"Results published today in The Journal of the Prevention of Alzheimers Disease JPAD describe analyses of Phase  data for the investigational amyloidtargeted drug tramiprosate in patients with Mild to Moderate Alzheimers disease AD. These efficacy analyses evaluated patient subgroups based on the number of e alleles of apolipoprotein E APOE a major genetic risk factor in up to  percent of patients with AD. The published results showed a genedose effect at the high dose of tramiprosate  mg twice daily with patients with two APOE alleles APOE homozygotes showing the largest clinical benefit those with one APOE allele APOE heterozygotes showing an intermediate benefit while APOE noncarriers showed no benefit from tramiprosate. The results published in JPAD are the first evidence from a large clinical trial to associate efficacy of an amyloidtargeted agent with APOE status in AD patients. The manuscript titled Clinical Benefits of Tramiprosate in Alzheimers Disease Are Associated with Higher Number of APOE Alleles The APOE GeneDose Effect is featured in the advanced online publication of The Journal of the Prevention of Alzheimers Disease JPAD with lead authors from Alzheon Inc. a biopharmaceutical company focused on treatments for neurodegenerative and neuropsychiatric disorders. Based on the analyses in the publication Alzheon is developing ALZ an optimized oral prodrug of tramiprosate and has refined the design of the pivotal clinical trial to evaluate ALZ as a potential diseasemodifying agent in symptomatic AD patients who are APOE homozygotes. Anton P. Porsteinsson MD Professor of Psychiatry at the University of Rochester School of Medicine and Dentistry and Director of the Alzheimers Disease Care Research and Education Program at the University of Rochester in Rochester NY and an investigator in the North American Phase  clinical trial commented The geneticallydefined population of APOE carriers has an  fold increased risk of developing AD and has more rapidly progressive disease usually becoming symptomatic a decade earlier than noncarriers of the APOE genotype. These analyses with tramiprosate in the APOE subgroups are compelling and suggest a meaningful clinical benefit on top of the existing symptomatic AD treatments in Alzheimers patients who are in great need of new treatments. We can apply these insights about the therapeutic response of APOE carriers to refine patient selection and potentially improve the success rate of new Alzheimers medicines. The efficacy and safety analyses with tramiprosate published in JPAD reveal a therapeutic effect in patients who are carriers of APOE after segmenting them from the larger nongeneticallydefined study population in the Phase  clinical program involving more than  AD patients in North America and Europe. In the overall Mild and Moderate AD study population with baseline MMSE of  and any APOE genotype the North American study did not demonstrate a significant benefit with either of two tramiprosate doses  mg BID and  mg BID compared to placebo during the week study period. As a result the European study was terminated before completion and the results were not previously published. To our knowledge this is the first time that the clinical benefits of an amyloidtargeted agent have been associated with the number of APOE alleles in Alzheimers patients. This new insight shows how we can apply a precision medicine approach in AD and develop this drug for the right patients namely patients with the APOE genotype which carries the highest risk as well as the earliest onset and faster disease progression said Martin Tolar MD PhD Founder President and CEO of Alzheon. These newlypublished findings form the basis for the design of our Phase  program and further support our companys commitment to advance ALZ into pivotal studies in APOE homozygous AD patients who represent up to  of AD patients. We are preparing to advance ALZ a promising new treatment for Alzheimers disease into confirmatory clinical studies in .  The observed genedose effects of tramiprosate in APOE carriers are consistent with the prevalence of amyloid pathology in AD patients. Amyloid imaging in AD clinical trials has shown the highest prevalence of positive amyloid scans in APOE homozygotes and the lowest prevalence in APOE noncarriers. As one of the few orallyadministered amyloidtargeted agents tramiprosate blocks the aggregation of beta amyloid monomers into toxic oligomers and was developed to show efficacy in patients with amyloid pathology and an accurate diagnosis of AD.  Efficacy Results in APOE Homozygous Patients from the JPAD Phase  Analyses The published results showed the largest clinical benefit in the Alzheimers APOE homozygous AD patients who represent approximately  percent of patients in the study. APOE homozygous patients who received the high dose of tramiprosate showed efficacy benefit compared to placebo on both cognitive and functional measures in the Phase  analyses. The effects on the ADAScog cognitive outcome were significant at Week  LS means difference from placebo . nominal p  . and Week  . nominal p  . and corresponded to  percent and  percent benefit from tramiprosate compared to placebo. These effects were supported by functional benefits on the CDRSB that showed a positive trend at Week  LS means difference from placebo . nominal p  . and were numerically in favor of tramiprosate at Week  . nominal p  ..  