Subcutaneous Injection Research Articles

A microfluidic in vitro method predicting the fate of peptide drugs after subcutaneous administration

For many biopharmaceuticals, subcutaneous (sc) administration is the only viable route. However, there is no in vitro method available accurately predicting the absorption profiles of subcutaneously injected pharmaceuticals. In this work, we show that a recently developed microfluidics method for interaction studies (MIS) has the potential to be useful in this respect. The method utilises the responsiveness of polyelectrolyte microgel networks to oppositely charged molecules as a means to monitor the interaction between peptides and hyaluronic acid (HA), a major constituent of the subcutaneous extracellular matrix. We use the method to determine parameters describing the strength of interaction between peptide and HA as well as the peptide’s aggregation tendency and transport properties in HA networks. The results from MIS studies of the peptide drugs exenatide, pramlintide, vancomycin, polymyxin B, lanreotide, MEDI7219 and AZD2820 are compared with results from measurements with the commercially available SCISSOR system and in vivo absorption and bioavailability data from the literature. We show that both MIS and SCISSOR reveal differences in the peptides’ diffusivity and tendency to aggregate in the presence of HA. We show that MIS is particularly good at discriminating between peptides forming aggregates stabilised by non-electrostatic forces in the presence of HA, and peptides forming complexes stabilised by electrostatic interactions with HA. The method provides two parameters that can be used to quantify the peptides’ aggregation tendency, the one describing the peptide packing density in complexes with HA and the other the apparent diffusivity upon release in a medium of physiological ionic strength and pH. The order of the peptides when ranked by increasing binding strength at pH 7.4 determined with MIS is shown to be in agreement with the order when ranked by the apparent 1st order absorption rate constant (ka) after sc administration in humans: lanreotide (Autogel) < exenatide (IRF) < AZD2820 < pramlintide < lanreotide (IRF) (IRF: Immediate release formulation). A correlation is found between the 1st order release rate constant determined with SCISSOR and ka for lanreotide (Autogel), exenatide and AZD2820. A mechanism relating the magnitude of ka to the peptides’ charge is proposed.

Patient and Healthcare Professional Satisfaction, Acceptability, and Preference Experiences With Mirikizumab Administration for Ulcerative Colitis: An International Survey.

There is a need to better understand ulcerative colitis (UC) patient and healthcare provider (HCP) treatment satisfaction, acceptability, and preferences. Two international, cross-sectional, web-based surveys were conducted among participants of a phase 3 mirikizumab study (NCT03519945). The questions captured moderate-to-severe UC patients' experience, HCPs' perception of patients' experience, and HCPs' own experience with mirikizumab administration through intravenous (IV) infusions and subcutaneous (SC) injections. Respondents included 93 patients and 42 HCPs from 11 countries. The majority of patients had UC >4 years (74.2%), were bionaive (68%), in remission at the time of the survey (63%). HCPs were primarily from the United States (57%), generally nurses (41%) or gastroenterologists (26%) with ≥6 years of experience in treating UC (57%). Most patients were "very satisfied/satisfied" (IV, 83%; SC, 91%), "completely/somewhat" accepting of mirikizumab administration (IV, 87%; SC, 97%), and agreed that improvement to their UC outweighed any administration dissatisfaction (90%). HCPs' perspectives of patients' experiences were higher: "very satisfied/satisfied" (IV, 93%; SC, 100%); "completely/somewhat" accepting (IV, 90%; SC, 98%). HCPs themselves were "very satisfied/satisfied" (IV, 81%; SC, 95%); gastroenterologists were "very satisfied" (IV, 82%; SC, 82%) more than nurses (IV, 29%; SC, 65%) who were generally at least "satisfied" (IV, 53%; SC, 35%). Two SC and monthly SC injections were "completely acceptable" by the patients (76% and 85%) and per HCPs' perceptions of patients' preferences (69% and 100%). Both patients and HCPs were satisfied with and accepted mirikizumab IV induction followed by monthly maintenance SC injections. UC improvement outweighed any administration dissatisfaction.

