Subcutaneous Treatment Research Articles

First-in-Class Oral Semaglutide: Overcoming Barriers of Incretinisation in the Indian Context.

Despite the availability of multiple therapeutic options and strategies, patients with type 2 diabetes mellitus (T2DM) the world over have inadequate glycaemic control and India is no exception. Patients with T2DM in India have benefitted from glucagon-like peptide-1 analogues similar to that of patients from other parts of the world. However, subcutaneous treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is limited by their injectable mode of administration. The present review highlights barriers to incretinisation with GLP-1RAs and the role of first-in-class oral semaglutide in the Indian context and provides guidance to physicians on its initiation and uses.

Anakinra reduces lung inflammation in experimental acute lung injury.

IntroductionAcute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life‐threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID‐19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)‐1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)‐induced ALI.MethodsWe evaluated the effects of a daily subcutaneous Anakinra treatment in a mouse model of LPS‐induced ALI. We monitored body weight to assess the general health status of the mice. Two days after ALI induction, we evaluated the inflammatory cytokine MIP‐2 as well as protein levels in bronchoalveolar lavage (BAL) fluids. Two and nine days after ALI induction, we evaluated infiltrating leukocytes in BAL fluid and lung tissue.ResultsAnakinra treatment reduced ALI‐induced weight loss compared to nontreated groups. At Day 2, Anakinra treatment reduced levels of MIP‐2 and protein in BAL fluids and reduced frequencies of NK cells and neutrophils in the lung tissue. Nine days after ALI induction, Anakinra treated mice displayed reduced levels of neutrophils and alveolar macrophages in BAL fluids.ConclusionsIL‐1 blockade using Anakinra reduced classical hallmarks of inflammation in a mouse model of ALI. Our data support ongoing and future research on the evaluation of Anakinra as a potential treatment option in ARDS.

891. Minimum Manufacturing Costs and National Prices for Weight Loss Treatments, as Potential Mitigation for Anti-Retroviral Related Weight Gain in HIV

BackgroundWeight gain is being observed for a wide range of antiretroviral treatments. Weight gains are higher for people taking first-line integrase inhibitor based treatments, especially those including TAF/FTC. Weight gains are higher for women and people of colour. Clinical obesity increases the risks of cardiovascular disease, diabetes, adverse birth outcomes and could lower survival rates. Anti-obesity treatments are needed to supplement lifestyle interventions and counteract progressive weight gains, but are not routinely provided as part of HIV care.MethodsCosts of production for FDA-recommended weight loss treatments and anti-diabetic medications (orlistat, naltrexone-bupropion, topiramate, phentermine, semaglutide, liraglutide and metformin) were estimated using an established and published methodology based on costs of active pharmaceutical ingredients (API), extracted from the global shipping records database Panjiva. This was compared with national drug list price data from a range of low, medium, and high-income countries. Figure 1. Example of methodology for calculating the estimated minimum cost of production for orlistatResultsWeight loss and anti-diabetic treatments can be generically manufactured at low per-course costs, e.g. &85 per person per year for oral treatments such as orlistat and &1 per person per month for metformin. However, prices for a year of treatment with orlistat are as high as &1,205 in the USA and as low as &11 in Vietnam. In comparison, a month of ARV treatment costs about &15 via global health institutions like CHAI. Price for injectable (subcutaneous) treatments were higher, ranging from &1,985 for liraglutide in USA to &330 in Morocco, whilst they could potentially be profitably sold for &155 for a 12-week course. No export price data was available for semaglutide. When compared against international list prices, we found wide variations between countries. Table 1. Summary of drug prices and minimum cost estimates Figure 2. Orlistat course costs in a range of countries, compared with estimated minimum cost Figure 3. Liraglutide course costs in a range of countries, compared with estimated minimum costConclusionWe show that weight loss treatments can be manufactured and sold profitably for low prices, but have a wide price range between countries. Government and non-governmental healthcare systems should be evaluating weight loss agents for inclusion within ART programmes. Disclosures All Authors: No reported disclosures

Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies

BackgroundAlthough migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM).MethodsThis analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo.ResultsThese pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843).ConclusionsThis pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine.Trial registrationClinicalTrials.gov identifiers: HALO CM: NCT02621931; HALO EM: NCT02629861; FOCUS: NCT03308968.

