Effectiveness and safety of rhIGF-1 therapy in patients with or without Laron syndrome

Objective The European Increlex® Growth Forum Database Registry monitors effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF-1; mecasermin, Increlex®) therapy in patients with severe primary IGF-1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design Ongoing, open-label, observational registry (NCT00903110). Methods Children and adolescents receiving rhIGF-1 therapy from 10 European countries were enrolled 2008-2017 (N = 242). The treatment-naïve/prepubertal (NPP) cohort (N = 138) was divided into subgroups based on reported genetic diagnosis of Laron syndrome (LS, N = 21 or non-LS, N = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score [SDS] gain ≥0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years’ treatment (P<0.05). Among the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P<0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 versus 7.00 years) at baseline and height SDS gain in year 1 (0.64 versus 0.70), although, NPP-non-LS-responders were taller (P<0.001) at baseline. Body mass index SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions In most NPP children with SPIGFD, with or without LS, rhIGF-1 therapy promotes linear growth. The safety profile was consistent with previous studies.

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Sequential measurements of IGF-I serum concentrations in adolescents with Laron syndrome treated with recombinant human IGF-I (rhIGF-I)

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2018-0139 ◽

2018 ◽

Vol 31 (8) ◽

pp. 895-902 ◽

Cited By ~ 1

Author(s):

Thomas Breil ◽

Carolin Kneppo ◽

Markus Bettendorf ◽

Hermann L. Müller ◽

Klaus Kapelari ◽

...

Keyword(s):

Serum Potassium ◽

Serum Insulin ◽

Standard Deviation Score ◽

Growth Failure ◽

Inverse Correlation ◽

Pharmacokinetic Data ◽

Recombinant Human Insulin ◽

Laron Syndrome ◽

Igf I ◽

Sequential Measurements

Abstract Background Recombinant human insulin-like growth factor 1 (rhIGF-I) has been approved as an orphan drug for the treatment of growth failure in children and adolescents with severe primary IGF-I deficiency (SPIGFD) with little pharmacokinetic data available. Therefore, sequential measurements of serum IGF-I, glucose, potassium, insulin and cortisol were performed in patients treated with rhIGF-I to evaluate their significance in safety and efficacy. Methods Repetitive blood samples were taken after meals before and 30, 60, 120, 180 and 360 min after rhIGF-I injections in two male patients with Laron syndrome at times of dose adjustments. Results Maximal IGF-I concentrations were observed 2 h after injections (495 ng/mL) and concentrations were still higher 6 h after injections than at baseline (303 ng/mL vs. 137 ng/mL). Thirteen percent of all and 33% of maximum IGF-I concentrations were greater than +2 standard deviation score (SDS) calculated for bone age (BA) (IGF-I SDS BA) rather than chronological age (CA) as BA was significantly delayed to CA by 3.2 years (p=0.0007). Height velocities correlated with individual maximum IGF-I SDS BA (ρ=0.735; p<0.0001). Serum insulin, cortisol and glucose did not correlate with IGF-I concentrations, but serum potassium showed a negative correlation (ρ=−0.364; p<0.0001) with IGF-I concentrations. Conclusions Sequential measurements of serum IGF-I, glucose and potassium in patients with Laron syndrome may aid in optimizing and individualizing rhIGF-I treatment. IGF-I concentrations should be referenced according to BA which better reflects the biological age. The inverse correlation of IGF-I and serum potassium concentrations after injections of rhIGF-I has not been reported before and warrants further consideration.

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Faculty Opinions recommendation of Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718020296.793478787 ◽

2013 ◽

Author(s):

Arthur Kim

Keyword(s):

Hepatitis C ◽

Phase 2 ◽

Genotype 1 ◽

Hepatitis C Infection ◽

Open Label ◽

Multicentre Phase ◽

Phase 2 Trial ◽

Treatment Naïve ◽

Peginterferon Alfa ◽

Ns3 Protease

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Faculty Opinions recommendation of Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725431366.793505980 ◽

2015 ◽

Author(s):

Philip Rosenthal

Keyword(s):

Hepatitis C ◽

Japanese Patients ◽

Fixed Dose Combination ◽

Fixed Dose ◽

Genotype 1 ◽

Open Label ◽

Phase 3 ◽

Treatment Naïve ◽

Dose Combination ◽

Previously Treated

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281 JAVELIN Medley VEGF: phase 2 study of avelumab + axitinib in patients with previously treated non-small cell lung cancer (NSCLC) or treatment naive, cisplatin-ineligible urothelial cancer (UC)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0281 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A307-A307

Author(s):

Gabriella Galffy ◽

Iwona Lugowska ◽

Elena Poddubskaya ◽

Byoung Chul Cho ◽

Myung-Ju Ahn ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Maintenance Treatment ◽

