Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

In a Plenary Paper, Young et al describe impressive favorable outcomes of emicizumab prophylaxis in children with hemophilia A and factor VIII inhibitors, reporting a 99% reduction in annualized bleeding, with 77% of patients having no treated bleeding events.

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In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC(last) was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin.

Prophylaxis with emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in persons with hemophilia A (PwHA). The primary efficacy, safety and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHA with/without factor VIII inhibitors who were enrolled in the Phase III HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies have been pooled to establish a long-term efficacy, safety and pharmacokinetic profile. Across a median (interquartile range) efficacy period of 120.4 (89.0-164.4) weeks (data cut-off May 15, 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval, 1.1-1.7). ABRs declined and then maintained at <1 in an analysis of 24-week treatment intervals; at Weeks 121-144 (n=170) the mean treated ABR was 0.7 (0-5.0). During Weeks 121-144, 82.4% of participants had zero treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported zero treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participants discontinued due to adverse events beyond the five previously described. This data-cut includes the previously reported 3 thrombotic microangiopathies (1 in the PwHA with fatal rectal hemorrhage), and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use; and additionally, a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHA of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified. Clinical trials registered as NCT02622321, NCT02795767, NCT02847637, NCT03020160.

Unimolecular dual incretins derived from hybridized glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) sequences have demonstrated synergistic reduction of adiposity in animal models and reductions of hyperglycemia in short-duration human trials. Here, we extend the characterization of NNC0090-2746 (also known as RG7697), a fatty-acylated dual agonist possessing in vitro balanced GIPR and GLP-1R agonism. In this 12-week, randomized, placebo-controlled, double-blind phase 2a trial, patients with type 2 diabetes inadequately controlled with metformin received 1.8 mg of NNC0090-2746 or placebo subcutaneously once daily. Liraglutide 1.8 mg (Victoza), starting with 2-week dose escalation, was administered subcutaneously once daily as an open-label reference arm. Measurements were collected at regular intervals after randomization. NNC0090-2746 significantly improved glycemic control and reduced body weight compared with placebo. Total cholesterol, alone among a range of lipid parameters, and leptin were both significantly reduced compared with placebo. Treatment with NNC0090-2746 was generally safe and well tolerated.

In this study, we investigated rational and reliable methods of using animal data to predict in humans the clearance of drugs which are mainly eliminated through hepatic metabolism. For 10 extensively metabolized compounds, adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro dramatically improved the predictions of human clearance compared to the approach in which clearance is directly extrapolated using body weight. Using hepatocyte data to normalize the in vivo clearances led to lower median deviations between the observed and predicted clearances in man compared to the approach normalizing data with brain weight (30-40% vs 60-80%, respectively). In addition, the approach integrating in vitro data appeared to be superior with respect to the range of deviations: approximately 2-fold underestimation, in the worst case, was observed by using in vitro data, whereas normalizing data by brain weight led to up to 10-fold underestimation of clearance in man. In addition, the integration of in vitro data provides a more rational basis to predict the metabolic clearance in man and may be applicable to compounds undergoing phase I and phase II metabolism as well.