Further Analyses of the Safety of Verubecestat in the Phase 3 EPOCH Trial of Mild-To-Moderate Alzheimer’s Disease

Background: Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. Methods: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. Results: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. Conclusions: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors

Climate geoengineering: issues of path-dependence and socio-technical lock-in

As academic and policy interest in climate geoengineering grows, the potential irreversibility of technological developments in this domain has been raised as a pressing concern. The literature on socio-technical lock-in and path dependence is illuminating in helping to situate current concerns about climate geoengineering and irreversibility in the context of academic understandings of historical socio-technical development and persistence. This literature provides a wealth of material illustrating the pervasiveness of positive feedbacks of various types (from the discursive to the material) leading to complex socio-technical entanglements which may resist change and become inflexible even in the light of evidence of negative impacts. With regard to climate geoengineering, there are concerns that geoengineering technologies might contribute so-called ‘carbon lock-in’, or become irreversibly ‘locked-in’ themselves. In particular, the scale of infrastructures that geoengineering interventions would require, and the issue of the so-called ‘termination effect’ have been discussed in these terms. Despite the emergent and somewhat ill-defined nature of the field, some authors also suggest that the extant framings of geoengineering in academic and policy literatures may already demonstrate features recognizable as forms of cognitive lock-in, likely to have profound implications for future developments in this area. While the concepts of path-dependence and lock-in are the subject of ongoing academic critique, by drawing analytical attention to these pervasive processes of positive feedback and entanglement, this literature is highly relevant to current debates around geoengineering

CORPORATIONS--CORPORATE POLICY, THE CURE-ALL FOR PROXY SOLICITATION AILMENTS

All too often lawyers and students of law are inclined to assume that some principle or formula· has become so deeply rooted in the law that it has acquired a sanctity which gives it an all-embracive effect, a cure-all, as it were, for legal ailments. This has been the usual approach when the question has arisen of the propriety of spending corporate funds to solicit proxies. The ever-faithful panacea has been to say, quite automatically, that where the intra-corporate contest is concerned with matters of policy as distinguished from personnel of management, then corporate funds may be used to inform the stockholders of the policy issues and to secure their support of the views advocated by the management. While there has been an occasional case which would seem to reject this approach, the policy formula as a justification for corporate expenditures has enjoyed some popularity. A statement of the Delaware court indicates that the formula may have even grown beyond the point of being a judicial cure accepted primarily because of its supposed virtues. The Delaware court has said, Moreover, for good or evil, the incumbent board of directors of a Delaware corporation may look to the corporation for payment of expenses incurred by them in soliciting proxies where a question of policy is involved

Modelling longevity bonds: Analysing the Swiss Re Kortis bond

A key contribution to the development of the traded market for longevity risk was the issuance of the Kortis bond, the world's first longevity trend bond, by Swiss Re in 2010. We analyse the design of the Kortis bond, develop suitable mortality models to analyse its payoff and discuss the key risk factors for the bond. We also investigate how the design of the Kortis bond can be adapted and extended to further develop the market for longevity risk

Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division

Rac1 regulates a wide variety of cellular processes. The polybasic region of the Rac1 C terminus functions both as a plasma membrane–targeting motif and a nuclear localization sequence (NLS). We show that a triproline N-terminal to the polybasic region contributes to the NLS, which is cryptic in the sense that it is strongly inhibited by geranylgeranylation of the adjacent cysteine. Subcellular fractionation demonstrated endogenous Rac1 in the nucleus and Triton X-114 partition revealed that this pool is prenylated. Cell cycle–blocking agents, synchronization of cells stably expressing low levels of GFP-Rac1, and time-lapse microscopy of asynchronous cells revealed Rac1 accumulation in the nucleus in late G2 and exclusion in early G1. Although constitutively active Rac1 restricted to the cytoplasm inhibited cell division, activated Rac1 expressed constitutively in the nucleus increased the mitotic rate. These results show that Rac1 cycles in and out of the nucleus during the cell cycle and thereby plays a role in promoting cell division