Conference Coverage

Can Anti-Tau Therapies Treat Neurodegenerative Disorders?


 

LONDON—Several experimental therapies targeting tau are currently under investigation in phase I and II clinical trials. Researchers at the 2017 Alzheimer’s Association International Conference described the design of, and early results from, studies of two monoclonal antibodies and an antisense oligonucleotide.

Geoffrey A. Kerchner, MD, PhD
Research has indicated that accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer’s disease and other primary tauopathies. “Tau is a compelling therapeutic target in Alzheimer’s disease,” said Geoffrey A. Kerchner, MD, PhD, of Genentech, San Francisco. “In autopsy studies, tau status in the brain correlates strongly with cognitive status right before death.” Furthermore, tau changes in the CSF and on PET imaging as patients progress from prodromal disease to mild-to-moderate disease. “Tau is present at the time patients are showing up at our clinics,” he said.

RO7105705 for Alzheimer’s Disease

Dr. Kerchner presented data from a phase I trial of RO7105705, a humanized anti-tau monoclonal antibody. RO7105705 binds specifically to tau and is intended to intercept tau in the extracellular space of the brain, blocking its cell-to-cell spread.

The primary objective of the study was to evaluate the safety of single and multiple doses of the drug, compared with placebo. The secondary objective was to look at the pharmacokinetic profile following IV and subcutaneous doses. Study participants included healthy volunteers ages 18 to 80 and patients with probable Alzheimer’s disease. Patients with Alzheimer’s disease were between ages 50 and 80 and had a Mini-Mental State Examination score of 16 to 28; a Clinical Dementia Rating global score of 0.5, 1.0, or 2.0; and 18F-florbetapir PET scan evidence of cerebral amyloid pathology.

In the single-dose escalation phase, six cohorts of eight healthy volunteers each received IV doses that ranged from 225 mg to 16,800 mg. Another cohort received 1,200 mg of the drug subcutaneously. In the multiple-dose phase, a cohort of healthy volunteers and a cohort of patients with mild-to-moderate Alzheimer’s disease received four weekly doses of 8.4 g.

“The drug was well tolerated, even at these high doses,” Dr. Kerchner said. “So far, there have been no dose-limiting adverse events, no serious adverse events, no deaths, and no one who stopped the drug due to adverse events.” In the single-dose cohorts, adverse events that occurred in more than one participant included headache, infusion/injection site reaction, upper respiratory tract infection, nausea, vomiting, and gastrointestinal viral infection. In the multiple-dose cohorts, adverse events that occurred in more than one participant included vessel puncture site complications and postural dizziness.

ABBV-8E12 for PSP and Alzheimer’s Disease

Kumar Budur, MD, of AbbVie, Chicago, presented the results of a phase I study of ABBV-8E12, a humanized anti-tau monoclonal antibody, in patients with progressive supranuclear palsy (PSP). He also gave an overview of two ongoing phase II studies of ABBV-8E12 for early Alzheimer’s disease and PSP.

“PSP is a chronic progressive neurodegenerative disorder that affects movement, control of gait and balance, speech, swallowing, vision, mood and behavior, and thinking,” Dr. Budur explained. “The time from the onset of symptoms to death is only seven years. There currently are no approved treatments for this condition.” PSP affects approximately 20,000 people in the United States, and symptoms typically begin after age 60.

The phase I trial in patients with PSP was a double-blind, placebo-controlled, single ascending dose study assessing the drug’s safety, tolerability, pharmacokinetics, and immunogenicity. Investigators randomized 30 participants to a single IV infusion of ABBV-8E12 (2.5, 7.5, 15, 25, or 50 mg/kg) or placebo in blocks of four subjects, with one subject in each block randomized to placebo and three to an active ABBV-8E12 dose. Researchers monitored safety and pharmacokinetics for 84 days post dosing.

Twenty-three patients received ABBV-8E12, and seven patients received placebo. At baseline, subjects’ mean age was 68.8; 16 (53%) were men. Patients had to be able to walk with minimal assistance to be included in the study. Twenty-seven subjects completed the 84-day follow-up and one subject (3.3%) withdrew from the study due to an adverse event.

Twenty-one subjects experienced an adverse event, including dermatitis (n = 5) and fall (n = 5). Three participants experienced serious adverse events. One patient had a subdural hematoma following two falls, one had agitation/anxiety/perseverative behavior, and one had hypertension. The serious adverse events occurred in the 15, 25, and 50 mg/kg cohorts, respectively. ABBV-8E12 exhibited an acceptable safety and tolerability profile to support repeat-dose testing in subjects with tauopathies, Dr. Budur said.

Dr. Budur and colleagues are recruiting subjects for a multinational phase II study evaluating ABBV-8E12 to delay the progression of Alzheimer’s disease. Eligible subjects (n = 400) will meet criteria for early Alzheimer’s disease and have a positive amyloid PET scan. “Subjects will be randomized to three doses of ABBV-8E12 versus placebo, 100 subjects per arm,” he said. In addition, investigators are recruiting patients with PSP for a phase II study evaluating the 52-week efficacy and safety of ABBV-8E12. The trial will assess whether the therapy can slow disease progression in 180 patients with PSP.

Antisense Oligonucleotide to Reduce Total Tau Expression in Mild Alzheimer’s Disease

Roger M. Lane, MD, MPH, of lonis Pharmaceuticals, Carlsbad, California, described a study that is designed to the test safety and pharmacokinetics of a tau-lowering antisense oligonucleotide (ASO) in patients with mild Alzheimer’s disease. The ASO, lonis-MAPTRX, targets microtubule-associated protein tau (MAPT) messenger RNA to reduce the synthesis of tau in the CNS, Dr. Lane said. “In contrast, current investigational biologic or small molecule anti-tau drugs target the tau protein,” he said.

Roger M. Lane, MD, MPH

In a recent study, DeVos and colleagues identified ASOs that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After a reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and pre-existing tau pathology was reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In nonhuman primates, ASOs distributed throughout the brain and spinal cord, and reduced tau mRNA and protein in the brain and spinal cord, and tau protein in the CSF.

Based on these findings, researchers are studying lonis-MAPTRX, a second generation 2’-O-methoxyethyl (2’-MOE) chimeric ASO identified as suitable for clinical trials. It is designed to bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein.

“The first clinical trial is set up in 12 centers in Canada and five European countries,” Dr. Lane said. “Patients aged 50 to 75 with mild Alzheimer’s disease are being randomized to multiple ascending doses of lonis-MAPTRX administered intrathecally.” The study drug will be given four times at monthly intervals, and there will be six months of follow-up. End points include CSF biomarkers, neuroimaging, and clinical outcomes. “We are expecting a 50–85% reduction in tau production in the cerebral cortex,” Dr. Lane said.

Adriene Marshall

Suggested Reading

DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374).

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