β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation.

ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a pan-Src-TKs inhibitor approved as anti-leukemic agent, increased muscle β-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-β-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β-DG in pathology progression, meanwhile confirming DAS mechanism of action over the long-term, along with its efficacy and tolerability. The 4-week old mdx mice underwent a 12-week treatment with DAS/HP-β-CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease-relevant readouts. Oral DAS/HP-β-CD efficiently distributed in mdx mice plasma and tissues in a dose-related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric-suitable DAS formulation for proper exposure and safety and for enhancing β-DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In-depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies.

The antidepressant-like effect of resolvin E1 in repeated prednisolone-induced depression model mice

Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from eicosapentaenoic acid. We previously demonstrated that intracerebroventricular (i.c.v.) and intra-medial prefrontal cortex (mPFC) infusions of RvE1 produce antidepressant-like effects in a lipopolysaccharide-induced depression mouse model. To further confirm the antidepressant-like effect of RvE1, the present study examined whether RvE1 ameliorated depression-like behavior induced by repeated injections of prednisolone (PSL), a synthetic glucocorticoid, in male ICR mice. We first ascertained whether repeated subcutaneous treatment with PSL (50 mg/kg, once a day) affected locomotor activity and anxiety-like behavior in the open field test (OFT; after a 5-day PSL treatment) and induced depression-like behavior in the tail suspension test (TST; after a 6-day PSL treatment) and forced swim test (FST; after a 7-day PSL treatment). Repeated PSL injections significantly increased immobility in the FST, which was not ameliorated by acute desipramine treatment (30 mg/kg, i.p.), but not in the TST, without affecting locomotor activity and anxiety-like behavior in the OFT. Subsequently, we investigated the therapeutic effects of i.c.v. (1 ng) and intra-mPFC (50 pg/side) infusions of RvE1 in the repeated PSL-induced depression mouse model using the OFT and FST after 5- and 6-day PSL treatments, respectively. The repeated PSL-induced increase in immobility in the FST was significantly attenuated by both i.c.v. and intra-mPFC infusions of RvE1 without affecting the locomotor activity and anxiety-like behavior. In addition, a single i.c.v. infusion of RvE1 immediately before the first or fourth injection of PSL also attenuated PSL-induced depression-like behavior in the FST, suggesting the preventive effect of RvE1. These results indicate that RvE1 produces antidepressant-like effects in a mouse model of repeated PSL-induced depression.

Utilizing HealthTree ® Cure Hub's Real-World Data to Assess Treatment Management of Patients with Multiple Myeloma during the COVID-19 Pandemic

Background: Patients with multiple myeloma (MM) are uniquely susceptible to viral and bacterial illnesses, including COVID-19, due to their immunocompromised state, age, treatments, and comorbidities. With the advent of COVID-19, changes to treatment were recommended whenever possible, in order to reduce visits to the clinic. The total effect of these changes on cancer patients with multiple myeloma remains unclear. The aim of this project was to assess treatment management by changes to treatment of patients with MM during the COVID-19 pandemic.Methods: We utilized HealthTree ® Cure Hub for Multiple Myeloma (healthree.org) and invited patients with active MM cancer or precursor conditions to participate in an online survey. We analyzed patient responses to questions regarding their myeloma treatments during the COVID-19 pandemic.Results: 978 MM patients participated in the survey between February to June 2021. Since March 2020, 151 patients (15%) either delayed, postponed, or stopped a myeloma treatment because of COVID-19. The four most common treatments were daratumumab (20%), lenalidomide (15%), stem cell transplant (13%) and zoledronic acid (11%). There were 110 patients that canceled a planned myeloma treatment. Of these patients, 55 (50%) canceled a planned chemotherapy, 15 (14%) canceled a stem cell transplant, 1 (1%) canceled radiation and 39 (35%) indicated other. Eight patients replaced an intravenous or subcutaneous treatment with an oral treatment because of COVID-19. There were 9 patients that started a new myeloma treatment because of COVID-19, the most common being daratumumab (44%), ixazomib (22%), lenalidomide (22%) and carfilzomib (11%). Finally, 15 patients had their lenalidomide (50%), steroid (42%) and carfilzomib (8%) dose changed.Conclusions: Our results show that decision-making regarding treatment changes were made on an individual basis and that patients who required a change in treatment were the minority. Aggregating real-world data can provide evidence that despite the changes, patients with MM still received and efficacious treatment and avoided putting these patients at risk or mortality. DisclosuresAhlstrom: Bristol Myers Squibb: Other: Patient Advisory; Janssen: Other: Patient Advisory; Pfizer: Other: Patient Advisory; Takeda: Other: Patient Advisory.

