Search

Key Points: Question: What is the safety and tolerability of lepodisiran, which is a short interfering RNA directed at hepatic production of apolipoprotein(a), and the effect on lipoprotein(a) serum concentrations at doses from 4 mg to 608 mg through 336 days (48 weeks) of follow-up? Findings: The trial enrolled 48 participants without cardiovascular disease and with lipoprotein(a) concentrations of 75 nmol/L or greater (or ≥30 mg/dL). A single serious adverse event occurred. The maximal median change from baseline in serum lipoprotein(a) concentrations was −5% in the placebo group, −41% in the 4 mg of lepodisiran group, −59% in the 12-mg dose group, −76% in the 32-mg dose group, −90% in the 96-mg dose group, −96% in the 304-mg dose group, and −97% in the 608-mg dose group. At day 337, the median change in lipoprotein(a) was −94% in the 608-mg dose group. Meaning: Lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations in this phase 1 trial; these findings support further study of lepodisiran. Importance: Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments. Objectives: To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after single doses of the drug; lepodisiran is a short interfering RNA directed at hepatic synthesis of apolipoprotein(a), an essential component necessary for assembly of lipoprotein(a) particles. Design, Setting, and Participants: A single ascending-dose trial conducted at 5 clinical research sites in the US and Singapore that enrolled 48 adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater (or ≥30 mg/dL) between November 18, 2020, and December 7, 2021; the last follow-up visit occurred on November 9, 2022. Interventions: Participants were randomized to receive placebo or a single dose of lepodisiran (4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg) administered subcutaneously. Main Outcomes and Measures: The primary outcome was the safety and tolerability of the single ascending doses of lepodisiran. The secondary outcomes included plasma levels of lepodisiran for 168 days after dose administration and changes in fasting lipoprotein(a) serum concentrations through a maximum follow-up of 336 days (48 weeks). Results: Of the 48 participants enrolled (mean age, 46.8 [SD, 11.6] years; 35% were women), 1 serious adverse event occurred. The plasma concentrations of lepodisiran reached peak levels within 10.5 hours and were undetectable by 48 hours. The median baseline lipoprotein(a) concentration was 111 nmol/L (IQR, 78 to 134 nmol/L) in the placebo group, 78 nmol/L (IQR, 50 to 152 nmol/L) in the 4 mg of lepodisiran group, 97 nmol/L (IQR, 86 to 107 nmol/L) in the 12-mg dose group, 120 nmol/L (IQR, 110 to 188 nmol/L) in the 32-mg dose group, 167 nmol/L (IQR, 124 to 189 nmol/L) in the 96-mg dose group, 96 nmol/L (IQR, 72 to 132 nmol/L) in the 304-mg dose group, and 130 nmol/L (IQR, 87 to 151 nmol/L) in the 608-mg dose group. The maximal median change in lipoprotein(a) concentration was −5% (IQR, −16% to 11%) in the placebo group, −41% (IQR, −47% to −20%) in the 4 mg of lepodisiran group, −59% (IQR, −66% to −53%) in the 12-mg dose group, −76% (IQR, −76% to −75%) in the 32-mg dose group, −90% (IQR, −94% to −85%) in the 96-mg dose group, −96% (IQR, −98% to −95%) in the 304-mg dose group, and −97% (IQR, −98% to −96%) in the 608-mg dose group. At day 337, the median change in lipoprotein(a) concentration was −94% (IQR, −94% to −85%) in the 608 mg of lepodisiran group. Conclusions and Relevance: In this phase 1 study of 48 participants with elevated lipoprotein(a) levels, lepodisiran was well tolerated and produced dose-dependent, long-duration reductions in serum lipoprotein(a) concentrations. The findings support further study of lepodisiran. Trial Registration: ClinicalTrials.gov Identifier: NCT04914546 This randomized clinical trial compares a single dose of lepodisiran vs placebo to assess the safety, tolerability, pharmacokinetics, and effects on lipoprotein(a) concentrations in adults without cardiovascular disease and with lipoprotein(a) serum concentrations of 75 nmol/L or greater at baseline. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

