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A study was conducted to characterize pharmacologically the inhibitory profile of S-3483, a novel inhibitor of the hepatic glucose-6-phosphatase system. The findings demonstrate for the first time in vivo a pharmacologically induced suppression of hepatic G-6-P activity with subsequent changes in blood glucose levels.

Background: GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two Phase III trials that investigated the efficacy and safety of gantenerumab, a subcutaneous fully human monoclonal antibody that binds aggregated forms of amyloid‐beta, in participants with early Alzheimer's disease (AD). Although the studies did not meet their primary endpoints, participant characteristics that might influence response to gantenerumab were evaluated. Method: Eligible participants with early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) were randomized 1:1 to receive gantenerumab or placebo. Gantenerumab‐treated participants were up‐titrated to 510 mg subcutaneous gantenerumab every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Secondary endpoints of cognition (ADAS‐Cog13) and function (ADCS‐ADL, FAQ) were assessed. Pre‐specified and exploratory post‐hoc subgroup analyses on these endpoints were performed. Result: Across endpoints, there were consistent trends towards larger point estimates of gantenerumab treatment effect compared with placebo at Week 116 in males (using CDR‐SB as representative example: GRADUATE I: 16% relative reduction (RR); GRADUATE II: 17% RR) vs females (GRADUATE I: 3% RR; GRADUATE II: –2% RR) and participants with MCI (GRADUATE I:15% RR; GRADUATE II:10% RR) vs mild AD (GRADUATE I: 4% RR; GRADUATE II: 2% RR). This pattern was not consistently seen when using CDR‐Global Score (0.5 vs >0.5) to define disease stage. Compliers, defined as participants who received ≥90% of the intended cumulative dose, had an increased point estimate of treatment effect (CDR‐SB: GRADUATE I: 17% RR; GRADUATE II: 18% RR) vs non‐compliers (CDR‐SB: GRADUATE I: –1% RR; GRADUATE II: –3% RR). In a pooled analysis, a larger point estimate of treatment effect vs placebo was observed in East‐Asian vs Non‐East‐Asian countries (CDR‐SB: RR 38% vs 5%). The East‐Asian population had lower baseline weight, greater treatment compliance, and accordingly higher plasma exposure, than the Non‐East‐Asian population, suggesting this observation is not driven by racial differences in treatment response. Conclusion: Subgroup analyses in the GRADUATE studies provide insights into participant characteristics that may influence the degree of clinical response to gantenerumab treatment. Higher gantenerumab exposure may result in greater clinical efficacy. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab is a subcutaneous fully human monoclonal antibody targeting aggregated forms of amyloid‐beta. Phase III GRADUATE I (NCT03444870) and II (NCT03443973) trials were designed based on previous key learnings to provide evidence on the benefit:risk profile of subcutaneous gantenerumab in early symptomatic AD. Although primary endpoints were not met, gantenerumab showed treatment effects on amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) and plasma biomarkers. Correlations of biomarkers with clinical outcomes in the GRADUATE studies were assessed to further evaluate their utility. Method: Participants aged 50‐90 years with mild cognitive impairment due to AD or mild AD dementia were randomised 1:1 to subcutaneous gantenerumab or placebo. Gantenerumab was up‐titrated over 36 weeks to target dose of 510 mg every 2 weeks. Changes in amyloid centiloid levels were obtained from [18F]Florbetaben or [18F]Flutemetamol PET. Regional changes in tau standardised uptake value ratio were obtained with [18F]GTP1 PET. Whole brain and regional atrophy were assessed via volumetric MRI. Fluid pharmacodynamics biomarkers were measured using Elecsys® immunoassays from Roche Diagnostics. Result: Significant (but not corrected for multiple testing) treatment effects of gantenerumab on change from baseline to Week 116 were observed for CSF biomarkers (pooled GRADUATE I and II population) including Aβ40 (–10.42%, p = 0.0188), Aβ42 (26.06%, p<0.0001), tTau (–16.49%, p<0.0001), pTau181 (–23.35%; p < 0.0001), NfL (10.76%; p = 0.0159), GFAP (–5.49%; p = 0.0003), and plasma biomarkers including Aβ42 (GRADUATE I: 65.1%, p<0.0001; GRADUATE II: 54.9%, p<0.0001) and pTau181 (GRADUATE I: –17.2%, p<0.0001; GRADUATE II: –15.3%, p<0.0001). Preliminary biomarker analyses showed changes in amyloid PET in gantenerumab‐treated participants had a numerically higher correlation with changes in plasma Aβ42 (R = –0.43), versus pTau181 (R = 0.34) and GFAP (R = 0.16). Biomarker changes in subgroups will also be presented. Conclusion: Phase III GRADUATE I and II study results provide evidence of the effect of subcutaneous gantenerumab on biomarkers of AD pathology and neurodegeneration in subgroups. [ABSTRACT FROM AUTHOR]