Effect of subcutaneous vs. intravenous tocilizumab in patients with severe COVID-19: a systematic review.

To systematically evaluate the efficacy of subcutaneous tocilizumab in the treatment of patients with severe COVID-19 and provide evidence for the rational use of subcutaneous tocilizumab in patients with severe COVID-19. This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched the Cochrane Library, PubMed, Embase, CNKI, SinoMed, and Wanfang Medical Network electronic databases up to 11 January 2023 to identify relevant studies. To obtain the most recent clinical studies of subcutaneous injection of tocilizumab for the treatment of patients with severe COVID-19, we also searched the preprint platforms medRxiv and ChinaXiv. Furthermore, we searched ClinicalTrials.gov for relevant unpublished studies. The studies were screened based on the PICOS principle. The included studies were classified and evaluated for quality based on research type. The RevMan 5.3 software was used to conduct the meta-analysis, and a descriptive analysis was performed to examine relevant outcome indicators. Five observational studies were obtained, involving a total of 498 patients (240 patients in the subcutaneous injection group and 258 patients in the intravenous injection group). All of the studies were of the highest quality. The meta-analysis of the included studies revealed that the mortality rate of patients who received subcutaneous tocilizumab to treat COVID-19 was not significantly higher than that of the intravenous injection group [23.3% (45/193) vs. 18.4% (39/212), RD = 0.06, 95% CI = - 0.01 ~ 0.13, P = 0.11]. Furthermore, there was no significant difference in the proportion of patients requiring mechanical ventilation between the two groups [24.5% (35/143) vs. 22% (35/159), RD = 0.03, 95% CI = - 0.07 ~ 0.12, P = 0.56]. The meta-analyses do not provide evidence that subcutaneous and intravenous tocilizumab formulations for the treatment of severe COVID-19 infection differ regarding their effectiveness. Considering that the meta-analyses cannot replace an appropriately powered non-inferiority study, subcutaneous formulations still need to be used with caution and only when intravenous formulations are in short supply. At present, there is a lack of randomized controlled trials of subcutaneous injection of tocilizumab for the treatment of severe COVID-19, and more clinical research should be conducted.

Systemic Multifunctional Nanovaccines for Potent Personalized Immunotherapy of Acute Myeloid Leukemia.

Hematological malignancies (HM) like acute myeloid leukemia (AML) are often intractable. Cancer vaccines possibly inducing robust and broad anti-tumor immune responses may be a promising treatment option for HM. Few effective vaccines against blood cancers are, however, developed to date partly owing to insufficient stimulation of dendritic cells (DCs) in the body and lacking appropriate tumor antigens (Ags). Here it is found that systemic multifunctional nanovaccines consisting of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and Toll-like receptor 9 (TLR9) agonists - muramyl dipeptide (MDP) and CpG, and tumor cell lysate (TCL) as Ags (MCA-NV) induce potent and broad immunity against AML. MCA-NV show complementary stimulation of DCs and prime homing to lymphoid organs following systemic administration. Of note, in orthotopic AML mouse models, intravenous infusion of different vaccine formulations elicits substantially higher anti-AML efficacies than subcutaneous administration. Systemic MCA-NV cure 78% of AML mice and elicit long-term immune memory with 100% protection from rechallenging AML cells. Systemic MCA-NV can also serve as prophylactic vaccines against the same AML. These systemic nanovaccines utilizing patient TCL as Ags and dual adjuvants to elicit strong, durable, and broad immune responses can provide a personalized immunotherapeutic strategy against AML and other HM.

