1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT) 3A receptor antagonist (K i ϭ 3.7 nM), h5-HT 7 receptor antagonist (K i ϭ 19 nM), h5-HT 1B receptor partial agonist (K i ϭ 33 nM), h5-HT 1A receptor agonist (K i ϭ 15 nM), and a human 5-HT transporter (SERT) inhibitor (K i ϭ 1.6 nM) (J Med Chem 54: 3206 -3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT 1B receptor agonist [EC 50 ϭ 460 nM, intrinsic activity ϭ 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT 7 receptor antagonist (K i ϭ 200 nM and IC 50 ϭ 2080 nM). In vivo, Lu AA21004 occupies the r5-HT 1B receptor and rSERT (ED 50 ϭ 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT 3 receptor antagonist in the Bezold-Jarisch reflex assay (ED 50 ϭ 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT 3 receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant-and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant-and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

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Drug development guidelines from regulatory authorities provide important information to sponsors on requirements for clinical evidence needed to support approval of new drugs. In the field of Alzheimer’s disease (AD), recently published guidelines are available from EU, US, and Japanese regulatory authorities. In this review, these three guidelines are compared and discussed with emphasis on the recommendations provided for demonstration of efficacy in pivotal clinical trials conducted in predementia stages of AD. Similarities and differences are highlighted, and impact for global drug development is discussed in the context of the new International Conference on Harmonization E17 guideline on multiregional clinical trials. The AD field is characterized by significant challenges as, to date, no drug approval precedence exists in predementia AD despite numerous and ambitious efforts to slow the progression of the disease by pharmacologic intervention. Despite these uncertainties regulatory authorities across regions have blazed a trail for proactive multistakeholder collaboration, involvement, and continuous dialogue, setting a positive example on how to foster a supportive environment for development of new and meaningful treatments for patients with AD globally.

Objective:The objective of this study was to ascertain to what extent adults with migraine value an early onset of efficacy for preventive migraine treatments.Background: In placebo-controlled clinical trials, treatment with eptinezumab resulted in a lower proportion of adults with migraine on the first day following infusion (day 1; 14% point-reduction for chronic migraine [CM] in PROMISE-2 and 8% pointreduction for episodic migraine [EM] in PROMISE-1).Methods: Adults with migraine completed an online preference-elicitation thresholding exercise to ascertain to what extent they value not having a migraine on day 1 postdosing relative to a clinically relevant reduction in number of migraine days during the first month postdosing (≥2 migraine-free days for CM and ≥1 migraine-free days for EM).Results: One hundred and one participants (mean age, 50.6 ± 12.4 years; 81 [80%] women) were included. In participants with CM, 29 of 50 (58%) considered the eptinezumabgenerated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in number of migraine days the first month postdosing, whereas 37 of 50 (74%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing. In participants with EM, 18 of 35 (51%) considered the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing, whereas 24 of 35 (69%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing. Conclusion:Most participants considered the reduction in the likelihood of migraine offered by eptinezumab on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing.

Background The FDA Patient-Focused Drug Development Initiative was launched to ensure the incorporation of the patient voice into drug development and evaluation. Since 2017, the FDA must publish a statement outlining patient experience data (PED) considered in the approval of new drugs. This study investigated the presence and role of PED in drug approval and translation into product label claims. Methods PED reported in approval packages of the 48 drugs approved by FDA’s Center for Drug Evaluation and Research in 2019 was identified and categorized. PED in the form of clinical outcome assessments (COAs) was characterized by endpoint positioning and outcome. The product labels were analyzed for PED-related claims. Results PED was reported as relevant for 39 of 48 (81.3%) drugs approved in 2019. COAs were the predominant PED type; other PED was identified for only 9 (18.8%) drugs, and none included qualitative or patient preference studies. COAs were the only type of PED for which associated claims were identified in the product labels. 27 out of 48 (56.3%) labels contained one or more efficacy claims based on COAs; of these, patient-reported outcomes were the most prevalent with claims identified in 19 labels (39.6%). Conclusion There are ample opportunities for incorporating PED beyond COAs to inform drug development and facilitate availability of medicines tailored to patient needs. A higher level of transparency on the role of PED in regulatory decision-making and a clear path to PED-based label claims could incentivize sponsors and enable patient empowerment in treatment decisions.