Jorg Taubel

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

BACKGROUND Inclisiran (ALN‐PCSsc) is a long‐acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low‐density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single‐ascending‐dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple‐dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side‐effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ‐glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single‐dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least‐squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least‐squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple‐dose regimens reduced the levels of PCSK9 (up to a least‐squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least‐squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic-pharmacodynamic (PK-PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo -7.48 ms, 90% CI -10.49, -4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK-PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50-200 mg b.d.) were not associated with QT prolongation in healthy subjects.

Shortening of the QT interval after food can be used to demonstrate assay sensitivity in thorough QT studies.

The effect of food was investigated under conditions of a thorough QT (TQT) study and with confirmation of assay sensitivity by the use of a positive control (400 mg of moxifloxacin). Fifty‐five healthy subjects were randomized to treatment and a sequence of fasted and fed baseline electrocardiography days. Subjects received standard breakfast 30 to 10 minutes prior to dosing. Measurement of QT interval was performed automatically with subsequent manual onscreen overreading using electronic calipers. A profound increase in heart rate of 9.4 bpm was observed in the fed condition compared with the fasted condition at 1.5 hours after dose with a corresponding shortening of QT (27 milliseconds); (baseline data). When corrected, QTcF interval was shortened significantly with the maximal effect observed at 2 hours after dose of 8.2 (95% confidence interval, 6–10) milliseconds. A concurrent shortening of the PR interval with a maximum value of 5.6 milliseconds was also observed. The findings of this study demonstrate that food alters the QT‐RR relationship and shortens QTc and PR for at least 4 hours after a carbohydrate‐rich meal. The findings are of regulatory interest as this study shows that normal physiological causes can shorten QTc significantly and that it could be used as a method to demonstrate assay sensitivity.

Bupivacaine Extended Release Liposome Injection Does Not Prolong QTc Interval in a Thorough QT/QTc Study in Healthy Volunteers

1441 2012 52 1441-1447 F surgery, effective postsurgical pain management is essential because most patients experience pain that often persists for several days or even weeks. For a wide range of surgical procedures, local anesthetics administered via an epidural injection, peripheral nerve blocks, or local infiltrations are commonly used to provide postoperative analgesia. However, the duration of analgesic action of local anaesthetics is typically less than 12 hours. Bupivacaine is among the most widely used long-acting local anesthetics with its moderate onset and long duration of action demonstrated in preclinical and clinical studies. However, longer acting local anesthetics are known to induce systemic toxicity, mostly in relation to the central nervous system (excitation) and cardiovascular system (depression). The cardiotoxicity of bupivacaine and its effects on the QTc interval have been demonstrated in preclinical studies. Besides its known sodium channel– blocking properties, it has been shown to block calcium and potassium channels. The effects of bupivacaine on human cloned cardiac delayed rectifier potassium channels have been described by Gristwood. Blocking potassium channels can lengthen cardiac action potential, leading to serious arrhythmias. One study in dogs showed that administration of 4 mg/kg bupivacaine significantly prolonged the QTc interval by more than 25%. Cardiovascular effects of bupivacaine were also demonstrated in clinical studies. In one such study, patients were administered 40 mL of bupivacaine 5 mg/mL for scheduled shoulder arthroscopy. A significant prolongation of the PQ interval was seen 125 minutes postapplication of bupivacaine, which remained significantly prolonged until 6 hours postdose. Double-blind crossover studies in healthy human volunteers have demonstrated that a maximum dose of 48 mg bupivacaine (maximum plasma concentration of 2.25 mg/L) significantly increased the QTc interval by 26.9 ms. Another study showed that in subjects receiving more than 75 mg bupivacaine, the maximum increase in the QTc interval was 24 ms (P = .022). EXPAREL, a new formulation of bupivacaine, given as a single injection after surgery, could provide adequate, continuous, and extended pain relief,

Thorough QT study of the effect of oral moxifloxacin on QTc interval in the fed and fasted state in healthy Japanese and Caucasian subjects

