Purpose: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. Design: Prospective, multicenter, randomized, sham-controlled phase 2 study. Participants: Two hundred forty-six patients with GA. Methods: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. Main Outcome Measures: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. Results: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9e49; P ¼ 0.008) and 20% (95% CI, 0e40; P ¼ 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P ¼ 0.0004) and 33% (P ¼ 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). Conclusions: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hematologic disease characterized by chronic complement-mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL-2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open-label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment-emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6-8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well-tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation. 1 | INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hematologic disease characterized by chronic complement-mediated hemolysis and thrombosis caused by the clonal expansion of hematopoietic stem cells that have acquired somatic mutations in the phosphatidylinositol glycan class A gene

Heat shock protein 90 (Hsp90) is a chaperone protein regulating PC-12 cell survival by binding and stabilizing Akt, Raf-1, and Cdc37. Hsp90 inhibitor Geldanamycin (GA) cytotoxicity has been attributed to disruption of Hsp90 binding, and the contribution of oxidative stress generated by its quinone group has not been studied in this context.Reactive oxygen species (ROS) and cell survival were assessed in PC-12 cells exposed to GA or Menadione (MEN), and Akt, Raf-1, and Cdc37 expression and binding to Hsp90 were determined. GA disrupted Hsp90 binding and increased ROS production starting at 1h, and cell death occurred at 6h, inhibited by N-acetyl cysteine (NAC) without preventing dissociation of proteins. At 24h, NAC prevented cytotoxicity and Hsp90 complex disruption. However MnTBAP antioxidant treatment failed to inhibit GA cytotoxicity, suggesting that NAC acts by restoring gluthathione. In contrast, 24h MEN induced cytotoxicity without disrupting Hsp90 binding. GA and MEN decreased Hsp90-binding proteins expression, and proteasomal inhibition prevented MEN, but not GA-induced degradation. In conclusion, while MEN cytotoxicity is mediated by ROS and proteasomal degradation, GA-induced cytotoxicity requires ROS but induces HSP90 complex dissociation and proteasome-independent protein degradation. These differences between MEN and GA-induced cytotoxicity, may allow more specific targeting of cancer cells.

IntroductionThe receptor specific for the IgA Fc region (Fc␣RI or CD89) is expressed on blood myeloid cells, including monocyte/macrophages, dendritic cells, Kupffer cells, neutrophils, and eosinophils. 1 It transmits IgA-mediated effector functions via an IgA-binding module (K a about 10 6 M Ϫ1 ) that can be expressed with or without physical association with the disulfide-linked signaling adaptor FcR␥. 2,3 The FcR␥-associated receptor has signaling functions that involve an immunoreceptor tyrosine-based activation motif (ITAM), consisting of a conserved sequence that is present in the cytoplasmic domain of FcR␥ and is shared by different signaling subunits associated with receptors such as TCR and BCR and other FcRs. Although the ITAM was initially reported to mediate activating responses, recent data suggest that, in certain conditions, this motif can also trigger inhibitory responses mediated by a variety of receptors. [4][5][6] The latter include Fc␣RI, a dual-function receptor that can mediate both activating and inhibitory responses depending on the type of interaction with its ligand. Sustained multimeric aggregation mediates activation of target-cell functions, such as superoxide production, cytokine release, and antigen presentation. 7-9 Monomeric targeting with IgA or with a variety of anti-Fc␣RI (A77, A59, or A62, but not A3) Fab fragments triggers an inhibitory response to heterologous immunoreceptors such as Fc⑀RI and Fc␥R. 5 Like the activating functions, the inhibitory cross-talk is dependent on the FcR␥ ITAM. However, in contrast to receptors bearing an immunoreceptor tyrosine-based inhibitory motif (ITIM), such as FcR␥IIB, 10 the inhibitory signal does not require coaggregation. Monomeric targeting of Fc␣RI also has powerful anti-inflammatory activity in vivo because administration of anti-Fc␣RI Fab suppresses manifestations of allergic asthma in Fc␣RI transgenic mice. 5 Activation of certain FcRs also promotes cell death. Thus, Fc␥RIIB expressed on B cells not only terminates the activation signals of coengaged receptors, via an ITIM-dependent mechanism, but, in case of isolated aggregation, is also able to trigger an apoptotic response. 11 The latter involves ITIM and Src homology 2 domain-containing inositide phosphatase (SHIP)-independent and c-abl-family kinase-dependent pathways. [12][13][14] Recruitment of the Src homology 2 domain-containing phosphatase (SHP)-1 to the B-and T-cell antigen receptors (BCR and TCR) was also shown to negatively correlate with the induction of apoptosis. 12,15 Indeed, SHP-1-deficient mice are unusually susceptible to clonal deletion of their B-and T-cell compartment. [15][16][17] Although the precise mechanisms whereby SHP-1 negatively regulates apoptosis remains unknown, a possible hypothesis is that SHP-1 raises the threshold required for antigen receptor signaling spread thereby linking it to other biologic outcomes such as cell death.Incubation of neutrophils with immobilized IgA or secretory IgA also induces apopotosis. 18 This likely involves Fc␣RI, t...