Assessing Romiplostim Dose and Platelet Response-Guided Titration to Support Use of Romiplostim in ITP Patients Less Than 12 Months from Diagnosis

Background: Romiplostim, a subcutaneous treatment for adult ITP, uses a platelet response-guided dose adjustment algorithm (USPI dosing, Table 1) to maintain patients' platelet count (PC). Romiplostim was recently approved for patients with ITP ≤ 12 months from diagnosis.Objectives: The primary objective of this analysis was to confirm the appropriateness of romiplostim dose and platelet response-guided titration for patients with ITP ≤ 12 months from diagnosis using a model based approach.Methods: Data from 268 adult patients with ITP ≤ 12 months from diagnosis was extracted from 7 previously conducted clinical studies and used to develop a model based on a previously published model of romiplostim dose-response in ITP patients (Perez-Ruixo et al, 2012). Following the model update, patient characteristics (time from diagnosis, PC at baseline, sex, age, weight, number of prior therapies, region, and use of rescue medications) were assessed to identify any potential factors influencing dose or platelet response in ITP patients ≤ 12 months from diagnosis. The model was qualified for simulation using standard methods modified to account for response-guided dosing. Additionally, observed and predicted platelet responses (incidence of durable response, sustained response, and duration of response) were compared for patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6, and 6 to ≤ 12 months). Simulations were then conducted using prescribed dosing guidance to predict PC and romiplostim doses over 52 weeks of treatment in patients ≤ 6 months and > 6 to ≤ 12 months from diagnosis.Results: The analysis dataset included 7854 PC from 268 patients (with median baseline PC of 18 x 10 9/L and median time since diagnosis of 3 months) receiving romiplostim weekly for up to 3 years at doses ranging from 1 to 15 mg/kg.The updated model (Figure 1) consisted of a drug-sensitive progenitor cell compartment (Pre), 4 maturation compartments (Transit), and a peripheral blood compartment (Circ). Romiplostim increased production of platelet precursors in Pre in 2 ways: 1. linearly with romiplostim exposure (immediate response), and 2. as a function of cumulative administered dose. Response to romiplostim was bimodal with approximately 50% of patients more sensitive to romiplostim treatment with drug sensitivity proportional to time since diagnosis. In the other 50% of patients, immediate response was reduced and there was no cumulative effect of romiplostim dosing on platelet response over time. Age was associated with average platelet transit time where a patient of 30, 60, or 90 years would have a platelet transit time of 6.3, 7.5, and 8.3 days respectively. No other covariates were found to influence any model parameters.Model predicted and observed platelet responses were similar for ITP patients stratified by time from ITP diagnosis (<3, 3 to ≤ 6 and 6 to ≤ 12 months). Simulations (Figure 2) showed that romiplostim prescribed dosing is effective in maintaining PC of 50 - 250 x 10 9/L following titration (approximately 65% of subjects) and minimizing the proportion <20 or >400 x 10 9/L regardless of time since ITP diagnosis or sensitivity to romiplostim treatment. The predicted <35% of subjects above 400 x 10 9/L is consistent with what was observed in the adult ITP safety datasets.Conclusions: An updated model of romiplostim dose and platelet response was developed using data from ITP patients ≤12 months from diagnosis. Clinical trial simulations using the updated model predicted that weekly dosing of romiplostim according to the dose titration rules in the label adequately maintained platelet counts in patients with ITP ≤ 12 months from diagnosis. [Display omitted] DisclosuresGibiansky: Amgen: Consultancy. Serrano Castillo: Amgen: Current Employment, Current equity holder in publicly-traded company. Saad: Amgen: Current Employment, Current equity holder in publicly-traded company. Chow: Amgen: Current Employment, Current equity holder in publicly-traded company. Doshi: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment.

