Purpose Patients with sickle cell disease (SCD) may experience sickle cell-related pain crises, also referred to as vaso-occlusive crises (VOCs), which are a substantial cause of morbidity and mortality. The study explored how VOC frequency and severity impacts health-related quality of life (HRQoL) and work productivity. Methods Three hundred and three adults with SCD who completed an online survey were included in the analysis. Patients answered questions regarding their experience with SCD and VOCs, and completed the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) and the Workplace Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP). Differences in ASCQ-Me and WPAI:SHP domains were assessed according to VOC frequency and severity. Results Nearly half of the patient sample (47.2%) experienced ≥ 4 VOCs in the past 12 months. The most commonly reported barriers to receiving care for SCD included discrimination by or trouble trusting healthcare professionals (39.6%, 33.3%, respectively), limited access to treatment centers (38.9%), and difficulty affording services (29.4%). Patients with more frequent VOCs reported greater impacts on emotion, social functioning, stiffness, sleep and pain, and greater absenteeism, overall productivity loss, and activity impairment than patients with less frequent VOCs (P < 0.05). Significant impacts on HRQoL and work productivity were also observed when stratifying by VOC severity (P < 0.05 for all ASCQ-Me and WPAI domains, except for presenteeism). Conclusions Results from the survey indicated that patients with SCD who had more frequent or severe VOCs experienced deficits in multiple domains of HRQoL and work productivity. Future research should examine the longitudinal relationship between these outcomes.

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BackgroundSickle cell disease (SCD) is a chronic condition associated with high mortality and morbidity. It is characterized by acute clinical symptoms such as painful vaso-occlusive crises, which can impair health-related quality of life (HRQL). This study was conducted to identify validated patient-reported outcome (PRO) instruments for use in future trials of potential treatments for SCD.MethodsA systematic literature review (SLR) was performed using MEDLINE and EMBASE to identify United States (US)-based studies published in English between 1997 and 2017 that reported on validated PRO instruments used in randomized controlled trials and real-world settings. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to assess the quality of PRO instruments.ResultsThe SLR included 21 studies assessing the psychometric properties of 24 PRO instruments. Fifteen of those instruments were developed and validated for adults and 10 for children (one instrument was used in both children and young adults aged up to 21 years). Only five of the 15 adult instruments and three of the 10 pediatric instruments were developed specifically for SCD. For most instruments, there were few or no data on validation conducted in SCD development cohorts. Of the 24 PRO instruments identified, 16 had strong internal reliability (Cronbach’s α ≥0.80). There was often insufficient information to assess the content validity, construct validity, responsiveness, or test-retest reliability of the instruments identified for both child and adult populations. No validated PRO instruments measuring caregiver burden in SCD were identified.ConclusionsThe evidence on the psychometric properties of PRO instruments was limited. However, the results of this SLR provide key information on such tools to help inform the design of future clinical trials for patients with SCD in the US.Electronic supplementary materialThe online version of this article (10.1186/s12955-018-0930-y) contains supplementary material, which is available to authorized users.

Pharmacoproteomics is the study of disease-modifying and toxicity parameters associated with therapeutic drug administration, using analysis of quantitative and temporal changes to specific, predetermined, and select proteins, or to the proteome as a whole. Pharmacoproteomics is a rapidly evolving field, with progress in analytic technologies enabling processing of complex interactions of large number of unique proteins and effective use in clinical trials. Nevertheless, our analysis of clinicaltrials.gov and PubMed shows that the application of proteomics in early-phase clinical development is minimal and limited to few therapeutic areas, with oncology predominating. We review the history, technologies, current usage, challenges, and potential for future use, and conclude with recommendations for integration of pharmacoproteomic in early-phase drug development.

Adherence and persistence improved significantly after switching from DFX-DT to DFX-FCT for all diseases, but especially MDS.

Adults reported QALY scores 20% higher than caregivers of adults (P=0.01) after ageadjustment. The mean VAS score was 79 (range: 30, 99) among adults, 55 (15, 90) among caregivers of adults, and 68 (30, 100) among caregivers of minors. Adults reported average VAS scores 24 points above caregiver groups after age adjustment (P,0.01). All groups met or exceeded the 75% instrument acceptability agreementrate (P,0.05). Conclusions: EQ-5D was responsive and acceptable for this multinational rare disease sample. While adults consistently rated their health higher than caregivers in preliminary data, the difference between groups was attenuated using the population-derived QALY estimates as compared to self-evaluation using the VAS.

