Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease, Cerebral Amyloid Angiopathy
U.S. FDA Status: Alzheimer's Disease (Discontinued), Cerebral Amyloid Angiopathy (Discontinued)
Approved for: None
Ponezumab (PF-04360365) is a therapeutic antibody originally developed by the small biotech company Rinat Neuroscience. It is a humanized IgG2δA monoclonal antibody that binds the free carboxy terminal amino acids 33-40 of the Aβ 1-40 peptide (see La Porte et al., 2012). The antibody drew widespread attention in 2006, when Pfizer acquired Rinat Neuroscience for a reported several hundred million dollars. Subsequent preclinical research reported a beneficial effect on reducing amyloid deposition in cerebral blood vessels along with improved vascular function, suggesting a possible application of ponezumab in cerebral amyloid angiopathy (CAA, see Bales et al., 2016).
Five Phase 1 trials tested ponezumab's safety and pharmacokinetics in Western and Japanese patients with mild to moderate disease. They showed acceptable safety without findings of antibody-induced microhemorrhage, amyloid-related imaging abnormalities (ARIA), or encephalitis, but only a small proportion of the antibody was detectable in the CSF.
Two Phase 2 trials concluded in 2011. One study of 198 patients with mild to moderate Alzheimer's confirmed adequate safety and showed a plasma Aβ40 increase with treatment, suggesting a potential peripheral sink effect. A second trial of 36 patients with mild to moderate AD, however, showed no efficacy on the primary endpoints of change in brain or CSF Aβ burden, nor on secondary endpoints of cognition and function (see Landen et al., 2017; Landen et al., 2017). Development of ponezumab for Alzheimer's disease was discontinued.
Between June 2013 and September 2015, Pfizer conducted a Phase 2 study of ponezumab in 36 patients with cerebral amyloid angiopathy (CAA). Three infusions of ponezumab or placebo over the course of 60 days were evaluated for changes in cerebrovascular reactivity as measured by BOLD fMRI, as well as for cerebral edema, infarcts, Aβ, cognitive change and other secondary outcomes. Ponezumab showed drug-placebo differences, but did not meet the primary endpoint (for details, see posted results).
In 2016, Pfizer dropped ponezumab from its pipeline.
For all ponezumab trials, see clincialtrials.gov.
Clinical Trial Timeline
- Landen JW, Cohen S, Billing CB Jr, Cronenberger C, Styren S, Burstein AH, Sattler C, Lee JH, Jack CR Jr, Kantarci K, Schwartz PF, Duggan WT, Zhao Q, Sprenger K, Bednar MM, Binneman B. Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy. Alzheimers Dement (N Y). 2017 Sep;3(3):339-347. Epub 2017 May 10 PubMed.
- Landen JW, Andreasen N, Cronenberger CL, Schwartz PF, Börjesson-Hanson A, Östlund H, Sattler CA, Binneman B, Bednar MM. Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study. Alzheimers Dement (N Y). 2017 Sep;3(3):393-401. Epub 2017 Jun 8 PubMed.
- La Porte SL, Bollini SS, Lanz TA, Abdiche YN, Rusnak AS, Ho WH, Kobayashi D, Harrabi O, Pappas D, Mina EW, Milici AJ, Kawabe TT, Bales K, Lin JC, Pons J. Structural basis of C-terminal β-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease. J Mol Biol. 2012 Aug 24;421(4-5):525-36. Epub 2011 Dec 13 PubMed.
- Bales KR, O'Neill SM, Pozdnyakov N, Pan F, Caouette D, Pi Y, Wood KM, Volfson D, Cirrito JR, Han BH, Johnson AW, Zipfel GJ, Samad TA. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity. Brain. 2016 Feb;139(Pt 2):563-77. Epub 2015 Oct 22 PubMed.
- Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing CB, Bales K, Alvey C, McCush F, Yang J, Kupiec JW, Bednar MM. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clin Neuropharmacol. 2013 Jan-Feb;36(1):14-23. PubMed.
- Burstein AH, Zhao Q, Ross J, Styren S, Landen JW, Ma WW, McCush F, Alvey C, Kupiec JW, Bednar MM. Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease. Clin Neuropharmacol. 2013 Jan-Feb;36(1):8-13. PubMed.
- Freeman GB, Brown TP, Wallace K, Bales KR. Chronic Administration of an Aglycosylated Murine Antibody of Ponezumab Does Not Worsen Microhemorrhages in Aged Tg2576 Mice. Curr Alzheimer Res. 2012 May 22; PubMed.
- Banerjee G, Carare R, Cordonnier C, Greenberg SM, Schneider JA, Smith EE, Buchem MV, Grond JV, Verbeek MM, Werring DJ. The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice. J Neurol Neurosurg Psychiatry. 2017 Nov;88(11):982-994. Epub 2017 Aug 26 PubMed.
- Miyoshi I, Fujimoto Y, Yamada M, Abe S, Zhao Q, Cronenberger C, Togo K, Ishibashi T, Bednar MM, Kupiec JW, Binneman B. Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study. Int J Clin Pharmacol Ther. 2013 Dec;51(12):911-23. PubMed.