Open-label Safety Study Research Articles

Long-term safety of zavegepant nasal spray for the acute treatment of migraine: A phase 2/3 open-label study.

Zavegepant is the first small molecule calcitonin gene-related peptide receptor antagonist for intranasal administration for the acute treatment of migraine. The objective of this study was to evaluate the safety and tolerability of zavegepant in the acute treatment of migraine under repeated, as-needed dosing for up to one year. This phase 2/3, one-year open-label safety study of zavegepant 10 mg nasal spray for the acute treatment of migraine enrolled adults aged ≥18 years with a history of two to eight moderate to severe monthly migraine attacks. Participants used one dose of zavegepant as needed to self-treat migraine attacks of any severity, up to eight times per month, for 52 weeks. Participants were enrolled between 29 June and 4 December 2020. Of the 608 participants entering long-term treatment, 603 were treated with study drug. Participants administered a mean (SD) of 3.1 (1.55) zavegepant doses per month. There were no deaths. Of the seven serious adverse events reported, none was considered related to treatment. Altogether, 6.8% (41/603) of treated participants had an adverse event leading to study drug discontinuation. The most frequent adverse event leading to discontinuation was dysgeusia (1.5% [9/603]). The most common treatment-emergent adverse events (≥5% of participants) were dysgeusia (39.1% [236/603]); nasal discomfort (10.3% [62/603]); COVID-19 (7.5% [45/603]); nausea (6.1% [37/603]); nasal congestion and throat irritation (5.5% [33/603] each); and back pain (5.3% [32/603]). Aminotransferases >3x the upper limit of normal occurred in 2.6% [16/603] of participants; none had concurrent elevations in bilirubin >2x upper limit of normal. One year of zavegepant 10 mg nasal spray up to eight times per month was safe and well tolerated.Trial registration: Clinicaltrials.gov: NCT04408794.

Immunogenicity and Safety of Extended-Interval 2-Dose Regimens of 9vHPV Vaccine.

Nine-valent human papillomavirus (9vHPV) vaccines can be administered in 2 doses 6 to 12 months apart in adolescents. The impact of extended dose intervals is unknown. We report immunogenicity and safety data in adolescents of a second 9vHPV vaccine dose administered ≥1 year after the first. This open-label safety and immunogenicity study (NCT04708041) assessed extended-interval 2-dose regimens of 9vHPV vaccine among adolescents (10 to 15 years) who received 2 9vHPV vaccine doses: the first ≥1 year before enrollment, and second, at enrollment (day 1). We measured serologic responses to vaccine-targeted human papillomavirus (HPV) types at enrollment day 1 (pre-dose 2) and 1 month post-dose 2 (month 1) using a competitive LuminexV® immunoassay. We estimated effects of dose interval on geometric mean titers (GMTs) using regression modeling. Participants reported adverse events (AEs) through 15 days after vaccination. We enrolled 146 adolescents (mean age 13.3 years) with median 25 months since first 9vHPV vaccine dose (range: 12-53 months). Across vaccine-targeted HPV types, GMTs increased from day 1 to month 1; seropositivity at month 1 was 100%. Anti-HPV GMTs at month 1 were not affected by differences in dose interval of 12 to 53 months, based on regression modeling. The most common AEs were mild-to-moderate injection site reactions; no serious AEs were reported. Extending the interval between first and second 9vHPV vaccine doses to 12 to 53 months did not affect antibody responses, with favorable safety profile. These results support feasibility of extended interval regimens for 9vHPV vaccine.

Results of the Phase 1 Open-Label Safety Study of Umbilical Cord Lining Mesenchymal Stromal/Stem Cells (Corlicyte®) to Heal Chronic Diabetic Foot Ulcers.