APOE homozygous AD patients are especially challenging since they are known to have the highest burden of amyloid pathology in cerebral cortex and blood vessels which explains their susceptibility to ARIAE with some amyloidtargeted treatments. In these new subgroup analyses the high dose of tramiprosate showed promising clinical effects in APOE homozygous AD patients already receiving maximal standard of care and this dose was not associated with any events of vasogenic edema said Susan Abushakra MD Chief Medical Officer of Alzheon and lead author on the JPAD publication. Replication of these findings in Alzheons planned Phase  study would provide a meaningful therapeutic advance for AD patients with the APOE genotype and we are now preparing to carry forward these results into the development of ALZ. Safety Results from the JPAD Phase  Analyses The safety profile of tramiprosate in  AD patients across the two studies was favorable and similar in the APOE carriers and noncarriers. The main adverse events were gastrointestinal nausea vomiting and weight loss which were mild or moderate in severity. New ARIAE safety analyses were reported in the JPAD publication. Brain magnetic resonance imaging MRI evaluations in  patients were conducted during the Phase  studies and did not reveal any events of vasogenic brain edema ARIAE or amyloidrelated imaging abnormalitiesedema on either dose of tramiprosate. Vasogenic edema or brain swelling is a side effect observed in clinical studies with some injectable antiamyloid antibodies which requires MRI monitoring and can occasionally be serious.  About Tramiprosate and the New Prodrug ALZ In  Alzheon obtained the license to tramiprosate and the associated portfolio of drug compounds along with the historical clinical dataset and applied new insights to the existing data. This led to the development of an optimized oral amyloidtargeted drug candidate ALZ. Alzheon developed ALZ as a novel oral prodrug of tramiprosate designed to improve the pharmacokinetic and gastrointestinal tolerability profile while retaining tramiprosate as the active agent in ALZ. Phase  studies in more than  subjects including healthy elderly showed that ALZ provides consistent plasma levels of tramiprosate with very low intersubject variability. The rate of nausea and vomiting was also lower than with tramiprosate tablets. ALZ at the dose of  mg provided equivalent systemic plasma exposures to tramiprosate  mg tablets. Alzheon is advancing ALZ into pivotal Phase  studies in the geneticallydefined APOE homozygous patients with Alzheimers disease. About Apolipoprotein E Apolipoprotein E or APOE is a gene that provides a predictive window into an individuals Alzheimers disease prognosis. APOE encodes for a protein called apolipoprotein E which combines with fats to form lipoproteins that can be moved throughout the body. In the brain apolipoprotein E helps shuttle cholesterol to neurons to support their normal function. There are three forms or alleles of the APOE gene called e e and e. The e allele has been found to correlate with high risk of developing Alzheimers disease. People who inherit one copy of the e allele APOE heterozygotes have an increased chance of developing the disease those who inherit two copies of the allele APOE homozygotes are at even greater risk and tend to have more aggressive disease. The e allele is significantly overrepresented in the Alzheimers disease population compared to the general population up to  percent of Alzheimers patients carry one or two copies of the e allele compared to about  percent of the general population.  About Alzheon Alzheon Inc. is committed to developing innovative medicines by directly addressing the underlying pathology of devastating neurodegenerative disorders. Our lead Alzheimers clinical candidate ALZ is a Phase ready firstinclass small molecule oral inhibitor of amyloid aggregation and neurotoxicity  hallmarks of Alzheimers disease. ALZ is a novel prodrug that builds on the safety and efficacy profile of the active compound tramiprosate which has been evaluated in clinical trials involving over  Alzheimers patients. Our clinical expertise and technology platform is focused on developing drug candidates using a precision medicine approach based on individual genetic and biological information to advance therapies with the greatest impact for patients.  Ward et al. Neuroepidemiology     Sevigny et al. Nature      Abushakra et al. J Prev Alz Dis . Advanced online publication http   Aisen et al Arch Med Science       Degenhardt et al. Psychosomatics     Sperling et al. Alzheimers  Dementia"