Weight loss has been associated with improvement in insulin sensitivity. It is consequently a cornerstone in the management of type 2 diabetes mellitus (T2DM). However, the strictly quantitative relationship between weight loss, insulin sensitivity, and clinically relevant glucose homeostasis biomarkers as well as changes therein as T2DM progresses is not yet fully understood. Therefore, the objective of our research was to establish a body weight–directed disease trial model for glucose homeostasis. To that end, we conducted a model‐based meta‐analysis using time course data of body weight loss (following lifestyle change or surgical procedure) and corresponding improvement of insulin sensitivity expressed as the Matsuda index. Changes in body weight were best described by a sigmoidal Emax model, whereas changes in the Matsuda index were best described by a linear model with a slope of 3.49. Once developed and verified, the model‐based meta‐analysis was linked to a disease‐drug trial model for T2DM previously developed by our group to characterize and predict the impact of weight loss on clinically relevant glucose homeostasis biomarkers. The joint model was then used to conduct clinical trial simulations, which showed that weight loss can greatly improve clinically relevant glucose homeostasis biomarkers in T2DM patients. [ABSTRACT FROM AUTHOR]

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), β‐cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed‐meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic β‐cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing β‐cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β‐cell responsivity, and disposition index following a mixed‐meal tolerance test utilizing a minimal model of glucose, insulin, and C‐peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β‐cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed‐meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age–dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P =.01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity. [ABSTRACT FROM AUTHOR]

Background: The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]).Methods: Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration.Results: Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro.Conclusions: Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

Geographically fine-grained population information is critical for various urban planning and management tasks. This is especially the case for the Chinese cities that are undergoing rapid development and transformation. However, detailed population data are rarely available in comprehensive and timely means. Therefore, appropriate approaches are needed to estimate populations from available data sets in a systematic way to support the continuous demand from urban analytics and planning. Population synthesis approaches such as Iterative Proportional Fitting (IPF) were developed to combine microdata samples with marginal statistics about population characteristics at aggregated spatial levels in order to expand the microdata sample into a complete synthetic population. This paper presents the framework for and the implementation of a geospatial platform for supporting the generation and exploration of spatially detailed urban synthetic populations. The platform provides analytical and visualization tools to support the quick generation of a full urban population with critical attributes based on the latest data available. The case of the synthetic population of Chongqing is used to illustrate the population information and types of visualization that are facilitated. [ABSTRACT FROM AUTHOR]

Agonists of G-protein-coupled receptor 142 (GPR142) are reported to increase insulin secretion and lower glucose in preclinical models. We identified a novel agonist, LY3325656 (LY) that selectively activates GPR142 in humans and mice. In preclinical models, LY increased glucose-dependent insulin secretion (GDIS) and secretion of glucagon and incretin hormones GLP-1 and GIP. To elucidate mechanisms of LY in humans, we designed a multi-part, single-dose study in 24 healthy volunteers (HV) and 12 patients with type 2 diabetes (T2D) (NCT03115099). LY was well tolerated through dose escalation up to 1950 mg in HV, with a median time to peak concentration of 4 hours and half-life of 4.59 hours. A graded glucose infusion evaluated GDIS, and LY demonstrated increased insulin secretion at higher doses (750-1950 mg). A 4-period, crossover design consisting of placebo (Pb), LY (1950mg), LY+DPP-IV inhibitor, and GLP-1R agonist treatment investigated glucose-lowering and incretin pharmacology in patients with T2D. LY significantly reduced post-meal glucose levels (2-hour glucose AUC) by >10% during a mixed meal tolerance test. Increases in post-meal GLP-1 AUC concentrations with LY compared to Pb were seen in a few, but not all patients with T2D. Serum glucagon levels were consistently increased by LY in patients with T2D and HV. We conclude that GPR142 activation in humans increases GDIS and augments glucagon secretion but does not substantively augment GIP or GLP-1 secretion. Our data suggest that acute stimulatory effects of GPR142 on insulin and glucagon secretion translate from preclinical models to man, unlike preclinical effects on gut peptide secretion. Innovative and efficient single-dose studies can provide key mechanistic understanding of the translatability of preclinical findings for the treatment of T2D. Disclosure: E.J. Pratt: Employee; Self; Eli Lilly and Company. T. Oura: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ma: Employee; Self; Eli Lilly and Company. H.V. Lin: Employee; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Ma: None. A.M. Efanov: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. [ABSTRACT FROM AUTHOR]