Once-weekly Subcutaneous Administration Research Articles

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

BackgroundJNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.MethodsAdult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).ResultsOverall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.ConclusionJNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels.Trial registration number ClinicalTrials.gov (No. NCT04991740).

Clinical Pharmacokinetics of Semaglutide: A Systematic Review.

The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Once-weekly Insulin Icodec Versus Once-daily Long-acting Insulin for Type II Diabetes: A Meta-analysis of Randomized Controlled Trials.

Insulin icodec is a novel basal insulin analog with once-weekly subcutaneous administration. We aim to estimate the efficacy and safety of insulin icodec vs long-acting insulin (insulin glargine and degludec) in type II diabetic patients. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching PubMed, Web of Science, SCOPUS, and Cochrane through May 29, 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI). Our primary outcome was glycated hemoglobin (HbA1C) change. We included 7 RCTs with a total of 3183 patients. Insulin icodec was associated with significantly decreased HbA1C (MD: -0.15 with 95% CI [-0.24, -0.06], P = .002) and increased percentage of time with glucose in range (TIR) (MD: 4.06 with 95% CI [2.06, 6.06], P = .0001). However, insulin icodec was associated with increased body weight (MD: 0.57 with 95% CI [0.45, 0.70], P = .00001). Also, there was no difference regarding any serious adverse events (AEs) (RR: 0.96 with 95% CI [0.76, 1.20], P = .7) or AEs leading to withdrawal (RR: 1.54 with 95% CI [0.84, 2.82], P = .16). However, insulin icodec was associated with increased any AEs incidence (RR: 1.06 with 95% CI [1.01, 1.12], P = .02). Insulin icodec was associated with decreased HbA1C, increased TIR, with similar hypoglycemic and serious AEs. However, it was also associated with increased body weight and the incidence of any AEs.

ODP178 Development and Validation of a Noncompetitive Immunoassay Optimized for the Assessment of Pharmacokinetics of Biologically Active Efruxifermin in Humans

Abstract Efruxifermin (EFX) is a novel fusion biotherapeutic consisting of two modified human fibroblast growth factor (FGF21) variants tethered via short linkers to a hIgG1 Fc domain. EFX is under clinical development by Akero Therapeutics, Inc. for treatment of non-alcoholic steatohepatitis (NASH). Fusion to the IgG Fc moiety extends the circulating half-life of EFX, enabling once-weekly subcutaneous administration. In addition, point mutations in the FGF21 moiety of EFX, relative to native human FGF21, protect against degradation of the C-terminus by the endogenous endopeptidase fibroblast activation protein (FAP), and increase affinity for the FGF21 co-receptor b-Klotho, which together enhance in vivo PD activity of EFX. Accordingly, to support clinical PK a sensitive and specific assay is needed for determination of biologically active (i. e., C-terminal intact) EFX serum concentrations that is minimally cross-reactive with endogenous FGF21 or potential inactive metabolites of EFX. Moreover, the assay needs to have reliability with serum samples from NASH patients, in whom hyperlipidemia and insulin resistance are prevalent. To achieve the analytical aims, we undertook development of a noncompetitive immunosorbent assay design, wherein a biotinylated version of a rat mAb directed against EFX's intact C-terminus serves as the capture reagent, while an affinity purified chicken anti-EFX pAb labeled with Sulfo-TAG functions as the detection reagent. This novel ECLIA design permits measurement of an electrochemiluminescence signal for maximizing assay sensitivity. In brief, serum samples are diluted 1: 10 in buffer and added to the MSD plate coated with rat mAb. After incubation and washing, bound EFX is detected using an affinity purified chicken anti-EFX PAB labeled with SULFO-TAG. After washing and addition of read buffer, the signal responses are measured in a SQ120 reader and concentration in test samples is estimated by dose-interpolation using a weighted 5-PL curve fit with an EFX standard curve ranging from 10–2,000 ng/mL. The new assay allows measurement of serum EFX at concentrations as low at 20 ng/mL. Upon pre-study validation, the assay has met analytical performance criteria outlined in BMV regulatory guidances. We conclude the optimized ECLIA will be useful for reliable assessment of EFX PK in patients with NASH. Presentation: No date and time listed

Population pharmacokinetic of paracetamol and atorvastatin with co-administration of semaglutide.

