Arrowhead’s blood-brain barrier tech is ‘arguably better’ than others, analysts say after data

 

Arrowhead Pharmaceuticals’ siRNA candidate achieved “compelling” tau reductions in an early study of healthy volunteers, with a magnitude of effect that seems to outperform other blood-brain barrier platforms, according to Stifel.

Arrowhead Pharmaceuticals’ investigational gene silencer lowered tau protein levels in an early study, suggesting that the biotech’s approach to bypass the blood-brain barrier may be better than competing technologies.

The findings “provide important clinical validation” for Arrowhead’s platform for targeting the central nervous system through subcutaneously administered drugs, Stifel analysts said in a Wednesday note.

Results from the Phase 1/2a study, disclosed Wednesday, showed a 40% average reduction in CSF tau at day 105 in healthy volunteers who were treated with the low 2.1-mg/kg dose of the siRNA candidate, called ARO-MAPT, on days 1, 8 and 15. In those given a 6.4-mg/kg dose on the same days, CSF tau dropped by 69% on average at day 105.

Meanwhile, a 12.8-mg/kg dose of ARO-MAPT injected on days 1 and 15 triggered a mean CSF tau reduction of 73% at day 105. The maximum CSF tau reduction reached 85% in the high-dose cohort.

The early trial is actively enrolling patients, with a target of 112 participants, including healthy volunteers for the study’s first part and patients with early Alzheimer’s disease for the second portion. Wednesday’s data came from healthy volunteers.

As for safety, the primary objective of the Phase 1/2a trial, Arrowhead said that ARO-MAPT was “generally well tolerated.” Treatment-emergent adverse events were largely mild, with no serious side effects, deaths or dropouts due to toxicities.

The data, while early, could set Arrowhead up to compete against Biogen, analysts say. Both companies are advancing tau-targeting therapies that work by suppressing the expression of the MAPT gene, which codes for the tau protein.

“While details are still relatively light, the data looking compelling,” Stifel told investors in a note on Wednesday, adding that the interim findings are “arguably better than what we’ve seen with other BBB platforms.”

The firm also hinted at a potential competitive edge for Arrowhead’s subcutaneous siRNA asset, writing that the CSF tau knockdown “looks better than [Biogen’s] BIIB080,” an anti-tau antisense oligonucleotide also known as diranersen that is injected directly into the spine. ARO-MAPT, meanwhile, can be delivered via an injection under the skin.

Phase 1b data for diranersen published in 2023 showed that, across various dose levels, CSF tau declined by an average of 30% to 49% at eight weeks after the final dose of Biogen’s asset. Diranersen’s tau-lowering effect persisted through 24 weeks after the last dose, hitting an average tau reduction of up to 56%. The trial enrolled 46 patients with mild Alzheimer’s disease, and its primary endpoint was safety; CSF tau was set as a key exploratory outcome.

There have been no direct head-to-head studies between ARO-MAPT and diranersen, which prompted Jefferies to be a bit more reserved about comparing the two assets. The firm in a Wednesday note pointed to differences in study populations and dose strengths.

In May, Biogen announced that diranersen failed to meet its primary goal of showing a dose-response effect in cognitive and functional outcomes in the Phase 2 CELIA study. Nevertheless, the company detected “robust reductions in tau pathology” that were consistent with the Phase 1b study. Biogen also touted cognitive improvements and slowing of decline, especially in patients who received the lowest dose of diranersen.

Based on these efficacy signals, Biogen has decided to push diranersen into registrational development, though the company has yet to specify a timeline for this.

Arrowhead is also moving forward with ARO-MAPT, with additional healthy volunteer and Alzheimer’s disease data expected next year. Arrowhead is also in talks with health regulators to enable studies in MAPT-associated frontotemporal dementia and progressive supranuclear palsy, according to the Wednesday announcement.

https://www.biospace.com/drug-development/arrowheads-blood-brain-barrier-tech-is-arguably-better-than-others-analysts-say-after-data-drop