Recommendations for Development and Validation of a Fit-For-Purpose Biomarker Assays Using Western Blotting; An-AAPS Sponsored Initiative to Harmonize Industry Practices.

Western blot (WB) assays are routinely used for detection and quantification of biomarkers. Although assay validation to measure biomarkers in complex matrices has become a mainstay process for ligand binding assays (LBA) and mass spectrometry (MS), no guidelines exist yet validate biomarker methods using WB techniques. In this cross-industry white paper, we outlined in detail the key steps for development and for validation of WB assays for protein biomarkers under different contexts of use (COU). In addition, we described how to determine the level of assay validation needed for biomarker assays using Western blotting. For simplicity, we described two paths of WB assay validation. The first path (Path 1) is for biomarkers being analyzed for exploratory research or for internal go- or no/go- decision making. The second path (Path 2) is for clinical decision making such as dose determination or drug response that need to be run in a regulated environment. This work is supported through AAPS Biomarkers and Precision Medicine subteam and represents AAPS members opinion.

[Development of homebased palliative care]. / Développement des soins palliatifs à domicile.

DEVELOPMENT OF HOME-BASED PALLIATIVE CARE. Early palliative care improves both the quality and the length of a patient's life and the attending physician is a key player. The care offered is graduated and adapted to all living environments (home, EHPAD, nursing homes, etc.). Symptoms of discomfort (respiratory, digestive, psychological, etc.) can thus be effectively treated, and end-of-life sedation at home can be envisaged.

DÉVELOPPEMENT DES SOINS PALLIATIFS À DOMICILE. Les soins palliatifs à domicile constituent un véritable enjeu de santé publique e t concernent l'ensemble des professionnels de santé quel que soit leur lieu d'exercice. La prise en charge palliative précoce améliore la qualité de vie mais également la durée de vie du patient, et le médecin traitant en est un acteur essentiel. L'offre de soins est graduée et adaptée à tous les lieux de vie (domicile, EHPAD, foyer…). Les symptômes d'inconfort (respiratoires, digestifs, psychologiques…) peuvent ainsi être efficacement traités et la sédation en fin de vie à domicile envisagée.

Reliance is key to effective access and oversight of medical products in case of public health emergencies.

INTRODUCTION: Responding to new threats and public health emergencies (PHE) creates serious challenges to regulators. The pandemic due to SARS-CoV-2 has been the catalyzer for change in global and local regulatory practices. Intensified collaboration, rapid and coordinated actions, and reliance mechanisms were key elements of the regulators' response to COVID-19 for all regulatory functions. AREAS COVERED: This article presents how collaboration and reliance among regulators were crucial tools for the regulatory responses to COVID-19, describes the reliance approaches for authorization of COVID-19 vaccines and other commodities, and the importance of reliance for other regulatory functions to avoid duplication and save resources where possible. This article also presents the results of a follow-up survey of reliance approaches in case of public health emergencies conducted between the International Pharmaceutical Regulators Programme (IPRP) members and discusses the forward-looking potential of reliance, analyzing the journey from theoretical concepts to real-life implementation. EXPERT OPINION: Regulatory reliance is an essential tool for regulators to act quickly and collectively in times of public health emergencies. Reliance approaches facilitate regulatory approvals and allow a more efficient use of resources, ultimately serving patients by facilitating earlier access to quality assured, safe and effective medicines.

Development, validation and application of a liquid chromatography-tandem mass spectrometry method for the activity and inhibition of DPP-4.

Background: Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) is a pharmaceutical treatment for type 2 diabetes. To demonstrate bioequivalence of enzyme inhibition of a new dosage form of the inhibitor vildagliptin, a method for enzyme activity was developed, validated and applied using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Results: The method was validated fit for purpose, including accuracy, precision as well as the stability of the activity and the inhibition of DPP-4 in human plasma. Conclusion: A method for the determination of the activity and inhibition of DPP-4 was developed using LC-MS/MS readout; the characteristics and performance of the method met predefined acceptance criteria and were fit for the purpose of a bioequivalence clinical trial.

