VXX-401, a novel anti-PCSK9 vaccine, reduces LDL-C in cynomolgus monkeys.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of disease burden in the world and is highly correlated with chronic elevations of LDL-C. LDL-C-lowering drugs, such as statins or monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), are known to reduce the risk of cardiovascular diseases; however, statins are associated with limited efficacy and poor adherence to treatment, whereas PCSK9 inhibitors are only prescribed to a "high-risk" patient population or those who have failed other therapies. Based on the proven efficacy and safety profile of existing monoclonal antibodies, we have developed a peptide-based vaccine against PCSK9, VXX-401, as an alternative option to treat hypercholesterolemia and prevent ASCVD. VXX-401 is designed to trigger a safe humoral immune response against PCSK9, resulting in the production of endogenous antibodies and a subsequent 30-40% reduction in blood LDL-C. In this article, VXX-401 demonstrates robust immunogenicity and sustained serum LDL-C-lowering effects in nonhuman primates. In addition, antibodies induced by VXX-401 bind to human PCSK9 with high affinity and block the inhibitory effect of PCSK9 on LDL-C uptake in a hepatic cell model. A repeat-dose toxicity study conducted in nonhuman primates under good laboratory practices toxicity indicated a suitable safety and tolerability profile, with injection site reactions being the main findings. As a promising safe and effective LDL-C-lowering therapy, VXX-401 may represent a broadly accessible and convenient option to treat hypercholesterolemia and prevent ASCVD.

Active immunotherapy and alternative therapeutic modalities for Alzheimer's disease.

As knowledge of Alzheimer's disease (AD) progression improves, the field has recognized the need to diversify the pipeline, broaden strategies and approaches to therapies, as well as delivery mechanisms. A better understanding of the earliest biological processes of AD/dementia would help inform drug target selection. Currently there are a number of programs exploring these alternate avenues. This meeting will allow experts in the field (academia, industry, government) to provide perspectives and experiences that can help elucidate what the pipeline looks like today and what avenues hold promise in developing new therapies across the stages of AD. The focus here is on Active Immunotherapies and Alternative Therapeutic Modalities. This topic includes active vaccines, antisense oligomers, and cell-based therapy among others, and highlights new clinical developments that utilize these modalities.

Kraepelinian and non-Kraepelinian schizophrenia subgroup differences in cerebral metabolic rate.

We studied two subtypes of schizophrenia. the Kraepelinian subtype (n = 10) characterized by an unremitting and severe course and the non-Kraepelinian subtype (n = 17) characterized by a remitting course and some periods of self-care. Patients were assessed with positron emission tomography (PET) with 18F-deoxyglucose (FDG) and high-resolution magnetic resonance imaging (MRI). A group of 32 age- and sex-matched normal volunteers served as comparison subjects. During the FDG tracer uptake period, patients performed a serial verbal learning task. MR images were segmented into gray, white and cerebrospinal fluid regions, and warped to average normal coordinates. PET images were coregistered to the MR images and similarly warpedfor analysis. Kraepelinian subtype patients were characterized by lower metabolic rates in the temporal lobe and cingulategyrus. and lower fronto/occipital ratios than non-Kraepelinian subtype patients. Exploratory statistical probability mapping alsorevealed lower metabolic rates in the right striatum in Kraepelinian versus non-Kraepelinian patients. These differences couldnot be attributed to differences in age, symptom severity, task performance during FDG uptake, or severity of involuntary movements. Factor analysis of the cortical surface identified significantly lower temporal lobe metabolic rates in Kraepelinian patients than non-Kraepelinian patients. A combined frontal/temporal deficit or greater cortical change may be associated with poorer longitudinal course.