Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey.

BACKGROUND: As their long-term prognosis improves, women with CF are increasingly choosing to have children, but the safety of CFTR modulators in pregnancy and breastfeeding is currently unknown. METHODS: A survey was sent to lead clinicians of adult CF centres in Europe, the United Kingdom (UK), United States of America (USA), Australia and Israel requesting anonymised data on pregnancy outcomes in women using CFTR modulators before and during pregnancy and lactation. RESULTS: We identified 64 pregnancies in 61 women taking IVA (n = 31), LUM/IVA (n = 26) or TEZ/IVA (n = 7), resulting in 60 live births. In 44 pregnancies, CFTR modulators were either continued throughout pregnancy or temporarily stopped and then restarted. Two maternal complications were deemed related to CFTR modulator therapy; cessation of modulator therapy resulted in clinical decline in 9 women prompting resumption of therapy during pregnancy. No modulator-related complications were reported in infants exposed in utero and/or during breastfeeding. CONCLUSIONS: CFTR modulators were reported to be generally well tolerated in pregnancy and breastfeeding, with only 2 maternal complications that were deemed related to CFTR modulator therapy. Women stopping CFTR modulators in pregnancy may experience a decline in clinical status and in the cases identified in this survey, restarting therapy led to a clinical improvement. Current experience remains limited and longer-term prospective follow-up is required to exclude delayed adverse effects.

Medication Options and Clinical Strategies for Treating Tardive Dyskinesia.

Valbenazine and deutetrabenazine are FDA-approved as treatment for tardive dyskinesia (TD). Both medications are vesicular monoamine transporter type 2 (VMAT2) inhibitors, and both are effective for reducing TD symptoms. Clinicians need to be aware of the adverse effects of valbenazine and deutetrabenazine, as well as other key differences between the two, in order to individualize treatment. Using the Abnormal Involuntary Movement Scale assists clinicians in assessing progress for each patient. Treating TD effectively with these new medications will reduce the burden of the condition for patients.

A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators.

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000-2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

A weight of evidence assessment approach for adverse outcome pathways.

The adverse outcome pathway (AOP) is a framework to mechanistically link molecular initiating events to adverse biological outcomes. From a regulatory perspective, it is of crucial importance to determine the confidence for the AOP in question as well as the quality of data available in supporting this evaluation. A weight of evidence approach has been proposed for this task, but many of the existing frameworks for weight of evidence evaluation are qualitative and there is not clear guidance regarding how weight of evidence should be calculated for an AOP. In this paper we advocate the use of a subject matter expertise driven approach for weight of evidence evaluation based on criteria and metrics related to data quality and the strength of causal linkages between key events. As a demonstration, we notionally determine weight of evidence scores for two AOPs: Non-competitive ionotropic GABA receptor antagonism leading to epileptic seizures, and Antagonist-binding and stabilization of a co-repressor to the peroxisome proliferator-activated receptor α (PPARα) signaling complex ultimately causing starvation-like weight loss.