Mesenchymal stromal/stem cells (MSCs) play a critical role in wound healing. Corlicyte® is an MSC product derived from allogeneic umbilical cord tissue donated under an institutional review board-approved protocol and processed in accordance with section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. This open-label phase 1 trial was performed under a United States Food and Drug Administration Investigational New Drug Application to establish the safety and tolerability of Corlicyte® in patients with diabetes and chronic diabetic foot ulcer (DFU). Escalating doses were applied topically twice a week for up to 8 weeks after ulcer debridement, wound photography, and measurement. Subjects were followed for 4 weeks after the treatment phase. Adverse events were assessed at every visit. Nine subjects in 2 dosing cohorts completed the trial. No subjects experienced a serious adverse reaction to Corlicyte® or the development of anti-human leukocyte antigen (HLA) antibodies. Sixty percentage of subjects in the lower dose cohort experienced ulcer closure by Day 70 of follow-up, while the mean ulcer size was reduced by 54-67% in the other subjects. Topical administration of Corlicyte®, a novel biologic therapy consisting of allogeneic umbilical cord lining MSCs, appeared safe and tolerable and resulted in a significant decrease in ulcer area, demonstrating its potential as a therapy for healing of chronic DFU.

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone. The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals. Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5-9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates. The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure. Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.

Serdexmethylphenidate/dexmethylphenidate effects on sleep in children with attention-deficit/hyperactivity disorder.

Sleep-related problems are common in children with attention-deficit/hyperactivity disorder (ADHD). Sleep disorders are also side effects of all stimulant ADHD medications. Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is a once-daily treatment approved for patients age 6 years and older with ADHD. In this analysis, sleep behavior was assessed during SDX/d-MPH treatment in children with ADHD. In a 12-month, dose-optimized, open-label safety study in 6- to 12-year-old participants (NCT03460652), a secondary endpoint was assessment of sleep behavior based on the Children's Sleep Habits Questionnaire (CSHQ) consisting of 8 sleep domains (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing, and daytime sleepiness). This post hoc analysis examined the individual sleep domains in the 12-month safety study. Of 282 participants enrolled, 238 were included in the sleep analysis. At baseline, mean (SD) CSHQ total sleep disturbance score was 53.4 (5.9). After 1 month of treatment, the mean (SD) CSHQ total score significantly decreased to 50.5 (5.4); least-squares mean change from baseline was -2.9 (95% CI: -3.5 to -2.4; p < 0.0001) and remained decreased up to 12 months. Mean sleep-score improvements from baseline to 12 months were statistically significant (p < 0.0001) for 5 of 8 sleep domains, including bedtime resistance, sleep anxiety, night wakings, parasomnias, and daytime sleepiness. Parasomnias and daytime sleepiness sleep domains showed the greatest mean improvement from baseline to 12 months. Sleep onset delay and sleep duration scores increased from baseline to 12 months. No statistically significant worsening occurred from baseline in sleep duration and sleep-disordered breathing domains; however, worsening of sleep onset delay was statistically significant. In this analysis of children taking SDX/d-MPH for ADHD, sleep problems did not worsen based on the mean CSHQ total sleep disturbance score. Statistically significant improvements in most CSHQ sleep domains were observed after 1 month and lasted for up to 12 months of treatment.

Analysis of Growth Velocity in Children with Attention-Deficit/Hyperactivity Disorder Treated for up to 12 Months with Serdexmethylphenidate/Dexmethylphenidate.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this post hoc analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. Methods: This was a post hoc analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height Z-score analyses were conducted. Z-score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Results: Subjects (N = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height Z-scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) Z-score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. Conclusion: The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Predictors of Achievement of Response With Cenobamate: Post-hoc Subset Analysis From a Phase 3, Open-Label Safety Study (S44.006)

Interim Analysis of Subject Impression Data for STS101 From the Phase 3 Open-Label ASCEND Study (P13-12.003)

Interim Analysis of Subject Impression Data for STS101 From the Phase 3 Open-Label ASCEND Study (P13-12.003)

Safety and Efficacy of Cenobamate for the Treatment of Focal Seizures in Older Patients (P4-1.002)