Anti-Emicizumab Antibodies Do Not Cross-React with Mim8 in Vitro

BackgroundPatients with severe hemophilia A may develop inhibitors against factor VIII (FVIII) in around 30% of cases. Recently, the introduction of non-replacement therapies such as emicizumab, a FVIII-mimicking agent administered as a subcutaneous injection, has revolutionized the treatment of patients with inhibitors. However, although rarely, some patients may develop antibodies against this drug. If neutralizing, these antibodies interfere with the activity of the drug, making it ineffective. Mim8 (Novo Nordisk®) is a novel experimental FVIII-mimetic human bispecific antibody that has a similar function as emicizumab, by bridging activated FIX (FIXa) and FX to activate FX, although with a different molecular structure compared to emicizumab. It is currently in phase II clinical trial for subcutaneous treatment of patients with hemophilia A with or without FVIII inhibitors (1, 2).It is currently unknown whether the antibodies developed against emicizumab by patients with hemophilia A could cross-react with Mim8.AimOur aim was to study the cross-reactivity of anti-emicizumab antibodies developed by patients with hemophilia A against Mim8 with an in-house detection method.MethodsWe studied the serum of three patients who developed anti-emicizumab antibodies. Plasma from one patient with persistent inhibiting antibodies was collected both during the treatment (thus also containing emicizumab at steady-state levels) and two years after treatment discontinuation due to inefficacy (neutralizing persistent antibodies). Plasma from two patients who developed transient antibodies against emicizumab were also tested in the course of treatment with emicizumab (non-neutralizing transient antibodies). The plate was coated both with emicizumab and with Mim8 provided by the pharmaceutical companies for research purposes. Plasma samples, diluted 1/20, were loaded into the coated wells and incubated 90 min at 37°C. The cross-reactivity to Mim8 was evaluated also by using the affinity purified anti-emicizumab IgG, which was loaded at 5 ug/mL. A properly adapted ELISA method already described (3) was used as reference assay. Then, biotinylated-emicizumab (1.5 ug/mL) or biotinylated-Mim8 (at 2 and 4 ug/mL) were added and the plate incubated 1 hour at 37°C. Moreover, a competition test was performed by using a mixture of biotinylated-emicizumab (1.5 ug/mL) and an excess of Mim8 (at 4, 8 and 40 ug/mL) in the detection phase.ResultsThe Mim8 molecule - either alone, or matched with emicizumab - used both in the capture phase and in the detection phase did not bind to neither patient's plasma antibodies nor to anti-emicizumab purified IgG, which were instead revealed with the reference assay. The binding of the anti-emicizumab antibodies to biotinylated-emicizumab was not inhibited by the addition of Mim8, even at 40 ug/mL.ConclusionsOur in-house method showed that anti-emicizumab antibodies do not react with Mim8 in vitro. Observational studies to test whether Mim8 can be used safely in patients with anti-emicizumab antibodies are needed to confirm our findings in vivo as well.

