Teva Pharmaceuticals (United States)

<b>Conclusions:</b> LAIs, especially SG formulations, are associated with reduced rehospitalization in BD-I compared to OAs, supporting their broader use to improve adherence and reduce readmissions.

a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1535:"<h3>Introduction</h3> Fremanezumab, a calcitonin gene-related peptide monoclonal antibody, is approved for preventive migraine treatment in adults. The multicentre, parallel-group, Phase 3 SPACE study (NCT04458857) evaluated the efficacy and safety of fremanezumab in children and adolescents with episodic migraine (EM). <h3>Methods</h3> Eligible participants (aged 6–17 years, migraine diagnosis for ≥6 months and history of ≤14 headache days/month) were randomised 1:1 to monthly fremanezumab (120 mg for &lt;45kg, 225 mg for ≥45kg) or placebo. Primary endpoint: least-squares mean change from baseline in monthly average number of migraine days (MMD) during the 3-month double-blind period (DBP). Secondary endpoints included the proportion of participants achieving ≥50% reduction in MMD and change from baseline in monthly headache days of at least moderate severity (MHD). <h3>Results</h3> In total, 234 randomised participants (fremanezumab, n=123 [120 mg, n=36; 225 mg, n=87]; placebo, n=111) were included in the efficacy analysis. Fremanezumab significantly reduced MMD versus placebo (–2.5 vs –1.4; p=0.0210) during the DBP, with a ≥50% response rate of 47.2% versus 27.0% (p=0.0016). Reductions in MHD were significantly greater with fremanezumab versus placebo (–2.6 vs –1.5; p=0.0172). <h3>Conclusion</h3> These findings suggest that fremanezumab provides an effective preventive migraine treatment option in children and adolescents with EM. mark.fredericks{at}tevauk.com ";}

Intravenous (IV) administration of therapeutic antibodies requires multiple in-use steps to ensure safety, purity and potency before patient administration. This review systematically examines 93 FDA-approved therapeutic antibodies administered via IV infusion, focusing on critical clinical in-use parameters reported in their prescribing information. Key parameters analyzed include storage conditions, drug concentrations, dosing regimens, dilution and diluents, infusion rates, priming and flushing procedures, needle and syringe specifications, IV bag and line materials, infusion filters, pumps, and venous access devices. The statistical analysis of these parameters highlights the most commonly used industry practices, providing a comprehensive reference for formulation scientists designing clinical in-use studies or drafting pharmacy manuals for antibody-based products. Our findings show that saline is the most frequently recommended diluent, though some antibodies recommend alternative diluents such as dextrose solutions or lactated Ringer's solution. Similarly, filters are recommended for 65% of the analyzed drug products, yet variations exist in pore size and material recommendations. Additionally, oncology-related antibodies often require graduated infusion rates to mitigate infusion-related reactions, and 31% of antibodies suggest adjusting infusion rates based on patient tolerance. These findings highlight the need for systematic in-use studies covering various scenarios and clinical settings to establish evidence-based recommendations. Well-designed clinical in-use studies, coupled with well-structured pharmacy manuals that clearly outline in-use preparation steps, enhance clarity, reduce preparation errors, and improve workflow efficiency to ultimately ensure safe and effective IV administration of therapeutic antibodies.

