Arrowhead reports tau reduction of up to 73% with experimental treatment in healthy volunteers
Key Facts
Arrowhead Pharmaceuticals announced interim results for its experimental treatment showing a mean reduction in total tau protein in cerebrospinal fluid of up to 73% at day 105 in healthy volunteers. The company said in its statement that the maximum reduction recorded in an individual participant was 85%, compared with the reported mean reduction. These results concern a biomarker measured in cerebrospinal fluid, while the treatment's effects on cognition, function and Alzheimer's progression need to be studied in patients. Arrowhead described the results as the "first successful clinical validation" of its platform for delivering small interfering RNA across the blood-brain barrier. The treatment aims to reduce tau production by silencing the gene responsible for it in the central nervous system.
The company said in its clinical presentation that enrollment was complete in all healthy volunteer cohorts in a placebo-controlled, dose-escalation trial. Each cohort is designed to include 6 participants receiving active treatment and 2 receiving placebo, according to the presentation. The trial's objectives include assessing safety and tolerability, as well as pharmacokinetics, which addresses the treatment's movement through the body, and pharmacodynamics, which concerns its effects. On safety, Arrowhead said no serious treatment-emergent adverse events were recorded in the reported interim results. It added that there were no deaths or withdrawals due to adverse events in the safety results presented alongside the announcement of the biomarker reduction.
Arrowhead's approach relies on silencing the MAPT gene in the central nervous system to reduce tau protein production, according to the company's description of the experimental treatment. The treatment is administered by subcutaneous injection, a method the company says allows its programs targeting the nervous system to avoid spinal injections. The approach involves a platform that uses a shuttle to cross the blood-brain barrier and deliver the treatment to its targets, according to the clinical presentation. Before announcing the interim human results, Arrowhead said in its webinar announcement that preclinical studies showed consistent distribution of the treatment in deep brain regions after subcutaneous injection. The company also has additional wholly owned programs in preclinical development targeting the central nervous system using a blood-brain barrier shuttle.
On dosing frequency, Arrowhead believes the sustained tau reduction supports the possibility of dosing at intervals of 3 months or longer. The company said the results support potential administration "once every 3 months," describing the possible interval between doses during future development. That possibility is tied to the continued biomarker reduction, according to the company's assessment of the interim results in healthy volunteers. The trial design includes multiple-dose cohorts alongside early Alzheimer's patient cohorts on which the company plans to provide an update. Determining the treatment's effects on cognition, functional ability and disease progression remains an area requiring study in patients, alongside biomarker monitoring.
The trial's Alzheimer's patient cohorts require participants to be between 50 and 80 years old, according to the inclusion criteria in the company's clinical presentation. Patient eligibility also requires biomarker evidence consistent with Alzheimer's, under the criteria Arrowhead set for these cohorts. That evidence can come from cerebrospinal fluid or plasma testing, or positron emission tomography imaging, according to the presentation. In its webinar announcement before the results, the company estimated that about 32 million people worldwide had Alzheimer's. The patient cohorts target early Alzheimer's, while the reported tau reduction results came from the healthy volunteer cohorts in which enrollment was complete, according to the company.
Arrowhead's next steps include engaging with the U.S. Food and Drug Administration in preparation for Phase 2 studies in other neurological diseases, according to the development plan presented. The plan includes MAPT-associated frontotemporal dementia among the diseases the company is seeking to prepare to study. It also includes progressive supranuclear palsy, which Arrowhead listed alongside frontotemporal dementia in its next steps for engagement with the regulator. For the multiple-dose healthy volunteer cohorts, the company targets a data update in 2027, according to its clinical presentation. The same targeted update timeframe includes data from the early Alzheimer's cohorts, in the next stage of follow-up for the treatment program in volunteers and patients.