Thyrointegrin αVβ3 Antagonist: Implications in Acute Myeloid Leukemia

Leukemic cells are able to receive and send several signals within bone marrow niche that play an important role in their survival. One of the important crosstalk is the interaction between the bone marrow microenvironment proteins (vitronectin, fibronectin, fibrinogen, and ostepontin) and thyrointegrin αVβ3 on leukemic cells, generating ligand-specific outside-in signals that are relevant to a variety of cell functions, including gene transcription, cell division, cell attachment, and motilityOur previous experiment using in vivo AML animal models with primary AML cells and cell lines have shown significant reduction of leukemic cell burden 74% and >95% (P<0.0001), respectively, after daily subcutaneous treatment with thyrointegrin αvβ3 antagonist fb-PMT (Ki 0.23 nM) at 3 and 10 mg/kg, for 3-4 weeks. In this study we focused on evaluations of the molecular effects of fb-PMT in leukemic cells. Acute myeloid leukemia cell lines (K562-Luc and KG1a cells) were cultured in 50 cm² cell culture flasks with 10 mL phenol red free RPMI media containing 10% fetal bovine albumin. The leukemic cells were treated (at 50% confluence) with 30 µM fb-PMT for 48 hours. Total RNA was immediately isolated from harvested cells using Triazole and used for microarray analysis. Overall, there were 370 significantly down-regulated gene expression records and 273 significantly up-regulated gene expression records, expression of which were changed at least 1.5-fold in fb-PMT-treated human leukemic cells. Significant examples of the fb-PMT-induced gene expression signatures (GES) of pathway's interference include SNAI, MYC, HIF1A, TWIST1, and TFAP2C (P<0.05). Notably, inference of potential contribution to the fb-PMT anticancer activity of the interference with these pathways seems highly congruent with their known biological functions such as cell cycle control (MYC), survival and maintenance of stem cells (HIF1A, TFAP2C), and essential features of the malignant phenotype (TWIST1, SNAI) (Figure 1).Consistently, examples of the fb-PMT-induced GES of transcriptional pathway's activation include RB1, IRF9, MAML1, RAP1A, and GATA4 pathways (P<0.05), known biological functions of which appear highly consistent with the hypothesis that activation of these pathways might contribute to fb-PMT anticancer activity. Finally, we found that fb-PMT interfered with estrogen signaling in human AML cells. The fb-PMT was associated with decreased phosphorylation and nuclear enrichment of Erα (Figure 1).Collectively, our in vivo study and genomic data have shown the key role thyrointegrin αvβ3 in leukemogenesis. The thyrointegrin αvβ3 antagonist fb-PMT demonstrated potent anticancer actions on human AML through the molecular interference mechanism with multiple signaling pathways supporting growth and survival of leukemic cells [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase 1b Study of Blinatumomab Including Subcutaneous Administration in Relapsed / Refractory (R/R) Indolent Non Hodgkin's Lymphoma (NHL)

A Phase 1b Study of Blinatumomab Including Subcutaneous Administration in Relapsed / Refractory (R/R) Indolent Non Hodgkin's Lymphoma (NHL)

A double-blinded placebo-controlled evaluation of adipose-derived mesenchymal stem cells in treatment of canine atopic dermatitis.

Mesenchymal stem cells (MSCs) have emerged as a new therapy for various immune-mediated inflammatory diseases. In this study we perform the first double-blinded, placebo-controlled evaluation of the efficacy of adipose-derived allogenic canine MSCs for the treatment of canine atopic dermatitis (cAD). Enrolled canine patients were randomly divided into placebo (PBS saline), low-dose (5 × 105 cells/kg), and high-dose (5 × 106 cells/kg) treatment groups. Each patient received three subcutaneous MSCs treatments or PBS saline at four-week intervals with injections at five sites. Patients were monitored by physical exams, pruritus visual analog scales (PVAS) signed by the primary caretaker, canine atopic dermatitis extent and severity index-4 (CADESI-4) scores by two veterinarians, and complete blood count and serum chemistry analysis along with laboratory analysis for potential biomarkers. Patients were kept off any immune-modulating drugs during the study period, and oral antibiotics and topicals were used for managing pruritus and secondary infections. The PVAS scores and the serum miR-483 levels were significantly lower in the high dose group compared to the placebo group at day90 post first-treatment. The CADESI-4 scores of the high dose group also showed downward trends. No severe adverse effects were observed in any patient in this study. The high dose MSC treatment is efficacious in alleviating the clinical signs of cAD until 30days after the last subcutaneous administration of MSCs, and miRNA-483 may be a reliable prognostic biomarker for cAD. The MSCs efficacy and potential biomarkers should be further explored by a larger scale clinical trial.

Effect of subcutaneous high-dose methotrexate treatment on the management of rheumatoid arthritis

Purpose: Methotrexate (MTX) is still the main treatment option for rheumatoid arthritis (RA). There is no consensus on drug administration routes and dosage when administered alone or in combination with other drugs. This study aims to identify the effects of early administration of a combination therapy containing high dose subcutaneous (SC) MTX on RA management.&#x0D; Materials and Methods: Forty-five patients with RA who newly diagnosed were divided into two groups randomly. The patients who took 12.5 mg SC MTX per week in the first 4 weeks defined as a "low dose group". The patients who took 25 mg SC MTX per week in the first 4 weeks defined as a "high dose group". Then, patients of both groups continued with 12.5 mg oral MTX per week. Clinical and laboratory findings, disease activity scores and response rates of the patients were recorded at the beginning, 3rd months and 6th months. &#x0D; Results: There was no significant difference between the two groups at 3rd month’s values. There were statistically significant improvements at 6th month’s values. Values were as follows in low and high dose groups: mean DAS28-CRP (3.5 vs 2.7), VAS pain score (3.3 vs 1.6), and TJC28 (3 vs 1.5), respectively. &#x0D; Conclusion: Early administration of high-dose SC MTX effectively controls disease activity and increases the quality of life in RA patients.

