate. The chemical species and possible precipitating minerals of lead were examined by a geochemical calculation code for typical underground water. Altered glass surfaces were investigated by SEM, TEM and XRD. XRD analysis showed that the main constituent phase of the altered layer was hydrocerussite, Pb3(CO3)2(OH)2, that was predicted by the geochemical simulation as well.

BACKGROUND: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment.OBJECTIVE: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection.DESIGN, SETTING, AND PARTICIPANTS: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics.RESULTS AND LIMITATIONS: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up.CONCLUSIONS: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns.PATIENT SUMMARY: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

Long-term treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogues is often necessary to achieve durable viral suppression. Therefore, current guidelines recommend the most potent drugs with optimal resistance profiles. Entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line monotherapies for CHB. All of these drugs are highly effective in suppressing viral replication but with slightly different safety profiles. This review provides an overview of the long-term efficacy and safety data that have become available over the 10 years since ETV and TDF were first approved for the treatment of chronic hepatitis, and recent data on TAF in patients with CHB.

Alopecia Areata is a common form of non-scarring hair loss that usually starts abruptly with a very high psychological impact. Due to the still not completely understood etiopathogenesis, at present there is no treatment that can induce a permanent remission and there is no drug approved for the treatment of this disorder. Areas covered: Leading existing treatment are briefly overviewed and then ongoing research on Janus Kinases Inhibitors is discussed, reviewing trials with oral and topical formulations so as new opportunities for other forms of alopecia, such as cicatricial alopecia. Expert opinion: JAK inhibitors represent a promise among alopecia treatments, but further studies are needed on long term safety. There is still no validated dosage for alopecia areata and the vehicles used for topical formulations seem not yet ideal in terms of skin penetration and reduced systemic absorption. Hopefully several studies are ongoing and we hope, in the near future, that JAK inhibitors will become part of the armamentarium to treat alopecia areata patients in terms of safety and costs.

BackgroundThe rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma.MethodsAfter 15 yr of clinical use, findings of a pharmacovigilance report (February 1996-March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed.ResultsSince receiving marketing authorization (February 21, 1996), ∼647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ∼31 000) is in line with the incidence observed with other four-factor PCCs.ConclusionsIn general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists. OA embargo

Background:Upadacitinib (UPA), an oral Janus kinase inhibitor, demonstrated significant improvements in signs, symptoms, and structural inhibition as monotherapy (mono) vs methotrexate (MTX) in MTX-naïve patients (pts) with rheumatoid arthritis (RA) through 48 weeks (wks).1Objectives:To report the efficacy and safety of UPA vs MTX mono up to 156 wks in pts with RA from the ongoing long-term extension (LTE) of the SELECT-EARLY trial.Methods:During the 48-wk double-blind study period, pts were randomized to UPA 15 or 30 mg once daily (QD) or MTX (titrated to 20 mg/wk by Wk 8). At Wk 26, pts who did not achieve Clinical Disease Activity Index (CDAI) remission (≤2.8) and had Results:Of 945 pts randomized and treated, 775 entered the LTE on study drug (including 57 rescued pts; MTX, 33; UPA 15 mg, 17; UPA 30 mg, 7). Overall, 161 (21%) pts discontinued during the LTE. At Wk 156, higher proportions of pts randomized to UPA achieved a 20/50/70% improvement in ACR response (ACR20/50/70), LDA, and remission vs MTX (Figure 1). Change from baseline in mTSS at Wk 96 favored UPA vs MTX (data not shown). Most AEs were numerically more frequent with UPA 30 mg. The overall rate of serious infection was numerically higher with UPA vs MTX (Table 1). Herpes zoster (HZ), neutropenia, non-melanoma skin cancer (NMSC), and creatine phosphokinase (CPK) elevation were more frequent with UPA vs MTX. Two active tuberculosis (TB) events were reported in each UPA arm; 3 adjudicated gastrointestinal (GI) perforation events were observed in the UPA 30 mg arm. Adjudicated major adverse cardiovascular events (MACEs) or venous thromboembolic events (VTEs) were comparable across treatment arms.Conclusion:UPA monotherapy showed sustained clinically meaningful responses including remission vs MTX through Wk 156 but higher rates of several AEs, including HZ, neutropenia, and CPK elevations; no new safety risks were observed compared with previous results.1,2References:[1]van Vollenhoven R, et al. Ann Rheum Dis 2019;78:376–7; 2. Cohen SB, et al. Ann Rheum Dis 2020;annrheumdis-2020-218510.Table 1.Safety overviewE/100 PY (95% CI)MTX mono(n=314; PY=601.9)UPA 15 mg QD mono(n=317; PY=703.4)UPA 30 mg QD mono(n=314; PY=687.6)Any AE240.2(228.0, 252.9)268.0(256.0, 280.4)292.5(279.8, 305.5)Any serious AE10.8 (8.3, 13.8)12.2 (9.8, 15.1)16.3 (13.4, 19.6)Any AE leading to discontinuation of study drug6.5 (4.6, 8.9)7.3 (5.4, 9.5)7.7 (5.8, 10.1)Any deatha0.7 (0.2, 1.7)0.9 (0.3, 1.9)1.0 (0.4, 2.1)Serious infection2.5 (1.4, 4.1)3.3 (2.1, 4.9)4.4 (2.9, 6.2)Opportunistic infection excluding TB and HZ0.2 (0.0, 0.9)0.1 (0.0, 0.8)0.3 (0.0, 1.1)HZ0.8 (0.3, 1.9)4.5 (3.1, 6.4)4.7 (3.2, 6.6)Active TB00.3 (0.0, 1.0)0.3 (0.0, 1.1)NMSC00.4 (0.1, 1.2)1.0 (0.4, 2.1)Malignancy other than NMSC1.0 (0.4, 2.2)0.6 (0.2, 1.5)1.2 (0.5, 2.3)Hepatic disorder14.1 (11.3, 17.5)12.5 (10.0, 15.4)15.0 (12.2, 18.2)GI perforationb000.4 (0.1, 1.3)Neutropenia2.2 (1.2, 3.7)4.5 (3.1, 6.4)5.7 (4.0, 7.8)CPK elevation1.8 (0.9, 3.3)7.7 (5.8, 10.0)15.4 (12.6, 18.6)MACEb0.3 (0.0, 1.2)0.4 (0.1, 1.2)0.6 (0.2, 1.5)VTEb0.3 (0.0, 1.2)0.4 (0.1, 1.2)0.6 (0.2, 1.5)Data were censored at the time of MTX or UPA addition for rescued ptsaIncludes treatment-emergent (≤30 days after the last dose of study drug) and non-treatment-emergent deaths. bAdjudicatedAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Ronald van Vollenhoven Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB, and Viela Bio, Consultant of: AbbVie, AstraZeneca, Biogen, Biotest, Bristol-Myers Squibb, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB, and Viela Bio, Grant/research support from: Bristol-Myers Squibb, GSK, Eli Lilly, Pfizer, Roche, and UCB, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Gilead, Mitsubishi Tanabe, Novartis, Pfizer, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Shionogi, Takeda, and UCB, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GSK, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi, Selecta, and UCB, Nilmo Chávez Speakers bureau: AbbVie, Janssen, and Pfizer, Consultant of: AbbVie, Janssen, and Pfizer, Grant/research support from: AbbVie, Galapagos, Gilead, Pfizer, and Sanofi, Pablo Mannucci Walter Consultant of: AbbVie, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Genentech/Roche, GSK, Janssen, and UCB, Atul Singhal Consultant of: AbbVie, Aclaris, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead, Idorsia, Novartis, Oscotec, Pfizer, Regeneron, Roche/Genentech, Sanofi, Selecta, Takeda, UCB, and Viela Bio, Grant/research support from: AbbVie, Aclaris, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead, Idorsia, Novartis, Oscotec, Pfizer, Regeneron, Roche/Genentech, Sanofi, Selecta, Takeda, UCB, and Viela Bio, Jerzy Swierkot Speakers bureau: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Grant/research support from: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Alan Friedman Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Justin Klaff Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Genentech/Roche, Gilead, GSK, Ichnos, Inmedix, Janssen, Kiniksa, MSD, Myriad Genetics, Novartis, Pfizer, Regeneron, Sandoz, Sanofi, Setpoint, and UCB

