PUPs A-LONG evaluated safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, Phase 3 study enrolled ...male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at study start, 20 (19%) had family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval CI: 21.8%–41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI: 8.8%–24.7%). The median (range) time to high-titer inhibitor development was 9 (4–14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 non–treatment-related death due to intracranial hemorrhage (onset prior to first rFVIIIFc dose). The overall median (interquartile range) ABR was 1.49 (0.00–4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within expected range, although high-titer inhibitor development was on the low end of the range reported in literature. rFVIIIFc was well-tolerated and effective as prophylaxis and for treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).
Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective ...targeted therapies.
To explore the effects of spesolimab treatment in patients with HS.
This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs).
In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases.
This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.
Introduction: Hidradenitis suppurativa (HS) is a chronic, inflammatory disorder characterized by painful inflammatory nodules (N), abscesses (A) and draining tunnels (dT), primarily affecting ...intertriginous areas. Interleukin-36 (IL-36) signaling has been notably expressed within HS inflammatory lesions. To address the need for targeted therapies, this Phase IIa proof-of-clinical-concept (PoCC) study (NCT04762277) explored the effect of spesolimab, an anti-IL-36 receptor monoclonal antibody, in patients with moderate-to-severe HS.
Methods: Eligible patients (N=52) were randomized (2:1) to receive spesolimab or placebo (1200 mg intravenous dosing once weekly for three weeks loading dose, followed by 1200 mg subcutaneous dosing every 2 weeks for 12 weeks). No formal statistical tests were performed, as this was an exploratory study. Of patients who completed the study, 45 were enrolled in an ongoing open-label extension (OLE) study (NCT04876391) with spesolimab. For each study, endpoints included change from baseline at Weeks 12 and 24 in total A, N and dT (ANdT) counts, and adverse events (AEs).
Results: Mean changes from baseline at Week 12 in dT, A and total ANdT counts were -1.30, -0.53 and -4.87 in the spesolimab arm, and 1.07, 3.07 and -0.86 in the placebo arm, respectively. Mean changes in N count were numerically similar between the spesolimab (-3.00) and placebo (-5.00) arms. Of patients with ≥1 dT at baseline, a numerically greater proportion had a decrease in dT count at Week 12 in the spesolimab (16/24, 66.7%) versus the placebo (5/13, 38.5%) arm. Least squares mean changes from baseline in total AN count at Week 12 were -38.8% and -34.7% in the spesolimab and placebo arms, respectively, which may have been affected by higher baseline AN and N counts in the spesolimab versus placebo arm. In the OLE, patients originally randomized to spesolimab (n=30) achieved sustained reductions in dT count and in International Hidradenitis Suppurativa Severity Score (IHS4) at Week 24. The safety profile of spesolimab was similar to that reported in other trials; among the 52 patients enrolled in the PoCC study, 77.8% (spesolimab) and 87.5% (placebo) of patients reported ≥1 AE. No patients receiving spesolimab reported serious AEs, and no new safety concerns were identified by Week 24. No deaths were reported.
Conclusion: Our findings show that spesolimab was well tolerated and decreased all HS lesions. These results support the development of spesolimab in HS.
This study was supported and funded by Boehringer Ingelheim.
PUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male ...PUPs (age <18 years) with hemophilia B (≤2 IU/dL of endogenous factor IX FIX) were to receive treatment with rFIXFc. Primary end point was occurrence of inhibitor development, with a secondary end point of annualized bleed rate (ABR). Of 33 patients who received ≥1 dose of rFIXFc, 26 (79%) were age <1 year at study entry and 6 (18%) had a family history of inhibitors. Twenty-eight patients (85%) received prophylaxis; median dosing interval was 7 days, with an average weekly dose of 58 IU/kg. Twenty-seven patients (82%) completed the study. Twenty-one (64%), 26 (79%), and 28 patients (85%) had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc, respectively. One patient (3.03%; 95% confidence interval, 0.08% to 15.76%) developed a low-titer inhibitor after 11 EDs; no high-titer inhibitors were detected. Twenty-three patients (70%) had 58 treatment-emergent serious adverse events; 2 were assessed as related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR was 1.24 (interquartile range, 0.00-2.49) for patients receiving prophylaxis. Most (>85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.
•PUPs B-LONG is the first study of extended half-life rFIXFc in previously untreated hemophilia B patients.•rFIXFc was effective and well tolerated in PUPs with hemophilia B, with an incidence of inhibitors of 3%.
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The feasibility of geometric magnetoresistance (MR) measurement from linear to saturation operation regime is demonstrated in ultrathin body and BOX fully depleted silicon-on-insulator devices from ...14-nm technology node. Besides, we propose a new physical compact model for MOSFET drain current under high field transport, which reproduces experimental MR mobility from linear to saturation operation region and serves as the basis for a new extraction method of carrier saturation velocity. A benchmarking with state-of-the-art saturation velocity extraction methodologies is also conducted. Our saturation velocity results indicate that, for this technology, nonstationary transport prevails as manifested by an overshoot velocity behavior, still far from the ballistic limit.
Nuclear magnetic resonance (NMR) study of the high magnetic field (H) part of the Bose-Einstein condensed (BEC) phase of the quasi-onedimensional (quasi-1D) antiferromagnetic quantum spin-chain ...compound NiCl2-4SC(NH2)2 (DTN) was performed. We precisely determined the phase boundary, Tc(H), down to 40 mK; the critical boson density, n_c(Tc); and the absolute value of the BEC order parameter S_perp at very low temperature (T = 0.12 K). All results are accurately reproduced by numerical quantum Monte Carlo simulations of a realistic three-dimensional (3D) model Hamiltonian. Approximate analytical predictions based on the 1D Tomonaga-Luttinger liquid description are found to be precise for Tc(H), but less so for S_perp(H), which is more sensitive to the strength of 3D couplings, in particular close to the critical field. A mean-field treatment, based on the Hartree-Fock-Popov description, is found to be valid only up to n_c = 4% (T < 0.3 K), while for higher n_c boson interactions appear to modify the density of states.
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