P.027 Efficacy and Safety of Eptinezumab Initiated During a Migraine Attack: Results from the RELIEF Study

Background: Eptinezumab is approved for migraine prevention, with demonstrated rapid onset of preventive benefit. RELIEF evaluated the efficacy and safety of eptinezumab initiated during a migraine attack. Methods: RELIEF (NCT04152083; parallel-group, double-blind, placebo-controlled) randomized adults with migraine (4-15d/mo in 3mo prior to screening) to eptinezumab 100mg or placebo, administered IV within 1-6h of qualifying migraine onset. Co-primary efficacy endpoints were time to headache pain freedom and time to absence of most bothersome symptom (MBS). Results: Eptinezumab (n=238) compared with placebo (n=242) achieved significantly faster headache pain freedom (median 4h vs 9h; hazard ratio=1.54, P=0.0006) and absence of MBS (2h vs 3h; 1.75, P<0.0001). At 2h, 23.5% and 12.0% (P=0.0009) of eptinezumab-treated and placebo patients, respectively, reported headache pain freedom, and 55.5% and 35.8% (P<0.0001) reported absence of MBS. Significantly fewer eptinezumab-treated patients used rescue medication within 24h (31.5% vs 59.9%; P<0.0001). Treatment-emergent adverse events occurred in 10.9% eptinezumab-treated and 10.3% placebo patients; no serious adverse events occurred. Conclusions: Infusion of the preventive migraine treatment, eptinezumab, during a migraine resulted in rapid and sustained freedom from headache pain and MBS vs placebo, starting 2h post-infusion, decreasing need for acute medication within 24h post-infusion. No notable safety findings were identified.

Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study

Background A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Methods Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. Results In triptan insufficient responders, lasmiditan was superior to placebo ( p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. Conclusions Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174)

A novel patient-reported outcome instrument assessing the symptoms of paroxysmal nocturnal hemoglobinuria, the PNH-SQ

Background Patient-reported outcome measures (PROs) used to measure symptoms of patients with paroxysmal nocturnal hemoglobinuria (PNH) in trials do not measure PNH symptoms comprehensively and do not assess daily fluctuations in symptoms. Following a literature review and consultation with a PNH expert, we drafted the PNH Symptom Questionnaire (PNH-SQ) and a patient-centric conceptual model of PNH symptoms and impacts. We then interviewed 15 patients with PNH to assess comprehensiveness of symptom capture from the patient perspective and to cognitively debrief the PNH-SQ. Patient interview data were also used to finalize the PNH conceptual model. Results Participants mentioned 27 signs or symptoms of PNH spontaneously or after being probed; 93% reported experiencing ≥ 1 PNH symptom. Concept saturation was reached for all PNH symptoms. Further, interviews confirmed the instrument captured the most common PNH symptoms, including fatigue (87%), abdominal pain (60%), and difficulty swallowing (47%), with fatigue ranked as the most bothersome symptom. The interviews demonstrated that participants understood the items of the PNH-SQ (90–100%); considered the symptoms relevant (> 50– > 90%); the recall period appropriate (> 80–100%); and the response options suitable (> 80–100%). Participants also suggested changes regarding item redundancy and relevance; this feedback was used to finalize the instrument. Conclusions The finalized PNH-SQ assesses the presence and severity of 10 symptoms—abdominal pain, chest discomfort, difficulty sleeping, difficulty swallowing, difficulty thinking clearly, fatigue, headache, muscle weakness, pain in the legs or back, and shortness of breath—over 24 h. The PNH-SQ is a content-valid questionnaire suitable for assessing daily symptom presence and severity in PNH clinical trials.

Progress in the Treatment of Migraine Attacks: From Traditional Approaches to Eptinezumab

Migraine is the second cause of disability and of lost years of healthy life worldwide. Migraine is characterized by recurrent headache attacks and accompanying disabling symptoms lasting 4–48 h. In episodic migraine, attacks occur in less than 15 days per month and in chronic migraine, in more than 15 monthly days. Whilst successful translation of pharmacological discoveries into efficacious therapeutics has been achieved in the preventative therapy of chronic migraine, treatment of acute migraine suffers the lack of effective advancements. An effective treatment affords complete freedom from pain two hours after therapy and provides the absence of the most bothersome symptom (MBS) associated with migraine after 2 h. However, available anti-migraine abortive treatments for acute attacks do not represent an effective and safe treatment for all the populations treated. In particular, the most used specific treatment is represented by triptans that offer 2-h sustained freedom from pain achieved in 18–50% of patients but they are contraindicated in coronary artery disease, stroke and peripheral vascular disease due to the vasoconstriction at the basis of their pharmacologic action. The most novel therapies, i.e., gepants and ditans, are without sufficient post-marketing data for secure use. Here, an attempt is proposed to analyse the rational basis and evidence in favour of investigating the efficacy and safety in acute migraine attacks of eptinezumab, i.e., monoclonal antibody (mAb) directed towards calcitonin gene-related peptide (CGRP) unique for intravenous infusion administration.

