Positive results from two phase 1b studies of ALZ-801 (Alzheon Inc.) have provided the clinical data necessary to move ALZ-801 into a pivotal phase 3 program in patients with Alzheimer’s disease (AD) who are homozygous for the epsilon-4 allele of the apolipoprotein E gene (APOE4/4). ALZ-801 is an “optimized” prodrug of tramiprosate. In 2009, tramiprosate failed to improve cognition in a broad set of AD patients.
The new results demonstrated favorable gastrointestinal (GI) tolerability and consistent, sustained plasma levels, and allowed the selection of an ALZ-801 clinical dose. These data will be presented at the Alzheimer’s Association International Conference (AAIC), now under way in Toronto, Canada.
During the past decade, the failure rate for investigational AD drugs has been a staggering 99%, according to FierceBiotech. While AD medications, such as donepezil (Aricept, Pfizer/Eisai) and others (as well as generics), are on the market, they do not have a long-term curative effect, and are described by physicians as merely “lifting the fog” for a few weeks or months, only to have the disease return.
The two phase 1b clinical studies of ALZ-801 were conducted in healthy elderly volunteers: a single-dose tablet bioequivalence study, and a multiple ascending-dose safety, tolerability, and pharmacokinetic study. In these investigations, ALZ-801 demonstrated favorable pharmacokinetic (PK) properties, including steady target plasma levels with low intersubject variability as well as sustained plasma concentrations for up to 24 hours. ALZ-801 also showed an equivalent or improved PK profile compared with that of tramiprosate, including plasma exposures and dose proportionality. Moreover, ALZ-801 achieved favorable safety and tolerability profiles, including improved GI tolerability with a lower incidence of nausea and vomiting, compared with those of previous studies with tramiprosate.
Clinical data analyses from prior phase 3 trials of tramiprosate, the active compound in ALZ-801, are also being presented at the AAIC. APOE4 subgroup analyses of the tramiprosate phase 3 studies showed clinically meaningful beneficial effects on cognitive and functional endpoints in patients with mild or moderate AD who were APOE4/4 homozygotes. The long-term safety profile was favorable in the phase 3 studies, and was similar in APOE4 carriers and noncarriers. AD patients who are APOE4/4 homozygotes have a high prevalence and burden of cortical and vascular amyloid pathology, and are at high risk for the occurrence of vasogenic edema with some amyloid-targeted drug agents. No brain edema occurred in the magnetic resonance imaging (MRI) subset of 426 patients treated with tramiprosate in the phase 3 studies.
APOE is a gene that provides a predictive window into a patient’s AD prognosis. The APOE gene encodes for the apolipoprotein E (APOE) protein, which combines with fats to form lipoproteins that can be moved throughout the body. In the brain, APOE helps transport cholesterol to neurons to support their normal function. There are three alleles (forms) of the APOE gene: epsilon-2, epsilon-3, and epsilon-4. The epsilon-4 allele has been found to correlate with a high risk of developing AD. People who inherit one copy of the epsilon-4 allele, APOE4 heterozygotes, have an increased chance of developing the disease; those who inherit two copies of the allele, APOE4 homozygotes, are at even greater risk and tend to have more-aggressive disease. The epsilon-4 allele is significantly over-represented in AD patients compared with the general population: approximately 60% of AD patients carry one or two copies of the epsilon-4 allele compared with approximately 25% of the general population.