Semaglutide is a glucagon‐like‐peptide‐1 (GLP‐1) analogue marketed for once‐weekly subcutaneous administration for type 2 diabetes mellitus. Like other long‐acting GLP‐1 analogues, semaglutide reduces gastric emptying and, potentially, alters the rate of absorption of orally co‐administered drugs. The objective of the current analysis was to evaluate the effects on the gastric emptying rate caused by semaglutide on pharmacokinetic model parameters of paracetamol and atorvastatin in healthy subjects. Non‐linear mixed effect modeling was used to estimate population pharmacokinetic model parameters of paracetamol and atorvastatin after single doses with or without semaglutide. The absorption rate (ka) of paracetamol decreased by 53% when co‐administered with semaglutide. For atorvastatin, ka and transit compartment rate (ktr) decreased by 72% and 91%, respectively. Thus, gastric emptying, measured as T50, i.e., drug disappearance from the absorption compartments, showed an additional 5‐min delay for paracetamol and a 67‐min delay for atorvastatin when co‐administered with semaglutide. Semaglutide affected pharmacokinetic model parameters of paracetamol and atorvastatin, and minor quantitative differences in gastric emptying between placebo vs. semaglutide administration were observed. However, these effects of semaglutide were considered not to be of clinical relevance.

Molecular and pharmacological characterization of insulin icodec: a new basal insulin analog designed for once-weekly dosing

IntroductionInsulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties...

Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide1 Receptor Agonists.

Obesity is a chronic disease associated with many complications. Weight loss of 5–15% can improve many obesity-related complications. Despite the benefits of weight reduction, there are many challenges in losing weight and maintaining long-term weight loss. Pharmacotherapy can help people with obesity achieve and maintain their target weight loss, thereby reducing the risk of obesity-related complications. The prevalence of obesity in the USA has been increasing over the past few decades, and despite the availability of approved anti-obesity medications (AOMs), people with obesity may not be accessing or receiving treatment at levels consistent with the disease prevalence. Reasons for low levels of initiation and long-term use of AOMs may include reluctance of public health and medical organizations to recognize obesity as a disease, lack of reimbursement, provider inexperience, and misperceptions about the efficacy and safety of available treatments. This article aims to inform primary care providers about the mechanism of action of one class of AOMs, glucagon-like peptide 1 receptor agonists (GLP-1RAs), in weight loss and longer-term maintenance of weight loss, and the efficacy and safety of this treatment class. GLP-1RA therapy was initially developed to treat type 2 diabetes. Owing to their effectiveness in reducing body weight, once-daily subcutaneous administration of liraglutide 3.0 mg has been approved, and once-weekly subcutaneous administration of semaglutide 2.4 mg is being investigated in phase III trials, for obesity management. Considerations regarding adverse effects and contraindications for different drug classes are provided to help guide treatment decision-making when considering pharmacotherapy for weight management in patients with obesity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01710-0.

Diabetes Drug AIDS Weight Reduction in Adults.

According to this study: In adults who were obese or overweight, once-weekly subcutaneous semaglutide administration in addition to lifestyle interventions resulted in sustained, clinically relevant weight loss.

Effects of Switching from Liraglutide or Dulaglutide to Subcutaneous Semaglutide on Glucose Metabolism and Treatment Satisfaction in Patients with Type 2 Diabetes: Protocol for a Multicenter, Prospective, Randomized, Open-Label, Blinded-Endpoint, Parallel-Group Comparison Study (The SWITCH-SEMA 1 Study).

IntroductionGlucagon-like peptide (GLP)-1 receptor agonists exert potent hypoglycemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent manner. Once-weekly subcutaneous administration of the GLP-1 receptor agonist semaglutide has beneficial effects on glycemic and body weight control, but it is currently unclear if semaglutide provides superior glycemic control compared to conventional GLP-1 receptor agonists in the Japanese population. We aim to compare the effects of once-weekly subcutaneous semaglutide with those of liraglutide or dulaglutide administration in Japanese patients with T2D.MethodsThis study is a multicenter, prospective, randomized, open-label, blinded-endpoint, parallel-group trial. In total, 100 participants with T2D who have been treated with liraglutide (0.9–1.8 mg/day in plan A) or dulaglutide (0.75 mg/week in plan B) for more than 12 weeks and have a glycated hemoglobin (HbA1c) level of 6.0–9.9% and a body mass index (BMI) of ≥ 22 kg/m2 will be randomized to either continue using their existing GLP-1 receptor agonist or switch to subcutaneous semaglutide once weekly for 24 weeks. Biochemical analysis, physical assessment, and a quality-of-life questionnaire (DTSQ) will be completed at baseline and at the end of the study. The primary endpoint is the effect of semaglutide on the change in HbA1c. The secondary endpoints are the mean changes in total DTSQ score, body mass, abdominal circumference, systolic and diastolic blood pressure, pulse rate, factors associated with improvement in HbA1c and secondary endpoints, side effects, and other laboratory parameters.Planned OutcomesThe results of the study will provide useful information regarding the effects of switching to semaglutide from other GLP-1 receptor agonists on glycemic control in patients with T2D.Ethics and DisseminationThe Hokkaido University Certified Review Board (CRB no. 1180001) has approved the protocol (no. 018-005). The results will be disseminated in peer-reviewed journals and at scientific conferences.Trial RegistrationUMIN000042369 in the University Hospital Medical Information Network (UMIN); jRCT1011200008 in the Japan Registry of Clinical Trials (jRCT); pre-results.

Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations.

Emicizumab is a factor (F)VIIIa-mimicking bispecific antibody recognizing FIXa and FX molecules. In the phase 1/2 clinical studies, once-weekly subcutaneous administration of emicizumab has shown a favorable safety profile with encouraging efficacy in the patients with hemophilia A (PwHA) irrespective of the presence of anti-FVIII inhibitors. Moreover, in the following phase 3 studies, emicizumab treatment by once-weekly, bi-weekly or tetra-weekly administration have been still well-tolerated, but some thromboembolic events or thrombotic microangiopathy were observed associated with the concomitant use of activated prothrombin complex concentrates (aPCC) for breakthrough bleeds. Since approved for routine prophylaxis in PwHA in the US, EU, and Japan, a compass on patient selection for emicizumab treatment and special considerations on the practical situations such as concomitant treatment by bypassing agents (BPAs) or clotting factor concentrates (CFCs) with less thrombotic risk, inhibitor eradication by immune tolerance induction (ITI) should be provided. There is no doubt that emicizumab is an alternate first-line therapy for any existing BPA as hemostatic treatment for PwHA with inhibitor, but we should be more cautious in combination with aPCC on breakthrough bleeds under emicizumab prophylaxis because of thrombotic risk. For severe PwHA without inhibitor, since most patients are under CFCs prophylaxis, switching from CFCs to emicizumab should be considered when the advantage of emicizumab prophylaxis surpasses that of CFCs prophylaxis from the viewpoint of hemostatic effect by treatment, physical activity according to the life stage, health condition of the joints, adherence and complication. There are pros and cons on the timing of introduction of emicizumab for cases scheduled to start ITI or cases of ongoing ITI. Introduction of emicizumab to previously untreated patients and nonsevere PwHA without inhibitor is also required to discuss in consideration of risk of inhibitor development and unforeseen safety issues.

Emicizumab, a bispecific antibody mimicking factor VIII: a novel alternative therapy for hemophilia A with inhibitors

Regular prophylaxis using factor (F) VIII products to prevent bleeding in patients with hemophilia A (PWHAs) results in markedly suppressed onset of arthropathy and greatly contributes to improved quality of life. However, some issues remain with the use of clotting factor replacement therapy. The need for multiple intravenous infusions is associated with substantial mental and physical burden, and the inhibitor development results in difficulty of hemostatic management. To overcome these unmet needs, a recombinant humanized anti-FIXa/FX bispecific antibody mimicking FVIIIa function (emicizumab) was created. In phase 1/2 clinical studies, Japanese patients with PWHAs were treated with once-weekly subcutaneous administration of emicizumab. The annual bleeding rates were markedly reduced, irrespective of inhibitor use. A phase 3 global study for PWHA with inhibitor demonstrated a statistically significant efficacy, whereas thrombotic microangiopathy and thromboembolism were reported in 5 patients treated with emicizumab concomitantly with multiple infusions of activated prothrombin complex concentrates. In Japan, emicizumab (HEMLIBRA®) was approved for treatment of PWHAs with inhibitor on March 2018. In conclusion, emicizumab has promising features. Its subcutaneous bioavailability and long half-life (T1/2; approximately 30 days) enable effective bleeding prophylactic treatment at inhibitor status. Additional studies are warranted to establish clinical data on its safety and to define suitable assays for hemostatic monitoring.

LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept

ObjectiveA novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). MethodsLY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176. ResultsLY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: −49.12 mg/dL [−78.14, −20.12] and −43.15 mg/dL [−73.06, −13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: −1.75 kg [−3.38, −0.12], −5.09 kg [−6.72, −3.46] and −4.61 kg [−6.21, −3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: −2.62 kg [−3.79, −1.45] and −2.07 kg [−3.25, −0.88], respectively.The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity. ConclusionsBased on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Emicizumab-mediated haemostatic function in patients with haemophilia A is down-regulated by activated protein C through inactivation of activated factor V.