AIMS The aims of this study were three-fold and were to (i) investigate the effect of food (fasted and fed state) on the degree of QT prolongation caused by moxifloxacin under the rigorous conditions of a TQT study, (ii) differentiate the effects on QTc that arise from changes in PK from those arising as a result of electrophysiological changes attributable to raised levels of C-peptide [11] offsetting in part the IKr blocking properties of moxifloxacin and (iii) characterize the QTc F profile of oral moxifloxacin (400 mg) in healthy Japanese volunteers compared with Caucasian subjects. METHODS The study population consisted of 32 healthy non-smoking, Caucasian (n = 13) and Japanese (n = 19), male and female subjects, aged between 20-45 years with a body mass index of between 18 to 25 kg m(-2). Female volunteers were required to use an effective contraceptive method or be abstinent. Subjects with ECGs which were deemed unsuitable for evaluation in a TQT study were excluded. ECGs were recorded in triplicate with subsequent blinded manual adjudication of the automated interval measurements. Electrocardiograms in the placebo arm were recorded twice in fasted and fed condition. RESULTS The results demonstrated a substantial change in the typical moxifloxacin effect on the ECG. The effect on ΔΔQTc in the fed state led to a significant delay and a modest reduction compared with the fasted state correcting both conditions with the corresponding placebo data. The largest QTc F change from baseline in the fed state was observed at 4 h with a peak value of 11.6 ms (two-sided 90% CI 9.1, 14.1). In comparison, the largest QTc F change observed in the fasted state was 14.4 ms (90% CI 11.9, 16.8) and occurred at 2.5 h post-dose. The PK of moxifloxacin were altered by food and this change was consistent with the observed QTc F change. In the fed state plasma concentrations of moxifloxacin were considerably and consistently lower in comparison with the fasted state, and this applied to both ethnicities. The concentration-effect analysis revealed that there was no change in slope and confirmed that the difference in this analysis was caused by a change in the PK profile of moxifloxacin. Comparisons of the moxifloxacin effect in the fed state compared with fasted placebo also revealed a pharmacodynamic effect whereby a meal appears to antagonize the effects of moxifloxacin on the lengths of the QTc interval. CONCLUSIONS Our findings demonstrate that the food effect by itself leads to a shortening of the QTc interval offsetting in part the effects of a 400 mg single dose of oral moxifloxacin. The typical moxifloxacin PK profile is also altered by food prior to dosing reducing the Cmax and delays the peak effects on QTc up to several hours thereby reducing the overall magnitude of the effect and delaying the peak QTc prolongation. The contribution of the two effects was clearly discernible. Given that moxifloxacin is sometimes given with food in TQT studies, consideration should be given to adequate baseline corrections and appropriate sampling time points. In this study the PK-PD relationship was similar for Japanese and Caucasian subjects in the fed and fasted conditions, thereby providing further evidence that the sensitivity to the QTc prolonging effects of fluoroquinolones was likely to be independent of ethnicity. The small differences observed between the two subpopulations were not statistically significant. However, future studies should give consideration to formal ethnic comparisons as a secondary outcome parameter as very little is known about the relationship between ethnicity and drug effects on cardiac repolarization.

Insulin at normal physiological levels does not prolong QTc interval in thorough QT studies performed in healthy volunteers

Food is known to shorten the QTc (QTcI and QTcF) interval and has been proposed as a non‐pharmacological method of confirming assay sensitivity in thorough QT (TQT) studies and early phase studies in medicines research. Intake of food leads to a rise in insulin levels together with the release of C‐peptide in equimolar amounts. However, it has been reported that euglycaemic hyperinsulinemia can prolong the QTc interval, whilst C‐peptide has been reported to shorten the QTc interval. Currently there is limited information on the effects of insulin and C‐peptide on the electrocardiogram (ECG). This study was performed to assess the effect of insulin, glucose and C‐peptide on the QTc interval under the rigorous conditions of a TQT study.

Concentration–effect modeling based on change from baseline to assess the prolonging effect of drugs on QTc together with an estimate of the circadian time course

As ICH E14 was adopted by the US FDA and the EU CPMC in 2005, thorough QT studies have routinely been analyzed by looking at the time‐matched difference between (baseline corrected) QTcF or QTcI under the supra‐therapeutic dose and placebo. A study is considered negative, if the two‐sided 90% confidence interval for this difference is below 10 ms for all investigated time points. ICH E14 suggests including a positive control, such as moxifloxacin, for assay sensitivity. Concentration–response analysis has been considered a more powerful alternative, but its application to parallel group studies was hampered as a double difference of QTcF per subject cannot be calculated. Recently, a new model based on change from baseline with fixed time and concentration effects has been proposed. It allows for a placebo‐corrected prediction of the drug effect with an unbiased standard error, and the estimate of a time effect can be used for assay sensitivity. We demonstrate this approach, utilizing 2 studies reported elsewhere with a crossover design. We compare the results from a conventional concentration–response analysis based on the difference to placebo with results from the novel analysis based on the change from average baseline that includes a fixed time effect.

The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study

Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around t max are missed.

Comparison of Six Commonly Used QT Correction Models and Their Parameter Estimation Methods

This paper compares six commonly used QT correction models and three available parameter estimation methods using five indices for QTc evaluation based on real and simulated electrocardiograph (ECG) datasets. The results show that the golden section approach always finds the correction factor making QTc interval uncorrelated to heart rate for all six formulas. However, the correction formulas derived from mixed model sometimes fail to make QTc interval invariant of heart rate. The performance of an individual least-square regression method lies between the golden section iteration approach and the mixed model in terms of QTc–RR relationship.

Pharmacokinetics and Pharmacodynamics of Lomitapide in Japanese Subjects

AIMS Lomitapide is a licensed treatment for patients with homozygous familial hypercholesterolaemia in the USA, the EU, Canada, and Mexico. This study was conducted to compare the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability of lomitapide between Japanese and Caucasian subjects with elevated low-density lipoprotein cholesterol (LDL-C) after single and multiple doses. METHODS In this randomized, double-blind, placebo-controlled study, 36 Japanese and 36 Caucasian subjects with LDL-C levels ≥110 mg/dL were administered an escalating lomitapide dose range of 10-60 mg or placebo. Subjects were assessed for safety, tolerability, and lipid levels. RESULTS Exposure to lomitapide as measured by Cmax was linear and increased over the dose range of 10-60 mg for both single- and multiple-dose administration. The correlation between AUC0-t and Ctrough demonstrated the lack of differences in the PK of lomitapide among ethnic groups. Lomitapide dose-dependent reductions in lipid parameters were observed and showed no ethnic differences. The safety assessments showed that the main treatment-related side effects identified were increases in hepatic enzymes and that the majority of treatment-related treatment-emergent AEs were gastrointestinal disorders. CONCLUSIONS Lomitapide was effective in reducing LDL-C levels in a dose-dependent manner. Similar PK, efficacy, and safety profiles were observed in Japanese and Caucasian subjects, which suggest no differences in lomitapide activity or metabolism between the two populations compared in this study.