Ulrike Lorch

Richmond Pharmacology, London

Acute hyperglycemia causes various cardiovascular responses; however, the underlying pathophysiology in vivo is myriad and complex, of which mutual interactions remain poorly understood. We analyzed the cardiovascular effects of acute hyperglycemia in comparison with those of hyperosmolality alone. Three g/kg of D-glucose (n = 4) or D-mannitol (n =...

Introduction Tumor immunotherapy is designed to control malignancies through the host immune response but requires circumventing tumor-dysregulated immunomodulation through immunostimulation, relieving immunorepression, or a combination of both approaches. Here we designed and characterized cavrotolimod (formerly AST-008), an immunostimulatory sphe...

Background Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. Purpose The aim of the current clinical Phase...

Cardiac microRNA-132-3p (miR-132) levels are elevated in people suffering with heart failure (HF) and mechanistically drive remodelling processes in the heart. Here we present CDR132L, a specific antisense oligonucleotide. It is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of this clinical P...

We aim to study kinetics of anti-SARS-CoV-2 IgG antibody levels in subjects with COVID-19 for up to 11 months and the potential influential factors. The study was a prospective longitudinal study. The analyses were based on 77 serum/plasma samples with a mean of 4 samples per participant (range 1-18) in 20 participants with at least one positive Po...

Atovaquone‐proguanil (ATV‐PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine‐pyrimethamine plus AQ for seasonal malaria chemoprevention (SMC) in African children. This randomized, double‐blind, placebo‐controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PK) of ATV‐PG plus A...

p>Background: Interleukin-12 is an active cytokine for cancer treatment, however the full potential has yet to be realized despite extensive exploration of dose, schedule, and route and method of administration. These approaches have been limited by systemic exposure, resulting in serious adverse events (SAEs) and/or unpredictable pharmacology. exo...

Aim: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac s...

Background and objectives In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomi...

Vaccination forms a key part of public health strategies to control the spread of SARS-CoV-2 globally. In the UK, two vaccines (BNT162b2-mRNA produced by Pfizer, and ChAdOx-1-S produced by Oxford-AstraZeneca) have been licensed to date, and their administration is prioritised according to individual risk. This study forms part of a longitudinal ass...

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch ser...

Research Question To study the effects of oxytocin receptor antagonist (OTR antagonist) nolasiban on uterine contractions, endometrial perfusion and endometrial mRNA expression. Design Increased uterine contractions during embryo transfer (ET) are negatively correlated with pregnancy rates, and endometrial blood flow was shown to be an important p...

To estimate the effectiveness of vaccines in development, a robust mechanism is required to understand immunity, risks of reinfection and measure the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and how this may change over time. This study is a longitudinal analysis of COVID-19 infection rates using PCR, membran...

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on impending change, innovation, and future challenges facing early phase drug development as we move into the second decade of the 21th century. The meeting opened with discussion around the technical revolution in pharmaceutical medicine over the...

Aims Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was t...

Two open‐label, single‐dose, randomized crossover studies were conducted in healthy Japanesemen to (1) assess dose proportionality of 5 doses (1.38, 2.75, 5.5, 8.25, and 11.0 mg) of Lafenta, a novel matrix‐type transdermal fentanyl patch with a rate‐controlling membrane; and (2) compare patch bioequivalence (11.0 mg) with a commercially available r...

Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials...

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single ascending dose study was...

Aims: This first-in-human clinical trial of P218, a novel dihydrofolate reductase inhibitor antimalarial candidate, assessed safety, tolerability, pharmacokinetics and food effect in healthy subjects. Methods: The study consisted of two parts. Part A was a double-blind, randomised, placebo-controlled, parallel group, ascending dose study compris...

Background: Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design a...

Background Exicure develops spherical nucleic acid (SNA) constructs, which are 3-dimensional arrangements of oligonucleotides where the nucleic acids are densely packed and radially oriented around a nanoparticle. SNAs have properties that are distinct from the “linear” nucleic acids (i.e., nucleic acids not arranged in the SNA format), which inclu...

Background Exicure develops spherical nucleic acid (SNA) constructs, which are 3-dimensional arrangements of oligonucleotides where the nucleic acids are densely packed and radially oriented around a nanoparticle. SNAs have properties that are distinct from the “linear” nucleic acids (i.e., nucleic acids not arranged in the SNA format), which inclu...

Purpose Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency’s first-in-human and early clinical trial guideline. The increasing complexity and size...

Aims: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development. Methods: Part A: open-label, randomized, 3-period crossover assessing coadministration of single dose...

Background:: Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design...

Background and Objectives Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API–API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib). Tramadol and celecoxib pharmacokinetics are modified after CTC administration versus administr...

Background: The peptide nangibotide is the first clinical-stage agent targeting the immunoreceptor TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) and is being investigated as a novel therapy for acute inflammatory disorders such as septic shock. Aims: This first-in-man, randomised, double-blind, ascending dose, placebo-controlled Phas...

Figure S1 Study disposition. Figure S2 Plots of plasma naloxone concentrations during 20 minutes for individual subjects. Table S1 Adverse events.

Aims: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F2α receptor (FP) has significant advantages for a tocolytic. The pro-drug OBE022 and its metabolite OBE002 are novel FP antagonists under development for treating preterm labour. Methods: We performed a prospective, first in human,...

