Extended Treatment With Recombinant Human Parathyroid Hormone (1-84) in Adult Patients With Chronic Hypoparathyroidism.

OBJECTIVE: Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is efficacious in patients with hypoparathyroidism but additional data supporting its prolonged use are needed. We evaluated whether efficacy, safety, and tolerability are maintained during long-term rhPTH(1-84) treatment of patients with chronic hypoparathyroidism. METHODS: This was a phase 4, single-center, open-label, single-arm, 3-year extension (NCT02910466) of the phase 3 Hypo Extended (HEXT) study (NCT01199614). Patients self-administered rhPTH(1-84) once daily by subcutaneous injection, with doses individualized based on clinical parameters. Albumin-adjusted serum calcium levels (primary outcome measure), other disease biomarkers, health-related quality of life, and safety of rhPTH(1-84) were assessed using descriptive statistics. RESULTS: All patients (n = 39) had been exposed to rhPTH(1-84) (mean exposure [SD] 8.5 [3.5] years) before the start of the study, resulting in a mean exposure of 10.8 years including the present study. Mean patient age was 51.9 years, 79.5% were female, and 97.4% were White. Mean albumin-adjusted serum calcium concentrations were within the target range, and mean serum phosphate, serum calcium-phosphate product, and 24-hour urinary calcium excretion levels were within reference ranges at end of treatment. Mean doses of supplemental calcium and active vitamin D were maintained throughout the study. Bone turnover marker levels were maintained from baseline to end of treatment. No clinically relevant changes in bone mineral density were observed. Patient-reported health-related quality-of-life scores were generally maintained throughout the study. Four adverse events were considered treatment related and no new safety signals were identified. CONCLUSION: The effects of rhPTH(1-84) on biochemical, skeletal, and health-related quality-of-life parameters did not wane with extended use.

Retacrit®, Biosimilar of Epoetin Alfa, in Chemotherapy-Induced Anemia in Routine Practice: Impact of Iron Supplementation.

INTRODUCTION: The aim of the study was to evaluate in real-life conditions the effectiveness and safety of a biosimilar of epoetin alfa (Retacrit®) in chemotherapy-induced anemia and the impact of iron supplementation. METHODS: This was a longitudinal, observational, prospective study of 12-16 weeks conducted in 195 French centers. The primary endpoint was the achievement of target Hb (with an increase of Hb ≥1 g/dL) or an increase of Hb ≥2 g/dL, in the absence of transfusion in the previous 3 weeks. RESULTS: 2,076 patients (women, 50.6%; mean age, 67.0 years) with malignant diseases (solid tumors, 79.8%; lymphomas, 12.7%; multiple myeloma, 6.6%) were analyzed. A total of 655 patients received oral iron (40.5%), intravenous iron (58.9%), or both (0.6%). At inclusion, 10.0% and 18.2% of patients without and with iron supplementation had serum ferritin <100 µg/L, respectively. Transferrin saturation (TSAT) ≤20% was more frequent in patients with supplementation (76.6%) than without supplementation (33.9%). The mean weekly doses of epoetin alfa biosimilar and planned duration of treatment were comparable regardless of iron supplementation. The primary endpoint was achieved in 70.5% and 70.2% of patients without and with iron supplementation, respectively. Three (0.1%) serious thromboembolic events related to treatment with epoetin alfa biosimilar were reported. CONCLUSION: Epoetin alfa biosimilar was effective and well tolerated for treating chemotherapy-induced anemia. Patients in subgroup with iron supplementation had lower TSAT at inclusion compared to subgroup without supplementation. Comparable mean Hb levels were achieved in both subgroups. The rate of patients with iron supplementation through the intravenous route was however insufficient.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Chinese herbal injections combined with rt-PA intravenous thrombolysis for acute ischemic stroke: A systematic review and meta-analysis protocol.