Background: Gantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia). Method: Eligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed. Result: GRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL). Conclusion: The GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined. [ABSTRACT FROM AUTHOR]

1. Tofogliflozin is a novel and selective SGLT2 inhibitor increasing glucosuria by inhibition of glucose re-absorption in the kidney for the treatment of type 2 diabetes mellitus. 2. In this study, the metabolism and the mass balance of tofogliflozin was evaluated following administration of a single oral dose of 20 mg [14C]-tofogliflozin to six healthy subjects. 3. Tofogliflozin underwent mainly oxidative metabolism in the ethylphenyl moiety, but also minor glucuronide conjugates of metabolites and the parent drug were formed. 4. In plasma, the parent drug and its major phenyl acetic acid metabolite M1 accounted for 42% and 52% of the total drug-related material, respectively. The hydroxyl metabolites and their successor ketone metabolite showed an exposure well below 5%, along with an acyl glucuronide of M1. 5. Tofogliflozin was completely absorbed with subsequent predominate metabolic clearance and a small contribution of direct urinary elimination. Approximately, 76% of the dose was excreted in urine and 20% in faeces within 72 h. The high absorption of tofogliflozin was exemplified by the small trace of parent drug in faeces. The phenyl acetic acid metabolite M1 was the major component excreted in urine and faeces accounting for more than half of the dose. Tofogliflozin demonstrated a high metabolic turnover. [ABSTRACT FROM AUTHOR]

Background: Human mass balance studies and the assessment of absolute oral bioavailability ( F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. Objectives: The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CL) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Methods: Six healthy male subjects received 20 mg [C/C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [C]tofogliflozin in plasma and urine and [C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. Results: The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state ( V) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma ( f) (eGFR × f 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CL contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CL by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. Conclusions: These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion. [ABSTRACT FROM AUTHOR]

Chlorogenic acid derivatives are potent inhibitors of hepatic glucose production by inhibition of the glucose-6-phosphate translocase component of the hepatic glucose-6-phosphatase system. The pharmacological proof of concept was clearly demonstrated during i.v. infusion of potent derivatives (S 4048, S 3483) in rats. However, the blood glucose lowering effect of S 4048 after bolus i.v. injection lasted only 60–90 min. Plasma clearance of S 4048 was very high, and the parent compound was rapidly and efficiently excreted into the bile of Wistar and GY/TR− rats, indicating that mrp-2 was not involved in this hepatobiliary elimination process. About 72% of the total administered radioactivity appeared in the bile within 20 min after i.v. bolus injection of the radiolabeled analogue [3H]S 1743 in a Wistar rat. However, in GY/TR− rats the dicarboxylic analogue of S 4048, S 3025, was cleared from the plasma less rapidly than its parent compound and its biliary elimination was comparatively low. In contrast, S 3025 exhibited comparable pharmacokinetics and biliary elimination profile as S 4048 in Wistar rats, suggesting that biliary elimination of S 3025 is facilitated by mrp-2, functionally absent in GY/TR− rats. Targeting to mrp-2 resulted in a significantly prolonged reduction of blood glucose levels in GY/TR− rats after i.v. bolus administration of S 3025. [Copyright &y& Elsevier]

Abstract: A series of novel 3,4-dihydro-2H-benzo[1,4]oxazine derivatives has been designed and synthesized as 5-HT6 receptor antagonists. Many of the compounds displayed subnanomolar affinities for the 5-HT6 receptor and good brain penetration in rats. The relationship of structure and lipophilicity to hERG inhibition of this series of compounds is discussed. [Copyright &y& Elsevier]