Evaluation of the impact of the polymer end groups and molecular weight on in vitro and in vivo performances of PLGA based in situ forming implants for ketoprofen

In situ forming implants are appealing long-acting dosage forms for both preclinical and clinical applications due to their simple manufacturing process and easy delivery. This study aims to develop extended-release in situ forming solid implants for subcutaneous administration using two types of commercially available triblock poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA) polymers, with either an acid or ester end group. Both types of polymers instantly form in situ implants when injected directly into an aqueous medium. The performance of these implants, containing a model compound ketoprofen, was evaluated by comparing the in vitro drug release profiles with the in vivo performance following subcutaneous administration in rats. Analytical characterizations of two representative in situ implants were conducted to understand their structural impact on polymer degradation and drug release. All tested in situ forming implants demonstrated prolonged drug release profiles both in vitro and in vivo. This study illustrates the successful preparation of sustained-release in situ forming implant formulations for ketoprofen using commercially available polymers, with the molecular weight and the end group of the polymers affecting their degradation and the drug release from the in situ formed implants.

Microcrystalline cellulose and itaconic acid pH sensitive semi interpenetrating network hydrogel for oral insulin delivery

Diabetes mellitus is one of the important causes of death worldwide. Generally, a subcutaneous route is used for insulin administration, but has showed low patient compliance. Extensive research has been conducted to identify molecules capable of delivering insulin orally, for this hydrogel based on microcrystalline cellulose and itaconic acid have been produced and explored. Free radical polymerization as a technique was employed for manufacturing the hydrogels using potassium persulphate as initiator and N, N′-methylene bisacrylamide (NNMBA) as a crosslinker. These pH- sensitive exhibited a swelling capacity of up to 20.38 g/g in distilled water and also revealed stronger swelling in glucose solutions than saline solutions. The pH sensitivity of the hydrogels was confirmed by studying the swelling in different pH solutions. Alkaline solutions showed higher swelling than acidic solutions. SEM established the porous nature, and the structure was examined by FTIR analysis. Thermal degradation was examined using TGA. In vitro release study was done by Bradford assay at 595 nm. The result was further confirmed by in-vivo investigations on male Wistar adult rats and hence is an excellent vehicle for oral insulin administration.

Efficacy and safety of apraglutide in short bowel syndrome with intestinal failure and colon–in–continuity: A multicenter, open-label, metabolic balance study

BackgroundApraglutide is a novel long-acting GLP-2 analog in development for short bowel syndrome with intestinal failure (SBS-IF). This multicenter, open-label, phase 2 study in SBS-IF and colon-in-continuity (CiC) investigates the safety and efficacy of apraglutide. MethodsThis was a 52-week phase 2 metabolic balance study (MBS) in 9 adult patients with SBS-IF-CiC receiving once-weekly subcutaneous apraglutide injections. Safety was the primary endpoint. Secondary endpoints included changes in absorption parameters (MBS at baseline, after 4 weeks with stable parenteral support (PS), and 48 weeks), PS needs (48-week PS adjustment period based on monthly 48-hour fluid balances) and intestinal morphology and motility (static and cine MRI at baseline and 4, 24 and 48 weeks). ResultsPS volume decreased by -4702mL/week (-52%; p<0.001) at week 52. Seven patients (78%) achieved ≥1 day off PS at week 52. At 4 weeks, fecal output was reduced by 253 g/day (p=0.013). At 48 weeks, increases in wet weight absorption by 316 g/day (p=0.039), energy absorption by 1134 kJ/day (p=0.041) and carbohydrate absorption by 56.1 g/day (p= 0.024) were observed. Moreover, small bowel length increased from 29.7 to 40.7 cm (p=0.012), duodenal wall thickness increased by 0.8 mm (p=0.02) and motility in the proximal colon was reduced (p=0.031). A total of 127 adverse events was reported, which were mostly mild to moderate. ConclusionApraglutide had an acceptable safety profile and was associated with significant reductions in PS needs and days off PS, improvements in intestinal absorption, and structural and functional intestinal changes in patients with SBS-IF-CiC.ClinicalTrials.gov, Number NCT04964986

