Adhesion Evaluation of AG200-15: An Investigational Transdermal Contraceptive Delivery System Abstract Introduction AG200-15, an investigational transdermal contraceptive delivery system or patch, is designed to be a low-dose, non-daily, combined hormonal contraceptive option for women. In this phase 1 study, the in vivo adhesion of the AG200-15 patch was compared to Xulane®, the only contraceptive patch available in the USA. Methods This phase 1, randomized, open-label, single-dose, two-treatment, two-period crossover adhesion study compared the 7-day adhesion of the AG200-15 and Xulane contraceptive patches. Eighty-three women, ages 18 to 35 years old, with body mass index (BMI) ≥ 19 kg/m2 and < 35 kg/m2, and weight ≥ 48 kg and < 90 kg were enrolled. Trained study site personnel used a five-point scale to assess patch adhesion daily. A score of 0 reflected at least 90% adhesion; while a score of 4 represented complete detachment of the patch. The primary objective was to compare the adhesion properties of the two patches; AG200-15 would be considered statistically non-inferior to Xulane if the upper 95% confidence limit (CL) of the mean difference in adhesion scores was below + 0.15. Results The overall mean (standard deviation) scores for AG200-15 (N = 78) and Xulane (N = 77) were 0.14 (0.28) and 0.39 (0.40), respectively (lower scores on the adhesion scale indicate better adhesion). The study demonstrated a difference in mean adhesion scores of − 0.24, meeting the prespecified non-inferiority criterion by demonstrating a one-sided upper CL of − 0.16. Thus, the in vivo adhesion of AG200-15 was shown to be non-inferior to that of Xulane. Most subjects experienced no skin irritation at the application site for either patch and no serious adverse event was reported in the study. Conclusion The in vivo adhesion of AG200-15 is non-inferior to that of Xulane on the basis of the prespecified criterion of the upper bound of the one-sided 95% CL for the mean adhesion score difference being below + 0.15. Both patches were generally well tolerated. Funding Agile Therapeutics, Inc.

Case Series of Combined XEN Implantation and Phacoemulsification in Chinese Eyes: One-Year Outcomes Abstract Purpose The outcome of XEN implantation in Chinese eyes has not been previously reported. The purpose of our study is to evaluate the efficacy and safety of combined cataract surgery and XEN implantation in Chinese eyes with glaucoma. Methods We conducted a prospective study of 31 consecutive Chinese patients who underwent combined phacoemulsification and XEN implantation at the National University Hospital (Singapore) in this study. Patients were assessed preoperatively and postoperatively on days 1 and 7, and months 1, 3, 6, and 12. The intraocular pressure (IOP), glaucoma medication use, Snellen visual acuity (VA), and complications were assessed at each visit. The Wilcoxon signed rank test for non-parametric data was used for the analysis of IOP and glaucoma medications at baseline versus 12 months after the procedure. Results The mean age of the patients was 70 ± 7.9 years and 48.4% were male. Twelve patients (38.7%) were diagnosed with primary open angle glaucoma and 19 patients (61.3%) were diagnosed with primary angle closure glaucoma. There was a significant decrease in IOP at 12 months (12.1 ± 2.6 mmHg) compared with preoperative medicated (15.6 ± 2.7 mmHg, p < 0.0001) and unmedicated IOP (22.1 ± 3.6 mmHg, p < 0.001). as well as a significant reduction in the number of glaucoma medications (1.4 ± 0.6 vs 0.1 ± 0.4, p < 0.0001). The most common complications were transient hypotony (12.9%) and ptosis (12.9%) and there were no sight-threatening intraoperative or postoperative complications. One patient required additional glaucoma surgery for uncontrolled IOP at 8 months after combined phacoemulsification and XEN implantation. Conclusion Combined XEN implantation with cataract surgery was effective in lowering the IOP and the number of glaucoma medications in Chinese eyes for at least 12 months, with a favorable safety profile.

