Name:	Ponezumab
Other Names:	PF-04360365
Therapeutic Applications:	Mild to moderate AD
Therapy Types:	Protein: humanized monoclonal antibody against Aβ
Mechanisms:	Designed to bind and remove the Aβ peptide that accumulates in the brain.
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Immunotherapy approaches to the treatment of Alzheimer disease is based on the ability of antibodies raised against Aβ peptides to bind to and clear Aβ from the brain, thus removing the peptide and inhibiting the damage to neurons that Aβ inflicts. Ponezumab (PF-04360365) is a humanized anti-amyloid monoclonal antibody (IgG2deltaA) that recognizes and binds the free carboxy terminal amino acids 33-40 of the amyloid beta 1-40 peptide and is a passive immunotherapy treatment. The treatment with antibodies should bind and clear Aβ, with the potential added benefit of a better safety and tolerability profile. Examples of passive immunotherapy include Intravenous Immunoglobulin, Bapineuzumab, Solanezumab and Ponezumab. Ponezumab specifically targets the C-terminal end (aa33-40) of Aβ, whereas Bapineuzumab targets the N-terminal end (aa1-5) and Solanezumab recognizes and binds an interior peptide sequence (aa16-24).
Role in Alzheimer's Disease:	Phase 1 studies of Ponezumab have been completed and have shown that plasma Aβ and time to Cmax (Tmax) increased dose-dependently. At the 10 mg/kg dose group, mean CSF Aβ percentage change from baseline at Day 29 increased 38%, 29%, and 15% for Aβ1-x, Aβ1-40, and Aβ1-42, respectively (Zhao et al 2010). Immunoprecipitation followed by MALDI-TOF MS (IP/MS) revealed the Aβ peptide profile in cerebrospinal fluid (CSF) from patients with mild-to-moderate AD before and after a single dose of ponezumab. Acute administration of ponezumab to AD patients elevated Aβ1-40 and Aβ11-40 in CSF, demonstrating that peripheral administration of ponezumab affects central Aβ levels (Wood et al., 2010).
Side Effects:	In Phase 1 testing of Ponezumab in Japanese patients with mild to moderate AD, a single-dose infusion of ponezumab was well-tolerated over the 0.1-10 mg/kg dose range. No serious adverse effects were observed. The most common adverse event was headache (in 4 patients), while neck pain, contact dermatitis, decreased weight, upper respiratory tract infection and herpes zoster were reported (2 patients each). No anti-drug antibodies (ADAs) were detected (Fujimoto et al 2010).
Companies:	Pfizer, Inc.
Notes:	Ponezumab became inactive in November 2011 (see ARF news story). For clinical trials of Ponezumab on clinicaltrials.gov see Ponezumab trials.

References

Zhao Q, Landen J, Burstein AH, et al. Pharmacokinetics and pharmacodynamics of ponezumab (PF-04360365) following a single-dose intravenous infusion in patients with mild to moderate Alzheimer's disease. Alzheimer Dement. 2010;6(4 suppl 1):S143-S143. Abstract

Fujimoto Y, Miyoshi I, Ishibashi T, Togo K, Abe S, Kupiec JW, Bednar MM. Safety of the anti-amyloid monoclonal antibody ponezumab (PF-04360365) following a single-dose intravenous infusion in Japanese patients with mild-to-moderate Alzheimer's disease: Preliminary results. Alzheimer's & Dementia 6 (4S): S310. Abstract

Wood KM, McCush F, Conboy JJ, et al. IP/MS analysis of human CSF Abeta following a single dose of the C-terminal anti-Abeta antibody ponezumab (PF-04360365) to Alzheimer patients. Alzheimer Dement. 2010;6(4 suppl 1):S311-S311. Abstract