By Bill Alpert
Antibody drugs that treat Alzheimer's disease have been on the market for several years. Their benefits are slight. One reason is the body's protective blood-brain barrier, which blocks 99% of a dose from reaching the brain.
The drug industry has been working on tricks to shuttle drugs through that barrier, and the results will become apparent this year.
Those working on brain-shuttling technologies include big names like Eli Lilly, Novartis, Biogen, and AbbVie, as well as smaller specialists like BioArctic, Alector, Voyager Therapeutics, and Sangamo Therapeutics. But leading the pack are Denali Therapeutics, which got the first U.S. approval for a shuttle-enhanced drug in March; and Roche Holding -- which is in pivotal trials with its barrier-crossing Alzheimer's antibody.
Success with these products could yield annual sales above $13 billion for Roche and turn around the fortunes of the biotechs.
The blood-brain barrier has hampered treatment of neurological disorders, says Luka Kulic, who heads early development in neuroscience and rare diseases at Roche. "This is a major hurdle and overcoming this barrier has been really the Holy Grail in neurology," he says.
To preserve the brain's delicate chemical balance, the capillaries serving it are lined with tightly joined cells that only grant passage to essentials -- like iron, glucose and amino acids -- while blocking most drugs and nearly all the large molecules that are today's cutting-edge treatments.
Doctors must administer high doses of Eisai/Biogen's Leqembi and Lilly's Kisunla, because only a fraction of 1% of the infused antibodies reach the amyloid plaque that chokes brain cells in Alzheimer's. The high doses raise risks of a side effect that can cause brain bleeds and swelling. To administer genetic medicines against the tau protein tangles that are Alzheimer's' other main pathology, doctors must inject them directly into the cerebrospinal fluid.
But scientists have been working for a couple of decades on a clever way to transport these big molecules through the blood brain barrier. The technique tags the drugs with skeleton keys that open the barrier to everyday nutrients, like iron.
Roche's anti-amyloid antibody trontinemab has a fragment that mimics the natural iron-shuttling molecule known as transferrin. When the antibody plugs into the capillary's transferrin receptor, a portal through the blood-brain barrier opens up. Transferrin receptors have become the industry's favored blood-brain portals, and the Swiss drug company calls its technology the BrainShuttle.
Early studies showed that the shuttle-delivered trontinemab reached concentrations in the brain's fluid that are eight times higher than standard antibodies, with much more uniform distribution around the brain. In Phase 2 trials reported last year, amyloid quickly fell to low levels, while swelling and bleeding side effects were rare.
Roche started pivotal Phase 3 trials for trontinemab in September, in patients with early symptoms of Alzheimer's. The two studies will run for 18 months. Another Phase 3 is trying the treatment before cognitive symptoms appear -- to see if it can prevent amyloid's harm rather than just clearing amyloid rubble from a damaged brain.
In patients with multiple sclerosis, Roche is running a Phase 1 study to protect brain cells with a BrainShuttle-enhanced version of the CD20 antibody. Standard CD20 antibodies are an established treatment for MS, with the antibodies targeting the renegade autoimmune cells that damage nerve sheaths.
Phase 3 success for Roche's BrainShuttle-powered trontinemab could make it the leading anti-amyloid treatment, said an Alzheimer's expert consulted for a December report by the analysts at H.C. Wainwright.
At Denali, CEO Ryan Watts says that engineering receptor-mediated shuttles has been his life for 20 years.
"You build on the brain's natural ability to bring in important things, like iron or amino acids, and catch a ride," he says. It is how he characterizes Denali's TransportVehicle architecture, a modular platform it adapts to carry amyloid antibodies, tau gene-silencing antisense oligonucleotides, or the enzymes that treat some rare, but fatal, genetic disorders.
In March, the U.S. Food and Drug Administration approved Avlayah, which taps the transferrin receptor to bring in the enzyme that is missing from the brain cells of children born with Hunter Syndrome. It's a rare, but deadly, disorder. Similar treatments for the enzyme deficiencies known as Sanfilippo, Pompe and Gaucher diseases are in early clinical trials, or soon will be. Denali believes the global market for each treatment could be half a billion to a billion dollars.
The company recently began clinical trials of a treatment that silences the genetic instructions for the Alzheimer's tau protein. Preclinical projects are testing transferrin receptor vehicles for delivering amyloid antibodies, and a variety of treatments for Parkinson's disease. The market for a successful Alzheimer's or Parkinson's treatment could exceed $5 billion, the company estimates.
Sweden's BioArctic was Eisai's partner in developing the amyloid-targeting antibody Leqembi. The companies have preclinical programs to link other Alzheimer's drugs with the blood-brain barrier platform that BioArctic calls BrainTransporter. The Swedish firm has other BrainTransporter partnerships with Bristol Myers Squibb and Novartis to target Alzheimer's and other neurodegenerative diseases. Over at GlaxoSmithKline, a partnership with Korea's ABL Bio will use the receptor for the insulinlike growth factor as a portal for neurology drugs.
To get gene therapies into cells, biotech companies have used hollowed-out viruses called capsids. Both Voyager Therapeutics and Sangamo Therapeutics are developing capsids that first open blood-brain portals, then deliver genetic cargoes to brain cells. Voyager will start clinical trials this year on a gene therapy for Alzheimer's, and another gene therapy for the motor-control disorder called Friedreich's ataxia (where it's joined with Neurocrine Biosciences). Sangamo is developing gene therapies in collaborations with Lilly, Astrellas, and Roche.
Many biotech firms have lost their Wall Street followings. Brain-shuttle technologies could put them back in the game.
Write to Bill Alpert at william.alpert@barrons.com
This content was created by Barron's, which is operated by Dow Jones & Co. Barron's is published independently from Dow Jones Newswires and The Wall Street Journal.
(END) Dow Jones Newswires
June 03, 2026 03:30 ET (07:30 GMT)
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