Descriptive analysis of safety and immunogenicity profiles of a 15-valent pneumococcal conjugate vaccine between subcutaneous and intramuscular administration in a phase 1 study of healthy Japanese infants (V114-028)

IntroductionSubcutaneous (SC) administration is typically used for pediatric inactivated vaccines in Japan, whereas intramuscular (IM) administration is used outside Japan. We previously reported the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), administered subcutaneously and intramuscularly in a Japanese phase 1 study (V114-028). Here, we report secondary descriptive analyses on V114 groups of the study to further assess the safety and immunogenicity profiles of V114 between the administration routes. MethodsA total of 133 healthy Japanese infants were randomized to receive V114-SC (n = 44), V114-IM (n = 45), or PCV13-SC (n = 44) at approximately 3, 4, 5, and 12–15 months of age. Adverse events (AEs) from Days 1–14 post-vaccination and vaccine-related serious AEs from Day 1 to 1-month post-dose 4 were reported. Serotype-specific immunoglobulin G (IgG) responses were measured across the vaccination series. ResultsProportions of participants with solicited systemic AEs (irritability, somnolence, decreased appetite, and urticaria) and pyrexia were generally comparable between the groups. Compared with V114-SC, patients receiving V114-IM had a lower incidence of irritability and somnolence, and higher incidence of decreased appetite. Proportion of participants with solicited injection-site erythema was lower with V114-IM (82.2%) than V114-SC (100.0%). Those with other solicited injection-site AEs (induration, swelling, and pain) were generally comparable between the groups, with lower observed proportions with V114-IM. Serotype-specific IgG responses were also generally comparable between the groups, including at pre-toddler dose. ConclusionsThese results suggest the utility of IM administration as an option for V114 vaccination in Japanese infants.

Injectable Gelled Multiple Emulsion for Glucose-Responsive Insulin Delivery.

A glucose-responsive insulin delivery system that sustains blood glucose equilibrium for an extended duration can address the low therapeutic window of insulin in diabetes treatment. Herein, insulin is loaded in a water-in-oil-in-water (W1/O/W2) gelled multiple emulsion using poly (4-vinylphenylboronic acid) (PVPBA) homopolymer as an effective emulsifier. The gelled multiple emulsion exhibits a high encapsulation efficiency (99%), enhanced stability and remarkable shear-thinning behavior, making it easy to inject. Under hyperglycemic conditions, the gelled emulsion system instantly binds to glucose molecules and reduces the hydrogen bonds of the PVPBA homopolymer, resulting in insulin release. In a streptozotocin-induced type 1 diabetic mouse model, a single subcutaneous injection of the gelled emulsion rapidly responds to high blood glucose concentration (BGC)and release insulin in a glucose dependent manner, thus prolonging the antihyperglycemic effect compared with free insulin.

Recaticimab Monotherapy for NonfamilialHypercholesterolemia andMixed Hyperlipemia: ThePhase 3 REMAIN-1 Randomized Trial.

Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have been used to reduce the level of low-density lipoprotein cholesterol (LDL-C), but require either biweekly or monthly dosing frequency. Recaticimab is a new humanized monoclonal antibody selectively targeting PCSK9, with long-acting characteristic. The purpose of this study was to assess the efficacy and safety of recaticimab monotherapy in patientswith nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk, and to explore different dosing strategies to provide patients with flexible administration options. This was a randomized, double-blind, placebo-controlled, phase 3 study conducted at 59 sites in China. Patients with fasting LDL-C≥2.6 to<4.9mmol/L, fasting triglyceride≤5.6mmol/L, and 10-year ASCVD risk score<10% were randomly assigned (2:2:2:1:1:1) to receive subcutaneous injections of recaticimab at 150mg every 4weeks (Q4W), 300mg every 8weeks (Q8W), or 450mg every 12weeks (Q12W), or matching placebo, on background lipid-lowering diet. Primary endpoint was percentage change in LDL-C from baseline to week 12 for 150mg Q4W and 450mg Q12W and to week 16 for 300mg Q8W. A total of 703 patients underwent randomization and received recaticimab (n=157, 156, and 155 for 150mg Q4W, 300mg Q8W, and 450mg Q12W, respectively) or placebo (n=78, 79, and 78, respectively). Compared with placebo, recaticimab further reduced LDL-C by 49.6% (95%CI: 44.2%-54.9%) at 150mg Q4W, 52.8% (95%CI: 48.3%-57.2%) at 300mg Q8W, and 45.0% (95%CI: 41.0%-49.0%) at 450mg Q12W (P< 0.0001 for all comparisons). Safety with recaticimab was comparable to placebo. After 12 or 16weeks of treatment, patients who received recaticimab continued treatment until week 24, whereas those allocated to placebo were switched to recaticimab treatment with the same dosing strategy. Both 24-week recaticimab and 12- or 8-week recaticimab switched from placebo were effective. With 24weeks of recaticimab treatment, the most common treatment-related adverse event was injection site reaction (n = 23 [4.9%]). Recaticimab monotherapy yielded significant LDL-C reductions and showed comparable safety vs placebo in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate ASCVD risk, even with an infrequent dosing interval up to Q12W.

Progesterone receptor status predicts aggressiveness of human endometriotic lesions in murine avatars

To utilize murine avatars for studying human endometriotic lesion response to two different hormonal regimens to determine if PR can prospectively predict response to progestin-based therapy. Endometriosis is a chronic gynecologic disease afflicting 1-in-10 reproductive-aged women; however response to medical therapy is highly variable as endometriotic lesions do not consistently respond to first-line, progestin-based therapy. We have previously demonstrated in a retrospective study that progesterone receptor (PR) status in lesions correlated with response to progestins. Here, we hypothesize that a prospective approach utilizing PR status to predict response to medical will allow clinicians to individualize effective, timely treatment for this debilitating disease. Patient-Derived Xenograft Murine Model SUBJECTS: Eight-week old NOD/SCID mice undergoing transplantation of endometrioma lesions collected from women undergoing surgery for endometriosis. Daily subcutaneous injections with vehicle (DMSO), Medroxyprogesterone acetate (MPA) or GnRH antagonist, Cetrorelix for 1 month. Lesion size 1 month post-treatment RESULTS: Lesions with high PR demonstrated a robust response to MPA compared to lesions with low PR. Average post-MPA treatment size in high PR lesions was 6-fold smaller than low PR lesions. Low PR lesions respond far more completely to GnRH antagonist than to MPA. Surprisingly, there were differences in response to GnRH antagonist between low and high PR lesions. High PR lesions responded almost completely to GnRH antagonist with a 21-fold smaller post-treatment size on average compared to low PR lesions. Use of murine avatars to test clinical response is a novel approach in endometriosis. Hormonal suppression of disease is a cornerstone of therapy, however response is not fully predictable. We have previously shown that women with low PR lesions respond poorly to progestin-based therapy. Here, we prospectively validate our prior work using a mouse xenograft model, demonstrating that lesions with low PR expression do not respond to progestin-based therapy; PR status predicted response to progestin-based therapy. Moreover, PR status identifies a more aggressive form of endometriosis that is not only progesterone resistant, however is also less dependent on estradiol for growth. Our findings highlight the need to develop novel, nonhormonal therapies aimed at targeting the more aggressive forms of endometriosis that do not rely on the usual hormonal signals.

A Novel Etanercept-loaded Nano-emulsion for Targeted Treatment of Inflammatory Arthritis via Draining Lymph Node.

Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production. The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG2000 and Ca(OH)2. A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG2000 and Ca(OH)2 were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model. Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN. NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.

Sigma-1 receptor targeting inhibits connexin 43 based intercellular communication in chronic neuropathic pain.