The Symptoms and Impact of Recurrent Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Conceptual Model of the Patient Experience Abstract Introduction We qualitatively examined the symptoms and impact of recurrent primary focal segmental glomerulosclerosis (rpFSGS) in kidney transplant recipients, compared with two related FSGS populations, to characterize the experience of patients with rpFSGS. Methods A literature review identified 58 articles concerning the experience of patients with pFSGS and/or rpFSGS in three groups: pre-transplant pFSGS, post-transplant rpFSGS, or post-transplant non-recurrent pFSGS. Literature findings were used to construct a preliminary conceptual model incorporating the symptoms and impact of rpFSGS, which was refined on the basis of qualitative interviews with clinicians. Twenty-five patients (rpFSGS: n = 15; pre-transplant pFSGS: n = 5; post-transplant non-recurrent pFSGS: n = 5) were interviewed to characterize the experience of patients with rpFSGS and compare it with other FSGS populations, and findings were used to finalize the conceptual model. Results The impact of pFSGS/rpFSGS described in the literature was diverse. Treatment-related symptoms, along with anxiety and depression, were considered important features of rpFSGS in addition to the findings from the literature review, according to clinicians. Patient-reported tiredness and swelling were the most common/disturbing symptoms associated with rpFSGS, while physical activity restrictions and adverse effects on work/social life were considered the most profound impact concepts. The collective disease experience was different for patients with rpFSGS and non-recurrent pFSGS, although psychological impact, including treatment-related anxiety and depression, were common to both groups. Conclusions Post-transplant recipients with rpFSGS display a greater symptom burden and experience a more diverse impact than those with non-recurrent pFSGS, highlighting the importance of effective patient monitoring and introducing effective treatments for the prevention and management of pFSGS recurrence. Funding Astellas Pharma Global Development, Inc.

Comparison of PARPis with Angiogenesis Inhibitors and Chemotherapy for Maintenance in Ovarian Cancer: A Network Meta-Analysis Abstract Introduction Seventy-five percent of ovarian cancer would relapse within 18–28 months after platinum-base chemotherapy. Evidence suggests that maintenance chemotherapy is effective in prolonging remission. Recent target therapies such as poly(ADP-ribose) polymerase inhibitors (PARPis) and angiogenesis inhibitors (AIs) are known to ease burden and recurrence of ovarian cancer. There is limited data for head-to-head comparison of PARPis, AIs, and chemotherapeutic agents (CTAs) as maintenance treatment. This network meta-analysis thus assessed the effectiveness and toxicity of these three maintenance therapies in patients with ovarian cancer. Methods We searched relevant sources (PubMed, EMBASE) to identify randomized controlled trials assessing efficacy and safety of maintenance therapy in patients with ovarian cancer. Primary outcome was progression-free survival (PFS) as assessed by blinded review; safety and tolerability were secondary outcomes. A network meta-analysis to compare three drug classes was performed using statistical software R. Results We included 24 trials (11,366 patients) assessing efficacy and safety of PARPis (n = 4), AIs (n = 12), and CTAs (n = 8). PARPis [hazard ratio (HR) 0.64; 95% credible intervals (CrI) 0.55–0.73] and AIs (HR 0.87; 95% CrI 0.81–0.93) showed significant improvement in PFS compared to placebo but not CTA (HR 1.00; 95% CrI 0.86–1.15). PARPis showed significant improvement in PFS compared to AIs (HR 0.73; 95% CrI 0.63–0.86) and CTA (HR 0.64; 95% CrI 0.52–0.78). Adverse events (AEs) leading to treatment discontinuation and dose reduction were lower in PARPis [incidence rate ratio (IRR) 0.60; CrI 0.31–1.18 and IRR 0.73, 95% CrI 0.50–1.06, respectively] compared to AIs, but the differences were not significant. Conclusion PARPi as maintenance treatment improved PFS in ovarian cancer and was relatively safer in terms of implications caused by AEs when compared to AIs. This network meta-analysis provides valuable evidence and significant insights into treatment of ovarian cancer.