Background:Bimekizumab (BKZ), a monoclonal antibody that selectively inhibits interleukin (IL)-17A and IL-17F, has demonstrated clinical efficacy and safety in patients with ankylosing spondylitis (AS) treated over a period up to 96 weeks.1,2Objectives:To report 3-year interim safety and efficacy of BKZ in patients with active AS from a phase 2b dose-ranging study (BE AGILE; NCT02963506) and its ongoing open-label extension (OLE; NCT03355573).Methods:BE AGILE study design has been described previously.1 Patients treated with BKZ 160 mg or 320 mg every 4 weeks (Q4W) at Week 48 in BE AGILE were eligible for OLE entry. All OLE patients received BKZ 160 mg Q4W. Treatment-emergent adverse events (TEAEs) are reported for the BE AGILE safety set (patients who received ≥1 dose of BKZ on study entry) for total exposure to BKZ across BE AGILE and the OLE. Efficacy outcomes are reported for the OLE full analysis set (patients who entered the OLE and had ≥1 dose of BKZ and ≥1 valid efficacy variable measurement in the OLE), and include: ASAS40, ASAS20, ASAS PR, ASDAS, ASDAS-CII, ASDAS-MI, ASDAS-ID (Results:262/303 (86%) patients randomised at BE AGILE study baseline completed Week 48 on BKZ 160 mg or 320 mg. At Week 48, 255/262 (97%) patients entered the OLE (full analysis set: 254); 219 patients had an efficacy assessment at Week 156. Over the 156 weeks, the exposure-adjusted incidence rate (EAIR) per 100 patient-years (PY) of TEAEs was 143.5, with an EAIR of 5.8 for serious TEAEs, 1.3 for serious infections, and 3.8 for Candida infections (Table 1). All Candida infections were mild or moderate; none were systemic or led to study discontinuation. Over 156 weeks, the EAIR of inflammatory bowel disease (1.2), anterior uveitis (0.8), and injection site reactions (0.5) remained low. Efficacy demonstrated at Week 48 in BE AGILE was maintained or improved up to Week 156 (Figure 1). Mean ASDAS improved from 3.9 at BE AGILE baseline to 2.0 and 1.8 at Weeks 48 and 156 respectively (by MI). At Week 156 in the NRI analyses, ASAS40 and ASAS PR were achieved by 62.6% (OC: 72.6%) and 32.7% (OC: 37.9%) patients respectively. ASDAS-ID and ASDAS Table 1.Safety for total exposure to BKZ across BE AGILE and the OLEBE AGILEWeeks 0–48BE AGILE + OLEWeeks 0–156n (%) [EAIR/100 PY]BKZ 160 mg(n=149;114.2 PY)BKZ 320 mg(n=150;119.6 PY)All BKZ(N=303;261.3 PY)All BKZ(N=303;781.0 PY)Any TEAE103 (69.1) [168.7]122 (81.3) [221.1]235 (77.6) [186.2]280 (92.4) [143.5]Serious TEAEs5 (3.4) [4.4]6 (4.0) [5.1]13 (4.3) [5.1]43 (14.2) [5.8]Key TEAEs of special monitoringSerious infections3 (2.0) [2.7]1 (0.7) [0.8]4 (1.3) [1.5]10 (3.3) [1.3]Candida infections10 (6.7) [9.1]9 (6.0) [7.9]19 (6.3) [7.5]28 (9.2) [3.8]Inflammatory bowel disease1 (0.7) [0.9]2 (1.3) [1.7]4 (1.3) [1.5]9 (3.0) [1.2]Anterior uveitis1 (0.7) [0.9]1 (0.7) [0.8]2 (0.7) [0.8]6 (2.0) [0.8]Study discontinuations due to TEAEs7 (4.7)10 (6.7)20 (6.6)38 (12.5)Drug-related TEAEs48 (32.2)54 (36.0)110 (36.3)149 (49.2)Deaths1 (0.7)01 (0.3)2 (0.7)TEAEs are reported for the BE AGILE safety set for total exposure to BKZ across BE AGILE and the OLE. There was one death in BE AGILE (cardiac arrest) and one in the OLE (road traffic accident); neither was considered treatment-related.Conclusion:The safety profile of BKZ in patients with AS was in line with previous observations.1.2 Patients treated with BKZ demonstrated sustained and consistent efficacy over 156 weeks.References:[1]van der Heijde D. Ann Rheum Dis 2020;79:595–604; 2. Baraliakos X. Arthritis Rheumatol 2020;72 (suppl 10).Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma, Employee of: Director of Imaging Rheumatology, Atul Deodhar Speakers bureau: Janssen, Novartis, Pfizer, Consultant of: AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB Pharma, Lianne S. Gensler Consultant of: AbbVie, Eli Lilly, Gilead, GSK, Novartis, Pfizer, UCB Pharma, Grant/research support from: Pfizer, Denis Poddubnyy Speakers bureau: AbbVie, BMS, Eli Lilly, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Biocad, Eli Lilly, Gilead, GSK, MSD, Novartis, Pfizer, Samsung Bioepis, UCB Pharma, Grant/research support from: AbbVie, MSD, Novartis, Pfizer, Alan Kivitz Shareholder of: Pfizer, Novartis, Speakers bureau: Amgen, Eli Lilly, Pfizer, Novartis, Consultant of: Novartis, UCB Pharma, Maxime Dougados Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, Novartis, Pfizer, UCB Pharma, Natasha de Peyrecave Employee of: UCB Pharma, Marga Oortgiesen Employee of: UCB Pharma, Thomas Vaux Employee of: UCB Pharma, Carmen Fleurinck Employee of: UCB Pharma, Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer, UCB Pharma