Neuropathic pain is a chronic condition characterized by aberrant signaling within the somatosensory system, affecting millions of people worldwide with limited treatment options. Herein, we aim at investigating the potential of asigma-1 receptor (σ1R) antagonist in managing neuropathic pain. A Chronic Constriction Injury (CCI) model was used to induce neuropathic pain. The potential of (+)-MR200 was evaluated following daily subcutaneous injections of the compound. Its mechanism of action was confirmed by administration of a well-known σ1R agonist, PRE084. (+)-MR200 demonstrated efficacy in protecting neurons from damage and alleviating pain hypersensitivity in CCI model. Our results suggest that (+)-MR200 reduced the activation of astrocytes and microglia, cells known to contribute to the neuroinflammatory process, suggesting that (+)-MR200 may not only address pain symptoms but also tackle the underlying cellular mechanism involved. Furthermore, (+)-MR200 treatment normalized levels of the gap junction(GJ)-forming protein connexin 43 (Cx43), suggesting a reduction in harmful intercellular communication that could fuel the chronicity of pain. This approach could offer a neuroprotective strategy for managing neuropathic pain, addressing both pain symptoms and cellular processes driving the condition. Understanding the dynamics of σ1R expression and function in neuropathic pain is crucial for clinical intervention.

Maternal ketone supplementation throughout gestation improves neonatal cardiac dysfunction caused by perinatal iron deficiency.

Iron deficiency (ID) is common during gestation and in early infancy and has been shown to adversely affect cardiac development and function, which could lead to lasting cardiovascular consequences. Ketone supplementation has been shown to confer cardioprotective effects in numerous disease models. Here, we tested the hypothesis that maternal ketone supplementation during gestation would mitigate cardiac dysfunction in ID neonates. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and throughout pregnancy. Throughout gestation, iron-restricted dams were given either a daily subcutaneous injection of ketone solution (containing β-hydroxybutyrate [βOHB]) or saline (vehicle). Neonatal offspring cardiac function was assessed by echocardiography at postnatal days (PD)3 and 13. Hearts and livers were collected post-mortem for assessments of mitochondrial function and gene expression profiles of markers oxidative stress and inflammation. Maternal iron restriction caused neonatal anemia and asymmetric growth restriction at all time points assessed, and maternal βOHB treatment had no effect on these outcomes. Echocardiography revealed reduced ejection fraction despite enlarged hearts (relative to body weight) in ID offspring, resulting in impaired oxygen delivery, which was attenuated by maternal βOHB supplementation. Further, maternal ketone supplementation affected biochemical markers of mitochondrial function, oxidative stress and inflammation in hearts of neonates, implicating these pathways in the protective effects conferred by βOHB. In summary, βOHB supplementation confers protection against cardiac dysfunction in ID neonates and could have implications for the treatment of anemic babies.

Efficacy and safety of visepegenatide as an add-on therapy to metformin in patients with type 2 diabetes: a randomised, double-blind, parallel, placebo-controlled, phase 3 study