BackgroundIL-2 plays a critical role in regulating the immune system by stimulating the proliferation and activation of T cells, and thus has the potential to enhance anti-tumor immunity. Nevertheless, the clinical use of IL-2 is severely limited by significant systemic toxicity and a narrow therapeutic window. To overcome these limitations, we developed an antibody-cytokine fusion protein, termed anti-PD1-IL2Att, that is composed of an anti-PD1 antibody fused to a highly attenuated variant of IL-2. This construct was designed to deliver attenuated IL-2 specifically to PD-1-expressing cells. Anti-PD1-IL2Att selectively stimulates PD-1+ effector T cells, while not inhibiting PD-1 receptor function. Since PD-1 expression is significantly higher in tumor-infiltrating T cells compared to circulating and tissue-resident T cells, targeting IL-2 to PD-1+ T cells may boost anti-tumor immunity, while avoiding systemic IL-2-related adverse effects. Here we describe the impact of anti-PD1-IL2Att activity on tumor progression and tumor-infiltrating lymphocytes in pre-clinical tumor models.MethodsThe anti-tumor effect of anti-PD1-IL2Att was evaluated using a mouse surrogate antibody-cytokine fusion protein (mAPD1-IL2Att) in a mouse model of MC38 colorectal adenocarcinoma in a dose escalation study, a repeated-dose administration study and a long-term immunity rechallenge study. Additionally, the ability of a human anti-PD1-IL2Att, TEV-56278, to induce anti-tumor immune responses was evaluated in humanized immune-system mouse models engrafted with human melanoma tumor cells. All models employed flow cytometry to characterize T cell population variations within the tumor microenvironment after treatment.ResultsAdministration of mAPD1-IL2Att in the MC38 mouse model resulted in dose-dependent reduction in tumor growth following single dose administration and complete tumor regression following repeated administration. Furthermore, mice responsive to mAPD1-IL2Att treatment were fully protected from secondary tumor re-challenge, indicating induction of long-term anti-tumor immunity. Additionally, TEV-56278 administration to humanized immune system mice engrafted with human melanoma tumors led to tumor growth inhibition similar to that observed in the MC38 model. Flow cytometry analysis of tumor-infiltrating lymphocytes revealed a shift in the immune response in both models following treatment. Specifically, we observed a significant increase in the proportion of effector T cells, accompanied by a decrease in regulatory T cells. Moreover, in the MC38 model terminally exhausted CD8+ T cells (CD8+CD44+CD62L-CD69+ki67+PD-1+Tim3+) were decreased following treatment. These findings collectively suggest a favorable immune-activated anti-tumor response.ConclusionsAnti-PD1-IL2Att treatment led to tumor regression, increased infiltration of T cells into the tumor, and establishment of durable immune memory. Our preclinical models highlight the potential of anti-PD1-IL2Att as an effective anti-tumor immunotherapy.Ethics ApprovalThe in vivo animal studies described in the abstract were approved by the following ethics review boards: IACUC #: NPC-TE-IL-2307-447 (Israel Ministry of Health); IACUC ASP #: 980701 (Charles River) and IACUC ASP #: 980702 (Charles River).

Background: Interleukin-11 (IL-11) is increased in patients with systemic sclerosis (SSc) and is thought to play a role in fibrosis. Many studies have reported decreased fibrosis when IL-11 is blocked, but few have examined factors that induce IL-11 expression. Because fibrosis has been linked to activated inflammasomes driving caspase-1 maturation and the secretion of IL-1β, we set out to determine if IL-11 expression was dependent on caspase-1 activity. Methods: Primary lung fibroblast cell lines derived from patients with SSc, IPF (fibrotic control), and healthy individuals were cultured at low passage. Gene expression for IL-11 and the IL-11 receptor (IL-11Rα1) was analyzed using qPCR and normalized to the control, and collagen production was measured using Sirius Red. Results: SSc and IPF fibroblasts expressed significantly more IL-11 transcripts than normal cells (3.35-fold and 9.97-fold more, p = 0.0396 and p = 0.0023, respectively). IL-11Rα1 was expressed 2.32-fold and 2.27-fold more in SSc and IPF (p = 0.0004 and p = 0.0032, respectively) than in normal cells. In SSc fibroblasts, inhibition of caspase-1 with YVAD decreased IL-11 expression by 49.59% (p = 0.0016) but did not affect IL-11Rα1 expression (p &gt; 0.05). IL-11 expression was increased 2.97-fold with TGF-β1 (p = 0.0030) and 22.24-fold with IL-1β (p &lt; 0.0001), while the expression of IL-11Rα1 was not induced with these two cytokines. LPS increased IL-11 expression in normal fibroblasts 1.52-fold (p = 0.0042), which was abolished with YVAD (p &lt; 0.0001). IL-11Rα1 gene transcripts were also increased with LPS 1.50-fold (p = 0.0132), but YVAD did not inhibit this expression. In these studies, we were unable to detect IL-11 protein nor were we able to induce COL1A1 expression or increase the total amount of collagen secreted by fibroblasts with human recombinant IL-11. Conclusions: IL-11 and its receptor, IL-11Rα1, are both elevated in fibrosis. IL-11 expression is dependent on inflammasome activation of caspase-1 and the downstream cytokines TGF-β1 and IL-1β, while IL-11Rα1 was only dependent on NF-kB.