Alzheon Announces Efficacy Analyses of Prior Tramiprosate Phase 3 Studies Showing Clinically Meaningful Benefits on Key Clinical Endpoints in Alzheimer's Disease Patients with APOE4 Genotype
Results Support Advancement of ALZ‐801 into Pivotal Clinical Studies in APOE4/4 Homozygous Subjects with Mild to Moderate Alzheimer's Disease
Data Presented at the 14th Annual International Athens/Springfield Symposium on Advances in Alzheimer Therapies Conference
March 11, 2016 12:01 AM Eastern Standard Time
FRAMINGHAM, Mass.--(BUSINESS WIRE)--Alzheon, Inc., today announced the presentations of new data analyses from two Phase 3 studies of tramiprosate in Alzheimer's disease (AD) patients based on their APOE4 genotype. Tramiprosate is the biologically active agent of ALZ-801, a prodrug developed by Alzheon and currently being advanced into pivotal Phase 3 studies in AD patients with the APOE4/4 homozygous genotype, a patient population known to have high prevalence and burden of cortical amyloid pathology, a hallmark of Alzheimer's disease.
The new subgroup analyses of the tramiprosate Phase 3 trials showed that patients with one or two copies of the ε4 allele of apolipoprotein E, referred to as APOE4, who received tramiprosate had clinically meaningful benefit on cognition and/or function on top of standard of care through 78 weeks of treatment. Data from the APOE4/4 homozygous subgroup in the North American study suggested a dose-dependent clinical benefit at the high dose of tramiprosate (150mg twice daily) compared to placebo (N = 147, nominal p-value = 0.04). APOE4 heterozygous subjects showed lower magnitude of effect with a significant clinical benefit on function at both doses, and positive trends on cognition at the 100mg twice-daily dose of tramiprosate. Patients who were APOE4 non-carriers did not show benefit from tramiprosate at either dose. The safety profile was similar in the APOE4 carriers and non-carriers, and consistent with published safety analyses in the overall study population.
These analyses are being presented today in podium presentations at the 14th Annual International Athens/Springfield Symposium on Advances in Alzheimer Therapies Conference, held March 9-12 in Athens, Greece.1 These data provide further support for Alzheon's plan for Phase 3 pivotal trials of ALZ‐801, an optimized prodrug of tramiprosate, in the genetically defined APOE4/4 homozygous population of subjects with Mild to Moderate Alzheimer's disease.
"These results are consistent with our understanding of the gene dose effect of amyloid pathology across APOE4/4 homozygous, APOE4 heterozygous, and APOE4 non-carrier patients with Alzheimer's disease," said Susan Abushakra, MD, Chief Medical Officer of Alzheon. "The APOE4 subgroups which are known to have the highest prevalence of amyloid pathology are the Alzheimer's patients showing the greatest benefit from tramiprosate, an agent that blocks aggregation and toxicity of soluble beta amyloid aggregates."
Data from the North American and European Phase 3 studies of tramiprosate described in the presentations summarize safety and efficacy based on the number of APOE4 alleles in Alzheimer's patients. The efficacy analyses describe clinical effects of two active doses of tramiprosate (100 mg and 150 mg twice daily) and placebo on the co‐primary clinical outcomes the Alzheimer's Disease Assessment Scale‐Cognitive subscale (ADAS-cog) and the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) in APOE4/4 homozygous and APOE4 heterozygous Alzheimer's patients.
In the merged data sets, tramiprosate showed a favorable safety profile that was similar across all three APOE4 subgroups. The most common adverse events were nausea and vomiting, and there was a dose-dependent increase in their incidence. In the APOE4/4 homozygous AD patients, the incidence of serious adverse events was similar to placebo. Of note, there were no events of vasogenic edema or amyloid related imaging abnormalities (ARIA) on active drug observed in the subset of patients who underwent MRI imaging in the two studies (N= 426).
"We are excited to present our findings that connect the molecular mechanism of tramiprosate to the APOE4 genotypes in patients with Alzheimer's disease. These results suggest utility of ALZ-801, an optimized prodrug of tramiprosate, in patients with the most aggressive disease course and the greatest need for an effective treatment," commented Martin Tolar, MD, PhD, Founder, President and Chief Executive Officer of Alzheon. "Together, the favorable safety profile and the meaningful efficacy results on top of standard of care support our accelerated plans for the development of ALZ-801 in APOE4/4 homozygous Alzheimer's patients, and we look forward to initiating the Phase 3 study for ALZ-801 in the near future."
About Apolipoprotein E
Apolipoprotein E, or APOE is a human gene that provides a predictive window into an individual's Alzheimer's disease prognosis. APOE gene 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 alleles, or forms, of APOE gene, called ε2, ε3 and ε4. The ε4 allele has been found to correlate with risk of developing Alzheimer's disease. People who inherit one copy of the ε4 allele, i.e., APOE4 heterozygous, have an increased chance of developing the disease; those who inherit two copies of the allele, i.e., APOE4/4 homozygous, are at even greater risk and tend to have more aggressive disease. The ε4 allele is significantly overrepresented in the Alzheimer's population compared to the general population: 60 percent of Alzheimer's patients carry one or two copies of the ε4 allele vs. 25 percent of the general population.
Alzheon, Inc. is committed to developing innovative medicines for patients suffering from Alzheimer's disease and other neurological and psychiatric disorders. Our lead clinical candidate, ALZ‐801, is a first in‐class, oral inhibitor of amyloid aggregation and neurotoxicity – hallmarks of Alzheimer's disease. ALZ‐801 is an optimized, novel prodrug that builds on the established safety and efficacy profile of the active compound in clinical trials of more than 2,000 patients. Our mission is to apply our discovery platform and development experience to unlock new classes of therapeutics that make a difference in patients' lives by directly addressing the underlying pathology of devastating neurodegenerative disorders. For more information, please visit www.alzheon.com.
1 The presentations will be included in the Emerging Novel Therapeutic Targets II session:
Title: "Tramiprosate, an oral amyloid anti-aggregation agent, shows robust cognitive efficacy in APOE4/4 homozygous AD Patients: Efficacy and safety analyses from two Phase 3 trials"
Presenter: Susan Abushakra
Authors: Susan Abushakra, Bruno Vellas, Jeffrey Cummings, Jakub Hort, Anton Porsteinsson, John A. Hey, Aidan Power, Martin Tolar
Title: "Efficacy of tramiprosate in APOE4 heterozygous patients with mild to moderate Alzheimer's disease: Combined sub-group analyses from two Phase 3 trials"
Presenter: Martin Tolar
Authors: Martin Tolar, Bruno Vellas, Jeffrey Cummings, Anton Porsteinsson, Susan Abushakra, Aidan Power, Jeremy Yu, John A. Hey
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