Visepegenatide, a once-weekly glucagon-like peptide-1 receptor agonist injection, demonstrated effective glycaemic control and good tolerability without the requirement of dose titration in the two completed phase 2 studies. We aimed to evaluate the efficacy and safety of visepegenatide in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin monotherapy in this phase 3 clinical study. This multicentre phase 3 clinical study included a 24-week, randomised, placebo-controlled, double-blind period followed by a 28-week open-label extended treatment period. Patients (N=620) aged ≥18 and≤75 years with glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% [≥53.0 and≤91.27mmol/mol], were randomized in a 1:1 ratio to receive visepegenatide 150-μg or placebo once-weekly subcutaneous injection during the double-blind period. Subsequently, the patients in the placebo group were switched to visepegenatide treatment (placebo→visepegenatide group), and the patients in the visepegenatide group continued the same treatment during the open-label extended treatment period. The primary endpoint was the change in HbA1c from baseline to week24. At week 24, the placebo-adjusted least squares mean (LSM) change of HbA1c was-0.57% (95% CI-0.71 to-0.43) with visepegenatide (p<0.001). The proportion of patients achieving HbA1c<7.0% and ≤6.5% [<53 and≤48mmol/mol] was higher in the visepegenatide group versus the placebo group (115 [40.5%] vs 50 [17.9%]; p<0.001, and 60 [21.1%] vs 17 [6.1%]; p<0.001). Visepegenatide demonstrated a significant reduction in fasting plasma glucose and 2-h postprandial glucose compared with placebo. Trends in the improvement of these variables were maintained during the open-label extended treatment period. No severe gastrointestinal adverse event or severe hypoglycaemia was reported during the 52-week study period. Once-weekly injection of visepegenatide 150μg as an add-on treatment to metformin therapy significantly improved glycaemic control and was generally well tolerated in Chinese patients with T2DM who were inadequately controlled with metformin monotherapy. The study was funded by PegBio Co., Ltd, Suzhou, China.

Investigation into the Acceptability of Moderate-to-Large Volume Subcutaneous Injections in Healthy Volunteers: Results from a Single-Center Randomized Controlled Study.

Therapeutic proteins are often delivered by subcutaneous (SC) autoinjector to enable self-administration. Autoinjectors typically deliver up to 1 mL injected volumes per dose. Delivery of larger volumes may be limited by injection site discomfort, including pain, swelling, and redness. Delivery at a slower rate may mitigate this discomfort. This single-center, randomized, crossover study evaluated the acceptability and tolerability of varying volumes and delivery rates of SC saline in healthy volunteers. Eligible participants were adults (18-65 years) with a body mass index of 18.5-32.0 kg/m2. Participants (N = 24) were randomized to multiple sequences of infusions over five visits, with infusions ranging from 1 to 5 mL at rates of 1.50-6.00 mL/minute (min) and including a 1 mL SC infusion in 10seconds (s) at a rate of 6.00 mL/min. The primary objective was to identify acceptable volume and delivery rates of SC saline, as assessed by visual analogue scale (VAS) pain scores, a tolerability and acceptability questionnaire, and infusion leakage. Infusions that met the acceptability criteria were 1 mL in 10s, 4 mL in 58s, and 3 mL in 2mins. Higher delivery volumes and rates were associated with higher VAS pain scores but remained within the VAS acceptability criteria. These findings may support the development of larger-volume injectors for self-administration of future medicines.

Jet injection through microneedles for large volume subcutaneous delivery

Subcutaneous (SC) drug delivery offers several advantages over intravenous (IV) delivery including: self-administration, improved patient experience, and reduced treatment costs. Unfortunately, each SC delivery is currently limited to ∼ 2.25 mL with IV administration required when the delivery volume exceeds this value. In this work, we explore a new technique for large volume subcutaneous drug delivery that uses microneedles to break through the epidermis then forms the liquid drug into many small jets that penetrate past the ends of the microneedles and into the subcutaneous (or muscle) tissue. By performing multiple simultaneous injections, this delivery approach avoids the volume limitations of SC delivery, and thus may be able to greatly increase the volume we can deliver to this space. Here, we present a novel multi-jet prototype that forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ∼ 1mm. The jet speed, shape, and volume of jets formed through these microneedles are measured to assess the consistency of jet production through the microneedles. We then perform jet injections of volumes up to 3.9 mL into ex vivo porcine tissue. The results demonstrate the successful delivery (>95 %) of 3.9 mL in just 0.3 s using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). We also find that jet speeds of 70 m/s and below do not achieve complete delivery of 3.9 mL with our prototype system, and that the addition of microneedles leads to more consistent large volume delivery than equivalent needle-free injections. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus potentially allow patient self-administration in many more delivery applications.