Locally Advanced ◽

Small Cell Lung ◽

Open Label ◽

Platinum Based Chemotherapy ◽

Open Label Phase ◽

Treatment Naïve ◽

Previously Treated ◽

Grade 3

BackgroundAvelumab, a human anti–PD-L1 monoclonal antibody, has shown a manageable safety profile and antitumor activity in multiple tumor types, including platinum-resistant metastatic or recurrent NSCLC,1 and is approved for patients with locally advanced or metastatic UC who have progressed after ≥1 previous line of platinum-based chemotherapy2 3 and as maintenance treatment for those who have not progressed with platinum-based chemotherapy.4 JAVELIN Medley VEGF (NCT03472560) evaluated the efficacy and safety of avelumab + axitinib, a potent inhibitor of VEGFR 1, 2, and 3, in patients with advanced or metastatic NSCLC or UC.MethodsEligible patients with NSCLC had received ≥1 prior platinum-containing therapy and ≤2 prior lines of systemic therapy for locally advanced or metastatic disease; patients with UC were treatment naive in the locally advanced or metastatic setting and ineligible for cisplatin-containing chemotherapy. Patients were immune checkpoint inhibitor naïve and received avelumab 800 mg intravenously every 2 weeks + axitinib 5 mg orally twice daily. The primary endpoint was confirmed objective response (OR) per investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS) and safety. PD-L1 expression was assessed in baseline tumor samples (Ventana SP263 assay). Data have not undergone standard quality checks and are subject to change due to COVID-19–related healthcare burden.ResultsA total of 41 patients with NSCLC and 20 with UC received avelumab + axitinib. The confirmed OR rate was 31.7% (95% CI, 18.1–48.1) in the NSCLC cohort and 10% (95% CI, 1.2–31.7) in the UC cohort (all partial responses); 16 patients (39.0%) and 5 (25.0%) had stable disease, respectively. Responses were observed regardless of PD-L1 expression status. Median PFS was 5.5 months (95% CI, 2.5–7.0) in the NSCLC cohort and 2.3 months (95% CI, 1.8–5.6) in the UC cohort. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 24 patients (58.5%) in the NSCLC cohort; the most common was hypertension (n=7 [17.1%]). Grade ≥3 TRAEs occurred in 9 patients (45.0%) in the UC cohort; the most common were amylase increased, asthenia, decreased appetite, and palmar-plantar erythrodysesthesia syndrome (n=2 [10%] each). One patient in each cohort experienced a TRAE that led to death (gastric perforation and urinary bladder hemorrhage).ConclusionsAvelumab + axitinib showed antitumor activity and a manageable safety profile in patients with advanced or metastatic NSCLC or UC consistent with findings from studies of each drug alone and in combination.Trial RegistrationNCT03472560Ethics ApprovalThe study was approved by each site’s independent ethics committee.ConsentN/AReferencesGulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599–610.Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51–64.Bavencio(avelumab) injection. [package insert] Darmstadt, Germany: Merck KGaA; 2019.US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 19, 2020.

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Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial

The Lancet Haematology ◽

10.1016/s2352-3026(21)00030-2 ◽

2021 ◽

Vol 8 (4) ◽

pp. e289-e298 ◽

Cited By ~ 1

Author(s):

Lu Sun ◽

Juan Wang ◽

Linlin Shao ◽

Chenglu Yuan ◽

Hongguo Zhao ◽

...

Keyword(s):

Immune Thrombocytopenia ◽

Phase 2 ◽

Open Label ◽

Phase 2 Trial ◽

Primary Immune Thrombocytopenia ◽

Open Label Phase ◽

Treatment Naïve

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Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker

Multiple Sclerosis Journal ◽

10.1177/1352458516667564 ◽

2016 ◽

Vol 23 (7) ◽

pp. 937-945 ◽

Cited By ~ 6

Author(s):

Teresa Órpez-Zafra ◽

Jose Pavía ◽

Isaac Hurtado-Guerrero ◽

Maria J Pinto-Medel ◽

Jose Luis Rodriguez Bada ◽

...

Keyword(s):

Multiple Sclerosis ◽

Serum Levels ◽

Cross Sectional Study ◽

First Year ◽

Diagnostic Biomarker ◽

Lower Serum ◽

Cross Sectional ◽

Treatment Naïve ◽

Β Receptor ◽

Multiple Sclerosis Patients

Background: The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs). Objective: To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker. Methods: The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory. Results: Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes. Conclusion: The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.

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Prospective, Randomized, Open Label Trial of Efavirenz vs Lopinavir/Ritonavir in HIV+ Treatment-Naive Subjects With CD4+<200 cell/mm3 in Mexico

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e3181cae4a1 ◽

2010 ◽

Vol 53 (5) ◽

pp. 582-588 ◽

Cited By ~ 44

Author(s):

Juan Sierra-Madero ◽

Angelina Villasis-Keever ◽

Patricia Méndez ◽

Juan Luis Mosqueda-Gómez ◽

Indiana Torres-Escobar ◽

...

