Elan and Wyeth recently announced results from Phase II clinical trials for the investigational Alzheimer’s drug bapineuzumab that shows the drug may be beneficial in patients who are non-carriers of the ApoE4 allele.
The study partners told Pharmacogenomics Reporter this week that it is too early to speculate whether they will develop a companion diagnostic for bapineuzumab. However, in Phase III studies, which began enrolling patients in December, patients will be stratified into ApoE carriers and non-carriers via blood sample-based ApoE genotyping.
Although the 18-month Phase II trial did not reach statistical significance on primary efficacy endpoints in the overall study population, post-hoc analyses showed that bapineuzumab yielded “statistically significant and clinically meaningful benefits” in ApoE4 non-carriers on a number of primary endpoints.
These included the Alzheimer's Disease Assessment Scale (ADAS-cog), the Neuropsychological Test Battery (NTB), the Mini Mental State Examination (MMSE), and the Clinical Dementia Rating - Sum of Boxes (CDR-SB).
“A favorable directional change” was also seen on the Disability Assessment Scale for Dementia (DAD), “although this was not statistically significant,” Elan reported in a statement.
Phase II study results supported the companies’ decision to move ahead with Phase III studies.
Wyeth and Elan declined to discuss whether bapineuzumab would be specifically indicated in the ApoE4 non-carrier population. “It would be inappropriate to speculate about potential labeling based on preliminary results of a Phase II study,” a Wyeth spokesperson told Pharmacogenomics Reporter.
While Wyeth and Elan also are not prepared to discuss the possibility of a companion diagnostic for bapineuzumab, there is already a commercially available ApoE4 test available on the market. Athena Diagnostics markets homebrew tests for the early onset of Alzheimer’s disease and the evaluation of Alzheimer’s based on its ADmark brand of assays.
The evaluation test detects ApoE2, ApoE3, and ApoE4 alleles through ELISA and Serial Invasive Signal Amplification Reaction. The early-onset test detects mutations in the PS-1, PS-2, and APP genes through PCR and DNA sequencing.
Phase II Results
Wyeth and Elan are touting bapineuzumab as “the first humanized monoclonal antibody in late-stage investigation for the potential treatment for Alzheimer's disease.” Bapineuzumab is designed to clear toxic beta amyloid proteins, comprising neuritic plaques in the brain, which are implicated in Alzheimer's disease pathology.
The study involving 240 mild-to-moderate Alzheimer’s patients was carried out at 29 sites in the US and tested four doses of bapineuzumab (0.15 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) with approximately 60 patients in each dose cohort.
As Alzheimer's disease progresses, patients lose brain volume and gain ventricular volume. Preliminary evaluation of MRI results in the study showed that ApoE4 non-carriers, which represent between 40 percent and 70 percent of the Alzheimer’s disease population, had less brain-volume loss among bapineuzumab-treated patients versus placebo patients.
“AIP research focuses on the beta amyloid hypothesis, as the companies believe that enhancing the clearance of beta amyloid in the brain may provide a new treatment approach for Alzheimer's disease.”
ApoE4 non-carriers treated with the drug also had less increases in ventricular volume over placebo-treated patients. While the former finding was statistically significant, the latter was not, the companies reported. Additionally, MRI results showed favorable treatment-related clinical changes in non-carriers.
In carriers of the ApoE4 allele, no clinical benefits or statistically significant effects were observed on efficacy endpoints or the brain-volume endpoint. However, “preliminary analyses suggest possible increase of ventricular volume in treated patients versus placebo patients,” Elan said in a statement, but added that the “clinical significance of this finding is currently unclear and analyses are ongoing.”
The randomized, double-blind, placebo-controlled Phase III program will involve 4,000 patients with mild-to-moderate Alzheimer’s disease. The studies will be carried out at 350 sites worldwide for 18 months of efficacy evaluation.
According to the Wyeth spokesperson, each of the four Phase III studies will have two primary endpoints, one cognitive and one functional, which will be evaluated using neuropsychiatric scales and imaging and biomarker analysis, as well as other methods.
There will be two studies in carriers of the ApoE4 allele, while two studies will focus on non-carriers. For both cohorts, one study will be in North America, and another will enroll patients from the EU, Australia, and South Africa.
In Phase II studies, adverse events were common in both placebo and bapineuzumab-treated patients, with a similar number of ApoE4 non-carriers and carriers experiencing serious adverse events. However, researchers observed serious adverse events more frequently in bapineuzumab-treated ApoE4 carriers than in placebo patients.
Particularly, vasogenic edema was reported in the treated population with an increased frequency in carriers and at higher doses of bapineuzumab. No cases of the adverse event were reported in placebo patients.
“In the ongoing Phase 3 studies, carriers of the ApoE4 allele are being treated with a lower dose to minimize the risk of vasogenic edema,” Elan reported. “The overall safety findings from this Phase II trial support their prior decision to move to Phase III studies.”
Bapineuzumab is the lead compound in Wyeth and Elan’s Alzheimer's Immunotherapy Program, formed in 2000. Under the collaboration, the companies aim to research, develop, and commercialize immunotherapeutic approaches to prevent the onset of Alzheimer's disease.
“AIP research focuses on the beta amyloid hypothesis, as the companies believe that enhancing the clearance of beta amyloid in the brain may provide a new treatment approach for Alzheimer's disease,” the Wyeth spokesperson said.
While Elan and Wyeth are claiming that bapineuzumab is the first monoclonal antibody in late stage clinical trials for Alzheimer’s, they are not the only companies looking at the role of ApoE4 alleles to develop a drug for the indication.
Broomfield, Colo.-based Accera and researchers at the University of Washington in 2002 studied the efficacy of a medical food product, called Ketasyn, in a subgroup of patients lacking the ApoE4 genotype. Accera is planning to submit its application sometime this summer to the US Food and Drug Administration for Ketasyn, an orally administered liquid compound that provides glucose-deprived brain cells an alternative energy source [see PGx Reporter 11-07-2007].
An Elan official told Pharmacogenomics Reporter that there were other treatments for Alzheimer’s under development as part of the AIP collaboration. However, the official did not elaborate on these projects, saying that the compounds are in various stages of clinical and pre-clinical development.