Immune thrombocytopenia (ITP) may occur in isolation (primary) or in association with a predisposing condition (secondary ITP [sITP]). Eltrombopag is a well-studied treatment for primary ITP, but evidence is scarce for sITP. We evaluated real-world use of eltrombopag for sITP using electronic health records. Eligible patients had diagnoses of ITP and a qualifying predisposing condition, and eltrombopag treatment. We described patient characteristics, treatment patterns, platelet counts, and thrombotic and bleeding events. We identified 242 eligible patients; the most common predisposing conditions were hepatitis C and systemic lupus erythematosus. Average duration of eltrombopag treatment was 6.1 months. Most (81.4%) patients achieved a platelet count ≥ 30,000/µL at a mean of 0.70 months, 70.2% reached ≥ 50,000/µL at a mean of 0.95 months, and 47.1% achieved a complete response of > 100,000/µL at a mean of 1.43 months after eltrombopag initiation. At eltrombopag discontinuation, 105 patients (43%) experienced a treatment-free period for a mean 3.3 months. Bleeding events occurred with similar frequency before and during eltrombopag treatment whereas thrombotic events were less frequent during eltrombopag treatment. Our results suggest similar rates of platelet response with eltrombopag in patients with sITP as compared with primary ITP. In addition, a treatment-free period is possible for a substantial minority of patients.

Background: Haemophilia A is caused by deficiency of Factor VIII (F.VIII), an essential blood-clotting cofactor. Prophylaxis or on-demand treatment with recombinant FVIII forms the current standard of care to prevent bleeding in Haemophilia A patients in the developed world. However, approximately 30% of severe haemophilia A patients develop inhibitory antibodies against F.VIII. Moreover, FVIII treatment requires venous access which is burdensome. The recent successful clinical trials and subsequent regulatory approval of a F.VIII-mimetic bispecific antibody, Hemlibra, in Haemophilia A patients with inhibitors have provided much needed hope for suffers and their family. However, whilst Hemilibra represents a major breakthrough in the field, there remain some concerns about balancing the risks of bleeding with those of thrombosis when using this agent. Aims: To develop a new fully human FVIII mimetic bispecific antibody that can support the assembly of a functional Factor IXa (F.IXa) and Factor X (F.X) complex, thereby replacing F.VIII function in vivo. Methods: Using Kymab's bispecific antibody platform, we developed KY1049, a fully human common light chain (CLC) bispecific antibody, to test as an effective functional mimetic of F.VIII. KY1049 bispecific heterodimer was purified using standard Protein A chromatography, followed by cation ion exchange chromatography (cIEX). The mass and heterodimer purity of the bispecific molecule was confirmed using Mass Spectrometry (MS). A combination of in vitro and ex vivo assays was used to characterize the cIEX purified bispecific antibody, including chromogenic FXase and Activated Partial Thromboplastin Time (aPTT). The affinities of the FIX arm and FX arm of KY1049 bispecific to FIX and FX, respectively, were determined using Surface Plasmon Resonance (SPR). Results: cIEX purified KY1049 molecule was confirmed as a single species by MS. After denaturing, the molecular weights of the two heavy chains and one light chain matches in silico predicted molecular weights. Purified KY1049 actively generated activated F.X (F.Xa) and functionally rescued the clotting defect in F.VIII-depleted plasma in the aPTT assay. Importantly, ex vivo activities of KY1049 indicates its therapeutic benefit is likely to be similar in efficacy to Hemlibra. KY1049 binds F.IX and F.X simultaneously by SPR, but the affinities are different from those reported of Hemlibra. Summary/Conclusion: We have developed KY1049, a FVIII mimetic bispecific antibody, that demonstrates biological activities comparable to those reported for Hemlibra. Its therapeutic benefit is likely to be at least as effective as Hemlibra. Furthermore, initial analysis of the KY1049 molecule also showed some differences between the two molecules which could be harnessed to enhance its physical properties and activity.