<h3>Objective:</h3> Safety (treatment-emergent adverse events [TEAEs] and efficacy with cenobamate were analyzed post-hoc for older adults aged 65–70 in a phase 3, open-label safety study. <h3>Background:</h3> Cenobamate is an antiseizure medication (ASM) approved in the US and EU for the treatment of uncontrolled focal seizures. <h3>Design/Methods:</h3> Adults 18–70 years old with uncontrolled focal seizures taking stable doses of 1–3 ASMs were enrolled. Concomitant ASM drug load changes from baseline to 1 year were measured (drug load defined as ratio of actual drug dose per day to the defined daily dose by the World Health Organization). <h3>Results:</h3> Of 1340 patients (mean age 39.7 years) who received ≥1 dose of cenobamate, 42 were aged 65–70 years (mean age 67.0 years). Median duration of exposure was 36.1 and 36.9 months for overall patients and older patients. 80%, 72%, and 68% of patients overall, and 76%, 71%, and 69% of older patients remaining on cenobamate at 1, 2, and 3 years, respectively. Discontinuation rates due to TEAEs were 13.6% (183/1340) in patients overall and 26.2% (11/42) in older patients. TEAEs reported in ≥20% of older patients were dizziness, somnolence, fall, fatigue, balance disorder, and upper respiratory tract infection. Efficacy (100% seizure reduction) was assessed in 240 patients with adequate seizure data available (n=18, ≥65 years). Rates of 100% seizure reduction within a 3-month interval during the maintenance phase increased over time for the overall population and older adults, reaching 52% and 77%, respectively by 24 months. Mean percent change in concomitant ASM drug load, not including cenobamate, was reduced in the overall population (29.44%) and older patients (31.18%). <h3>Conclusions:</h3> Results from this post-hoc analysis showed notable rates of efficacy in older patients when treated with adjunctive cenobamate. Further reductions in concomitant ASMs may be needed in older patients when starting cenobamate. See also abstract by Aboumatar et al. <b>Disclosure:</b> Dr. O’Dwyer has nothing to disclose. Mr. Stern has received personal compensation for serving as an employee of SK Life Science. Mr. Wade has nothing to disclose. Dr. Guggilam has received personal compensation for serving as an employee of SK Life Science, Inc. The institution of Dr. Rosenfeld has received personal compensation in the range of $500,000-$999,999 for serving as a Consultant for SK Life Science. Dr. Rosenfeld has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for SK Life Science. The institution of Dr. Rosenfeld has received research support from SK Life Science. The institution of Dr. Rosenfeld has received research support from UCB Pharma.

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

Long-Term Safety and Tolerability of Zavegepant 10 mg Nasal Spray During Concomitant Use of CGRP Monoclonal Antibodies: Results From a 1-Year Open-label Safety Trial (P10-12.009)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

A Phase 2/3 Open-label, Long-term, Safety Trial of Zavegepant 10 mg Nasal Spray for the Acute Treatment of Migraine (P9-12.002)

Significant Improvements in SEIzure InterVAL (Time Between Seizure Clusters) Across Time Irrespective of Age or Change in Concomitant Treatments in a Long-Term, Open-Label Safety Study of Diazepam Nasal Spray (P9-1.010)

Significant Improvements in SEIzure InterVAL (Time Between Seizure Clusters) Across Time Irrespective of Age or Change in Concomitant Treatments in a Long-Term, Open-Label Safety Study of Diazepam Nasal Spray (P9-1.010)

Concomitant Cannabidiol Does Not Impact Safety and Effectiveness of Diazepam Nasal Spray for Seizure Clusters: Post Hoc Analysis of a Phase 3 Safety Study (P9-1.012)

