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INTRODUCTION The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O‐GlcNAcylation, an important post‐translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O‐GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O‐GlcNAcase (OGA) catalyzes the removal of O‐GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD. METHODS A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure‐based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O‐GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy. RESULTS Ceperognastat is a potent, central nervous system (CNS)‐penetrant, low‐dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat. DISCUSSION Ceperognastat is an orally available, highly potent, CNS‐penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O‐GlcNAc‐tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program. Highlights Ceperognastat is a highly potent, CNS‐penetrant OGA inhibitor. Ceperognastat is both orally available and CNS‐penetrant even when given at low doses. Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain. Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.

The impact of first-generation covalent KRAS G12C inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS G12C inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS G12C -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS G12C even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS G12C inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS G12C mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically. The success of KRAS G12C mutation specific inhibitors in patients with KRAS-driven tumours is limited by the emergence of acquired resistance. Here, the authors characterise olomorasib, a next-generation covalent KRAS G12C-mutant inhibitor, demonstrating efficacy in the presence of clinically relevant resistance mutations in preclinical KRAS-driven cancer models.

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)) 1 , 2 . Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K IV ) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3 – 7 ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K IV 7–8. We identify compounds that bind to apo(a) K IV 7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a). Biochemical screening and optimization identify small molecules that inhibit the formation of lipoprotein(a), and these inhibitors reduce the levels of Lp(a) in several animal models, suggesting that they could provide a therapeutic option in humans.

The impact of first-generation covalent KRAS inhibitors has been reduced due to the development of drug resistance, tolerability and challenges combining with immunotherapy. We designed olomorasib, a next-generation GDP-binding KRAS inhibitor, for nanomolar potency as well as selectivity over wild-type inhibition. In both in vitro and in vivo models of KRAS -mutant cancers, olomorasib reduces RAS activity and pERK levels, leading to substantial and significant tumor growth inhibition. Additionally, olomorasib combined with immune checkpoint inhibitors demonstrates greater anti-tumor activity compared to monotherapy. Furthermore, we demonstrate that olomorasib binds tightly to KRAS even in the presence of clinically relevant second site mutations, a known mechanism of resistance and limitation to currently approved KRAS inhibitors. These findings suggest that olomorasib could be effective for patients with KRAS mutant cancers either as monotherapy or in combination with immunotherapy. Olomorasib monotherapy and combination treatments are currently being investigated clinically.

Abstract SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection. One Sentence Summary LY-CoV555, an anti-spike antibody derived from a convalescent COVID-19 patient, potently neutralizes SARS-CoV-2 and protects the upper and lower airways of non-human primates against SARS-CoV-2 infection. Competing Interest Statement M.J.M. has research grant funding from NIH/NIAID, Pfizer, and Sanofi; and personal fees from Meissa Vaccines, Inc. B.E.J., P.LB., J.D., T.P.C., C.M.W., J.L.B., B.A.H., R.E.H., D.B., D.F., M.H.P., F.J.T., J.H., A.P., A.C.A. and S.J.B. are employees and stockholders of Eli Lilly and Company. K.W., R.B., L.K., S.J.H., S.S., B.C.B, and E.F. are employees of AbCellera Biologics Inc. C.L.H., R.G., D.P., P.X., Y.H., R.B., K.R.J. M.A.S., S.Z., D.W.C., and S.A.T. are employees and stockholders of AbCellera Biologics Inc.. K.M. is a former employee and stockholder of AbCellera Biologics Inc. M.D. received a contract from Eli Lilly and Company to support the studies reported herein. Authors from AbCellera Biologics Inc., National Institute of Allergy and Infectious Diseases (K.S.C., B.S.G., and J.R.M.), and Eli Lilly and Company are inventors on patent applications related to the work described here. R.S.B., D.R.M., R.W.C., T.W.G, V.B., O.A., L.W., H.M.B., M.D.V., A.D., M.S., J.A.G., C.L.H., N.V.J., J.S.M., and D.W. declare no competing interests. Footnotes * References have been updated in the main text and supplemental