Experimental Arrowhead RNAi drug hints at Alzheimer’s benefit

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Dive Brief:

• An experimental RNA interference drug developed by Arrowhead Pharmaceuticals lowered levels of an Alzheimer’s-linked protein in an early trial in healthy volunteers, signaling the medicine might be helpful in treating the memory-robbing condition.
• Arrowhead said the highest dose of its drug, administered in two injections spaced two weeks apart, dropped levels of that protein, “tau,” by an average of 73% after 105 days. The findings suggest the medicine, called ARO-MAPT, could be injected once every three months.
• The news comes as developers of RNA-modulating medicines have been increasingly exploring ways to overcome a longstanding research limitation by aiming their treatments at targets outside the liver. Arrowhead said the results from this early-stage trial “provide clinical validation” of a development platform that enables its drugs to reach cells elsewhere, including those in the central nervous system protected by the “blood-brain barrier.”

Dive Insight:

After years of research, the first disease-modifying drugs in decades for Alzheimer’s won approval in the early 2020s in the form of Aduhelm, Leqembi and Kisunla. These medicines address one of the main biological signs of Alzheimer’s, the buildup of toxic clumps of a protein called amyloid beta in patients’ brains.

Leqembi and Kisunla have notable limitations, however, such as a safety warning not to prescribe them in people taking commonly used blood thinners. Moreover, their benefits are modest. Kisunla, for example, removed nearly all the amyloid lesions in the brains of most of the enrollees in a Phase 3 trial, but didn’t stop, let alone reverse disease progression.

The accumulation of tau is also believed to be implicated in disease progression, making the protein another popular target among drugmakers. Multiple would-be medicines have struggled to show a clear benefit, though research remains ongoing.

With its announcement Wednesday, Arrowhead has displayed a novel way to drop levels of tau. But substantially more work will be necessary to demonstrate an impact on the disease.

ARO-MAPT silences a gene that leads to expression of tau in the central nervous system. The early trial Arrowhead’s been conducting focuses primarily on safety. The company also evaluated whether the treatment appears to work as intended.

Arrowhead enrolled about 64 healthy volunteers to take one of three dose levels: a subcutaneous shot of 2.1 or 6.4 milligrams per kilogram of body weight at day one, eight and 15 of the trial; or 12.8 milligrams-per-kilogram doses on days one and 15.

At 2.1 mg, tau was reduced 40% at day 105 and at 6.4 mg levels fell by 69%. Arrowhead said that tau levels in the high-dose arm fell by as much as 85%. Side effects were mild, and included injection site reactions, bruising, respiratory infections and headaches.

The results “look compelling and, with subcutaneous delivery, arguably look [better] than what we've seen” with other drugs designed to cross the blood-brain barrier, wrote Stifel analyst James Condulis in a note to clients. Condulis cautioned, however, that the drug still is in very early development stages and that tau has yet to be clearly proven as a good Alzheimer’s target.

The rest of the trial will include both healthy volunteers and people with mild Alzheimer’s disease receiving up to five shots. The company is also planning trials in other conditions linked to tau, including frontotemproal dementia and progressive supranuclear palsy.