<h3>Objective:</h3> To examine potential effects of concomitant cannabidiol on safety and effectiveness of diazepam nasal spray (Valtoco^®). <h3>Background:</h3> Cannabidiol (CBD) is used as an antiseizure drug with multiple mechanisms of action. In clinical studies, the FDA-approved oral solution of CBD (Epidiolex^®) has altered the safety and effectiveness of benzodiazepines, especially clobazam. Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. This post hoc analysis from a long-term, open-label safety study examines safety and effectiveness of diazepam nasal spray in patients also receiving CBD treatment. <h3>Design/Methods:</h3> Patients (6–65 years) received age- and weight-based doses of diazepam nasal spray to treat seizure clusters. Seizures and drug administration were recorded in patient diaries. CBD use and treatment-emergent adverse events (TEAEs) were collected. Diazepam nasal spray second dose usage within 24 hours of the first was a proxy for effectiveness. <h3>Results:</h3> Of 163 patients treated with ≥1 dose of diazepam nasal spray, 119 (73.0%) did not receive CBD, 23 (14.1%) received oral-solution CBD, and 21 (12.9%) received other CBD. Patients receiving any CBD were more likely to have epileptic encephalopathies than patients with no CBD (63.6% vs 30.3%). Rates of TEAEs and serious TEAEs were higher in patients receiving CBD (90.9%, 45.5%) than no CBD (79.0%, 25.2%); treatment-related TEAEs were similar (18.2% vs 17.7%). Effectiveness measured by second dose use was similar between the CBD (14.7%) and no CBD groups (11.5%). <h3>Conclusions:</h3> CBD does not appear to influence the safety of diazepam nasal spray. In this cohort, incidence of epileptic encephalopathies in patients receiving CBD may underlie the overall rates of TEAEs in this population. Treatment-related TEAEs were similar across groups. These results suggest that CBD does not alter safety/effectiveness of diazepam nasal spray and support concomitant use in appropriate patients. <b>Disclosure:</b> Dr. Peters has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Peters has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurelis. Dr. Peters has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis. Dr. Puri has received personal compensation for serving as an employee of neurelis. Dr. Puri has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurelis. Dr. Puri has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Neurelis. Dr. Puri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Dr. Segal has received personal compensation for serving as an employee of Lundbeck. Dr. Segal has received personal compensation for serving as an employee of Eisai. Dr. Segal has received personal compensation for serving as an employee of Neurelis. Dr. Segal has received personal compensation for serving as an employee of Zogenix. Dr. Segal has received personal compensation for serving as an employee of Aquestive. Dr. Segal has received personal compensation for serving as an employee of Greenwich Biosciences. Dr. Segal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Aquestive. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Segal has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Greenwhich Bioscience. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Greenwhich Bioscience. Dr. Segal has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurelis. Dr. Gustin has received personal compensation for serving as an employee of Neurelis. Dr. Gustin has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for The Recovery Research Network Foundation. Dr. Misra has received personal compensation for serving as an employee of Neurelis, Inc. An immediate family member of Dr. Misra has received personal compensation for serving as an employee of Neurocrine Biosciences. Dr. Misra has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RubiconMD. Dr. Misra has received intellectual property interests from a discovery or technology relating to health care. Dr. Rabinowicz has received personal compensation for serving as an employee of Neurelis, Inc. Dr. Rabinowicz has stock in Neurelis, Inc. Enrique Carrazana has received personal compensation for serving as an employee of Neurelis. Enrique Carrazana has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Neurelis, Alexza, Zogenix. Enrique Carrazana has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Hawaii-Biotech, CND Life Sciences. Enrique Carrazana has stock in Neurelis, Marinus, .

Immunogenicity of DaxibotulinumtoxinA for Injection in Glabellar Lines.

DaxibotulinumtoxinA-lanm for injection (DAXI), a novel botulinum toxin type A formulation, contains a purified 150-kD core neurotoxin (daxibotulinumtoxinA) and proprietary stabilizing peptide (RTP004), and is approved for glabellar line treatment. As with any biologic product, DAXI may potentially be immunogenic and elicit unwanted antibody formation, possibly resulting in partial or complete treatment failure. The immunogenicity of DAXI was assessed in two double-blind, placebo-controlled, single-dose studies and an open-label safety study of up to 3 repeat treatments. Of the 2737 evaluable subjects, none developed neutralizing antibodies to daxibotulinumtoxinA and 0.8% developed treatment-related non-neutralizing anti-daxibotulinumtoxinA-binding antibodies. Of evaluable subjects exposed to RTP004 with either DAXI or placebo, 1.3% developed treatment-related anti-RTP004-binding antibodies, which were mostly transient. No subject developed binding antibodies to both daxibotulinumtoxinA and RTP004. All subjects with treatment-related binding antibodies to daxibotulinumtoxinA or RTP004 achieved a clinical response (none or mild glabellar line severity) at Week 4 following each DAXI treatment cycle. The duration of clinical response was not different between treatment cycles when antibodies were detected versus when they were absent. Although the analysis population was small compared with the number of patients likely to receive repeated treatment in clinical practice, these results suggest that DAXI administration at the approved glabellar lines dose has low immunogenic potential and that non-neutralizing antibodies to daxibotulinumtoxinA or RTP004 occur infrequently and often transiently, and have no impact on clinical efficacy, safety, or duration of action. Real-world data encompassing larger numbers of patients is needed to substantiate these results.

