Phase I Trial of Anti-Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration.

PURPOSE: RG7716 is a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and another key angiogenic factor, angiopoietin 2. A phase I study of intravitreal RG7716 was conducted to evaluate single-dose and multiple-dose safety in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single and multiple ascending-dose study. PARTICIPANTS: Twenty-four patients diagnosed with neovascular AMD with best-corrected visual acuity (BCVA) of 20/40 to 20/400 (Snellen equivalent) and refractory subfoveal choroidal neovascularization defined as leakage on fluorescein angiography or fluid on spectral-domain optical coherence tomography despite 3 or more intravitreal anti-VEGF treatments in the preceding 6 months. METHODS: Single intravitreal doses of 0.5 mg, 1.5 mg, 3 mg, and 6 mg RG7716 were administered in stepwise dose-escalation groups, each with 3 patients. In the multiple-dose phase, 6 patients were enrolled and received 3 treatments each of 3 mg and 6 mg RG7716. MAIN OUTCOME MEASURES: Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST). RESULTS: There were no dose-limiting toxicities in either the single-dose or multiple-dose group. Treatment-emergent ocular adverse events were mild. There was a single withdrawal and 1 serious adverse event, both deemed to be unrelated to the study drug by principal investigators. In the combined single-dose groups and in the 6-mg multiple-dose group, BCVA increased from baseline to 28 days after the last dose administration by a median of 7 letters (range, 0-18 letters; n = 11) and 7.5 letters (range, 3-18 letters; n = 6), respectively. The corresponding median reduction from baseline in CST were 42 µm (range, -101 to 10 µm; n = 11) and -117 µm (range, -252 to -7 µm; n = 6), respectively. After multiple 3-mg RG7716 doses, no changes were observed in either BCVA (median, -0.5 letters; range, -9 to 8 letters; n = 6) or CST (median, -9 µm; range, -188 to -1 µm; n = 6). CONCLUSIONS: RG7716 was well tolerated and exhibited an overall favorable safety profile, with evidence of improvements in BCVA and anatomic parameters. These data support further evaluation of RG7716 in phase II trials.

Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children.

BACKGROUND: This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children. METHODS: The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90. RESULTS: No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29-0.88], p = 0.02). CONCLUSION: These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT00513669.

Elevated CO2 reduces sap flux in mature deciduous forest trees.

We enriched in CO2 the canopy of 14 broad-leaved trees in a species-rich, ca. 30-m-tall forest in NW Switzerland to test whether elevated CO2 reduces water use in mature forest trees. Measurements of sap flux density (JS) were made prior to CO2 enrichment (summer 2000) and throughout the first whole growing season of CO2 exposure (2001) using the constant heat-flow technique. The short-term responses of sap flux to brief (1.5-3 h) interruptions of CO2 enrichment were also examined. There were no significant a priori differences in morphological and physiological traits between trees which were later exposed to elevated CO2 (n=14) and trees later used as controls (n=19). Over the entire growing season, CO2 enrichment resulted in an average 10.7% reduction in mean daily JS across all species compared to control trees. Responses were most pronounced in Carpinus, Acer, Prunus and Tilia, smaller in Quercus and close to zero in Fagus trees. The JS of treated trees significantly increased by 7% upon transient exposure to ambient CO2 concentrations at noon. Hence, responses of the different species were, in the short term, similar in magnitude to those observed over the whole season (though opposite because of the reversed treatment). The reductions in mean JS of CO2-enriched trees were high (22%) under conditions of low evaporative demand (vapour pressure deficit, VPD <5 hPa) and small (2%) when mean daily VPD was greater than 10 hPa. During a relatively dry period, the effect of elevated CO2 on JS even appeared to be reversed. These results suggest that daily water savings by CO2-enriched trees may have accumulated to a significantly improved water status by the time when control trees were short of soil moisture. Our data indicate that the magnitude of CO2 effects on stand transpiration will depend on rainfall regimes and the relative abundance of the different species, being more pronounced under humid conditions and in stands dominated by species such as Carpinus and negligible in mono-specific Fagus forests.