Background: Preterm birth remains the major cause of perinatal mortality and morbidity. OBE022 is a novel, orally-active prostaglandin F2alpha; receptor antagonist under development for treatment of preterm labour. In clinical practice, tocolytics are co-administered with betamethasone for lung maturation and MgSO4 for neuroprotection. Tocolytic dr...

Background: Risk management is an essential element of integrated, adaptive early phase protocols. Toxicities are major factors determining whether a study continues or is suspended, thus any rules regarding toxicities will significantly define study structure and progression. The revision to the European Medicines Agency's first-in-human and early...

Background: Current practice favors integrated protocols in early phase clinical trials. Adaptively combining clinical trial protocols has been shown to have advantages in increasing participant safety, the effectiveness of data gathered in the study as well as increasing the speed of completion. The data presented here shows how an early phase pro...

Background: Evaluation of drug effects on the QTc interval, in accordance with ICH (E14), can now be integrated into early phase clinical trials. The concentration-QTc assessment in early stages of clinical development commonly evaluates higher investigational drug concentrations than later stages because the aim is to define dose-limiting toxicity...

BACKGROUND: The circulating white blood cell count is a common inclusion criterion for clinical studies. Generally the thresholds for these values are not defined by the time of day that samples are obtained nor do they vary by the ethnic group from which the subjects are recruited. We have characterised the variance in circulating white cell level...

Introduction: Preterm birth remains a significant risk for later disability. The inhibition of the prostaglandin F2alpha (PGF2alpha; or FP) receptor has significant advantages for a tocolytic. The pro-drug OBE022 and its parent metabolite OBE002 are novel FP receptor antagonists. OBE022 is orally active and is under development for treating preterm...

Background: Drug-induced hypertension is a serious toxic effect of several medication classes such as sympathetomimetics, corticosteroids and vasoconstrictors, therefore assessment of a concentration-effect relationship for investigational medical products is valuable where vascular effects are possible. Method: The diurnal variation of blood press...

Background and aims: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and...

Session title: Master Protocols: New approaches to enrolling hard-to-find subjects and expediting drug development

PurposeEmerging data on selumetinib, a MEK1/2 inhibitor in clinical development, suggest a possible difference in pharmacokinetics (PK) between Japanese and Western patients. This pooled analysis sought to assess the effect of ethnicity on selumetinib exposure in healthy Western and Asian subjects, and to identify any association between genetic va...

Introduction: Rupatadine is a marketed second generation antihistamine, with anti-PAF activity, indicated for symptomatic treatment of allergic rhinitis and urticaria. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of rupatadine in healthy Japanese subjects after single and multiple o...

Aim: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). Methods: This was a randomised, double-blind, placebo and positive-controlled, four-way crossover...

In December 2015, the International Conference of Harmonization (ICH) E14 guideline generated guidance on how exposure-response modelling can be used to characterise the potential for a drug to affect cardiac repolarisation and to modulate the QTc interval. The released Q&A document describes how data from Phase I ascending dose SAD and MAD studies...

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 cholestero...

Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics Vol. 46 Suppl. 2015

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 pow...

E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time...

BACKGROUND: The ICH E14 guidance suggests that concentration-effect (CE) modelling can complement the primary analysis. Recently, the understanding of this technique has improved and novel methods have been proposed. Based on 3 Phase I studies; we compare CE to conventional per time point analysis to prove its validity for QT prolongation detectio...

The presentation summarises the aims of the EU Clinical Trials Regulation and its new transparency requirements affecting Phase 1 studies. It describes the regulatory requirements in relation to public accessibility of�Phase 1 clinical trials’ registration information and summary reports in the US and those of the International Committee of Medical...

In this randomized, double-blind, placebo controlled study, the safety of therapeutic (675 mg) and supra-therapeutic (2,700 mg) doses of nitazoxanide was evaluated in accordance with the ICH E14 guidelines. Fifty six (56) subjects participated in four treatment periods and received single doses of nitazoxanide 675 mg, nitazoxanide 2,700 mg, moxiflo...

This article attempts to define terminology and to describe a process for writing adaptive, early phase study protocols which are transparent, self-intuitive and uniform. It provides a step by step guide, giving templates from projects which received regulatory authorisation and were successfully performed in the UK. During adaptive studies evolvin...

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 a...

Aims: Food is known to shorten the QT(c) (QT(c)I and QT(c)F) 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...

The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values...

The interest in adaptive study design is evident from the growing amount of clinical research employing this model in the mid to later stages of medicines development. Little has been published on the practical application and merits of adaptive study design in early phase clinical research. This paper describes a retrospective analysis performed o...

To characterize the effects of levofloxacin on QT interval in healthy subjects and the most appropriate oral positive control treatments for International Conference on Harmonization (ICH) E14 QT/QTc studies. Healthy subjects received a single dose of levofloxacin (1000 or 1500 mg), moxifloxacin (400 mg) or placebo in a four-period crossover design...

The pharmacokinetics and pharmacodynamics of rivastigmine were compared in Japanese and white healthy participants who were given ascending single doses of the novel rivastigmine transdermal patch. Rivastigmine patch strengths were 4.6 mg/24 h (5 cm2, 9 mg rivastigmine loaded dose), 9.5 mg/24 h (10 cm2, 18 mg), and 13.3 mg/24 h (15 cm2, 27 mg) (per...

To characterize the effects of lamotrigine on QT interval in healthy subjects. 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 moxifloxac...