The cenobamate-clobazam interaction- evidence of synergy in addition to pharmacokinetic interaction

ObjectivesReport insights into the pharmacokinetic and pharmacodynamic interaction between cenobamate (CNB) and clobazam (CLB), derived from data in patients enrolled at our center in a global multicenter open-label safety study of CNB. Materials & MethodsPatients in this study either took CLB at baseline (n = 6) or had CLB added after CNB titration to maximal dose (n = 5) in addition to other antiseizure medications. Clobazam was always administered as a single bedtime dose. Random serum concentrations of CLB and N-desmethylclobazam (N-CLB) were obtained. ResultsBaseline daily CLB doses were 20–50 mg. Sedation began in the six baseline CLB patients at CNB doses of 25–100 mg. The N-CLB/ CLB ratio increased proportionally to the CNB dose. CLB was stopped in all six patients, five of whom were ≥50% responders. Seizure control deteriorated after stopping CLB, with only one remaining responder. Clobazam was restarted at 5 mg/d in five of the six patients. At the last follow-up, four of these patients were continuing CLB; two were seizure-free and 2 were ≥50% responders. Among the five patients that added 5 mg/d CLB de novo, three were responders. All patients were still on CNB at the end of the study. DiscussionData suggest starting CLB dose reduction at CNB doses of 25–100 mg/d. Due to possible synergy, the addition of low-dose CLB could be considered in patients with incomplete response to CNB.

Suprachoroidal triamcinolone acetonide injectable suspension for macular edema associated with noninfectious uveitis: an in-depth look at efficacy and safety.

Patients with macular edema (ME) associated with uveitis (UME) are at risk for vision loss and decreased quality of life, and they often experience high health care costs and rates of workforce absenteeism. Systemically or locally delivered corticosteroids are the mainstay of treatment for UME. Although traditional corticosteroid treatments may demonstrate high levels of efficacy, systemic delivery carries the risk of potentially serious systemic adverse effects (AEs), and standard local modes of delivery may be associated with low bioavailability in posterior ocular tissues and steroid-associated AEs due to anterior ocular tissue exposure. Drug injection into the suprachoroidal space (SCS) allows for targeted delivery to chorioretinal tissues with high bioavailability in the posterior segment, as well as for inherent drug sequestration away from the anterior segment, which may lower the risk of AEs associated with anterior tissue exposure to steroids. A novel triamcinolone acetonide (TA) injectable suspension formulated for administration to the SCS, SCS-TA (Xipere®; Bausch + Lomb), received FDA approval in 2021 for the treatment of UME. It is administered via the SCS Microinjector® (Clearside Biomedical, Inc), a device specifically designed for SCS delivery of ocular therapeutics. This approval was based on results from the phase 3 PEACHTREE clinical trial (NCT02595398) that demonstrated the clinical efficacy-including significantly increased visual acuity and decreased central subfield thickness-and safety of SCS-TA in patients with UME. Results from this trial, as well as from its long-term observational extension (MAGNOLIA; NCT02952001) and an open-label safety study (AZALEA; NCT03097315), support the possibility that treatment with SCS-TA may address the burden of disease in patients with UME.