Leber’s Hereditary Optic Neuropathy as a Promising Disease for Gene Therapy Development Abstract Leber’s hereditary optic neuropathy (LHON) is a relatively common, rapidly progressing inherited optic neuropathy wherein LHON-affected eyes undergo optic nerve atrophy due to retinal ganglion cell (RGC) loss. It is a maternally inherited (or sporadic) mitochondrial disorder caused primarily by mutations in genes that encode components of respiratory complex (RC)1 in mitochondria. Mitochondrial deficiency of RC1 compromises ATP production and oxidative stress management in RGCs. The most common LHON-causing mutations are 11778G>A, 3460G>A, and 14484T>C point mutations in MT-ND4, MT-ND1, and MT-ND6. The unusually high mitochondrial load of RGCs makes them particularly sensitive to these mutations. Patients with LHON may be prescribed ubiquinone (a component of RC3) or idebenone, a ubiquinone analogue with enhanced bioavailability to act downstream of RC1. The challenge of accessing the inner mitochondrial membrane with gene therapy for LHON, and other mitochondrial diseases, may be overcome by incorporation of a specific mitochondrion-targeting sequence (MTS) that enables allotropic expression of a nucleus-transcribed ND4 transgene. Because LHON penetrance is incomplete among carriers of the aforementioned mutations, identification of environmental factors, such as heavy smoking, that interact with genetics in the phenotypic expression of LHON may be helpful toward preventing or delaying disease development. LHON has become a model for mitochondrial and neurogenerative diseases owing to it having a clearly identified genetic cause and its early onset and rapid progression characteristics. Hence, LHON studies and genetic treatment advances may inform research of other diseases.

Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis Abstract Introduction Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA naïve for the drug. Methods We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements. Results At baseline, patients with established RA had a median DAS28 of 4.8 (3.2–8.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged. Conclusion The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk.

Comparison of Excimer Laser Versus Femtosecond Laser Assisted Trephination in Penetrating Keratoplasty: A Retrospective Study Abstract Introduction To compare the impact of non-mechanical excimer-assisted (EXCIMER) and femtosecond laser-assisted (FEMTO) trephination on outcomes after penetrating keratoplasty (PK). Methods In this retrospective study, 68 eyes from 23 females and 45 males (mean age at time of surgery, 53.3 ± 19.8 years) were included. Inclusion criteria were one surgeon (BS), primary central PK, Fuchs’ dystrophy (FUCHS) or keratoconus (KC), no previous intraocular surgery, graft oversize 0.1 mm and 16-bite double running suture. Trephination was performed using a manually guided 193-nm Zeiss Meditec MEL70 excimer laser (EXCIMER group: 18 FUCHS, 17 KC) or 60-kHz IntraLase™ femtosecond laser (FEMTO group: 16 FUCHS, 17 KC). Subjective refractometry (trial glasses) and corneal topography analysis (Pentacam HR; Casia SS-1000 AS-OCT; TMS-5) were performed preoperatively, before removal of the first suture (11.4 ± 1.9 months) and after removal of the second suture (22.6 ± 3.8 months). Results Before suture removal, mean refractive/AS-OCT topographic astigmatism did not differ significantly between EXCIMER and FEMTO. After suture removal, mean refractive/Pentacam/AS-OCT topographic astigmatism was significantly higher in the FEMTO (6.2 ± 2.9 D/7.1 ± 3.2 D/7.4 ± 3.3 D) than in the EXCIMER patients (4.3 ± 3.0 D/4.4 ± 3.1 D/4.0 ± 2.9 D) (p ≤ 0.005). Mean corrected distance visual acuity increased from 0.22 and 0.23 preoperatively to 0.55 and 0.53 before or 0.7 and 0.6 after suture removal in the EXCIMER and FEMTO groups, respectively. Differences between EXCIMER and FEMTO were only pronounced in the KC subgroup. Conclusion Non-mechanical EXCIMER trephination seems to have advantages regarding postoperative corneal astigmatism and visual acuity compared with FEMTO trephination, especially in KC. A bigger sample size and longer follow-up are needed to evaluate the long-term impact of EXCIMER and FEMTO trephination on postoperative topographic and visual outcomes.

