Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death

POS1060 A PROSPECTIVE, LONGITUDINAL STUDY TO EVALUATE REAL-WORLD PATIENT EXPERIENCES AND TREATMENT SATISFACTION WITH SECUKINUMAB FOR PSORIATIC ARTHRITIS

Background:Psoriatic arthritis (PsA) is an inflammatory disease that impairs quality of life. Despite therapeutic advances, up to a third of patients do not respond or are unable to sustain a treatment response. Thus, data on patient treatment experience in PsA is critical.Objectives:To assess real-world experiences of patients with PsA treated with secukinumab.Methods:This is an ongoing 12-month, prospective, longitudinal, web-based survey study of patients with PsA initiating secukinumab. Patient demographics and medical history are collected at baseline using a rheumatologist case report form. Patient experience data are collected at baseline, 3, 6, 9, and 12 months by patient surveys. The primary endpoint is change in the Psoriatic Arthritis Impact of Disease 12-item questionnaire (PsAID12) from baseline to 3 months. In addition, this study will explore other changes at 3 months, including PsA symptoms, treatment satisfaction with secukinumab, and other patient-reported outcome measures. Baseline and available month 3 data from patients enrolled to date were analyzed descriptively.Results:Baseline demographic and medical history data were available for 72 patients; 32 (44.4%) were male, 59 (81.9%) were White, and 15 (20.8%) reported modifying their diet because of PsA. The mean (SD) time since symptom onset (n = 29) and since PsA diagnosis (n = 53) was 56.3 (45.6) and 34.4 (44.7) months, respectively. More than half of the patients who started treatment with secukinumab were biologic experienced (38/62; 61.3%). Primary and secondary loss of effectiveness were the main reasons for previous biologic discontinuation (Table 1). At 3 months (n = 49), the mean (SD) PsAID12 change from baseline was –1.8 (1.8) points. Additionally, 24.5% of patients reported their PsA symptoms to be “much better,” 40.8% reported “moderately better,” and 32.7% “a little better” compared with baseline; none reported “no change” or worsened symptoms. On a scale of 1-10, patients rated their overall satisfaction with secukinumab treatment at month 3 with a mean (SD) score of 6.8 (2.1). Patients were also highly satisfied with their symptom improvement, speed to symptom improvement, and the mode and frequency of secukinumab administration (Table 1).Table 1.Summary of Prior PsA Treatment and Treatment Satisfaction with Secukinumab at Month 3Physician-reported treatment characteristicsBaseline measure(N = 62)Most recent PsA biologic prior to secukinumab, n (%)n = 31Adalimumab12 (38.7)Certolizumab pegol8 (25.8)Etanercept6 (19.4)Infliximab, including -dyyb3 (9.7)Golimumab1 (3.2)Unknown/not sure1 (3.2)Primary reasons for discontinuing previous PsA biologic treatment, n (%)an = 30Primary and secondary loss of effectiveness25 (83.3)Disease progression6 (20.0)Worsening of or new comorbidities1 (3.3)How the medication was taken2 (6.7)Adverse effects/intolerance4 (13.3)Otherb1 (3.3)Patient-reported treatment satisfaction with secukinumab, mean (SD)cMonth 3 (N = 49)Symptom improvement6.7 (2.3)Speed of symptom improvement6.9 (2.0)Dose frequency7.4 (1.9)cMethod of administration7.2 (1.5)Ease of use8.2 (1.5)Side effects, if any7.9 (1.9)Patient support services by manufacturer8.3 (1.7)PsA, psoriatic arthritis.a Rheumatologists may list &gt; 1 reason. Data tabulated based on the number of case report forms received from rheumatologists at analysis cutoff (n = 30).b Other reasons included availability of new treatment, patient request, or family history of disease.c n = 48.Conclusion:Most patients were biologic experienced and reported primary or secondary loss of effectiveness as the main reason for discontinuation of their previous biologic. Patients reported overall symptom improvement and satisfaction with secukinumab treatment at 3 months after initiation.Disclosure of Interests:M Elaine Husni Consultant of: AbbVie, Amgen, Janssen, Novartis, Eli Lilly, UCB, and Regeneron, Michael Bozyczko Employee of: National Psoriasis Foundation, Daniel Wolin Employee of: RTI Health Solutions, Carolyn Sweeney Employee of: RTI Health Solutions, Eric Davenport Employee of: RTI Health Solutions, Steven Hass Employee of: Novartis, Esther Yi Employee of: Novartis, Peter Hur Employee of: Novartis, Linda Grinnell-Merrick Consultant of: AbbVie, Amgen (previously Celgene), Novartis, Pfizer, and Regeneron.</jats:sec