From paediatric formulations development to access: Advances made and remaining challenges.

Developing suitable paediatric formulations and ensuring access to them by the greatest number of the 2.2 billion children worldwide are equally important to provide optimal pharmacotherapy. This review focuses on the progress made over the last two decades with paediatric oral formulations with respect to evidence for acceptability and dosing flexibility of liquid and solid oral dosage forms. It also discusses the clinical needs for, and the access to, paediatric formulations for existing authorised medicines. A significant body of new knowledge now supports the acceptability of solid oral dosage forms in children, resulting in an increasing number of medicines commercialised as multiparticulates, including minitablets that are starting to be brought to market. However, there are gaps with these formulations that deserve more research. Even though efforts have been made to identify medicines in need of age-appropriate formulations, there is no common priority list shared internationally. Such prioritisation would help to develop paediatric formulations with the greatest potential for providing a health benefit to children worldwide. In addition, available data highlight that paediatric formulation access is fragmented and unequal, with commercialisation of suitable paediatric formulations too often limited to some countries/regions. We propose actions to better align decisions during the development of paediatric formulations and promote a more globalised approach to facilitate registration pathways between different jurisdictions. Furthermore, discussions about alignment between approval, pricing and reimbursement processes should also happen, leaving working in siloes behind us. It is time for adults to start thinking outside the box for children.

Therapeutic equivalence of vildagliptin 100 mg once daily modified release to 50 mg twice daily immediate release formulation: An open-label, randomized, two-period, single- and multiple-dose, 6-day crossover study.

BACKGROUND AND AIMS: Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes mellitus, is available as immediate release (IR) tablets administered at 50 mg twice daily (BID). A 100 mg modified release (MR) formulation was developed for once daily (QD) dosing. This study aimed to compare the therapeutic equivalence of vildagliptin 100 mg MR QD (test) and 50 mg IR BID (reference) formulations at steady state under fasting conditions. METHODS: This was an open-label, randomized, two-period, single- and multiple-dose, two-way crossover, steady state study conducted in healthy adult subjects. Both vildagliptin formulations were administered for six days. Endpoints included pharmacodynamic equivalence, pharmacokinetic parameters, and tolerability of both formulations. RESULTS: Thirty subjects were enrolled and 26 completed both treatments. Maximum plasma concentration and exposure achieved with test was lower than reference formulation on day 1 and 6. The DPP-4 enzyme inhibition over time (DPP-4-AUEC0-24) was comparable between the formulations. Both formulations were well tolerated. CONCLUSION: This study confirms the therapeutic equivalence of vildagliptin IR and MR formulations for DPP-4 enzyme inhibition over time. The study supports vildagliptin 100 mg MR QD as a useful therapeutic alternative to 50 mg IR BID formulation to possibly improve treatment adherence and patient compliance. Long-term safety of the vildagliptin 100 mg MR QD formulation is not evaluated in this study.

Pediatric COVID-19 Therapeutics: Seizing the Right Research and Development Opportunities to Accelerate Access for Children.

Children, although at lower risk of poor outcomes from COVID-19 relative to adults, still stand to benefit from therapeutic interventions. Understanding of COVID-19 clinical presentation and prognosis in children is essential to optimize therapeutic trials design. This perspective illustrates how to collectively accelerate pediatric COVID-19 therapeutic research and development, based on the experience of the Global Accelerator for Paediatric Formulations.

Association of Intrarenal Resistance Index and Systemic Atherosclerosis After Kidney Transplantation.