6461 VRDN-003, a Full Antagonist Antibody to the IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic Results of Subcutaneous Administration in Healthy Volunteers

6461 VRDN-003, a Full Antagonist Antibody to the IGF-1 Receptor for Thyroid Eye Disease (TED): Safety and Pharmacokinetic Results of Subcutaneous Administration in Healthy Volunteers

Targeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia. Crucial role of ApoB100 conformational stabilization

Backgroundand aims; Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly1127-Cys1140 of LRP1, efficiently inhibits LDL aggregation and foam cell in vitro formation. Here, we investigate whether DP3 modulates atherosclerosis in a humanized ApoB100, LDL receptor (LDLR) knockout mice (Ldlr–/–hApoB100 Tg) and determine the potential LDL-related underlying mechanisms. MethodsTg mice were fed an HFD for 21 days to induce atherosclerosis and then randomized into three groups that received a daily subcutaneous administration (10 mg/kg) of i) vehicle, ii) DP3 peptide, or iii) a non-active peptide (IP321). The in vivo biodistribution of a fluorescent-labeled peptide version (TAMRA-DP3), and its colocalization with ApoB100 in the arterial intima, was analyzed by imaging system (IVIS) and confocal microscopy. Heart aortic roots were used for atherosclerosis detection and quantification. LDL functionality was analyzed by biochemical, biophysical, molecular, and cellular studies. ResultsIntimal neutral lipid accumulation in the aortic root was reduced in the DP3-treated group as compared to control groups. ApoB100 in LDLs from the DP3 group exhibited an increased percentage of α-helix secondary structures and decreased immunoreactivity to anti-ApoB100 antibodies. LDL from DP3-treated mice were protected against passive and sphingomyelinase (SMase)-induced aggregation, although they still experienced SMase-induced sphingomyelin phospholysis. In patients with familial hypercholesterolemia (FH), DP3 efficiently inhibited both SMase-induced phospholysis and aggregation. ConclusionsDP3 peptide administration inhibits atherosclerosis by preserving the α-helix secondary structures of ApoB100 in a humanized ApoB100 murine model that mimicks the hallmark of human hypercholesterolemia.

Pharmacokinetic comparison of subcutaneously administered CT-P13 (biosimilar of infliximab) via autoinjector and pre-filled syringe in healthy participants.

CT-P13, a biosimilar of infliximab, is used to treat inflammatory diseases that arise from immune system complications, resulting in excessive and persistent inflammation. The subcutaneous (SC) formulation of CT-P13 overcomes the drawback of prolonged administration associated with the intravenous (IV) infliximab biosimilar, necessitating autoinjector (AI) administration. This randomized, open-label, two-arm, parallel-group, single-dose clinical pharmacology study aimed to evaluate the pharmacokinetics (PK) and safety of CT-P13 SC administration via AI compared with the existing pre-filled syringe (PFS) method. A total of 147 healthy participants were randomized into two groups, of which 139 completed the study. Blood samples were collected from before CT-P13 SC administration to 2016 h after the start of the administration. Serum concentrations were analyzed using the Meso Scale Discovery electrochemiluminescence method. Geometric mean ratios (90% confidence interval) of the AUCinf (areas under the concentration-time curve from zero to infinity) and Cmax (The maximum serum concentration) for CT-P13 SC AI versus CT-P13 SC PFS groups, were 94.15% (85.02%-104.26%), 92.48% (84.66%-101.01%), respectively. CT-P13 SC AI and CT-P13 SC PFS achieved comparable PK because the 90% CI was within the predefined equivalence margin. At the end of the study, immunogenicity results revealed that 70 (97.22%) and 73 (98.65%) participants tested positive for anti-drug antibody (ADA) in the CT-P13 SC AI and CT-P13 SC PFS groups, respectively. They were tested positive for neutralizing antibodies. No other significant safety differences were observed between the treatment groups. In conclusion, both administrations demonstrated PK equivalence and were both safe and well-tolerated.