BACKGROUND: Acute ischemic stroke (AIS) is an important factor leading to adult death and disability globally. For AIS patients who meet certain conditions, recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis is an important method recommended by national guidelines to achieve vascular recanalization. However, complications such as hemorrhagic transformation and vascular reocclusion after thrombolysis are still unsolved problems in clinical. Several systematic reviews of clinical randomized controlled trials (RCTs) in the past have shown that Chinese herbal injections (CHIs) can improve the neurological function of patients, increase the tolerance of ischemic tissues to hypoxia, and inhibit platelet aggregation. Therefore, this study conducted a meta-analysis of AIS treatment with intravenous thrombolysis alone and compared it with the combined application of CHIs. To evaluate whether CHIs have a synergistic effect on thrombolytic therapy and provide a basis for clinical application. METHODS: The following databases will be searched until September 2020: ①English databases: PubMed, Cochrane Library, Embase; ②Chinese databases: CNKI, Wanfang database, Weipu database, SinoMed. RCTs will be included to compare the efficacy of thrombolysis combined with CHIs and thrombolysis alone in the treatment of AIS. Data extraction and risk of bias assessments will be carried out by 2 verifiers independently. The risk of bias will be evaluated through the Cochrane risk of bias tool. Review Manager software 5.3 will be used for statistical analysis. RESULTS: This study will provide comprehensive evidence for the treatment of AIS by CHIs combined with intravenous thrombolysis from multiple aspects. CONCLUSION: The conclusion of the meta-analysis will provide a basis for judging whether CHIs combined with intravenous thrombolysis is an effective measure for the treatment of AIS. ETHICS AND DISSEMINATION: Ethical approval is not needed because this study will be based on data that already published. We will publish the findings of this study in a peer-reviewed journal and related conferences. PROSPERO REGISTRATION NUMBER: CRD42020215546.

Clinical Trial of High-Dose Pegylated-Interferon-Alfa-2b Combined With Phototherapy in Advanced Stage Mycosis Fungoides.

The combination of Interferon-α-2b (IFN-α-2b) and phototherapy is highly effective in treating mycosis fungoides (MF) but side effects often lead to discontinuation of therapy.1.

A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy.

PURPOSE: The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. RESULTS: Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. CONCLUSION: ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.

Switch from enzyme replacement therapy to oral chaperone migalastat for treating fabry disease: real-life data.

The treatment options for Fabry disease (FD) are enzyme replacement therapy (ERT) with agalsidase alfa or beta, and the oral pharmacological chaperone migalastat. Since few data are available on the effects of switching from ERT to migalastat, we performed a single-center observational study on seven male Fabry patients (18-66 years) to assess the effects of the switch on renal, cardiac, and neurologic function, health status, pain, lyso-Gb3, α-Gal A activity and adverse effects. Data were retrospectively collected at time of diagnosis of FD (baseline, T0), and after 12 months of ERT (T1), and prospectively after 1 year of therapy with migalastat (T2). No patient died or reported renal, cardiac, or cerebrovascular events during the study period. The predefined measures for cardiac, renal and neurologic function, and FD-related symptoms and questionnaires were stable between baseline and the switch, and remained unchanged with migalastat. However, a significant improvement was observed in left ventricular mass index from baseline to T2 (p = 0.016), with a significative difference between the treatments (p = 0.028), and in median proteinuria from T2 vs T1 (p = 0.048). Moreover, scores of the BPI improved from baseline to T1, and remained stable with migalastat. Plasma lyso-Gb3 levels significantly decreased from baseline to T1 (P = 0.007) and T2 (P = 0.003), while did not significantly differ between the two treatments. α-Gal A activity increased from T0 to T2 (p < 0.0001). The frequency of adverse effects under migalastat and ERT was comparable (28% for both drugs). In conclusion, switching from ERT to migalastat is valid, safe and well tolerated.

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

CONTEXT: Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). OBJECTIVE: To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. DESIGN: Prospective open-label trial. SETTING: Tertiary medical center. PARTICIPANTS: Twenty-four subjects with hypoparathyroidism. INTERVENTION: Treatment with rhPTH(1-84) for 8 years. MAIN OUTCOME MEASURES: Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. RESULTS: PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean ± SE, 4.6% ± 1.5%; P = 0.01) and 8 years (2.6% ± 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean ± SE, -3.5% ± 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon. CONCLUSION: rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.

Andexanet Alfa: First Global Approval.

