Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Traumatic Brain Injury
U.S. FDA Status: Alzheimer's Disease (Phase 1), Traumatic Brain Injury (Phase 1)
Company: Pinteon Therapeutics
PNT001 is a monoclonal antibody to the cis isomer of tau phosphorylated at threonine 231, a form of pathological tau suspected to play a role in traumatic brain injury, chronic traumatic encephalopathy, vascular dementia, and Alzheimer’s disease.
Phosphorylated T231 tau exists in cis and trans conformations, as modulated by the peptidyl-prolyl cis/trans isomerase Pin1 (Galas et al., 2006; Hamdane et al, 2006). Cis pT231 has been detected in brain tissue from people with AD and CTE and increases acutely after traumatic brain injury in humans and rodent models. In humans, its levels in CSF correlate with severity of brain injury (Sisakht et al., 2022). Cis pT231 is resistant to dephosphorylation and degradation, and promotes aggregation (Nakamura et al., 2012; reviewed in Lu et al., 2016).
In preclinical models of brain injury, a mouse monoclonal antibody to cis pT231 prevented axonal pathology, astrogliosis, tau oligomerization and tangle formation, brain atrophy, and behavioral and other deficits (Kondo et al., 2015; Albayram et al., 2017; Albayram et al., 2019).
Cis pTau appears to contribute to vascular dementia. It was found to be elevated in brains of people with vascular dementia, who lacked tau tangles. In mouse models of vascular dementia, a cis-tau targeted monoclonal antibody reduced neurodegeneration and improved cognitive impairment. The cis mAb ameliorated progression of AD-like neurodegeneration and cognitive impairment in mice expressing human tau (Qui et al., 2021).
In September 2019, Pinteon began a Phase 1 safety and tolerability study of PNT001 in healthy adults. In the trial, 49 people received single doses of 33, 100, 300, 900, 2,700, or 4,000 mg antibody or placebo, infused over 30 to 60 minutes. Primary outcomes were adverse events and abnormalities on clinical and laboratory measures after 16 weeks. Other outcomes included antibody concentration in serum and CSF, measures of total tau, cis pT231 tau, pT231 tau, and NfL in CSF, as well as serum NfL and antidrug antibodies. According to data presented at AD/PD 2021, the antibody produced dose-linear blood and CSF concentrations that stayed constant for 28 days, and was well tolerated. For doses of 900 mg and above, CSF antibody concentrations exceeded the minimum required for tau binding (Mar 2021 conference news).
In December 2020, the company began a Phase 1 study of multiple ascending doses in 64 hospitalized patients with acute traumatic brain injury. Each patient will receive three doses of 1,000 or 2,700 mg, or placebo. The first dose will occur within 24 hours of injury; the time frame for subsequent doses is not specified. Safety, tolerability, pharmacokinetic, biomarker, imaging and cognitive data are to be collected over 12 weeks.
For details on PNT001 trials, see clinicaltrials.gov.
Last Updated: 26 Jan 2022
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