BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity.This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS:Patients with obesity (BMI, 35-50 kg/m 2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon.RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes. K E Y W O R D S clinical trial, continuous glucose monitoring (CGM), incretins, obesity therapy, phase I-II study, weight control

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium‐glucose co‐transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo‐controlled, double‐blind, 2‐week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066:TRPCB [FT]: 0.88; 90% CI: 0.70‐1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066:TRPCB [A4]: 0.81; 90% CI: 0.68‐0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066:TRPCB [DHEAS]: 0.76; 90% CI: 0.65‐0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066:TRPCB [MAXI]: 0·26; 90% CI:0.20‐0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066:TRPCB [AUCI]: 0.32; 90% CI: 0.25‐0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1β (IL-1β) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1β signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle–brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier:

Immune-stimulator antibody conjugates (ISACs) combining tumor-targeting monoclonal antibodies with immunostimulatory agents allow targeted delivery of immune activators into tumors. NJH395 is a novel, first-in-class ISAC comprising a toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 via a non-cleavable linker-payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase 1, multicenter, open-label study in patients with HER2+ non-breast advanced malignancies (NCT03696771). Data from patients enrolled in single-ascending dose-escalation demonstrated delivery of the TLR7-agonist payload in HER2+ tumor cells and induction of type I IFN responses, which correlated with immune modulation in the tumor microenvironment. Cytokine release syndrome was a common, but manageable, drug-related adverse event. Anti-drug antibodies and neuroinflammation at high doses represented significant clinical challenges. Data provide proof-of-mechanism and critical insights for novel immunotherapies.

BackgroundNJH395 is a first-in-class immune stimulator antibody conjugate (ISAC) consisting of a toll-like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody. Antibody-mediated delivery of TLR7 may limit systemic toxicities previously seen with TLR agonists, while enhancing long-lasting antitumor immune response. In preclinical studies, NJH395 showed promising activity in HER2 expressing xenograft mouse models, and demonstrated immunogenicity and cytokine release in mice and nonhuman primates.MethodsThis phase 1, first-in-human, open-label, multicenter study (NCT03696771) is evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of NJH395 in patients with nonbreast HER2+ advanced malignancies. The study design includes two parts: single-ascending dose (SAD), followed by multiple-ascending dose. Primary endpoint is safety; key secondary endpoints include assessment of pharmacokinetics, immunogenicity, and overall response rate. Tumor response was evaluated 3 weeks after treatment in SAD. Evaluation of pharmacodynamic markers including tumor-infiltrating lymphocytes is the key exploratory objective.ResultsHere, we report the results of the SAD part of this phase 1 study. As of July 01, 2020, 18 patients (10 males, 8 females; median age, 52.5 years [range, 42–74 years]) were enrolled in 5 dose cohorts (0.1–1.6 mg/kg). The tumor types included HER2+ colorectal cancer (N=11), gastroesophageal adenocarcinoma (N=2), non–small cell lung cancer (N=1), nasopharynx adenocarcinoma (N=1), pancreatic adenocarcinoma (N=1), bladder cancer (N=1), and small intestine adenocarcinoma (N=1). Seventeen patients reported 124 treatment-related adverse events. The most common (occurring in ≥ 20%) adverse events (AEs) of any grade (G), regardless of study drug relationship were cytokine release syndrome (55.6%, G ≤ 2), pyrexia (44.4%), nausea (44.4%), vomiting (33.3%), headache (33.3%), increased aspartate aminotransferase (AST, 33.3%), increased alanine aminotransferase (ALT, 27.8%), and lymphopenia/lymphocyte count decrease (27.8%). The most common ≥ G3 AEs (occurring in ≥ 10%) were lymphopenia/lymphocyte count decrease (27.8%) and increased AST (11.1%). Five dose-limiting toxicities, all G3, were reported in 3 patients: 2 cases of AST increase (1 at 0.2 mg/kg; 1 at 1.6 mg/kg), 1 ALT increase (1.6 mg/kg), 1 aseptic meningitis (1.6 mg/kg), and 1 meningism (1.6 mg/kg). No complete/partial response was seen; 9 patients had stable disease by RECIST v1.1 at 3 weeks post treatment. An increase in CD8-positive T-cells was detected in on-treatment tumor biopsies in 5 patients. Pharmacokinetics showed a greater than dose proportional exposure of NJH395; anti-drug antibodies were detected in all tested patients (14/14).ConclusionsSingle dosing of NJH395 showed significant but manageable toxicities in patients with nonbreast HER2+ advanced malignancies. Biomarker analysis is ongoing.AcknowledgementsThe authors thank all patients who participated in the study. The authors acknowledge Kavita Garg, PhD of Novartis Healthcare Pvt Ltd for providing medical editorial assistance with this abstract.Trial RegistrationClinicalTrials. gov Identifier: NCT03696771Ethics ApprovalThe study was performed in accordance with ethical principles of the declaration of Helsinki and good clinical practice guidelines. The protocol and its amendments were approved by institutional review boards of each participating site.ConsentWritten informed consent was obtained from each patient prior to enrolment in the study.