BACKGROUND/AIM: Patients after kidney transplants are at risk of cardiovascular morbidity. An elevated resistance index (RI) is associated with renal graft failure, while a decreased RI can be due to a renal artery stenosis. The RI can also be measured in the carotid artery. Whether a correlation between intrarenal RI after kidney transplant in adult patients and the RI of the internal carotid artery exists is still unclear. PATIENTS AND METHODS: In this prospective cross-sectional study, RI of kidney transplants and of the internal carotid artery were measured with duplex sonography. Carotid intima-media thickness as well as the Framingham risk score and the Augmentation index, all known markers of atherosclerosis, were assessed. Correlations between the RI in Carotid artery and the RI of the kidney transplant were based on Spearmen test with the level of significance set at p<0.05. RESULTS: Ninety-eight consecutive patients [60% male, mean age of 48.7 (±15.6)] were included. The mean interval after transplantation was 27.5 (±8.5) months and mean serum creatinine was 308 (±220.3) mmol/ml The RI of the internal carotid artery and the renal transplant were significantly correlated (p<0.05). A correlation between the RIs and the Augmentation Index was found. CONCLUSION: The RI of the kidney transplant is correlated with the RI of the carotid artery and to markers of general atherosclerosis. This observation may be helpful to identify patients after kidney transplant with higher risk for cardiovascular events and gain indirect information on transplant renal artery stenosis.

Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.

BACKGROUND: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. METHODS: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. FINDINGS: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). INTERPRETATION: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. FUNDING: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Reliance: a smarter way of regulating medical products - The IPRP survey.

Introduction: A survey was conducted among national regulatory authorities' members of the International Pharmaceutical Regulators Programme (IPRP) to collect and share experiences of reliance approaches. Reliance allows formally, or informally, one regulatory authority to use assessments made by other regulatory authorities while remaining responsible for the final decision. Reliance is an essential concept to increase the efficiency of the global regulatory oversight of medical products by national regulatory authorities.Areas covered: This article describes the findings and recommendations from the IPRP survey. It shows that reliance in the area of medical product oversight is broadly accepted. The first part presents the acceptance and reasons for accepting reliance including the need for trust, then gives examples of the most common areas for reliance, and explains the difference between unilateral or reciprocal reliance. Finally, the article analyzes the lessons learned including challenges and opportunities for reliance on regulatory authorities to facilitate patient access in their jurisdictions.Expert opinion: Regulatory reliance facilitates regulatory approvals and allows to use resources in a more efficient way and ultimately serves patients by facilitating earlier access to quality-assured, safe, and effective medicines.

Prevalence of carotid plaque stenosis after head and neck radiotherapy - an observational study of 156 survivors.

Background: Radiotherapy for head and neck cancer (HNC) represents a well-known predisposing factor for asymptomatic carotid artery lesions and acute cerebrovascular accidents. Our aim is to provide contemporary estimates on the prevalence, severity, and characteristics of carotid artery lesions in HNC survivors. Patients and methods: We prospectively included HNC patients who underwent radiotherapy and were free from the disease at the time of duplex ultrasound evaluation. Patients were re-contacted telephonically and those who agreed to participate were invited for an ambulatory visit when the investigators collected clinical information and performed duplex ultrasound examination based on a predefined protocol. Results: A total of 156 patients were included and underwent duplex ultrasound examination after a mean of 65.2 months from the last session of radiotherapy. A total of 36 patients (23.1%) had normal carotid arteries; mild, non-stenotic lesions were observed in 49.4% (n = 77) of patients; severe stenotic plaques were found in 27.5% (n = 43) of patients. One patient found with an asymptomatic occlusion of the left ICA. The prevalence of major cardiovascular risk factors and high radiation dose increased proportionally with plaque severity. Low echogenicity plaque was found in 59 (37.8%) patients on the right side and 57 (36.5%) on the left side; long segment plaque in 49 (31.4%) patients on the right side and in 47 (30.1%) on the left side; an atypical location of the lesions in 42 (26.9%) patients on the right side and in 48 (30.8%) on the left side. Conclusions: The prevalence of occlusion and severe stenosis after radiotherapy for HNC was very low in our study population. Low echogenicity plaque, long segment plaque, and an atypical location were common findings. Classic cardiovascular risk factors appear to have had a causative role: a routine screening of radiotherapy-treated patients might be necessary only in patients with concomitant cardiovascular risk factors or exposed to high-dose neck radiation.