Activated protein C (APC) inactivates activated factor V (FVa) and moderates FVIIIa by restricting FV cofactor function. Emicizumab is a humanized anti-FIXa/FX bispecific monoclonal antibody that mimicks FVIIIa cofactor function. In recent clinical trials in haemophilia A patients, once-weekly subcutaneous administration of emicizumab was remarkably effective in preventing bleeding events, but the mechanisms controlling the regulation of emicizumab-mediated haemostasis remain to be explored. We investigated the role of APC-mediated reactions in these circumstances. APC dose-dependently depressed thrombin generation (TG) initiated by emicizumab in FVIII-deficient plasmas, and in normal plasmas preincubated with an anti-FVIII antibody (FVIII-depleted). FVIIIa-independent FXa generation with emicizumab was not affected by the presence of APC, protein S and FV. The results suggested that APC-induced down-regulation of emicizumab-dependent TG was accomplished by direct inactivation of FVa. The addition of APC to emicizumab mixed with FVIII-depleted FV-deficient plasma in the presence of various concentrations of exogenous FV demonstrated similar attenuation of TG, irrespective of specific FV concentrations. Emicizumab-related TG in FVIII-depleted FVLeiden plasma was decreased by APC more than that observed with native FVLeiden plasma. The findings indicated that emicizumab-driven haemostasis was down regulated by APC-mediated FVa inactivation in plasma from haemophilia A patients without or with FV defects.

Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

AbstractEmicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.

Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial

Semaglutide is a novel glucagon-like peptide-1 (GLP-1) analogue, suitable for once-weekly subcutaneous administration, in development for treatment of type 2 diabetes. We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin, thiazolidinediones, or both. We did a 56-week, phase 3a, randomised, double-blind, double-dummy, active-controlled, parallel-group, multinational, multicentre trial (SUSTAIN 2) at 128 sites in 18 countries. Eligible patients were aged at least 18 years (or at least 20 years in Japan) and diagnosed with type 2 diabetes, with insufficient glycaemic control (HbA1c 7·0-10·5% [53·0-91·0 mmol/mol]) despite stable treatment with metformin, thiazolidinediones, or both. We randomly assigned participants (2:2:1:1) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily, subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily, oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly, or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly. The two oral sitagliptin 100 mg groups (with semaglutide placebo 0·5 mg and 1·0 mg) were pooled for the analyses. The primary endpoint was change in HbA1c from baseline to week 56, assessed in the modified intention-to-treat population (all randomly assigned participants who received at least one dose of study drug); change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint. Safety endpoints included adverse events and hypoglycaemic episodes. This trial is registered with ClinicalTrials.gov, number NCT01930188. Between Dec 2, 2013, and Aug 5, 2015, we randomly assigned 1231 participants; of the 1225 included in the modified intention-to-treat analysis, 409 received semaglutide 0·5 mg, 409 received semaglutide 1·0 mg, and 407 received sitagliptin 100 mg. Mean baseline HbA1c was 8·1% (SD 0·93); at week 56, HbA1c was reduced by 1·3% in the semaglutide 0·5 mg group, 1·6% in the semaglutide 1·0 mg group, and 0·5% with sitagliptin (estimated treatment difference vs sitagliptin -0·77% [95% CI -0·92 to -0·62] with semaglutide 0·5 mg and -1·06% [-1·21 to -0·91] with semaglutide 1·0 mg; p<0·0001 for non-inferiority and for superiority, for both semaglutide doses vs sitagliptin). Mean baseline bodyweight was 89·5 kg (SD 20·3); at week 56, bodyweight reduced by 4·3 kg with semaglutide 0·5 mg, 6·1 kg with semaglutide 1·0 mg, and 1·9 kg with sitagliptin (estimated treatment difference vs sitagliptin -2·35 kg [95% CI -3·06 to -1·63] with semaglutide 0·5 mg and -4·20 kg [-4·91 to -3·49] with semaglutide 1·0 mg; p<0·0001 for superiority, for both semaglutide doses vs sitagliptin). The proportion of patients who discontinued treatment because of adverse events was 33 (8%) for semaglutide 0·5 mg, 39 (10%) for semaglutide 1·0 mg, and 12 (3%) for sitagliptin. The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature: nausea was reported in 73 (18%) who received semaglutide 0·5 mg, 72 (18%) who received semaglutide 1·0 mg, and 30 (7%) who received placebo, and diarrhoea was reported in 54 (13%) who received semaglutide 0·5 mg, 53 (13%) who received semaglutide 1·0 mg, and 29 (7%) who received placebo. Seven (2%) patients in the semaglutide 0·5 mg group, two (<1%) in the semaglutide 1·0 mg group, and five (1%) in the sitagliptin group had blood-glucose confirmed hypoglycaemia. There were six fatal events (two in the semaglutide 0·5 mg group, one in the semaglutide 1·0 mg group, and three in the sitagliptin group); none were considered likely to be related to the trial drugs. Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin, thiazolidinediones, or both, and had a similar safety profile to that of other GLP-1 receptor agonists. Semaglutide seems to be an effective add-on treatment option for this patient population. Novo Nordisk A/S.

