Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616.

BACKGROUND: MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia. OBJECTIVES: This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia. METHODS: This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period. RESULTS: Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group. CONCLUSIONS: MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

[Microorganisms in the biological control of insects and phytopathogens]. / Los microorganismos en el control biológico de insectos y fitopatógenos.

In this review we cover the biological control of insects, bacteria and fungus that affect different crops. Using different microorganism as bacteria viruses and fungus can do the biological control of these important problems. In this work we describe with detail the mode of action of the different microorganisms used to control insects and plant diseases. We also present novel strategies to improve the efficiency of these microorganisms against their targets and we present the development and production of several formulations to be used in the fields for the biological control of some plant problems.