Background:In the SELECT-PsA 1 study, through 24 weeks (wks), once daily upadacitinib 15 mg (UPA15) and 30 mg (UPA30) showed improvements in musculoskeletal symptoms, psoriasis, physical function, pain, fatigue, and quality of life, as well as inhibition of radiographic progression in patients (pts) with psoriatic arthritis (PsA) and inadequate response or intolerance to ≥1 non-biologic disease-modifying antirheumatic drug (DMARD).1Objectives:To report the efficacy and safety of UPA vs adalimumab (ADA) up to 56 wks from the ongoing long-term extension of SELECT-PsA 1.Methods:Pts received UPA15 or UPA30, ADA 40mg every other wk for 56 wks, or PBO through wk 24 switched thereafter to either UPA15 or UPA30 until wk 56. Efficacy endpoints as listed and defined in the Table 1 were analyzed at wk 56. Results for binary endpoints are based on non-responder imputation analysis; treatments were compared using the Cochran-Mantel-Haenszel test. Results for non-radiographic continuous endpoints are based on mixed model repeated measures model based on as observed data. Radiographic endpoints were analyzed based on linear extrapolation. Treatment-emergent adverse events (TEAEs) per 100 pt years (PY) were summarized for pts who received ≥1 dose of study drug.Table 1.Efficacy Endpoints at Week 56EndpointPBO → UPA15PBO → UPA30UPA15UPA30ADAACR20, %73.074.174.474.7#68.5ACR50, %54.560.459.7*60.5#51.3ACR70, %29.935.840.6*43.7#31.2Minimal Disease Activity, %29.435.844.847.3#39.6PASI75a, %58.360.265.463.361.1PASI90a, %41.753.749.149.546.9PASI100a, %22.338.934.639.531.3Resolution of enthesitis by Leeds Enthesitis Index b, %38.145.559.358.154.0Resolution of dactylitis by Leeds Dactylitis Index c, %47.759.075.074.874.0Δ from BL in Bath Ankylosing Spondylitis Disease Activity Index d-3.1-3.1-3.3-3.2-2.8Δ from BL in modified total Sharp/van der Heijde Score (mTSS)0.44e-0.05†0.02‡-0.06* and †, p≤0.05; for UPA15 vs ADA and PBO, respectively; # and ‡, p≤0.05; for UPA30 vs ADA and PBO, respectively.a for pts with psoriasis affecting ≥3% of body surface area at BL. b for pts with LEI >0 at BL. c for pts with LDI >0 at BL. d for pts with psoriatic spondylitis at BL. epooled PBO.ACR20/50/70, ≥20%/50%/70% improvement in American College of Rheumatology criteria; ADA, adalimumab; BL, baseline; PASI75/90/100, ≥75%/90%/100% improvement in Psoriasis Area and Severity Index; PBO, placebo; pts, patients; UPA, upadacitinib.Results:Of 1704 pts who received ≥1 dose of study drug, 1419 (83.2%) completed 56 wks of treatment on study drug. Across all treatment groups, the proportions of pts who had achieved ACR20/50/70, MDA, PASI75/90/100, resolution of enthesitis, and resolution of dactylitis were maintained or further improved from wk 241 through wk 56; these proportions were generally greater for pts originally randomized to UPA vs ADA (Table 1). At wk 56, mean change from BL in mTSS was similar with UPA15, UPA30, and ADA. Improvements in pts who switched from PBO to UPA were generally similar to those originally randomized to UPA at wk 56. Through wk 56, the rates of TEAEs and serious AEs, including serious infections, were similar in the UPA15 and ADA arms and higher with UPA30 (Figure 1). The rate of herpes zoster was higher with UPA vs ADA in a dose-dependent manner. Malignancies were reported at similar rates among all treatment groups. Adjudicated venous thromboembolic events and major adverse cardiovascular events were reported in all groups with comparable rates. Two deaths were reported with UPA15, 2 with UPA30, and 1 with ADA; 1 death was reported with PBO during the 24-wk PBO-controlled period.Conclusion:Efficacy responses were maintained or further improved with UPA15 and UPA30 over 56 wks and were numerically higher vs ADA. The inhibition of radiographic progression was maintained at wk 56 and was similar with UPA and ADA. At wk 56, improvements in efficacy were observed in pts who switched from PBO to UPA. No new safety findings were observed with longer exposure to UPA.References:[1]McInnes IB et al. Ann Rheum Dis, 2020; 79:12Figure 1Acknowledgements:AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial. AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. Medical writing support was provided by Ramona Vladea, PhD of AbbVie Inc.Disclosure of Interests:Iain McInnes Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, UCB Pharma, Koji Kato Shareholder of: AbbVie, Employee of: AbbVie, Marina Magrey Consultant of: UCB, Novartis, Eli Lilly, Pfizer and Janssen, Grant/research support from: Amgen, AbbVie, and UCB Pharma, Joseph F. Merola Consultant of: Merck, Bristol-Myers Squibb, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and Leo Pharma, Mitsumasa Kishimoto Consultant of: AbbVie, Amgen-Astellas BioPharma, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Celgene, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, Teijin Pharma, and UCB Pharma, Cesar Francisco Pacheco Tena Consultant of: Eli Lilly, AbbVie, Roche, Pfizer, Janssen, Astra-Zeneca, UCB, Gilead, R-Pharm, Sanofi Regeneron, Grant/research support from: Eli Lilly, AbbVie, Roche, Pfizer, Janssen, Astra-Zeneca, UCB, Gilead, R-Pharm, Sanofi Regeneron, Derek Haaland Speakers bureau: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Sanofi Genzyme, Takeda, Consultant of: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi Genzyme, Takeda, UCB, Grant/research support from: AbbVie, Adiga Life-Sciences, Amgen, Bristol-Myers Squibb, Can-Fite Biopharma, Celgene, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, UCB, Liang Chen Shareholder of: AbbVie, Employee of: AbbVie, Yuanyuan Duan Shareholder of: AbbVie, Employee of: AbbVie, Patrick Zueger Shareholder of: AbbVie, Employee of: AbbVie, Jianzhong Liu Shareholder of: AbbVie, Employee of: AbbVie, Ralph Lippe Shareholder of: AbbVie, Employee of: AbbVie, Aileen Pangan Shareholder of: AbbVie, Employee of: AbbVie, Frank Behrens Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche, Chugai, BMS, UCB Pharma, Grant/research support from: Pfizer, Janssen, Chugai, Celgene and Roche.

