Search

Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine.Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine.This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose.Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity.Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine.

Neuregulin-1β (NRG-1β) is a growth and differentiation factor with pleiotropic systemic effects. Because NRG-1β has therapeutic potential for heart failure and known growth effects in skeletal muscle, we hypothesized that it might affect heart failure-associated cachexia, a severe co-morbidity characterized by a loss of muscle mass. We therefore assessed NRG-1β’s effect on skeletal muscle gene expression in a swine model of heart failure using recombinant Glial Growth Factor 2 (USAN - cimaglermin alfa), a version of NRG-1β currently being tested in humans with systolic heart failure. Animals received one of two intravenous doses (0.67 or 2 mg/kg) of NRG-1β bi-weekly for 4 weeks, beginning one week after infarct. Skeletal muscle was collected at the time of euthanasia from the intercostal space and paired-end RNA sequencing performed. NRG-1β treatment altered expression of 583 transcripts including 242 transcripts altered at both doses. These included genes required for myofiber growth, maintenance and survival such as MYH3, MYHC, MYL6B, KY and HES1 . Importantly, NRG-1β altered the directionality of at least 85 genes associated with cachexia, including myostatin, which negatively regulates myoblast differentiation by down-regulating MyoD expression. Consistent with this, MyoD was increased in NRG-1β treated animals. In vitro experiments with myoblast cell lines confirmed that NRG-1β induces skeletal muscle differentiation with an absolute requirement for ERBB signaling on myoblast differentiation. These findings suggest a NRG-1β-mediated anti-atrophic, anti-cachexia effect that may provide additional benefits to this potential therapy in heart failure.

Date Presented 4/20/2018 This study analyzed the knowledge, skills, and dispositions considered necessary by occupational therapy practitioners who own a private practice. A total of 162 U.S. private practitioners responded. Study results have implications for occupational therapy curricula, fieldwork placement, and continuing education. Primary Author and Speaker: Brenda Coppard Additional Authors and Speakers: Maureen Turner, Samantha Preuss, Sarah Fisher, Samuel Troia, Abigail Murphy Contributing Authors: Christine Apodaca; Yongyue Qi

Background Neuregulin‐1β ( NRG ‐1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 ( GGF 2) isoform of NRG ‐1β improves cardiac function in rodents after myocardial infarction ( MI ), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF 2 on ventricular remodeling, cardiac function, and global transcription in post‐ MI swine, as well as potential mechanisms for anti‐remodeling effects. Methods and Results MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post‐ MI , survivors (n=13) received GGF 2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post‐ MI , fractional shortening was higher (32.8% versus 25.3%, P =0.019), and left ventricular ( LV ) end‐diastolic dimension lower (4.5 versus 5.3 cm, P =0.003) in GGF 2‐treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF 2‐treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG ‐1β reduces myoFbs, and suppresses TGF β‐induced phospho‐ SMAD 3 as well as α SMA expression. Conclusions These results suggest that GGF 2/ NRG ‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart.

Neuregulin-1 (NRG-1) mediates cell-cell interactions and is a critical growth and developmental signaling molecule in the heart. We have been examining whether the recombinant NRG-1 isoform known as glial growth factor 2 (GGF2) has therapeutic potential for heart failure. In rats and swine with experimental myocardial infarction we have found that GGF2 treatment improves myocardial function and limits progressive myocardial remodeling. To understand potential mechanisms for this effect, we compared gene expression in these animals using microarrays. In rats we compared Sham operated, MI treated with vehicle, and MI treated with GGF2 at a single dose. We found that GGF2 treatment was associated with correction of mitochondrial and metabolic genes altered by MI compared to Sham-operated rats. When compared to 9 published datasets of ∼400 samples from rodents and human heart failure, we identified 563 genes associated with heart failure that were also reversed in expression in response to GGF2. Ingenuity pathway analysis demonstrated clusters of genes associated with energy production and cardiovascular tissue development as particularly enriched in GGF2-treated versus untreated MI rats. In swine our analysis was confined to animals with MI +/- GGF2 treatment at two doses. There were 527 genes altered by GGF2 at both doses compared to untreated controls, with a clear GGF2 dose response. Transcripts altered in response to GGF2 treatment were mainly those associated with extracellular matrix structure and function, MAPK signaling, and p53-mediated apoptosis. Electron microscopy of remote infarct left ventricular tissue from swine confirmed extreme morphological differences in mitochondria from GGF2-treated and vehicle-treated control pigs. Most striking was recovery of intercalated discs in response to GGF2, compared to severe disruption of intercalated disc structures in vehicle-treated control animals.