Researchers have long been vexed by the brain’s ability to shut out drugs. Now, Denali Therapeutics is offering evidence in mice and monkeys that a new drug delivery system can successfully sneak large molecules like antibodies and enzymes past the blood-brain barrier at levels needed to make an impact on a disease. Denali expects a clinical study of the first drug candidate to use the technology, an enzyme replacement therapy for Hunter Syndrome, to start soon.
“The holy grail for us, and generally for biotherapeutics, is the ability to transport large molecules across the blood-brain barrier safely and at therapeutic levels,” Denali CEO Ryan Watts says. It’s a problem Watts has been plugging away at for well over a decade, first at Genentech, where he led neuroscience research, and now at Denali, which he helped found in 2015 with an investor commitment of $217 million—at the time the largest initial funding ever for a biotech firm.
Denali outlined the invention of its transport vehicle in a paper in Science Translational Medicine (2020, DOI: 10.1126/scitranslmed.aay1359). To create the vehicle, Denali researchers used combinatorial protein engineering to build libraries containing hundreds of millions of protein variants, each with a slightly different patch of amino acids in a region called the Fc domain.
Using a process called directed evolution, they screened the libraries to identify variants that could bind to the transferrin receptor, which transports iron-containing transferrin out of the blood and into the brain. The process was repeated again and again to engineer specific properties, such as improved binding affinity for the receptor. The transport vehicle is then tethered to a therapeutic molecule, be it an antibody or an enzyme.
Denali researchers tested out the transporter using an antibody targeting β-secretase 1, an enzyme implicated in amyloid build-up in the brains of people with Alzheimer’s disease. They showed their antibody-transport vehicle construct could effectively cross the blood-brain barrier to lower levels of amyloid in the brains of both mice and monkeys.
In a second paper, the researchers tethered the transport vehicle to an enzyme called iduronate 2-sulfatase (IDS), which is missing in a lysosomal storage disorder called Hunter syndrome. IDS works to break down sugar molecules called glycosaminoglycans (GAGs) (Sci. Transl. Med. 2020, DOI: 10.1126/scitranslmed.aay1163). Without it, GAGs build up inside cells around the entire body, causing patients to develop a laundry list of serious symptoms.
In 2006, the drug company Shire gained approval for Elaprase, an enzyme replacement therapy for Hunter syndrome, but it can only treat symptoms that affect the body. The majority of people with Hunter syndrome have progressive cognitive decline, “and basically the patients succumb to the disease because of the neurodegeneration,” says Barbara Burton, a pediatrics professor at Northwestern Medicine who specializes in inherited metabolic disorders.
Denali’s paper showed that the transport vehicle shuttled 20 times the IDS into the brains of mice compared to the amount delivered by the naked enzyme, in turn lowering levels of the sugar molecules. Denali scientist Anastasia G. Henry notes that the team was particularly excited to see the distribution of the enzyme across the entire brain, including in key cell types often damaged by the build-up of GAGs.
Denali’s transport vehicle is a twist on the “Trojan horse” approach to drug delivery, which has been around since the 1980s, says University of Washington professor William A. Banks. The idea is fairly simple: tether a therapy to an antibody or antibody fragment featuring a receptor, in this case for transferrin, that can carry a drug across the blood-brain barrier. For 40 years, the approach has largely failed, Banks says. “In some ways, I think the Trojan horse hypothesis has seduced many drug companies into a blind alley.”
But after reviewing Denali’s two papers, Banks is impressed that the biotech firm was able to show a clear increase in the amount of IDS getting into the brains of mice. A lysosomal storage disorder is a relatively unforgiving disease because it can be corrected only by delivering enzyme to the brain, he says. “It’s a tough test of anybody’s system—plus, these enzymes are huge,” Banks adds.
“It’s a very frustrating field, and yet I think he’s got a pretty good home run here in two papers,” Banks says of Denali’s Watts.
Hunter syndrome made sense as the first clinical test of the technology, Watts says, because it affords the opportunity to go “from invention to its first validation with very robust biomarkers,” including GAG levels. If the clinical trial, which should start enrolling by the end of June, proves successful, the technology could be applied to other lysosomal storage disorders. The company is also eager to use it to deliver drugs, including antibodies, proteins, and oligonucleotides.
Even if the transport technology works, Denali must prove the therapy can treat Hunter syndrome. “Ultimately, they’ve got to show their therapy makes a difference for the brain,” Burton says.
But designing clinical trials is difficult because Hunter syndrome is such a heterogeneous disease—some people decline rapidly, while others can have a several-year period of relative stability. Choosing the right tests to measure a cognitive effect can be difficult, Burton says, because kids with the disease often have short attention spans, display hyperactivity, and have behavioral issues. “Sometimes you’ll see a patient who you know can do certain tasks—you’ve seen them do it at home—and you go into a testing setting and they won’t do it,” she says.
Denali isn’t the only company trying to develop a brain-penetrant Hunter syndrome therapy, Burton notes. Shire has spent nearly a decade trying to develop a form of IDS that is delivered intrathecally, or via the spinal cord. JCR Pharmaceuticals is running trials of a drug in Japan and Brazil. Burton, an investigator on the Shire study and the upcoming Denali trial, says an eventual approval of the Shire drug could make it tough for Denali to recruit patients.
Melissa Hogan, whose son Case has been part of Shire’s intrathecally-delivered IDS study for nearly a decade, says one appeal of the Denali drug is that it can simultaneously address both the body and brain components of the disease. By contrast, Shire’s intrathecal drug must be combined with Elaprase, which is delivered intravenously. And a gene therapy in development for Hunter syndrome would only replace IDS in the brain, and thus would similarly also still require Elaprase.
Hogan, who consults on clinical trial design for rare disease companies, including Denali, says the quality of life the simpler regimen could offer is really important to families. “These kids suffer from a lot of medical trauma between all the specialists and tests,” she says. “The ability to take what is a lumbar puncture every 4 weeks and a weekly infusion and put that into one infusion has advantages.”