Metreleptin is an approved treatment for patients with generalized lipodystrophy but still under investigation for patients with partial forms of the disease in the US. This open-label single-arm study in partial lipodystrophy (PL) allowed continued treatment of patients who volunteered and completed treatment under our previous 1-year protocol and who derived significant clinical benefit. The primary outcome was percent change in fasting triglyceride levels and the secondary outcome was percent change in hemoglobin A1c levels (time frame: 5 years on metreleptin or last observation carried forward in both instances). The hypothesis was that these metabolic parameters would stay stable over the observation period. The study enrolled 11 participants (11 females; 3 ≤ 18 years; 8 between 18–65 years). Four patients had familial partial lipodystrophy type 2 (FPLD2) caused by LMNA pathogenic variants (R482Q in two subjects, R482W in one subject, and R349W in one subject), two patients had POLD1 associated PL (E1067K), four patients had FPLD1, and one patient had atypical PL. Variants of uncertain significance (VUS) in genes of interest were detected in two patients with FPLD1 and one patient with atypical PL. Four subjects completed 48 months (actual 60 months on metreleptin). Data from 3 subjects were excluded from final data analyses due to early loss to follow-up (n = 1), serious adverse event withdrawal (n = 1; development of persistent neutralizing antibody shortly after 18 months of drug exposure), and death (n = 1). The remaining 4 subjects withdrew from the study either through their own volition or due to the investigator decision (last observation carried forward in these 4 subjects). As expected, the median percent change from baseline triglyceride and hemoglobin A1c levels were not significant (55.76 percent (range: -66.79 to 203.80; p > 0.05), and 2.55 percent (range: -27.52 to 25.00; p > 0.05), respectively). Serious adverse events were reported in 8 of 11 patients and additional adverse events were observed in all patients. Apart from neutralizing antibody development in one subject causing substantial metabolic derangement, adverse events were considered not to be directly related to the study drug. Death was caused by a sudden cardiac event related to the specific molecular etiology (LMNA R349W) in one case. This interventional study provided valuable information on the efficacy and safety of long-term metreleptin in PL. Although nonsignificant fluctuations were observed in triglycerides, hemoglobin A1c levels were generally stable over time and the initial improvement seen in the first year were sustained. Adverse events were common but more likely due to the complex nature of the underlying disease. Although rare, neutralizing antibodies can develop in patients with PL treated with metreleptin.

Introduction Radiation therapy in patients with axial flow left ventricular assist devices (LVAD) has not been associated with significant device malfunction. However, the effects of radiation on the fully magnetically levitated HeartMate 3 (Abbott, Abbott Park, IL) LVAD are not well known. We report two cases of stereotactic bone radiation therapy (SBRT) in patients with a HeartMate 3 LVAD implantation. Case Report Patient 1 71-year-old woman with history of chronic systolic heart failure status post HeartMate 3 LVAD and history of left upper lobe non-small cell lung cancer status post lobectomy was found to have an incidental left lateral thorax wall mass on CT imaging with subsequent biopsy consistent for recurrent oligometastatic lung adenocarcinoma. She consequently underwent 5 fractions of 600 cGy SBRT to her left lateral chest wall over a period of 10 days. Mild fatigue was reported following radiation, however LVAD log files sent subsequent to each fraction were unremarkable. On follow up, no cardiac symptoms were reported and LVAD parameters were normal with flow 4.6 L/min, speed 5600 rpm, pulse index 2.8 and power 4.4 watts. Device malfunction has not been witnessed during 1 year follow up. Patient 2 70-year-old man with history of advanced systolic heart failure status post HeartMate 3 LVAD implantation was found to have a right upper lobe nodule and mediastinal lymphadenopathy on CT imaging. Ensuing biopsy diagnosed squamous cell lung cancer without metastatic disease. SBRT was initiated and 5 treatments of 1000 cGy were delivered to the right upper lobe lesion within 10 days. No LVAD complications or symptoms of heart failure were witnessed during treatment. On follow up, patient denied any symptoms and LVAD function remained normal with observed with flow 4.3 L/min, speed 5200 rpm, pulse index 4.8 and power 3.8 watts. Device malfunction has not been witnessed during 1 year follow up. Summary Our 2 cases suggests that SBRT in patients with HeartMate 3 LVAD implantation may be safe and likely not associated with device malfunction. Larger studies are required to better evaluate this relationship and to determine long term safety profile.

