A real-world, observational study of erenumab for migraine prevention in Canadian patients.

OBJECTIVES: To assess real-world effectiveness, safety, and usage of erenumab in Canadian patients with episodic and chronic migraine with prior ineffective prophylactic treatments. BACKGROUND: In randomized controlled trials, erenumab demonstrated efficacy for migraine prevention in patients with ≤4 prior ineffective prophylactic migraine therapies. The "Migraine prevention with AimoviG: Informative Canadian real-world study" (MAGIC) assessed real-world effectiveness of erenumab in Canadian patients with migraine. METHODS: MAGIC was a prospective open-label, observational study conducted in Canadian patients with chronic migraine (CM) and episodic migraine (EM) with two to six categories of prior ineffective prophylactic therapies. Participants were administered 70 mg or 140 mg erenumab monthly based on physician's assessment. Migraine attacks were self-assessed using an electronic diary and patient-reported outcome questionnaires. The primary outcome was the proportion of subjects achieving ≥50% reduction in monthly migraine days (MMD) after the 3-month treatment period. RESULTS: Among the 95 participants who mostly experienced two (54.7%) or three (32.6%) prior categories of ineffective prophylactic therapies and who initiated erenumab, treatment was generally safe and well tolerated; 89/95 (93.7%) participants initiated treatment with 140 mg erenumab. At week 12, 32/95 (33.7%) participants including 17/64 (26.6%) CM and 15/32 (48.4%) EM achieved ≥50% reduction in MMD while 30/86 (34.9%) participants including 19/55 (34.5%) CM and 11/31 (35.5%) EM achieved ≥50% reduction in MMD at week 24. Through patient-reported outcome questionnaires, 62/95 (65.3%) and 45/86 (52.3%) participants reported improvement of their condition at weeks 12 and 24, respectively. Physicians observed improvement in the condition of 78/95 (82.1%) and 67/86 (77.9%) participants at weeks 12 and 24, respectively. CONCLUSION: One-third of patients with EM and CM achieved ≥50% MMD reduction after 3 months of erenumab treatment. This study provides real-world evidence of erenumab effectiveness, safety, and usage for migraine prevention in adult Canadian patients with multiple prior ineffective prophylactic treatments.

New View on the Canadian Burden of Stroke: Productivity Loss in Adults Who Return to Work.

An often overlooked facet of the indirect costs affecting working-age stroke survivors is the challenges experienced by those who return to work. This study quantified the productivity loss in 20 stroke survivors who returned to work which amounted to 53.0 missed work days and an average indirect cost of $10,298 (CAD) in the year following a stroke. Despite the quantified productivity loss, 75% of patients reported no significant disability and a high proportion were self-employed compared to the Canadian population, indicating that socioeconomic factors may be driving patient decisions to return to work.

Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.

Real-world persistence with liraglutide 3.0 mg for weight management and the SaxendaCare® patient support program.

OBJECTIVE: Weight management medications can significantly increase patients' chances of achieving a clinically meaningful weight loss if patients persist with treatment. This retrospective observational study of de-identified medical records of 311 patients is the first real-world study examining persistence with liraglutide 3.0 mg in Canada, and also investigates associations between the SaxendaCare® patient support program and persistence and weight loss. METHODS: Overall persistence was assessed, as well as associations of enrollment in SaxendaCare®, persistence and weight loss. RESULTS: Overall mean (standard deviation) persistence with liraglutide 3.0 mg was 6.3 (4.1) months, and 67.5% (n = 210) and 53.7% (n = 167) of patients persisted for ≥4 and ≥ 6 months, respectively. Enrollment in SaxendaCare® was associated with significantly longer persistence with liraglutide 3.0 mg and greater weight loss. Patients enrolled in SaxendaCare® (n = 119) persisted for 7.9 (4.0) versus 5.2 (3.8) months for those not enrolled (n = 184) (p < 0.001), and had significantly greater percent weight loss after 6 months regardless of the duration of their persistence (-7.9% vs -5.5% from baseline, p < 0.01). CONCLUSIONS: These findings suggest that, in clinical settings, persistence with liraglutide 3.0 mg can exceed 6 months, and that enrolling in SaxendaCare® may be associated with comparatively longer persistence and, regardless of persistence, greater weight loss.

Weight loss and persistence with liraglutide 3.0 mg by obesity class in the real-world effectiveness study in Canada.

OBJECTIVE: Liraglutide 3.0 mg is associated with clinically significant weight loss in clinical trials, but real-world data are lacking. In this analysis, weight loss and persistence outcomes with liraglutide 3.0 mg were assessed across obesity classes, in a real-world clinical setting. METHODS: Secondary analysis of an observational, retrospective study of liraglutide 3.0 mg for weight management (as adjunct to diet and exercise) at six Wharton Medical Clinics in Canada. Patients were categorized by body mass index (BMI, kg/m2) into obesity class I (BMI 30-34.9); class II (BMI 35-39.9); and class III (BMI ≥40). Change in weight, categorical weight loss, time to maintenance dose (defined as the time to reach the full liraglutide 3.0 mg maintenance dose) and persistence were assessed for each class and for differences between classes. RESULTS: Of 308 patients, 70 (22.7%) had obesity class I, 83 (26.9%) obesity class II and 155 (50.3%) obesity class III. Similar percentage change in weight was observed between obesity classes (mean [standard deviation, SD]: -7.0% [6.0], -6.6% [6.0] and -6.1% [5.0], respectively; p = .640), and similar proportions achieved ≥5% weight loss (60.4%, 62.0% and 55.3%, respectively; p = .717) at 6 months. Mean time to maintenance dose (SD) was 64.2 (56.4) d, 76.4 (56.3) d and 71.4 (54.5) d for obesity classes I, II and III, respectively (p = .509). Persistence with medication was also similar between obesity classes (p = .358). CONCLUSIONS: These findings suggest that real-world treatment with liraglutide 3.0 mg, regardless of obesity class, is associated with similar clinically significant weight loss, time to maintenance dose and medication persistence.