Keyword(s):

Hiv Treatment ◽

Open Label ◽

Treatment Naïve ◽

Open Label Trial

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The Effect of Phosphate Supplementation on Linear Growth in Children with X-Linked Hypophosphatemia

PEDIATRICS ◽

10.1542/peds.94.4.478 ◽

1994 ◽

Vol 94 (4) ◽

pp. 478-481

Author(s):

Mouin G. Seikaly ◽

Richard H. Browne ◽

Michel Baum

Keyword(s):

Vitamin D ◽

Standard Deviation ◽

Linear Growth ◽

Standard Deviation Score ◽

Initial Therapy ◽

Current Therapy ◽

Height Standard Deviation Score ◽

Z Score ◽

Z Scores ◽

Phosphate Supplementation

Background. X-linked hypophosphatemia is the most common inherited cause of rickets. Current therapy for this disorder includes vitamin D and phosphate supplementation; however, phosphate therapy has been associated with nephrocalcinosis. The purpose of this study is to evaluate the effect of oral phosphate therapy on growth in patients with X-linked hypophosphatemia treated with either calcitriol or dihydrotachysterol (vitamin D). Methods. We retrospectively evaluated the prepubertal growth of 36 children with X-linked hypophosphatemia. The height standard deviation score (Z-score) of patients initially treated with vitamin D alone and the Z-scores of patients treated with vitamin D and phosphate therapy were compared. In addition, the growth of patients treated with vitamin D was compared with that of patients treated with vitamin D and phosphate from the outset of therapy. Results. Patients treated with vitamin D alone for 5.36 ± 2.18 years had an improvement in Z-score from -3.18 ± 1.10 to -2.49 ± 0.66 SDS, ,P < .05. Adding phosphate therapy for patients initially treated with vitamin D alone for 4.83 ± 2.99 years did not further improve Z-score (-2.49 ±0.66 vs -2.35 ± 0.83). Initial therapy with vitamin D and phosphate for 4.33 ± 2.19 years also improved Z-score, (-2.84 ± 1.02 vs -1.98 ± 0.82, P < .05). The change in Z-score was similar to the group treated with vitamin D alone compared with the group treated initially with vitamin D and phosphate (0.65 ± 0.54 vs 0.85 ± 0.65, respectively). Conclusion. These data demonstrate that both vitamin D alone and in combination with phosphate improved linear growth. Adding oral phosphate for children initially treated with vitamin D alone did not improve Z-score. Initial therapy with vitamin D and vitamin D plus phosphate produced similar changes in linear growth.

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Characterisation of macular neovascularisation in geographic atrophy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-318820 ◽

2021 ◽

pp. bjophthalmol-2021-318820

Author(s):

Riccardo Sacconi ◽

Maria Brambati ◽

Alexandra Miere ◽

Eliana Costanzo ◽

Vittorio Capuano ◽

...

Keyword(s):

Fundus Autofluorescence ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

First Year ◽

Age Related ◽

Treatment Naïve ◽

Type 3 ◽

Endothelial Growth Factor

AimTo characterise macular neovascularisation (MNV) developing in eyes affected by geographic atrophy (GA).MethodsIn this multicentric longitudinal study involving three retina referral centres, patients previously affected by GA who developed an active MNV were included. Patients were investigated using structural optical coherence tomography (OCT), fundus autofluorescence, OCT-angiography and dye angiographies. Patients were treated with ProReNata antivascular endothelial growth factor (VEGF) injections and were revaluated after treatment.ResultsAmong 512 patients previously diagnosed with GA, 40 eyes of 40 patients (mean age 80.8±7.9 years, mean GA area 8.73±7.39 mm2) presented with treatment-naïve exudative MNV (accounting for an estimated prevalence of 7.81%; 5.49 to 10.13, 95% CIs) and thus were included in the analysis. 67.5% of MNVs were classified as type 2 MNV, 25% as type 1, 2.5% as type 3 and 5% as mixed phenotype. In 92.5% of cases, active MNV in GA showed subretinal hyperreflective material with or without evidence of subretinal/intraretinal hyporeflective exudation. During a mean follow-up of 28±25 months, patients were treated with 6.6±6.3 anti-VEGF injections, with 2.9±1.4 injections in the first year of treatment. No patient developed GA enlargement in the area of MNV.ConclusionsMNVs in GA showed different features and therapeutic response in comparison to previously reported features of MNV in age-related macular degeneration (AMD) without GA. For these reasons, the combined phenotype (ie, GA with neovascular AMD) should be considered as a distinct entity in the research and clinical setting.

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