Efficacy of Cipargamin (KAE609) in a Randomized, Phase II Dose-Escalation Study in Adults in Sub-Saharan Africa With Uncomplicated Plasmodium falciparum Malaria.

BACKGROUND: Cipargamin (KAE609) is a potent antimalarial in a phase II trial. Here we report efficacy, pharmacokinetics, and resistance marker analysis across a range of cipargamin doses. These were secondary endpoints from a study primarily conducted to assess the hepatic safety of cipargamin (hepatic safety data are reported elsewhere). METHODS: This phase II, multicenter, randomized, open-label, dose-escalation trial was conducted in sub-Saharan Africa in adults with uncomplicated Plasmodium falciparum malaria. Cipargamin monotherapy was given as single doses up to 150 mg or up to 50 mg once daily for 3 days, with artemether-lumefantrine as control. Key efficacy endpoints were parasite clearance time (PCT), and polymerase chain reaction (PCR)-corrected and uncorrected adequate clinical and parasitological response (ACPR) at 14 and 28 days. Pharmacokinetics and molecular markers of drug resistance were also assessed. RESULTS: All single or multiple cipargamin doses ≥50 mg were associated with rapid parasite clearance, with median PCT of 8 hours versus 24 hours for artemether-lumefantrine. PCR-corrected ACPR at 14 and 28 days was >75% and 65%, respectively, for each cipargamin dose. A treatment-emerging mutation in the Pfatp4 gene, G358S, was detected in 65% of treatment failures. Pharmacokinetic parameters were consistent with previous data, and approximately dose proportional. CONCLUSIONS: Cipargamin, at single doses of 50 to 150 mg, was associated with very rapid parasite clearance, PCR-corrected ACPR at 28 days of >65% in adults with uncomplicated P. falciparum malaria, and recrudescent parasites frequently harbored a treatment-emerging mutation. Cipargamin will be further developed with a suitable combination partner. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03334747).

New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk.

The very high occurrence of cardiovascular events presents a major public health issue, because treatment remains suboptimal. Lowering LDL cholesterol (LDL-C) with statins or ezetimibe in combination with a statin reduces major adverse cardiovascular events. The cardiovascular risk reduction in relation to the absolute LDL-C reduction is linear for most interventions without evidence of attenuation or increase in risk at low LDL-C levels. Opportunities for innovation in dyslipidaemia treatment should address the substantial risk of lipid-associated cardiovascular events among patients optimally treated per guidelines but who cannot achieve LDL-C goals and who could benefit from additional LDL-C-lowering therapy or experience side effects of statins. Fresh approaches are needed to identify promising drug targets early and develop them efficiently. The Cardiovascular Round Table of the European Society of Cardiology (ESC) convened a workshop to discuss new lipid-lowering strategies for cardiovascular risk reduction. Opportunities to improve treatment approaches and the efficient study of new therapies were explored. Circulating biomarkers may not be fully reliable proxy indicators of the relationship between treatment effect and clinical outcome. Mendelian randomization studies may better inform development strategies and refine treatment targets before Phase 3. Trials should match the drug to appropriate lipid and patient profile, and guidelines may move towards a precision-based approach to individual patient management. Stakeholder collaboration is needed to ensure continued innovation and better international coordination of both regulatory aspects and guidelines. It should be noted that risk may also be addressed through increased attention to other risk factors such as smoking, hypertension, overweight, and inactivity.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Integration of patient-reported outcomes in multiregional confirmatory clinical trials.

INTRODUCTION: The increasing complexities of conducting multiregional trials and an evolving regulatory environment contribute to unprecedented new challenges for use of patient-reported outcome measures (PROMs)(1) within clinical trials. This paper presents these challenges and potential solutions. METHODS: Real-world examples and situations are reviewed from an industry and patient-reported outcome (PRO)(2) expert position. CONCLUSIONS: An increase in the pursuit of new therapeutic targets, changes to the regulatory environment, and business pressures to expand clinical trials to more countries have significantly increased the complexity of confirmatory clinical studies that incorporate PROMs. Decisions to participate in collaborative efforts for endpoint development or proceed independently are made in the context of competing priorities of drug development timelines, drug differentiation strategies, the need for patient-related value messages, and the depth of a sponsor pipeline within specific disease areas. Study logistics are critically important; factors such as concept cultural relevancy, respondent literacy level, and quality of cross-cultural adaptation of PROMs must be evaluated when integrating into confirmatory clinical trials. Awareness of the issues relating to PROs in multiregional studies will enable companies to better plan studies and interpret results.

The Effect of Calcium Channel Antagonists on Spontaneous and Evoked Epileptiform Activity in the Rat Neocortex In Vitro.

Calcium influx through voltage-activated calcium channels may play a crucial role in the propagation and maintenance of seizure activity. We have examined the contribution of various types of calcium currents to epileptogenesis by studying the effects of various calcium channel blockers on epileptiform activity. N-methyl-d-aspartate receptor-mediated epileptiform activity was induced by removal of magnesium ions superfusing the cortex, or by low-frequency stimulation of the underlying white matter. CoCl2, CdCl2 and omega-conotoxin, acting at the N- and L-type calcium channels, significantly reduced epileptiform activity. L-channel antagonists nifedipine and verapamil, and the agonist BAY K 8644, increased spontaneous bursting in cortical wedges, but had no effect upon evoked activity. The T-channel blocker NiCl2 had variable effects on epileptiform activity, whereas phenytoin consistently reduced such activity. These results suggest that calcium influx underlying epileptiform activity in the rat neocortex may occur at least partially via the activation of the N-type calcium channel. However, contributions from other calcium channel types cannot be excluded.