Intravenous andexanet alfa [coagulation factor Xa (recombinant), inactivated-zhzo; Andexxa®] is a first-in-class recombinant modified factor Xa protein that has been developed by Portola Pharmaceuticals as a universal antidote to reverse anticoagulant effects of direct or indirect factor Xa inhibitors. In May 2018, andexanet alfa received its first global approval in the USA for use in patients treated with rivaroxaban and apixaban, when reversal of anticoagulant effects is required in life-threatening or uncontrolled bleeding. Intravenous andexanet alfa is under regulatory review in the EU and is undergoing clinical development in Japan. This article summarizes the milestones in the development of andexanet alfa leading to this first global approval for reversing anticoagulation of rivaroxaban and apixaban in adults.

Computational antimicrobial peptide design and evaluation against multidrug-resistant clinical isolates of bacteria.

There is a pressing need for new therapeutics to combat multidrug- and carbapenem-resistant bacterial pathogens. This challenge prompted us to use a long short-term memory (LSTM) language model to understand the underlying grammar, i.e. the arrangement and frequencies of amino acid residues, in known antimicrobial peptide sequences. According to the output of our LSTM network, we synthesized 10 peptides and tested them against known bacterial pathogens. All of these peptides displayed broad-spectrum antimicrobial activity, validating our LSTM-based peptide design approach. Our two most effective antimicrobial peptides displayed activity against multidrug-resistant clinical isolates of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci strains. High activity against extended-spectrum ß-lactamase, methicillin-resistant S. aureus, and carbapenem-resistant strains was also observed. Our peptides selectively interacted with and disrupted bacterial cell membranes and caused secondary gene-regulatory effects. Initial structural characterization revealed that our most effective peptide appeared to be well folded. We conclude that our LSTM-based peptide design approach appears to have correctly deciphered the underlying grammar of antimicrobial peptide sequences, as demonstrated by the experimentally observed efficacy of our designed peptides.

Engineering Glucose Responsiveness Into Insulin.

Insulin has a narrow therapeutic index, reflected in a small margin between a dose that achieves good glycemic control and one that causes hypoglycemia. Once injected, the clearance of exogenous insulin is invariant regardless of blood glucose, aggravating the potential to cause hypoglycemia. We sought to create a "smart" insulin, one that can alter insulin clearance and hence insulin action in response to blood glucose, mitigating risk for hypoglycemia. The approach added saccharide units to insulin to create insulin analogs with affinity for both the insulin receptor (IR) and mannose receptor C-type 1 (MR), which functions to clear endogenous mannosylated proteins, a principle used to endow insulin analogs with glucose responsivity. Iteration of these efforts culminated in the discovery of MK-2640, and its in vitro and in vivo preclinical properties are detailed in this report. In glucose clamp experiments conducted in healthy dogs, as plasma glucose was lowered stepwise from 280 mg/dL to 80 mg/dL, progressively more MK-2640 was cleared via MR, reducing by ∼30% its availability for binding to the IR. In dose escalations studies in diabetic minipigs, a higher therapeutic index for MK-2640 (threefold) was observed versus regular insulin (1.3-fold).

Systematic Review and Meta-analysis of Endostar Combined With Transcatheter Arterial Chemoembolization (TACE) Versus TACE Alone for Hepatocellular Carcinoma.

Many studies have investigated the efficacy of Endostar combined with transcatheter arterial chemoembolization (TACE) versus TACE alone for hepatocellular carcinoma (HCC). A systematic review was conducted to evaluate the efficacy of Endostar. PubMed, Embase, and other databases were searched, and meta-analysis was performed using RevMan 5.3 software. Nine studies, all of which were clinical randomized controlled trials, involving 411 participants were included. The overall response rate, disease control rate and α-fetoprotein negative conversion ratio, and the 6- and 12-month survival rate of HCC patients treated with combined Endostar and TACE were higher than those treated with TACE alone ( P < .01). Furthermore, the incidence of tumor progression was low after Endostar treatment ( P = .005). The incidence of adverse effects (leukocytopenia, liver function damage, and vomiting) was similar in Endostar with TACE and in TACE alone ( P > .05). However, large studies and more randomized trials are necessary to determine the effects of Endostar on HCC.

Safety and Efficacy of Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism Randomly Assigned to Receive Fixed 25-µg or 50-µg Daily Doses.