Once-weekly subcutaneous administration of bortezomib in patients with multiple myeloma.

In patients with multiple myeloma (MM), once-weekly intravenous injection or twice-weekly subcutaneous injection (SC) of bortezomib has been proven to offer non-inferior efficacy to standard twice-weekly intravenous administration, with an improved safety profile. However, whether once-weekly SC bortezomib can further reduce the incidence rate of peripheral neuropathy (PN) and not compromise the efficacy remains to be investigated. 25 patients of MM treated with once-weekly SC bortezomib were reviewed in this study. The median treatment cycles were 4 (range, 2-9 cycles). Complete response (CR) rate was 52%, ≥very good partial response (VGPR) rate was 72%, and ≥partial response (PR) rate was 84%. 1-year and 2-year PFS rate was 63.0% and 34.3%, respectively, and 2-year OS rate was 100%. Any grade of PN was reported in 9 patients (36.0%), with 7 patients (28.0%) had grade 1 PN, and 2 patients (8.0%) had grade 2 PN. No patients reported grade 3/4 PN in this cohort. In conclusion, once-weekly subcutaneous administration of bortezomib offers excellent efficacy with a further improved safety profile, especially with regard to PN. It needs to be validated in future prospective randomized trials.

Anti‐factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation

We previously reported that a humanized anti-factorIXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophiliaA. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation. To elucidate the invivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use. A non-human primate model of acquired hemophiliaA was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2days. Bleeding symptoms were monitored for 3days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed. A single bolus of 1 or 3mgkg-1 ACE910 showed hemostatic activity comparable to that of 10Ukg-1 (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis. ACE910 may offer an alternative on-demand treatment option for patients with hemophiliaA, as well as user-friendly and aggressive routine supplementation.

Comparison of extended release GLP-1 receptor agonist therapy versus sitagliptin in the management of type 2 diabetes

Exenatide once weekly (EQW), the first glucose-lowering agent for type 2 diabetes that is dosed one time per week, contains exenatide encapsulated in microspheres of a dissolvable matrix, which release active agent slowly and continuously into the circulation following subcutaneous injection. In two direct head-to-head comparisons, EQW resulted in better long-term glucose control, greater reductions in fasting plasma glucose, and more significant weight loss than sitagliptin. In other trials, glucose-lowering effects of EQW compared favorably with those of metformin, pioglitazone, and basal insulin. Patients on EQW exhibited a higher incidence of nausea than those on sitagliptin, although gastrointestinal adverse events occurred primarily during the first 6–8 weeks of therapy and declined thereafter. EQW was also associated with a lower incidence of nausea than two other glucagon-like peptide-1 receptor agonists, exenatide twice daily and liraglutide. Mild hypoglycemic episodes were uncommon with EQW, although risk of hypoglycemia increased in combination with sulfonylureas. When choosing between EQW and a dipeptidyl peptidase-4 (DPP-4) inhibitor, such as sitagliptin, clinicians and patients should consider the differences between the two medications in terms of glucose control (EQW superior to DPP-4 inhibitors), weight control (EQW superior to DPP-4 inhibitors), gastrointestinal tolerability during treatment initiation (EQW inferior to DPP-4 inhibitors), and mode of administration (once-weekly subcutaneous administration versus once-daily oral administration).

Reproduction and juvenile animal toxicology studies in the rat with a new allergy vaccine adjuvanted with monophosphoryl lipid A (MPL ®) for the treatment of grass pollen allergy

Pollinex ® Quattro Grass has been developed for the prevention or relief of allergic symptoms caused by pollen in both adults and children. Reproduction and juvenile animal toxicology studies have been performed. Subcutaneous injection on Day 14 prior to pairing and on Days 6 and 13 of gestation to pregnant rats at 2000 SU/0.5 mL elicited no signs of maternal or embryo-foetal toxicity. Mating, fertility, fecundity and pup parameters were all unaffected by treatment. Once-weekly subcutaneous administration at ascending doses of 300, 800, 2000 and 2000 SU/0.5 mL followed by a 4 week non-dose period to juvenile rats from 3 weeks of age showed no signs of obvious toxicity. As in a previously performed adult animal toxicology study with the vaccine, not unexpected, but relatively minor, immuno-stimulatory effects were seen in this study along with injection site reaction which can largely be attributed to the presence of tyrosine in the formulation.