Changes in RAPD-DNA Markers and Plasma Protein Profile in Progesterone-Treated Chicken

The abuse of contraceptive pills as growth promoters in the poultry industry has serious health concerns. Consumption of hormonal residues in animal products results in reproductive disorders and an increased risk of cancers in humans. This study aimed to investigate the effect of treatment with progesterone hormone on the plasma proteins and RAPD-DNA markers of broiler chickens. One hundred, one-day-old broiler chicks were equally divided into 5 groups (n = 20). Four groups were treated daily with progesterone hormone either subcutaneously or orally (1.0 mg, 1.5mg/kg). The 5th group was control non-treated chicken. Sodium dodecyl sulfate polyacrylamide gel-electrophoresis (SDS-PAGE), and RAPD assays in conjunction with productive parameters such as growth rate were assessed. SDS-PAGE and RAPD-DNA patterns were significantly affected by progesterone hormone treatment. Either or oral or subcutaneous progesterone hormone treatments increased the body weight of chicks compared to control. Treatment with progesterone hormone induces effects on both DNA and plasma proteins in broiler chickens. Changes at the genomic DNA level may be due to specific modifications in RAPD patterns or arise as a consequence of hot spot DNA changes and/or mutations.

Phase 3 trial of a small-volume subcutaneous 6-month duration leuprolide acetate treatment for central precocious puberty

CONTEXT Gonadotropin-releasing hormone agonists (GnRHas) are standard of care for central precocious puberty (CPP). A 6-month subcutaneous injection has recently been approved by the Food and Drug Administration. OBJECTIVE Determine efficacy, pharmacokinetics, and safety of 6-month 45-mg subcutaneous leuprolide acetate for CPP. DESIGN Phase 3 multicenter, open-label, single-arm study. SETTING 25 sites in 6 countries. SUBJECTS 64 GnRHa-naive children with CPP (age: 7.5 ± 0.1 years) received study drug: 59 completed the study. INTERVENTION(S) 2 doses of 45-mg subcutaneous leuprolide acetate (0.375 mL) at 0 and 24 weeks; children were followed for 48 weeks. MAIN OUTCOME MEASURE(S) Percentage of children with serum luteinizing hormone (LH) <4 IU/L 30 minutes following GnRHa stimulation at week 24. RESULTS 54/62 (87%) children achieved poststimulation LH <4 IU/L at week 24; 49/56 (88%) girls and 1/2 boys maintained peak LH <4 IU/L at week 48. Mean growth velocity decreased from 8.9 cm/year at week 4 to 6.0 cm/year at week 48. Mean bone age was advanced 3.0 years beyond chronological age at screening and 2.7 years at week 48. Breast pubertal stage regressed or was stable in 97% of girls and external genitalia development regressed in both boys. Adverse events were mild and did not cause treatment discontinuation. CONCLUSIONS A small volume of 45-mg subcutaneous leuprolide acetate administered at a 6-month interval effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression. This long-acting GnRHa preparation of leuprolide acetate is a new, effective, and well-tolerated therapy for children with CPP.

Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies.

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect a patient's quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigate attack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks. Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020. Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once daily for the prevention of HAE attacks in patients ages ≥ 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as long-term prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage. Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and self-limited. Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard to the administration route of their HAE prophylactic treatment.

Subcutaneous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy.