Evaluation of the Cost Per Patient Achieving Treatment Targets with Oral Semaglutide: A Short-Term Cost-Effectiveness Analysis in the United States Abstract Introduction Oral semaglutide is the first orally administered glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes, and has been evaluated in the PIONEER clinical trial program. These trials assessed the proportions of patients achieving single and composite endpoints, encompassing glycemic control [defined in terms of glycated hemoglobin (HbA1c)], weight loss, and hypoglycemia. The present study assessed the cost of control with oral semaglutide versus empagliflozin, sitagliptin, and liraglutide in the US. Methods Four endpoints were evaluated: (1) HbA1c ≤ 6.5%; (2) HbA1c < 7.0%; (3) ≥ 1.0%-point HbA1c reduction and weight loss ≥ 3.0%; and (4) HbA1c < 7.0% without hypoglycemia and without weight gain. The proportions of patients achieving each endpoint were sourced from the PIONEER 2, 3 and 4 trials. Treatment costs were accounted over an annual time-period in 2019 US dollars (USD), based on wholesale acquisition cost. Cost of control was calculated by dividing treatment costs by the proportion of patients achieving each target. Results Oral semaglutide was consistently associated with the lowest cost of control for all four endpoints. For the targets of HbA1c ≤ 6.5% and HbA1c < 7.0%, oral semaglutide 14 mg was associated with lower cost of control than empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg by USD 15,036, 14,697, and 6996, respectively, and USD 931, 346 and 4497, respectively. For the double composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 525, 32,277 and 13,011, respectively versus empagliflozin 25 mg, sitagliptin 100 mg and liraglutide 1.8 mg. For the triple composite endpoint, cost of control was lower with oral semaglutide 14 mg by USD 1255, 7510 and 5774, respectively. Conclusion Oral semaglutide was associated with lower cost of bringing patients with type 2 diabetes to four clinically-relevant treatment targets versus empagliflozin, sitagliptin, and liraglutide in the US. Funding Novo Nordisk A/S.

Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve, HCV-Infected Patients with APRI ≤ 1 in a Single-Arm, Open-Label, Multicenter Study Abstract Introduction The presence or absence of cirrhosis in patients with chronic hepatitis C virus (HCV) infection influences the type and duration of antiviral therapy. Non-invasive markers, like serum aspartate aminotransferase (AST) to platelet ratio index (APRI), may help identify appropriate HCV treatment-naive patients for 8-week treatment with the pangenotypic regimen of glecaprevir/pibrentasvir. Methods This single-arm, open-label, international, prospective study (NCT03212521) evaluated the efficacy and safety of 8-week glecaprevir/pibrentasvir regimen in HCV treatment-naïve adults with chronic HCV genotypes 1–6 infection, APRI ≤ 1, and no prior evidence of cirrhosis. The primary and secondary outcomes were sustained virologic response at 12 weeks post-treatment (SVR12) by modified intent-to-treat (mITT) and intent-to-treat (ITT) analyses, respectively. Additional endpoints included virologic failures, treatment adherence, and genotype-specific SVR12 rates. Results Among the 230 patients enrolled, most were less than 65 years old (90%); 37% and 43% had a history of injection drug use or psychiatric disorders, respectively. SVR12 rates were 100% (222/222; 95% CI 98.3–100%) and 96.5% (222/230; 95% CI 94.2–98.9%) by mITT and ITT analyses, respectively. There were no virologic failures. ITT SVR12 rates were greater than 94% for all HCV genotypes. In patients with available data, treatment adherence was 99% (202/204). There were no grade 3 or higher laboratory abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and low rates of serious adverse events (2%). Conclusions Glecaprevir/pibrentasvir was highly efficacious and well tolerated in HCV treatment-naïve patients with APRI ≤ 1 and no prior evidence of cirrhosis. Trial Registration ClinicalTrials.gov number, NCT03212521. Funding AbbVie. Plain Language Summary Plain language summary available for this article.

Real-World Effectiveness and Tolerability of Pazopanib as First Targeted Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Chart Review in Latin America Abstract Introduction Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC). Methods A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized. Results A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6 years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800 mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2 months. The median time on treatment was 10.0 months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9 months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%). Conclusions Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib. Funding Novartis Pharmaceuticals Corporation, Inc.