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Background: Sickle cell disease (SCD) is a lifelong, inherited blood disorder, resulting from a mutation in the hemoglobin (Hb) subunit β gene, that leads to sickle hemoglobin (HbS) formation. Polymerization of HbS causes red blood cell sickling and damage, leading to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Patients with SCD are at higher risk of end-organ damage, increased morbidity, and early mortality as a result of low Hb and increased hemolysis. Voxelotor (Oxbryta ®) tablets, a HbS polymerization inhibitor, are approved in the US for treatment of SCD in adults and adolescent patients aged ≥12 years. The randomized, placebo-controlled HOPE trial showed that significantly more patients treated with voxelotor 1500 mg achieved a >1 g/dL Hb increase compared with placebo (89% vs 25%, respectively) at any time up to week 72. These Hb increases were associated with reductions in markers of hemolysis (eg, indirect bilirubin, reticulocyte percentage). To confirm the safety and efficacy of long-term voxelotor use, we report an interim analysis of an ongoing open-label extension (OLE) of the HOPE trial. Methods: Patients who completed the phase 3 HOPE trial were eligible to enroll in the multicenter OLE study and receive treatment as long as they continued to receive clinical benefit and/or until they had access to voxelotor through commercialization or a managed access program. All patients, including those who previously received placebo or voxelotor 900 mg, received voxelotor 1500 mg as ongoing treatment. Adverse event data were collected beginning on the date of informed consent through 28 days after discontinuation of voxelotor. Measurements of Hb and clinical markers of hemolysis are ongoing and summarized here for 48 weeks of treatment in the OLE. Central laboratory assessments were used for the US and Europe, and local laboratory assessments were used for the rest of the world. Data presented are based on an interim data cut (December 31, 2020). Results: Of the 199 patients who completed the HOPE trial, 178 (89.4%) were enrolled and dosed in the OLE. Median age at enrollment was 25 years (15.7% adolescents, 84.3% adults). At the cutoff date, the median duration of voxelotor exposure the OLE was 69.9 weeks (range: 1.9-102.0 weeks), with 78 patients treated for ≥72 weeks. Of these 78 patients, 52 had previously received voxelotor in the randomized part of the study, for a combined exposure duration of ≥144 weeks. Among those who previously received placebo, the mean (SD) change in Hb from baseline (ie, the start of the OLE) to week 48 was 1.3 (1.51) g/dL, consistent with the HOPE trial results. Mean (SD) Hb changes for patients who previously received voxelotor 900 mg and 1500 mg were 0.7 (1.48) g/dL and 0.2 (1.15) g/dL, respectively, indicating durability of response. Markers of hemolysis improved from baseline to week 48 in patients who received placebo in the HOPE trial (-39.5% indirect bilirubin; -28.6% reticulocyte percentage). Patients who received voxelotor during the HOPE trial showed a stable response at week 48 (-2.0% and 1.1% indirect bilirubin, -14.6% and -21.0% reticulocytes for voxelotor 900 mg and 1500 mg, respectively). The annualized incidence rate of VOCs was 1.3 (95% CI: 1.1-1.4) events per year across all patients. A total of 83.7% of patients (149/178) experienced a non-SCD-related treatment-emergent adverse event (TEAE), with the most commonly reported being arthralgia, headache, pain, nausea, and pain in extremity (Table). Most non-SCD-related TEAEs were grade 1 or 2 in severity. Eleven patients (6.2%) had an adverse event that led to treatment discontinuation. No TEAEs consistent with lack of tissue oxygenation were observed. Conclusions: In this OLE study, treatment with voxelotor 1500 mg resulted in improvements in Hb and clinical measures of hemolysis at 48 weeks in patients who received placebo in the HOPE trial. Treatment with voxelotor 1500 mg showed durability of response in patients previously treated with voxelotor of any dosage in the HOPE trial. The safety profile in the OLE was consistent with the findings from the HOPE trial, and no new safety signals were identified with exposure through a combined 144 weeks of treatment. Based on these results, long-term use of voxelotor is safe, well tolerated, and effective in reducing anemia and hemolysis, with a low rate of VOCs, in patients with SCD. Funding: This study was supported by Global Blood Therapeutics. Figure 1 Figure 1. Disclosures Achebe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Consultancy. Hassab: Global Blood Therapeutics: Research Funding. Alkindi: Global Blood Therapeutics: Speakers Bureau; Emmaus: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brown: Global Blood Therapeutics: Consultancy, Research Funding; Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding. Telfer: BlueBirdBio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Terumo: Honoraria; ApoPharma: Membership on an entity's Board of Directors or advisory committees. Biemond: Sanquin: Research Funding; Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Novo Nordisk: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria. Gordeuk: Modus Therapeutics: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Incyte: Research Funding; Novartis: Research Funding; CSL Behring: Consultancy. Lipato: Global Blood Therapeutics: Speakers Bureau. Tonda: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Howard: Resonance Health: Honoraria; Bluebird Bio: Research Funding; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Consultancy; Novo Nordisk: Consultancy; Novartis: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy; Imara: Consultancy, Honoraria.

