Safety and Pharmacology of Ponezumab (PF-04360365) After a Single 10-Minute Intravenous Infusion in Subjects With Mild to Moderate Alzheimer Disease

Burstein, Aaron H.; Zhao, Qinying; Ross, Joel; Styren, Scot; Landen, Jaren W.; Wendy, Weidong; McCush, Fred; Alvey, Christine; Kupiec, James W.; Bednar, Martin M.

doi:10.1097/wnf.0b013e318279bcfa

Cited by 46 publications

(19 citation statements)

References 11 publications

(9 reference statements)

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“…Immunotherapeutic agents like bapineuzumab, solanezumab, gantenerumab, ponezumab and crenezumab have a high affinity to antigenic determinant epitopes of beta-amyloid 6 . They are then recognized by the B and T cells and cleared from the brain (Burstein et al 2013). A vaccine CAD106 undergoing phase 1 trial may be able to reduce beta-amyloid accumulation by binding to the amyloid aggregates and blocking cellular toxicity.…”

Section: Introductionmentioning

confidence: 99%

Can the retina be used to diagnose and plot the progression of Alzheimer's disease?

Mahajan

Votruba

2017

Acta Ophthalmologica

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Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of senile dementia. It impairs the quality of life of a person and their family, posing a serious economic and social threat in developed countries. The fact that the diagnosis can only be definitively made post‐mortem, or when the disease is fairly advanced, presents a serious problem if novel therapeutic interventions are to be devised and used early in the course of the disease. There is therefore a pressing need for more sensitive and specific diagnostic tests with which we can detect AD in the preclinical stage. The tau proteins and beta‐amyloid proteins start to accumulate 20 years before the symptoms begin to manifest. Detecting them in the preclinical stage would be a potential breakthrough in the management of AD. A high degree of clinical suspicion is needed to correlate problems in cognition with the changes in the eye, particularly the retina, pupil and ocular movements, so that the disease can be detected early and managed in the prodromal phase. In this systematic review, we ask the question whether the retina can be used to make a specific and early diagnosis of AD.

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Section: Introductionmentioning

confidence: 99%

Can the retina be used to diagnose and plot the progression of Alzheimer's disease?

Mahajan

Votruba

2017

Acta Ophthalmologica

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“…A short single intravenous infusion of ponezumab results in a very marked increase in plasma levels of both Ab42 and Ab40 (Burstein et al, 2013). This was verified in a phase I randomized, double-blind, placebo-controlled clinical trial in mild-to-moderate AD patients, which also showed that ponezumab, to a much lesser extent, increased the CSF Ab level (Landen et al, 2013).…”

Section: Passive Immunotherapymentioning

confidence: 71%

“…Ponezumab (PF-04360365) is a humanized monoclonal anti-Ab antibody with an epitope on the C terminus (AbX-40) of the Ab protein (La Porte et al, 2012;Burstein et al, 2013). Ponezumab binds only to soluble Ab, but not to fibrillar Ab or plaques, probably as the C terminus is not as exposed as the N terminus in Ab fibrils and plaques (Landen et al, 2013).…”

Section: Passive Immunotherapy With Anti-ab Antibodiesmentioning

confidence: 99%

Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer’s Disease

Blennow

Hampel

Zetterberg

2013

Neuropsychopharmacol

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Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.

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“…Following these encouraging studies in mice, a phase I clinical trials was initiated. Reportedly, Ponezumab increased plasma and CSF Aβ 40 levels in a dose dependent fashion with minimal adverse effects (Burstein et al 2013; Landen et al 2013). Similarly, a phase II trial demonstrated increased plasma Aβ 40 levels with good tolerance.…”

Section: Passive Immunization Targeting Aβmentioning

confidence: 98%

Antibody Therapeutics Targeting Aβ and Tau

Gallardo

Holtzman

2017

Cold Spring Harb Perspect Med

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Safety and Pharmacology of Ponezumab (PF-04360365) After a Single 10-Minute Intravenous Infusion in Subjects With Mild to Moderate Alzheimer Disease

Abstract: Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma Aβ species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.

Cited by 46 publications

References 11 publications

Can the retina be used to diagnose and plot the progression of Alzheimer's disease?

Can the retina be used to diagnose and plot the progression of Alzheimer's disease?

Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer’s Disease

Antibody Therapeutics Targeting Aβ and Tau

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