Immunoglobulin G (IgG) therapy is an established long‐term treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) that is commonly administered intravenously (IVIg). The subcutaneous immunoglobulin (SCIg) administration route is a safe and effective alternative option, approved by the United States Food and Drug Administration (FDA) in 2018, for maintenance treatment of adults with CIDP. Physicians and patients alike need to be aware of all their treatment options in order to make informed decisions and plan long‐term treatment strategies. In this review, we collate the evidence for SCIg in CIDP from all published studies and discuss their implications and translation to clinical practice. We also provide guidance on the practicalities of how and when to transition patients from IVIg to SCIg and ongoing patient support. Evidence suggests that IVIg and SCIg have comparable long‐term efficacy in CIDP. However, SCIg can provide additional benefits for some patients, including no requirement for venous access or premedication, and reduced frequency of systemic adverse events. Local‐site reactions are more common with SCIg than IVIg, but these are mostly well‐tolerated and abate with subsequent infusions. Data suggest that many patients prefer SCIg following transition from IVIg. SCIg preference may be a result of the independence and flexibility associated with self‐infusion, whereas IVIg preference may be a result of familiarity and reliance on a healthcare professional for infusions. In practice, individualizing maintenance dosing based on disease behavior and determining the minimally effective IgG dose for individuals are key considerations irrespective of the administration route chosen.

Quality of life patients treated with rituximab intravenous versus subcutaneous in B-cell lymphomas: results from outpatient Hematooncology Clinic in Lodz

Introduction: Nowadays, rituximab is available both as intravenous (IV) and subcutaneous (SC) formulations. The aim of this study is to compare quality of life (QOL) of patients treated in Hematooncology Clinic in Lodz with B-cell nonHodgkin lymphoma (B-NHL) treated with rituximab IV and SC.&#x0D; &#x0D; Material and Methods: In 50 adult patients with B-NHL diagnosis we assessed QOL by three different questionnaries (EORTC QLQ-C30, FACT/ GOG-NTx and EQ-5D). We compared it between patients treated with rituximab IV and SC.&#x0D; &#x0D; Results: In comparison of general condition in EQ-5D-3L and EORTC QLQ-C30 questionnaire patients treated with rituximab SC felt statistically better than with IV administration (p&lt;0.01). In SC group general health was evaluated for 72 while in IV for only 58,1. According to FACT/GOG-NTx questionnaire SC group had significantly better physical well-being. In SC group we observed statistically more complete responses (CR) 21 (88%) versus 17 (65%) in IV group. Moreover, trend was observed in emotional well-being in favor of SC treatment.&#x0D; &#x0D; Discussion: In our study we observed for the first time in the literature statistical difference in frequency of vomiting, nausea, and lack of appetite mentioned from our patients in questionnarie. It is very important that this findings were not published in any other study comparing SC and IV route od administration. Also looking at economic side of SC administration, this type of dosing. As a result it should be preferred form for B-cell lymphoma patients.

STING Agonist Combined to a Protein-Based Cancer Vaccine Potentiates Peripheral and Intra-Tumoral T Cell Immunity.

Combining different immunotherapy approaches is currently building the future of immunotherapy, with the view to maximize anti-tumoral efficacy for larger patient population. The KISIMA™ platform allows the development of protein-based cancer vaccines able to induce tumor-specific T cell response resulting in anti-tumoral efficacy in various mouse models. Intra-tumoral administration of stimulator of interferon gene agonists (STINGa) was shown to induce a potent inflammatory response leading to the development of tumor-specific immunity. Here, we explored the efficacy and mechanisms of action of subcutaneous STINGa treatment combined with therapeutic vaccination in various mouse tumor models. This combinatory treatment highly enhanced frequency and effector function of both peripheral and intra-tumoral antigen-specific CD8 T cells, promoting potent IFNγ and TNFα production along with increased cytotoxicity. Moreover, combination therapy favorably modulated the tumor microenvironment by dampening immune-suppressive cells and increasing CD4 T cell infiltration together with their polarization toward Th1 phenotype. Combination with STINGa treatment improved the effect of therapeutic vaccination, resulting in a prolonged control and slower growth of B16-OVA and TC-1 tumors. Altogether, the results presented here highlight the potential of combining STINGa with a therapeutic protein vaccine for cancer treatment.