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Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening disease characterized by complement mediated hemolysis and thrombosis. Current C5-inhibitors, such as eculizumab and ravulizumab, are able to partially treat these symptoms by controlling intravascular but not extravascular hemolysis, manifesting as persistent anemia in up to 72% of treated patients and transfusion dependence in up to 36% of patients. Pegcetacoplan (PEG) is a Food and Drug Administration (FDA)-approved C3-inhibitor that controls both intravascular and extravascular hemolysis (IVH and EVH). In the PEGASUS phase 3, multi- center, active-comparator controlled, randomized trial (NCT03500549), improvements in hemoglobin levels from baseline to Week 16 demonstrated the superiority of PEG over eculizumab; 85% of the patients receiving PEG achieved transfusion independence when compared with the 15% of patients on eculizumab. The extension study will evaluate the long-term safety and efficacy of PEG in patients with PNH. Acute hemolytic (AH) events occurred during the PEG clinical development program. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with PEG Aims: Determine the long-term safety and efficacy of PEG for PNH treatment, as well as evaluate a treatment regimen to address acute hemolytic (AH) events in these patients. Study Design: The PEG extension study (NCT03531255) is an active, multi-center, open-label, non-randomized trial with an estimated enrollment of up to160 adult PNH patients (≥18 years), who have completed prior PEG trials - phase 1b PADDOCK (NCT02588833) and PHAROAH (NCT02264639), phase 2a PALOMINO (NCT03593200), and the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) trials. The main study will determine long-term safety and efficacy of PEG dosing on complement-mediated hemolytic activity, hemoglobin levels, and transfusion independence in PNH patients. For enrolled subjects experiencing AH episodes, a substudy to evaluate safety and efficacy of intensive SC or IV dosing of PEG acute treatments will be offered. Dose adjustments will be offered for AH subjects declining to enter the substudy, but continuing to participate in the main study. Inclusion criteria for the management of AH substudy specify that lactate dehydrogenase (LDH) levels in patients must be >2 times the upper limit of normal, accompanied by new or worsening clinical signs of hemolysis (hemoglobinuria, fatigue, decreased hemoglobin, etc.). Notable exclusion criteria include subjects who have withdrawn from a previous PEG trial, co-morbidities and infections that can enhance risk profiles for adverse events or confound study interpretation, and complement deficiency. The safety population consisting of patients that will receive at least one dose of the drug will be used for all efficacy analyses. Descriptive statistics will be used in documenting changes from baseline, along with qualitative descriptors (improved, maintained, or worsened). Intervention: Patients in the long-term extension study receive subcutaneous (SC) administration of 1080 mg PEG twice weekly, every 3 days, or 3 times weekly. For AH events substudy, patients with steady-state PEG dose of 1080 mg SC twice weekly will receive a loading dose of 1080 mg IV once, or 1080 mg SC every 24 hours for 3 doses, followed by increase in maintenance dose to 1080 mg SC every 3 days; for those receiving 1080 mg SC every 3 days, identical loading dose will be followed by subsequent maintenance dose of 1080 mg SC 3 times weekly. Primary and Secondary Outcome Measures: The study will monitor safety outcomes such as occurrence and severity of adverse events within a 2-year timeframe from baseline. Additional biomarkers include recurrent acute hemolysis, thromboembolism, laboratory and electrocardiogram (ECG) parameters. Efficacy endpoint measurements over a 48-week timeframe include mean change from baseline levels of hemoglobin, LDH, and indirect bilirubin, absolute reticulocyte counts, RBC transfusions, and functional assessment of fatigue scale scores. Results: Trial results are anticipated in 2022, upon study completion. Disclosures Hoffman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Machaidze: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weitz: Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Novartis Corporation: Consultancy, Honoraria; Sanofi Genxyme: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is a Food and Drug Administration approved C3-inhibitor that controls both intravascular and extravascular hemolysis. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with pegcetacoplan.

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Background: The post-HERCULES trial (NCT02878603) evaluated long-term safety and efficacy of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (aTTP; also known as immune-mediated TTP), and efficacy of repeated use of caplacizumab for aTTP recurrence. Methods: Patients who completed the HERCULES trial were invited to participate in the post-HERCULES study and attend twice-yearly visits for 3 years. In case of aTTP recurrence, patients could receive open-label (OL) caplacizumab with therapeutic plasma exchange (TPE) and immunosuppression (IST). Safety was assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences. TTP-related events (recurrence, mortality, or major thromboembolic events) were assessed in the efficacy ITO population. The ITO population (n=104) included all enrolled patients, grouped by whether they received caplacizumab during HERCULES (randomized or switched to OL after exacerbation). The efficacy ITO population (n=78) included those without aTTP recurrence during HERCULES or prior to the beginning of post-HERCULES. The recurrence population (n=19) included patients with ≥1 recurrence during post-HERCULES; the repeat-use population (n=9) was a subset treated at least twice with caplacizumab (received caplacizumab in HERCULES or treated twice in post-HERCULES). Pharmacodynamics and immunogenicity were assessed in the ITO population. The study was conducted in accordance with the Declaration of Helsinki. Results: Of 104 patients enrolled in post-HERCULES, 75 were treated with caplacizumab along with TPE+IST during HERCULES (caplacizumab group) and 29 were treated with TPE+IST only (placebo group). During the overall post-HERCULES study period, incidence of adverse events (AEs) and serious AEs was similar between the groups. In the ITO population, recurrence occurred in 11/75 patients (15%) in the caplacizumab group and 8/29 patients (28%) in the placebo group. In the efficacy ITO population, TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab versus 38% (11/29) randomized to placebo (Table 1). Prior rituximab use during HERCULES was similar in both groups (21/49 patients [43%] randomized to caplacizumab and 12/29 [41%] randomized to placebo). Incidence of recurrence by prior rituximab use (with vs without) was 10% (2/21) versus 7% (2/28) among patients randomized to caplacizumab, and 17% (2/12) versus 35% (6/17) among patients randomized to placebo. Of 19 patients with ≥1 recurrence, 13 were treated with caplacizumab and 6/13 received concomitant rituximab. Recurrences were resolved (12/13) or resolving (1/13) for all patients treated with caplacizumab, including 9 patients with repeat caplacizumab use. One patient who did not receive caplacizumab in either HERCULES or post-HERCULES died as an outcome of recurrence. Safety profile of caplacizumab for treatment of recurrence was consistent with that observed in HERCULES (Table 2) . The most common treatment-emergent AEs (TEAEs) with caplacizumab during the first recurrence (n=13) were headache and constipation (n=3 each). In the repeat-use population (n=9), bleeding events were reported in 5/9 patients (56%) for the first recurrence; 2 patients had a serious treatment-related TEAE of genitourinary or gastrointestinal bleeding; 2 patients had treatment-emergent anti-drug antibodies (ADAs) positive in a functional neutralizing antibody assay. No apparent impact of treatment-emergent ADAs on RICO activity or change from baseline in von Willebrand factor antigen concentration was found. Conclusions: The long-term safety profile of patients exposed to caplacizumab together with TPE+IST was similar to those who received IST+TPE only, with no observed increases in recurrence of aTTP. Repeat caplacizumab use was efficacious, with no evidence of safety concerns or boosting of ADA response. Funding: This research was funded by Ablynx, a Sanofi company. Figure 1 Figure 1. Disclosures Scully: Shire: Research Funding; Novartis: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octopharma: Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Celgene, Takeda, Janssen, Sanofi: Honoraria; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy. Pavenski: Alexion: Honoraria, Research Funding; Bioverativ: Research Funding; Ablynx: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria. Metjian: Momenta/Johnson & Johnson, Sanofi Aventis, Takeda: Research Funding; Ablynx/Sanofi: Consultancy; Sanofi Aventis, Takeda: Other: Advisory. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Sanofi Genzyme: Consultancy. Coppo: Alexion Pharmaceuticals, Sanofi Aventis, Octapharma AG: Consultancy, Other: Advisory; Alexion Pharmaceuticals, Sandoz, Sanofi Aventis, Takeda: Other: Speakers Bureau; Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremer Hovinga Strebel: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Speaker at symposia; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Other: Speaker at symposia; Roche: Other: Speaker at symposia; Siemens: Other: Speaker at symposia. Minkue Mi Edou: Sanofi: Current Employment, Other: May hold shares and/or stock options. de Passos Sousa: Sanofi: Current Employment, Other: May hold shares and/or stock options. Callewaert: Sanofi: Current Employment, Other: May hold shares and/or stock options. Gunawardena: Sanofi: Current Employment, Other: May hold shares and/or stock options. Lin: Sanofi: Current Employment, Other: May hold shares and/or stock options.

