Choriogonadotropin alfa 250micrograms/0.5ml solution for injection pre-filled syringes

PURPOSE: To investigate whether the ovarian stimulation with follitropin delta in an individualized algorithm-based manner is inferior to recombinant human-follicle stimulating's follitropin alfa or follitropin beta conventional dosing regarding a series of established primary endpoints. METHODS: We conducted a registered systematic review (CRD42024512792) on PubMed-MEDLINE, Web of Science™, Cochrane Database of Systematic Reviews, and Scopus. Our search was designed to cover all relevant literature, particularly randomized controlled trials. We critically and comparatively analyzed the outcomes for each primary endpoint based on the intervention, reflected by the positive βhCG test, clinical pregnancy, vital pregnancy, ongoing pregnancy, live birth, live birth at 4 weeks, and multiple pregnancies. RESULTS: Six randomized controlled trials were included in the quality assessment as priority manuscripts, revealing an 83.3% low risk of bias. Follitropin delta led to non-significant differences in each parameter of interest from positive βhCG test (691; 53.44% vs. 602; 46.55%), ongoing pregnancies (603; 53.79% vs. 518; 46.20%), clinical and vital pregnancies (1,073; 52.80% vs. 959; 47.19%), to live birth and at 4 weeks (595; 54.14% vs. 504; 45.85%) with only 2 losses, and even multiple pregnancies (8; 66.66% vs. 4; 33.33%). However, follitropin delta was well-tolerated among hypo- and hyper-responders without significant risk of ovarian hyperstimulation syndrome and/or preventive interventions in contrast with follitropin alfa or follitropin beta. CONCLUSION: The personalized individualized-based algorithm dosing with follitropin delta is non-inferior to conventional follitropin alfa or follitropin beta. It is as effective in promoting a similar response in women without significant comparable adverse effects.

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Abstract Rationale A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (−214.89 ml and −235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Abstract licence: CC BY-NC-ND

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA , leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was −0.36 mL/min/1.73 m 2 /year [−2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of −3 mL/min/1.73 m 2 /year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

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The lutropin-choriogonadotropin (LH/CG) receptor is a cell surface receptor comprised of two domains of roughly equivalent size. The amino-terminal half of the receptor is relatively hydrophilic and is located extracellularly, whereas the carboxyl-terminal half of the receptor shares amino acid homology with other receptors that couple to G proteins and is similarly thought to span the plasma membrane seven times, ending with a relatively short carboxyl-terminal tail. In order to test the role of the extracellular domain in binding hormone, we constructed a mutated rat luteal LH/CG receptor cDNA (termed pCLHR-D2), which encodes for only the extracellular domain, and used it to transiently transfect human kidney 293 cells. Here we report that the expressed extracellular domain of the LH/CG receptor is capable of binding human CG with a high affinity, comparable with that of the full-length receptor. Thus, not only is the extracellular domain of the glycoprotein hormone receptors involved in binding hormone, but it alone is capable of conferring high affinity binding. Unexpectedly, it was also found that this truncated receptor is not secreted into the culture media but remains trapped within the cells.

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The follicle-stimulating hormone receptor (FSHR) has been targeted therapeutically for decades, due to its pivotal role in reproduction. To date, only purified and recombinant/biosimilar FSH have been used to target FSHR in assisted reproduction, with the exception of corifollitropin alfa; a modified gonadotropin in which the FSH beta subunit is joined to the C-terminal peptide of the human choriogonadotropin beta subunit, to extend serum half-life. Assisted reproduction protocols usually entail the trauma of multiple painful injections of FSH to initiate and promote folliculogenesis, which has prompted the development of a number of orally-available low molecular weight (LMW) chemical scaffolds targeting the FSHR. Furthermore, the recently documented roles of FSHR in diverse extragonadal tissues and conditions, such as cancer, fat metabolism and bone density regulation, has highlighted the potential utility of LMW modulators of FSHR activity. Despite these chemical scaffolds encompassing a spectrum of in vitro and in vivo activities and pharmacological profiles, none have yet reached the clinic. In this review we discuss the major chemical classes of LMW molecules targeting the FSHR, and document their activity profiles and current status of development, in addition to discussing potential clinical applications.

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Efanesoctocog alfa (Altuviiio,TM Sanofi-SOBI) is a B domain-deleted single-chain Factor VIII (FVIII) connected to D'D3 domain of von Willebrand Factor (vWF). Its ingenious design allows efanesoctocog alfa to operate independently of endogenous vWF and results in an outstanding 3-4 times longer half-life compared to standard and extended half-life (EHL) FVIII products. The prolonged half-life ensures sustained high levels of factor activity, maintaining normal to near-normal ranges for the majority of the week, facilitating the convenience of once-weekly administration. Efanesoctocog alfa received regulatory approval in 2023 for application in both adults and children with inherited hemophilia A in the United States and Japan. Its sanctioned use encompasses both prophylaxis and 'on demand' treatment for bleeding episodes. The European Medicines Agency (EMA) is currently undertaking a comprehensive review of Altuviiio. TM This comprehensive review focuses on the immunological profile of efanesoctocog alfa, a highly sophisticated new class of EHL FVIII molecule. The integration of the vWF D'D3 domain, XTEN polypeptides, and potential regulatory T-cell epitopes within various segments of efanesoctocog alfa collectively serves as a mitigating factor against the development of a neutralizing T-cell-mediated immune response. We hypothesize that such distinctive attribute may significantly reduce the risk of neutralizing antibodies, particularly in previously untreated patients. The discussion extends beyond regulatory approval to encompass the preclinical and clinical development of efanesoctocog alfa, including considerations for laboratory monitoring. The review also highlights areas that warrant further investigation to deepen our understanding of this groundbreaking therapeutic agent.

Abstract licence: CC BY-NC

Aim: This study compared the cost-effectiveness of two recombinant follicle-stimulating hormones (rFSH) formulations, Follitropin Delta and Follitropin Alfa, in controlled ovarian stimulation using cumulative live birth rates as an efficacy indicator. Methodology: This retrospective study was conducted across five clinics in Japan from April 2022 to December 2023, involving 446 first assisted reproductive technology (ART) cycles (200 with Follitropin Delta and 246 with Follitropin Alfa) were treated with rFSH monotherapy using either Follitropin Delta or Follitropin Alfa. We compared clinical outcomes such as cumulative pregnancy and live birth rates and analyzed cost-effectiveness using the cumulative live birth rates as the efficacy indicator and the incremental cost-effectiveness ratio (ICER). Results: The Follitropin Delta group had a significantly lower incidence of ovarian hyperstimulation syndrome (15.90% vs. 27.00%, P = 0.045) and higher cumulative pregnancy rates than the Follitropin Alfa group (87.30% vs. 76.20 %; P = 0.03) after propensity score matching (PSM). Although cumulative live birth rates showed no significant differences (85.70% vs. 76.20%, P = 0.08) and Follitropin Delta demonstrated higher cost than Follitropin AlfaFollitropin Alfa (832,036 yen and 826,936 yen), ICER indicated low costs per percentage of live births (538.58 yen/%: 95% confidence interval [CI]: 275.34-12,568.69 yen). Conclusions: Using Follitropin Delta for controlled ovarian stimulation in ART may be more cost-effective than Follitropin Alfa under Japan’s Health Care Insurance System, offering higher cumulative live birth rates and minimal additional costs.

Abstract licence: CC BY