A Novel Von Willebrand Factor Fragment Acts As a Chaperone to Prolong the Half-Life of Recombinant Human FVIII (Simoctocog Alfa) in Hemophilia a Dogs and FVIII/VWF Double Knockout Mice

Introduction/Objective: Subcutaneous (SC) drug delivery represents a convenient method of administration compared to intravenous (IV) delivery. However, due to very low bioavailability this route is not yet applicable for the administration of FVIII as a therapy for hemophilia A (HA). von Willebrand factor (VWF), in particular the D'D3 domains, is known to protect FVIII from proteolytic degradation, rapid clearance and binding to membranes. Therefore VWF represents a promising candidate for a strategy to increase FVIII bioavailability after SC treatment. Different VWF fragments containing at least the D'D3 domains were engineered in order to achieve high FVIII binding affinity, prolonged half-life of the VWF fragment, and consequently high bioavailability of FVIII.Materials/Methods: A modified VWF fragment (OCTA12) or an unmodified D'D3 domain, both with a C-terminal Strep-Tag, was transiently expressed in HEK293 cells and purified by Strep-Tactin® affinity chromatography. Recombinant human FVIII (rhFVIII, simoctocog alfa) complexed with OCTA12, D'D3 or full-length plasma-derived VWF (flVWF, Wilate®) was administered via IV route to FVIII/VWF double knockout (FVIII/VWF DKO) mice at 240 IU FVIII/kg in order to test the ability of the fragments to stabilize FVIII in circulation. Blood samples were taken at 5 minutes and 1, 4, 8, 12, 24, 36 and 48 hours after treatment and analyzed for FVIII activity. Subsequently, IV and SC administration of the complex of rhFVIII and OCTA12 or rhFVIII alone was evaluated in a HA dog model. For this purpose, HA dogs were treated according to the scheme presented in Table 1. Blood samples were taken at 0.5, 1, 2, 4, 8, 12, 24, 32, 48, 72 and 94 hours after treatment and analyzed for FVIII activity.Results: Five minutes after IV administration of rhFVIII complexed with different VWF variants to FVIII/VWF DKO mice, peak activity levels were determined (expressed in % mean ± SEM, n = 15): rhFVIII alone 78.9 ± 6.1; rhFVIII/D'D3 351.2 ± 22.3; rhFVIII/OCTA12 295.9 ± 17.4; rhFVIII/flVWF 404.4 ± 20.5. The FVIII activity levels were significantly higher (statistically evaluated by Student's t-test) when rhFVIII was administered with any VWF variant in comparison to rhFVIII administered alone. The three co-administered VWF species D'D3, OCTA12 or flVWF did not differ significantly in terms of measured FVIII levels. rhFVIII administered alone was rapidly cleared from the circulation (T1/2 = 0.07 h). Co-administration with flVWF or D'D3 resulted in a 4.5- or 6.4-fold prolongation of the half-life respectively (T1/2 = 0.32 h and T1/2 = 0.45 h respectively). The highest half-life prolonging effect (14.7-fold) was measured when rhFVIII was co-administered with OCTA12 (T1/2 = 1.03 h). The IV administration of rhFVIII alone (200 IU/kg) or complexed with OCTA12 (100 IU/kg) in the HA dog resulted in peak FVIII activity level of 215% or 134% respectively at 30 minutes post-infusion (mean of two injections). The SC administration of rhFVIII complexed with OCTA12 resulted in a 10.8% activity level at 30 minutes post-infusion and reached a peak level of 24.6% at 8 h post-infusion (mean of three injections). For calculation of bioavailability, the area under the curve (AUC) of FVIII activity after IV administration of rhFVIII alone was defined as 100%. The AUC of IV-administered rhFVIII/OCTA12 complex at 100 IU/kg (half the dose) was 90%. Bioavailability of FVIII after SC administration of the rhFVIII/OCTA12 complex was 37.7%.Conclusions: The co-administration of rhFVIII with the novel engineered VWF fragment OCTA12 results in high FVIII bioavailability after SC administration in HA dogs. The bioavailability of FVIII was also increased after IV administration of the FVIII/OCTA12 complex in FVIII/VWF DKO mice and HA dogs. Moreover, when complexed with OCTA12, FVIII exhibits prolonged half-life in FVIII/VWF DKO mice. [Display omitted] DisclosuresSolecka-Witulska:Octapharma Biopharmaceuticals GmbH: Employment. Kannicht:Octapharma Biopharmaceuticals GmbH: Employment.