PURPOSE: The present study examined the efficacy and safety of a lower rhPTH(1-84) dose. METHODS: RELAY was a dose-blinded, multicenter, 8-week study of patients with hypoparathyroidism randomized to fixed 25- or 50-µg/d doses of subcutaneous rhPTH(1-84). The primary end point was the percentage of patients at week 8 with supplement reductions in calcium to ≤500 mg/d and in calcitriol to ≤0.25 µg/d, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. The secondary end point was the percentage of patients at week 8 with a ≥50% reduction in calcium and calcitriol doses, while maintaining serum calcium levels between 1.875 mmol/L and the upper limit of normal. FINDINGS: Forty-two patients were randomized (25-µg group, n = 19; 50-µg group, n = 23). At week 8, the primary end point was achieved by 4 (21%; 95% CI, 6%-46%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. The secondary end point was achieved by 2 (11%; 95% CI, 1%-33%) and 6 (26%; 95% CI, 10%-48%) of the patients receiving 25 and 50 µg/d of rhPTH(1-84), respectively. Treatment-emergent adverse events were reported by 11 (58%) patients in the 25-µg group and 17 (74%) patients in the 50-µg group. IMPLICATIONS: Doses as low as 25 µg/d of rhPTH(1-84) are well tolerated and may be effective for a subset of patients. ClinicalTrials.gov identifier: NCT01268098.

Evaluation of piggyBac-mediated CHO pools to enable material generation to support GLP toxicology studies.

Generating purified protein for GLP toxicology studies (GLP-Tox) represents an important and often rate limiting step in the biopharmaceutical drug development process. Toxicity testing requires large amounts of therapeutic protein (>100 g), typically produced in a single 500-2,500 L bioreactor, using the final CHO clonally derived cell line (CDCL). One approach currently used to save time is to manufacture GLP-Tox material using pools of high-producing CHO CDCLs instead of waiting for the final CDCL. Recently, we reported CHO pools producing mAb titers >7 g/L using piggyBac-mediated gene integration (PB CHO pools). In this study, we wanted to leverage high titer PB CHO pools to produce GLP-Tox material. A detailed product quality attribute (PQA) assessment was conducted comparing PB CHO pools to pooled Top4 CDCLs. Four mAbs were evaluated. First, we found that PB CHO pools expressed all four mAbs at high titers (2.8-4.4 g/L in shake flasks). Second, all four PB CHO pools were aged to 55 generations (Gen). All four PB CHO Pools were found to be suitable over 55 Gen. Finally, we performed bioreactor scale-up. PB CHO pool titers (3.7-4.8 g/L) were similar or higher than the pooled Top 4 CDCLs in 5 L bioreactors (2.4-4.1 g/L). The PQAs of protein derived from PB CHO pools were very similar to pooled Top 4 CHO CDCLs according to multiple orthogonal techniques including peptide mapping analysis. Taken together, these results demonstrate the technical feasibility of using PB CHO pools to manufacture protein for GLP-Tox. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1436-1448, 2017.

[NOAC: Real-life data and the role of antidotes for the treatment of bleeding]. / NOAK: Real-life-Daten und Therapie von Blutungen mit Antidots.

The non-vitamin K antagonists (NOAC) are an integral component of our antithrombotic prevention and therapy. For four of the NOAC, their non-inferiority or even superiority versus vitamin K antagonists (VKA) has been proven. Thus, the management of special patient cohorts or the management of active bleeding complications is a focus of current discussion.In addition to prospective trials, numerous retrospective analyses of health insurers or public health provider data have been analyzed and published as "real life" or "real-world evidence" data. In almost all data sets the results of the NOAC approval trials were confirmed, demonstrating their non-inferiority or even superiority versus VKA. Attempts to compare the various NOAC with each other must be viewed critically since the real-world evidence (RWE) analysis provides very divergent results depending on the cohorts analyzed. Thus, a substantial prescriber-bias must be taken into account and never be excluded.In order to improve the management of bleeding complications, NOAC antidotes were developed. While the factors Xa antidote, andexanet alpha, a modified coagulation factor deleted of an intrinsic activity, will not be available before 2018, the dabigatran antidote idarucizumab is already in clinical use. Idarucizumab, a monoclonal antibody fragment directed against dabigatran, is able to completely antagonize the effect of dabigatran within minutes. Therefore, the drug has the potential to terminate life-threatening bleeding complications earlier and make emergency surgical or interventional procedures possible without an elevated bleeding risk.

Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence.

Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men. The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60 days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

Noninvasive markers of liver fibrosis: on-treatment changes of serum markers predict the outcome of antifibrotic therapy.