Levetiracetam is approved as an add-on therapy to treat refractory partial seizures in pediatric patients over four years old. The efficacy and safety in pediatric patients with epilepsy in Uygur, China, is unknown. Therefore, the objective of this study was to investigate the safety, efficacy, and tolerability of levetiracetam in pediatric patients with epilepsy in Uygur, China.This retrospective study compared the efficacy and safety of levetiracetam monotherapy and in combination with other antiseizure medications (ASMs) in 1055 pediatric patients with epilepsy treated with levetiracetam. The seizure frequencies at 1, 2, and 3 years after starting levetiracetam therapy were recorded and compared with the baseline yearly frequency. Safety variables included the incidence and type of adverse reactions.A total of 680 (64%) pediatric patients responded to levetiracetam therapy with a more than 50% reduction in the frequency of seizures. Seizure-free rates increased over time, 13%, 15%, and 18% at 1, 2, and 3 years, respectively. The number of baseline ASMs and the order of levetiracetam introduction were highly significant, impacting the likelihood of seizure remission during a 3-year follow-up period (p 0.001). During levetiracetam treatment, 233 pediatric patients (22%) experienced at least one adverse reaction.These significant findings indicate that levetiracetam is likely to become a widely prescribed ASM for epilepsy in pediatric clinical practice because of its long-term safety, efficacy, and tolerability.

Background: Coagadex is a high-purity plasma-derived factor X concentrate (pdFX) developed to treat hereditary factor X deficiency (FXD). Objective: Evaluate the efficacy and safety of pdFX administered to patients with hereditary FXD. Methods: This was an open-label, multicenter, retrospective analysis of patients receiving pdFX for compassionate use. Efficacy end points included treatments administered, the number and treatment of bleeds, and investigator assessments. Adverse drug reactions (ADRs) were monitored. Results: Fifteen patients were included: seven received routine prophylaxis, seven received on-demand treatment, and one alternated. Most were aged ?12 years (n = 13) and had severe hereditary FXD (n = 12). The median follow-up time was 19.2 months (range, 3.5-48.8). The number of infusions per patient per month was higher for the routine prophylaxis group (median [range], 5.4 [1.4-10.1]) than for the on-demand group (0.8 [0.1-2.3]), as was the dose per infusion (27.9 [21.9-53.6] IU/kg vs 20.0 [13.6-27.7] IU/kg). Patients experienced 88 bleeds (34 minor, 7 major, 47 unclassified). The monthly bleed rate per patient was 0.04 in the routine prophylaxis group (based on 17 bleeds in four patients) and 0.8 in the on-demand group (based on 71 bleeds in eight patients). pdFX was used to treat 79 bleeds and was rated effective in all instances. In an overall assessment, investigators rated pdFX as excellent for 14 patients (93.3%) and good for 1 patient (6.3%). No ADRs or safety concerns were reported. Conclusions: This analysis supports the use of pdFX as a safe, effective treatment for hereditary FXD. Routine prophylaxis with pdFX may reduce bleed frequency. © 2021 Bio Products Laboratory. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH)., This study was funded by Bio Products Laboratory Ltd. Bio Products Laboratory (Elstree, UK) provided funding for medical writing and editorial assistance in the development of this manuscript. Mollie Marko, PhD (Ashfield MedComms, an Ashfield Health company, Middletown, CT, USA), drafted and revised the manuscript based on input from authors, and Joshua Safran (Ashfield MedComms) copyedited and styled the manuscript per journal requirements., This study was funded by Bio Products Laboratory Ltd.

This article belongs to the Special Issue Research on Charcot-Marie-Tooth Disease, from Molecules to Therapy 2.0; International audience; Charcot–Marie–Tooth disease (CMT) is the most frequent hereditary peripheral neuropathies. It is subdivided in two main groups, demyelinating (CMT1) and axonal (CMT2). CMT1 forms are the most frequent. The goal of this review is to present published data on 1—cellular and animal models having opened new potential therapeutic approaches. 2—exploration of these tracks, including clinical trials. The first conclusion is the great increase of publications on CMT1 subtypes since 2000. We discussed two points that should be considered in the therapeutic development toward a regulatory-approved therapy to be proposed to patients. The first point concerns long term safety if treatments will be a long-term process. The second point relates to the evaluation of treatment efficiency. Degradation of CMT clinical phenotype is not linear and progressive.

