Arrowhead Pharmaceuticals reported that its experimental drug ARO-MAPT sharply lowered levels of tau, one of the two hallmark proteins of Alzheimer’s disease, in an early trial in healthy volunteers. Just as notable is how it got there: the drug was given as an injection under the skin and still reached the brain, which the company describes as a first for an RNA interference medicine.
The results
The trial enrolled about 64 healthy volunteers across three dose levels, given as a few injections over two weeks. By day 105, tau levels had fallen by about 40% on the lowest dose and about 69% on the middle dose. At the highest dose, the average reduction was about 73%, with some participants reaching 85%. Side effects were mild: injection site reactions, bruising, respiratory infections and headaches. Because RNAi drugs act for weeks to months after each dose, the lasting reduction from just a few injections suggests treatment could eventually be given infrequently, perhaps every few months, if later trials confirm the effect.
Why tau
Alzheimer’s is defined by two abnormal proteins. Amyloid builds up in plaques between brain cells, and is the target of the approved antibodies Leqembi and Kisunla. Tau forms tangles inside neurons and spreads through the brain as the disease progresses. Tau tracks symptoms more closely than amyloid does: where tau tangles appear, brain cells die and the corresponding abilities decline. Many researchers believe that lowering tau could slow the disease in ways that clearing amyloid alone cannot.
How the drug works
ARO-MAPT is an RNA interference (RNAi) medicine. It targets the messenger RNA of the MAPT gene, which carries the instructions for making tau, and causes it to be destroyed, so cells make less of the protein. The approach lowers all forms of tau, healthy and toxic, which is why proving it is safe over the long term will be essential. Tau has normal jobs in neurons, though studies in animals and people with naturally lower levels suggest a substantial reduction can be tolerated.
The delivery breakthrough
Getting drugs past the blood-brain barrier, the tightly sealed lining of the brain’s blood vessels, is one of medicine’s hardest problems. Previous RNA-based drugs for the brain, such as antisense medicines, are injected directly into the spinal fluid through a lumbar puncture, a procedure patients would need to repeat for years. Arrowhead says its TRiM delivery platform let ARO-MAPT cross into the brain after a simple injection under the skin. If that holds up, it could matter well beyond Alzheimer’s, opening a route for RNA drugs to treat many brain diseases. Stifel analyst James Condulis said the results look compelling and arguably compare favorably with other brain-penetrating drugs, given the subcutaneous delivery.
What the trial does not show
Despite some headlines, this trial did not test whether the drug helps people with Alzheimer’s. Its participants were healthy volunteers, and it measured safety and tau levels, not memory or thinking. Condulis cautioned that the drug is in very early development and that tau has not been clearly proven as a good treatment target: several earlier tau-directed drugs, mostly antibodies aimed at tau outside cells, failed to show clinical benefit. Lowering tau inside cells, as RNA drugs do, is a different strategy, and early results from another tau-lowering RNA drug, an antisense medicine from Biogen, have been encouraging, but proof in a large trial is still lacking.
A crowded but difficult target
Tau-lowering drugs are now one of the most active areas of Alzheimer’s research, because the amyloid antibodies, while a milestone, leave most of the disease’s progression untouched. Companies are attacking tau with antibodies, vaccines, antisense drugs given into the spinal fluid, and now RNAi. The ones that act on tau inside cells by reducing its production are attracting the most optimism, since most tau lives inside neurons where antibodies cannot easily reach. A key unanswered question is timing: whether lowering tau helps once symptoms have begun, or whether it must start earlier, before tangles spread widely. That is one reason Arrowhead is also looking at rarer diseases where tau is clearly the primary cause and benefit may be easier to demonstrate.
What comes next
The next part of the trial will include people with mild Alzheimer’s as well as healthy volunteers, with up to five injections. Arrowhead also plans to test ARO-MAPT in other diseases driven by tau, including frontotemporal dementia and progressive supranuclear palsy, where the case for targeting tau is especially strong because the protein is the main culprit. Meaningful evidence of benefit would take larger, longer trials.
Why it matters
Today’s Alzheimer’s drugs slow decline modestly, require regular infusions and carry a risk of brain swelling and bleeding (see our comparison of Leqembi and Kisunla). A drug that lowers tau with an occasional injection under the skin would be a very different proposition. It is a long way from that point, but this is a meaningful technical step. This is research news, not medical advice.