AIM: The utility of noninvasive serum markers to longitudinally monitor liver fibrosis is not established. METHODS: A total of 70 patients with chronic hepatitis C who had previously failed antiviral therapy were randomized to receive pegylated interferon with or without silymarin for 24 months. Enhanced Liver Fibrosis (ELF) tests (hyularonic acid, terminal peptide of procollagen III, tissue inhibitor of matrix metaloproteinase-1) were performed on patient sera obtained before, during and at the end of the study (0, 12, 24 months) and liver histology obtained before and at the end of the study. RESULTS: At 24 months, absolute changes in Ishak fibrosis stage and ELF ranged from -4 to +4 and from -2.41 to +2.68, respectively. Absolute changes in ELF at 12 months were significantly associated with changes in both ELF and histology at 24 months. A model combining both baseline ELF and change of ELF at 12 months could predict the 24-month ELF (R=0.609, P<1×10), a decrease in ELF at 24 months [area under the curve (AUC): 0.80-0.85] and an increase in ELF at 24 months (AUC: 0.81-0.85). Furthermore, a model combining both baseline histologic stage and ELF together with the change of ELF at 12 months could predict 24-month histology (R=0.601, P<1×10, AUC: 0.88-0.92), histologic fibrosis regression (AUC: 0.81-0.84) and progression (AUC: 0.86-0.91). CONCLUSION: Our observations suggest that a change in the serum marker ELF predicts changes in liver fibrosis over a longer period. These data support the use of ELF as a surrogate marker of liver fibrosis evolution in monitoring antifibrotic treatments, thus permitting 'response-guided' therapy by the early identification of patients who will benefit from prolonged treatment.

Idarucizumab and factor Xa reversal agents: role in hospital guidelines and protocols.

As expected with all antithrombotic agents, there is a risk of bleeding complications in patients receiving direct oral anticoagulants (DOACs) because of the DOAC itself, acute trauma, invasive procedures, or underlying comorbidities. For many bleeding events, a prudent course of action will be to withdraw the DOAC, then "wait and support" the patient, with the expectation that the bleeding event should resolve with time. Likewise, DOAC therapy may be interrupted ahead of a planned procedure, the stopping time being dependent on the agent involved and the patient's renal function. However, urgent reversal of anticoagulation is required in patients with serious or life-threatening bleeding or in those requiring urgent surgery or procedures. Novel specific reversal agents, either under development or recently approved, will need to be incorporated into local anticoagulation reversal protocols. For dabigatran-treated patients, idarucizumab recently has been approved for clinical use in cases of life-threatening or uncontrolled bleeding or when patients require emergency surgery or urgent procedures, both associated with a high risk of bleeding. As clinical experience with individual specific reversal agents grows, their roles in managing major bleeding events in DOAC-treated patients will become better defined. Future research, as well as ongoing use of idarucizumab, should help establish when it is appropriate to re-dose with idarucizumab, coadminister with prothrombin complex concentrates, or re-initiate DOAC after idarucizumab use. Ongoing trials should help identify the appropriate doses and expected durations of effect for andexanet alfa and ciraparantag, which are likely to vary depending on the individual oral anticoagulants.

BAY 81-8973 (Octocog Alfa; Kovaltry®): A Review in Haemophilia A.

BAY 81-8973 (octocog alfa; Kovaltry®) is an unmodified, full-length, recombinant factor VIII (FVIII) concentrate with the same amino acid sequence as Kogenate® FS, but produced with innovative manufacturing technologies. This narrative review discusses the clinical efficacy and tolerability of BAY 81-8973 in haemophilia A, as well as summarizing its pharmacological properties. Results of the LEOPOLD I, LEOPOLD II and LEOPOLD Kids trials demonstrated that routine prophylaxis with intravenous BAY 81-8973 was associated with a low annualized bleeding rate (ABR) in previously treated adult and paediatric patients with severe haemophilia A. In terms of the ABR, BAY 81-8973 prophylaxis was more effective than on-demand treatment. Intravenous BAY 81-8973 was generally well tolerated, with no inhibitor development reported in previously treated patients in the completed LEOPOLD trial programme. In conclusion, BAY 81-8973 is a useful option for prophylaxis and treatment in adult and paediatric patients with haemophilia A.