Purpose Although adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs. Methods The SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18–65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up. Results A total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up. Conclusions In this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.

SummaryWhat is known and objective Postmenopausal osteoporosis is becoming an urgent health problem in China. A once-yearly infusion of zoledronic acid can be very effective for the treatment of postmenopausal osteoporosis in significantly reducing the risk of hip, vertebral and other fractures. This study aimed to investigate zoledronic acid treatment on postmenopausal osteoporosis in Uighur and Han patients in Xinjiang province, China. Methods A self-controlled and prospective trial design was adopted. A total of 155 Uighur and 151 Han patients were enrolled. All subjects received an intravenous infusion of zoledronic acid (5 mg) at day 0 (baseline) and at 12 months. Patients were followed up for 24 months; the bone mineral density (BMD) of the left total hip and L1–L4 vertebrae was measured at day 0 and at 24 months. Results and discussion BMD was significantly higher after zoledronic acid treatment compared with baseline levels in all patients, as assessed at 24 months. Moreover, the BMD of left total hip increased with 2.7% in the Han group was significantly higher than that of the Uighur group with 1.4% (left total hip, 95% CI: 2.6% to 2.8% in Han group vs 1.2% to 1.4% in Uighur group). The BMD of L1–L4 vertebrae increased with 2.2% in the Han group was significantly higher than that of the Uighur group with 1.6% (L1–L4 vertebrae, 95% CI, 2.0% to 2.4% in Han group vs 1.4% to 1.7% in Uighur group); P .05). What is new and conclusion Zoledronic acid appears to be more effective in postmenopausal osteoporosis in Han than in Uighur subjects. The reasons for this require further investigation.

Emicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.

Purpose: this paper concentrates on the development and validation of an approach enabling to identify radiologically relevant radionuclides in radioactive waste at different stages of their management, as well as to implement their direct instrumental control. Material and methods: The research was carried out by comparing relevant radiological effects produced by radionuclides contained in activation RW from VVER-440 unit (reactor vessel, vessel internals and fuel rod cladding) on human at different stages of RW management. AKDAM-2.0 complex was used to evaluate the changes in the radionuclide inventory of materials during their irradiation and cooling. Results: The study enabled to calculate relevant contribution of different radionuclides to the overall activity and dose rate from external and internal human exposure at different stages of RW management. This paper proposes a novel approach to identify radiologically relevant radionuclides based on a comparative evaluation of their contribution to the dose rate their activity, half-lives and migration properties. Relevant lists of radionuclides were developed for the studied materials. These radionuclides should be considered in the safety assessments of RW management practices and the post-closure safety demonstration for deep geological disposal facilities (DGDF). The study suggests that direct instrumental control is feasible for a number of radionuclides along with the use of an integrated approach enabling to evaluate the content of other radionuclides. Conclusions: Further validation proved the viability of the proposed approach in the development of lists of radiologically relevant radionuclides. It has been found that the generated list is consistent with international practice used to demonstrate DGDF safety. It should be noted that only a small number of radionuclides should be considered radiologically relevant notwithstanding a variety of radionuclides generated due to material activation. In some cases, certain radionuclides are required to be added to the lists specified in the appendices to Radiation Safety Standards (RSS). However, the direct instrumental control covering the entire list of radiologically relevant radionuclides (for each RW management stage) is considered not feasible and hard to implement. The study shows that an integrated approach combining direct instrumental control for certain radionuclides, periodic destructive tests and inventory calculations is a preferred option. At the stage of periodic radiation monitoring in the disposal facility, such instrumental control should be focused on the evaluation of disposal system properties affecting its safety (hydrogeochemical, hydrogeological characteristics and etc.).

The encapsulation of metallic waste occurring from the fuel decladding process into cementitious formulations is a typical path within the British nuclear community. The metallic–grout mixture is stored in stainless steel drums which are maintained temporarily in ambient conditions before ultimate disposal. Some of these drums have exhibited bulges ascribed to internal metallic corrosion. The corrosion products, which occupy larger volume than the parent metals, generate stresses on the surrounding material, which inhibit the long term safety of the containment. Herein, finite element modelling was used to address the effects of the internal volume expansion on the grout and the steel integrity. A parametric study is presented to determine how several factors including the type of the grout, the location and the size of encapsulated metallic parts and the friction at the material interfaces may alter the system’s behaviour.

Purpose Endovascular treatment of coarctation of aorta (CoA) by self-expandable Nitinol stents is one of the recognized treatment methods and may be an alternative to surgery or balloon-expandable stent implantation for CoA but there is little information about midterm to long term results of self-expandable stents. Methods Sixty-two patients with CoA (40 men), with a mean age of 30.7 ± 11 years, (range 17–63 years) underwent stent implantation with Optimed self-expandable Nitinol stents between 2005 and 2014. Successful outcome was defined as peak systolic pressure gradient ≤20 mmHg after stent implantation. The patients were followed-up clinically and by echocardiography and in patients, in whom there was suspicion of recoarctation, CT angiography or recatheterization was performed. Results 65 stents were successfully implanted in all 62 patients. Peak systolic pressure gradient decreased from mean 62.4 ± 18 mmHg (range 35–100 mmHg) to mean 2.8 ± 5 mmHg (range 0–15 mmHg; P

This paper illustrates the results of a questionnaire designed to explore the full range of topics and concerns related to the potential impacts of CO 2 geological storage. The questionnaire was compiled online by 45 European and international stakeholders from 16 different countries, including researchers, operators and regulators. The results provide a comprehensive picture of the variety of aspects that the respondents consider important from the point of view of impacts and long term safety of storage sites. The themes span from impacts on the environment to socio-economic and operational such as for instance building and management of storage sites.

Proton pump inhibitors (PPIs) have become known for both their therapeutic effect and good safety profile. An application was submitted to the US Food and Drug Administration for approval of a reformulated PPI product that failed bioequivalence testing, but was submitted on the basis of the long history of PPI use as a "surrogate" for equivalence. This review evaluates the safety data for PPIs, discuss variability of pharmacokinetic parameters of PPIs in the reformulation setting, and potential implications of those changes for long-term safety.