Immunotherapy Regimes Dependent On APOE Status

a technology of immunotherapy and apoe status, applied in the direction of antibody medical ingredients, instruments, drug compositions, etc., can solve the problems of neuronal cell death and unroutinely performed genetic screening for e4 , to improve the safety of bapineuzumab

Inactive Publication Date: 2009-06-18
WYETH LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048]The invention further provides a method for improving the safety of bapineuzumab in patients having one or two ApoE4 alleles, comprising advising the physician to administer a lower dose of bapineuzumab to a patient having one or two ApoE alleles relative to that of a patient having zero ApoE alleles.
[0049]The invention further provides a method for improving the safety of bapineuzumab in patients having one or two ApoE4 alleles, comprising advising the physician to monitor the patient by MRI more frequently than a patient having one or two ApoE alleles relative to that of a patient having zero ApoE alleles.

Problems solved by technology

Accumulation of amyloid plaques in the brain eventually leads to neuronal cell death.
Nonetheless, even persons with two E4 alleles do not always get Alzheimer's disease.
Genetic screening for E4 has not been routinely performed, because it has not been known how to use this information for a therapeutic regime.

Method used

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  • Immunotherapy Regimes Dependent On APOE Status
  • Immunotherapy Regimes Dependent On APOE Status
  • Immunotherapy Regimes Dependent On APOE Status

Examples

Experimental program
Comparison scheme
Effect test

example 1

Phase 1 Trial

[0334]111 patients with a diagnosis of probable Alzheimer's disease (mild to moderate) were administered the humanized antibody bapineuzumab at doses ranging from 0.15 to 2.0 mg / kg in a multiple ascending dose study (MAD). Antibody was administered by intravenous infusion every thirteen weeks until the dosing regime is complete. Patients were also classified for ApoE4 status. Table 2 shows that eleven patients in the study experienced vasogenic edema detected by MRI. Table 2 also shows symptoms experienced in some of these patients; in other patients the vasogenic edema was asymptomatic. Table 3 shows the risk of vasogenic edema stratified by genotype irrespective of dose. The risk is only 2% in patients lacking an E4 allele but is 35% in patients with two E4 alleles. Table 4 shows the risk of vasogenic edema in only the highest dose group (2 mg / kg). The risk of vasogenic edema for patients with two E4 alleles is 60% and that for patients with one allele is 35%.

[0335]Ta...

example 2

Phase 2 Trial

[0336]A randomized double-blind placebo-controlled multiple ascending dose study was conducted on a population of 234 patients randomized from an initial population of 317 screened patients. Patients were assessed for ApoE4 carrier status, but carriers (homozygous and heterozygous) and non-carriers received the same treatment. Inclusion criteria were: probable Aβ diagnosis; aged 50-85 years; MMSE score 16-26; Rosen Modified Hachinski Ischemic score ≦4; Living at home or in a community dwelling with a capable caregiver; MRI consistent with diagnosis of Aβ; MRI scan of sufficient quality for volumetric analysis; stable doses of medication for treatment of non-excluded conditions; stable doses of AchEIs and / or memantine for 120 days prior to screen. The main exclusion criteria were: current manifestation of a major psychiatric disorder (e.g., major depressive disorder); current systemic illness likely to result in deterioration of the patient's condition; history or eviden...

example 3

Clinical Study of Subcutaneous Administration of Bapineuzumab in Alzheimer's Patients

[0360]Subcutaneous injections are generally easier to administer, which can be a consideration for patients with impaired mental function and coordination, or caregivers administering to an uncooperative patient. It is also easier to do at home, which is less upsetting to the patient, as well as less expensive. Finally, subcutaneous administration usually results in a lower peak concentration of the composition (Cmax) in the patient's system than intravenous. The reduced peak can reduce the likelihood of vasogenic edema.

[0361]For these reasons, a clinical study was designed for subcutaneous administration of bapineuzumab. The primary endpoints for the initial study are safety and bioavailability. Once these are established for subcutaneous administration, the cognitive tests described above will be administered to determine efficacy.

[0362]Under the initial regime, bapineuzumab is administered subcut...

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Abstract

The invention provides methods of immunotherapy of Alzheimer's and similar diseases in which the regime administered to a patient depends on the ApoE genotype of the patient.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]Provisional U.S. Application Nos. 60 / 999,423 and 61 / 083,827, filed Oct. 17, 2007 and Jul. 25, 2008, respectively, are incorporated by reference in their entirety for all purposes.REFERENCE TO A SEQUENCE LISTING[0002]The Substitute Sequence Listing written in file Sequence_Listing_for—15270C-000420US.txt is 164,721 bytes and was created on Oct. 14, 2008 for the instant application. The information contained in this file is hereby incorporated by reference.BACKGROUND OF THE INVENTIONI. General[0003]Alzheimer's disease (AD) is a progressive disease resulting in senile dementia. See generally Selkoe, TINS 16:403 (1993); Hardy et al., WO 92 / 13069; Selkoe, J. Neuropathol. Exp. Neurol. 53:438 (1994); Duff et al., Nature 373:476 (1995); Games et al., Nature 373:523 (1995). Broadly speaking, the disease falls into two categories: late onset, which occurs in old age (65+ years) and early onset, which develops well before the senile period, i.e., bet...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395C07K16/00C07H21/00A61P25/28
CPCA61K2039/505C07K16/18C07K16/2896C07K2317/24C07K2317/56C07K2317/34C07K2317/732C07K2317/734C07K2317/77G06Q99/00C07K2317/71
Inventor BLACK, RONALDEKMAN, LARSLIEBERBURG, IVANGRUNDMAN, MICHAELCALLAWAY, JAMESGREGG, KEITH M.JACOBSEN, JACK STEVENGILL, DAVINDERTCHISTIAKOVA, LIOUDMILAWIDOM, ANGELA
Owner WYETH LLC
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