Fatigue in Systemic Lupus Erythematosus: An Update on Its Impact, Determinants and Therapeutic Management

Fatigue is a complex and multifactorial phenomenon which is often neglected by clinicians. The aim of this review was to analyze the impact, determinants and management of fatigue in patients with Systemic Lupus Erythematosus (SLE). Fatigue is one of the most prevalent symptoms in SLE, reported by 67% to 90% of patients. It is also described as the most bothersome symptom, considering that it may impair key aspects of health-related quality of life, while also leading to employment disability. It is a multifactorial phenomenon involving psychological factors, pain, lifestyle factors such as reduced physical activity, whereas the contribution of disease activity remains controversial. The management of fatigue in patients with SLE should rely upon a person-centered approach, with targeted interventions. Some pharmacological treatments used to control disease activity have demonstrated beneficial effects upon fatigue and non-pharmacological therapies such as psychological interventions, pain reduction and lifestyle changes, and each of these should be incorporated into fatigue management in SLE.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

Background While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. Methods Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. Results Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time. Conclusions This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. Trial Registration SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Pelvic organ prolapse surgery and overactive bladder symptoms—a population-based cohort (FINPOP)

Introduction and hypothesis It is unclear how compartment of pelvic organ prolapse (POP) impacts overactive bladder (OAB) symptom severity or improvement after POP surgery. We hypothesized that anterior and apical prolapse are more strongly associated with OAB symptoms than posterior compartment prolapse. Methods A total of 2933 POP surgeries from a prospective population-based cohort were divided into two groups: (1) anterior and/or apical compartment surgery (± posterior repair), N = 2091; (2) posterior repair only, N = 478. Urinary frequency and urgency urinary incontinence (UUI) were evaluated using PFDI-20 (bothersome symptom: score 3–4) at baseline, 6, and 24 months. Association between degree of POP in specific compartments and symptoms at baseline was estimated with generalized linear models and between compartment of surgery and symptom improvement with generalized estimating equations. Results At least one bothersome symptom was reported by 40% at baseline, 14% at 6, and 19% at 24 months. At baseline, urinary frequency was associated with degree of anterior and apical and UUI with anterior compartment prolapse. Women undergoing surgery for anterior/apical compartment started with worse symptoms and experienced greater improvement than women undergoing posterior compartment surgery. Bothersome frequency resolved in 82% after anterior/apical and in 63% after posterior compartment surgery. Bothersome UUI resolved in 75% after anterior/apical and in 61% after posterior compartment surgery. After surgery, symptom severity was comparable between groups. Bothersome de novo symptoms occurred in 1–3%. Conclusions OAB symptoms are more strongly related to anterior and apical than to posterior compartment prolapse, but improvement is seen after surgery for any vaginal compartment.

A neuroanatomical mechanism linking perinatal TCDD exposure to lower urinary tract dysfunction in adulthood

Benign Prostatic Hyperplasia / Lower Urinary Tract Dysfunction (BPH/LUTD) is a classic disease of aging which affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging existing paradigms about when this disease process begins. We delivered a single bolus dose of a widespread environmental contaminant, present in the serum of most Americans (2,3,7,8 tetrachlorodibenzo-p-dioxin, TCDD, 1 µg/kg), and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation does not resolve, but rather persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency, a bothersome symptom in men. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.

Ubrogepant: An Oral Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist for Abortive Migraine Treatment

Objective To review the pharmacology, efficacy, and safety of ubrogepant as an abortive migraine treatment. Data Sources A literature search of MEDLINE and PubMed was performed (January 2006 through May 2021) using the following search terms: ubrogepant, calcitonin gene related peptide, and abortive migraine therapy. Study Selection and Data Extraction Relevant studies evaluating ubrogepant’s pharmacology, efficacy, and safety in humans for the treatment of migraine were considered Data Synthesis Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for the acute treatment of migraine via data from ACHIEVE I and II. From ACHIEVE I, ubrogepant demonstrated superiority to placebo in freedom from migraine pain at 2 hours postdose (50-mg dose: odds ratio [OR] = 1.83, 95% CI = 1.25-2.66; 100-mg dose: OR = 2.04, 95% CI = 1.41-2.95) and freedom from most bothersome symptom (MBS; 50-mg dose: OR = 1.70, 95% CI = 1.27-2.28; 100-mg dose: OR = 1.63, 95% CI = 1.22-2.17). ACHIEVE II trial demonstrated efficacy of ubrogepant 50 mg compared with placebo (2-hour pain freedom: OR = 1.62, 95% CI = 1.14-2.29; 2-hour MBS freedom: OR = 1.65, 95% CI = 1.25-2.20). Relevance to Patient Care and Clinical Practice Ubrogepant is a viable option for patients who are unable to tolerate nonsteroidal anti-inflammatory drug or triptan therapy because of ineffective relief or contraindications that limit use. Conclusions Ubrogepant is a well-tolerated effective abortive migraine treatment that bridges a gap in therapy for many patients who previously could not tolerate other first-line treatments.