Detection of CSF1 rearrangements deleting the 3' UTR in tenosynovial giant cell tumors.

Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements of CSF1, thought to drive overexpression of macrophage colony-stimulating factor (CSF1), thereby promoting tumor growth and recruitment of non-neoplastic mononuclear and multinucleated inflammatory cells. While fusions to collagen promoters have been described, the mechanism of CSF1 overexpression has been unclear in a majority of cases. Two cohorts of TGCT were investigated for CSF1 rearrangements using fluorescence in situ hybridization (FISH) and either RNA-seq or DNA-seq with Sanger validation. The study comprised 39 patients, including 13 localized TGCT, 21 diffuse TGCT, and five of unspecified type. CSF1 rearrangements were identified by FISH in 30 cases: 13 translocations, 17 3' deletions. Sequencing confirmed CSF1 breakpoints in 28 cases; in all 28 the breakpoint was found to be downstream of exon 5, replacing or deleting a long 3' UTR containing known miRNA and AU-rich element negative regulatory sequences. We also confirmed the presence of CBL exon 8-9 mutations in six of 21 cases. In conclusion, TGCT in our large cohort were characterized by variable alterations, all of which led to truncation of the 3' end of CSF1, instead of the COL6A3-CSF1 fusions previously reported in some TGCTs. The diversity of fusion partners but consistent integrity of CSF1 functional domains encoded by exons 1-5 support a hypothesis that CSF1 overexpression results from transcription of a truncated form of CSF1 lacking 3' negative regulatory sequences. The presence of CBL mutations affecting the linker and RING finger domain suggests an alternative mechanism for increased CSF1/CSF1R signaling in some cases.

Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study.

BACKGROUND: Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome. METHODS: This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029. FINDINGS: Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96-9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. INTERPRETATION: To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. FUNDING: Novartis Pharma.

Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes.

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1-dependent mechanisms are also involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1-mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5× the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. Most adverse events (AEs) were low-grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free, unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK across doses from 0.01 to 20 mg/kg, with faster apparent elimination at lower doses or concentrations; this finding was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies.

Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity.

OBJECTIVES: To evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren's syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study. METHODS: Patients with pSS, EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity. RESULTS: A similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration. CONCLUSIONS: Overall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia.

BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme. METHODS: In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up. RESULTS: Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient. CONCLUSION: BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP. TRIAL REGISTRATION: Clinicaltrials.gov NCT01406977. FUNDING: Novartis Institutes for BioMedical Research, Basel, Switzerland.

Metasynthesis of the Views about Treatment of Anorexia Nervosa in Adolescents: Perspectives of Adolescents, Parents, and Professionals.

BACKGROUND: Anorexia nervosa in adolescents can be a difficult-to-treat disease. Because qualitative research is a well-established method for deepening our understanding of subjective experiences, such as eating disorders and their treatment, we sought to perform a systematic review of qualitative studies to synthesize the views of adolescents with this disease, their parents, and their healthcare providers about its treatment. METHODS: We performed a thematic synthesis to develop the central themes that summarize all of the topics raised in the articles included in our review. The quality of the articles was assessed by the Critical Appraisal Skills Program. RESULTS: We included 32 articles from seven different countries. Two central themes were inductively developed from the analysis: (1) the treatment targets (i.e., symptoms and patients in context), and (2) a therapeutic tool-a relationship, specifically the core concept of the therapeutic relationship. CONCLUSION: Our results underline the difficulty in establishing a therapeutic alliance, the barriers to it, especially the risk that professionals, adolescents, and parents will not converse about treatment; although such a dialogue appears to be an essential component in the construction of a therapeutic alliance.