A Preliminary Analysis of Athn 16: Safety of Coagulation Factor VIIa (recombinant)-Jncw for the Treatment of Bleeding Events in Patients with Congenital Hemophilia a or B with Inhibitors

Background: Eptacog beta (rFVIIa-jncw) (brand name SEVENFACT®) was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of bleeding events (BEs) in individuals 12 years of age and older with hemophilia A or B (HAB) complicated by inhibitors. ATHN 16: Safety of Coagulation Factor VIIa (recombinant)-jncwforthe Treatment of Bleeding Events in Patients with Hemophilia A or B with Inhibitors was designed to collect real-world evidence on the safety of eptacog beta. Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without FDA-approved prophylactic treatment. Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multicenter, open-label safety study enrolling participants with HAB with inhibitors aged 12 years and older, who are either on an FDA-approved prophylaxis and at risk of experiencing a breakthrough BE or who are not on prophylactic treatment and may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study will be up to 2 years from the time of enrollment. Safety of eptacog beta is evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor (FVII) development, thrombosis, cardiovascular events, malignancies, neurological events, and deaths. After informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history are recorded for the baseline data. Each participant receives nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta is administered by the participant or by study staff at the time of a BE. The doses and duration of treatment are determined at the discretion of the treating physician. BE details including timing of BE, any treatments associated with the BE (including eptacog beta) and timing of resolution of the event, are collected as well as surgical procedures, EUHASS events, adverse events of special interest (AESIs), and serious adverse events (SAEs). Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is rolled out to ATHN-affiliated sites across the United States. The study is currently open to enrollment at 11 sites and an additional 21 sites are proceeding with start-up approvals. A total of seven participants have been enrolled. One BE, unrelated to study product, has been reported. One SAE, unrelated to study product, has been reported. Conclusions: To date, a total of seven participants have enrolled in ATHN 16. One bleeding event has been treated with eptacog beta. The results will be updated, and all safety endpoints will be updated prior to the December 2022 meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of DaxibotulinumtoxinA for Injection on Brow Position and Frontalis Muscle Activity Following Treatment of Glabellar Lines.

Botulinum toxin type A (BoNTA) injections for the treatment of facial lines may lead to pleasant or undesirable changes in eyebrow height and position. The aim of this study was to evaluate the impact of glabellar injection of DaxibotulinumtoxinA for Injection (DAXI), a novel BoNTA formulation, on eyebrow position and frontalis activity. This study involved the post hoc analysis of adult patients from the Phase 2a forehead lines (FHL, N = 60) and open-label safety (OLS, N = 175) studies who received a single dose of DAXI 40 U to the glabella and for whom facial photographs were taken at rest and at maximum eyebrow elevation. Median vertical and horizontal displacement of the brows and median forehead strain (an objective quantitative assessment of frontalis activity) from baseline to 2 weeks after glabellar DAXI injection were measured. Two weeks after glabellar DAXI injection, vertical eyebrow movement (at rest) of the lateral brow was observed. In both studies, vertical movement was greatest in the lateral (0.6-0.9 mm) and mid (0.5-0.7 mm) brow regions; movement in the medial brow was negligible (0-0.23 mm). In both studies, a graded reduction in forehead strain was observed 2 weeks post glabellar DAXI injection, with the greatest reduction being in the lower segment (FHL, -73%; OLS, -82%). Treatment with DAXI showed improvements in FHL wrinkle severity. Glabellar injection of DAXI showed a positive reduction in dynamic frontalis activity that maintained or had a positive effect on eyebrow position. Vertical movement of the brow was suggestive of an improved eyebrow shape with a mild lateral arch.

1531P Primary results from IMfirst, a phase IIIb open label safety study of atezolizumab (ATZ) + carboplatin (CB)/cisplatin (CP) + etoposide (ET) in an interventional real-world (RW) clinical setting of extensive-stage small cell lung cancer (ES-SCLC) in Spain

IMpower133 Phase III study showed that the addition of ATZ to CB+ET in 1L ES-SCLC statistically and clinically improved overall survival (OS) and progression-free survival (PFS) compared to CB+ET alone. IMfirst evaluates the safety of ATZ+CB/CP+ET in an interventional RW clinical setting of ES-SCLC. An induction safety analysis was previously reported and here we present primary safety and efficacy results.