Real-World Clinical Effectiveness of Liraglutide 3.0 mg for Weight Management in Canada.

OBJECTIVE: Real-world clinical effectiveness of liraglutide 3.0 mg, in combination with diet and exercise, was investigated 4 and 6 months post initiation. Changes in absolute and percent body weight were examined from baseline. METHODS: A cohort of liraglutide 3.0 mg initiators in 2015 and 2016 was identified from six Canadian weight-management clinics. Post initiation values at 4 and 6 months were compared with baseline values using a paired t test. RESULTS: The full cohort consisted of 311 participants, with 210 in the ≥ 4-month persistence group and 167 in the ≥ 6-month persistence group. Average baseline BMI was 40.7 kg/m2 , and weight was 114.8 kg. There was a significant change in body weight 6 and 4 months after initiation of treatment in persistent subjects (≥ 6-month: -8.0 kg, P < 0.001; ≥ 4-month: -7.0 kg, P < 0.001) and All Subjects, regardless of persistence (-7.3 kg; P < 0.001). Percentage change in body weight from baseline was -7.1% in the ≥ 6-month group and -6.3% in the ≥ 4-month group, and All Subjects lost 6.5% body weight. Of participants in the ≥ 6-month group, 64.10% and 34.5% lost ≥ 5% and > 10% body weight, respectively. CONCLUSIONS: In a real-world setting, liraglutide 3.0 mg, when combined with diet and exercise, was associated with clinically meaningful weight loss.

Platinum(II) phenanthroimidazole G-quadruplex ligand induces selective telomere shortening in A549 cancer cells.

Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere shortening and the potential activation of ALT pose a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping). G-quadruplex ligands stabilize structures generated from single-stranded G-rich 3'-telomere end (G-quadruplex) folding, which in principle, cannot be elongated by telomerase, thus leading to telomere shortening. Ligands can also mediate rapid anti-proliferative effects by telomere uncapping. We previously reported that the G-quadruplex ligand, phenylphenanthroimidazole ethylenediamine platinum(II) (PIP), inhibits telomerase activity in vitro[47]. In the current study, a long-term seeding assay showed that PIP significantly inhibited the seeding capacity of A549 lung cancer cells and to a lesser extent primary MRC5 fibroblast cells. Importantly, treatment with PIP caused a significant dose- and time-dependent decrease in average telomere length of A549 but not MRC5 cells. Moreover, cell cycle analysis revealed a significant increase in G1 arrest upon treatment of A549 cells, but not MRC5 cells. Both apoptosis and cellular senescence may contribute to the anti-proliferative effects of PIP. Our studies validate the development of novel and specific therapeutic ligands targeting telomeric G-quadruplex structures in cancer cells.

Platinum(II) phenanthroimidazoles for targeting telomeric G-quadruplexes.

A rationally designed progression of phenanthroimidazole platinum(II) complexes were examined for their ability to target telomere-derived intramolecular G-quadruplex DNA. Through the use of circular dichroism, fluorescence displacement assays, and molecular modeling we show that these complexes template and stabilize G-quadruplexes from sequences based on the human telomeric repeat (TTAGGG)(n). The greatest stabilization was observed for the p-chlorophenyl derivative 6((G4)DC(50) =0.31 µM). We also show that the G-quadruplex binding complexes are able to inhibit telomerase activity through a modified telomerase repeat amplification protocol (TRAP-LIG assay). Preliminary cell studies show that complex 6 is preferentially cytotoxic toward cancer over normal cell lines, indicating its potential use in cancer therapy.

TGFbeta-induced GRK2 expression attenuates AngII-regulated vascular smooth muscle cell proliferation and migration.

Through diametric actions, the transforming growth factor beta (TGFbeta) and Angiotensin II (AngII) play important roles in regulating various biological responses such as cell proliferation and migration. Signaling initiated by TGFbeta and AngII occurs through two structurally and functionally distinct receptor super families,the serine/threonine kinase and G protein-coupled receptors (GPCRs). Previously, we identified the Gprotein-coupled receptor kinase-2 (GRK2), a key regulatory factor in the desensitization of GPCRs, as a direct downstream target of the TGFbeta signaling cascade. GRK2 acts through a negative feed-back loop mechanism to terminate TGFbeta-induced smad signaling. To investigate the impact of TGFbeta-induced GRK2 expression on GPCR signaling, we examined its effect on AngII signaling in vascular smooth muscle cells (VSMCs). In this study, we show that activation of the TGFbeta signaling cascade in VSMCs results in increased GRK2 expression levels, which consequently inhibits AngII-induced ERK phosphorylation and antagonizes AngII-induced VSMC proliferation and migration. Moreover, the inhibitory effect of TGFbeta on AngII signaling occurs at the Mek-Erk interface and is abrogated when an anti-sense oligonucleotide directed against GRK2 is used. Thus,we conclude that TGFbeta signaling antagonizes AngII-induced VSMC proliferation and migration through the inhibition of ERK phosphorylation and that GRK2 is a key factor mediating the cross-talk between these two receptor super families.