Companies Devise New Ways to Smuggle Drugs Across the Blood-Brain Barrier

Pictured: abstract bokeh optical light/iStock, Oleksandr Bushko

The blood-brain barrier: It’s neuroscience’s next frontier, and a presentation on Roche’s trontinemab at the Clinical Trials on Alzheimer’s Disease conference last month sparked new optimism that researchers might be getting close to breaking through it.   

A diffusion barrier, the blood-brain barrier (BBB) prevents about 98% of small molecule drugs and essentially 100% of large molecule drugs from entering the brain “under normal conditions,” according to a paper published in The Journal of Investigative Medicine.

Trontinemab—an investigational antibody targeting amyloid beta—combines, by recombinant fusion technology, an anti-beta IgG1 framework with a so-called Brainshuttle module. This Brainshuttle module binds to the transferrin receptor. “This is an active and rapid transport mechanism across the endothelial cell layer of the blood-brain barrier . . . to get the molecule into the brain,” said Luka Kulic, therapeutic area leader for dementias, expert scientist and medical director of Neuroscience and Rare Diseases at Roche.

At CTAD, Roche presented data from the Phase Ib/IIa Brainshuttle AD study of trontinemab in 44 participants with early or mild-to-moderate Alzheimer’s disease. Trontinemab elicited dose-dependent amyloid plaque lowering, with the highest 1.8 mg/kg cohort showing the best response.

“I think the data were very encouraging,” said Eric M. Reiman, CEO of Banner Research and executive director at Banner Alzheimer’s Institute. While noting that Roche’s study was small, he emphasized the advantages of the Brainshuttle approach. “By rapidly shuttling amyloid plaque-reducing antibody therapies into the brain, it may be possible to augment the clearance of plaques and reduce the risk of ARIA, improving the treatment’s efficacy, safety and tolerability.”

Early signals bear this out. In a first-in-human study of healthy volunteers, trontinemab showed “substantially higher CNS exposure due to shuttling” than Roche’s failed antibody, gantenerumab, with an eight-fold increase in cerebrospinal fluid/plasma ratio, according to the company’s presentation.

Reiman also noted Brainshuttle’s potential safety advantages. First, it may be possible to use lower doses of the antibody than has been necessary with antibodies such as Eisai and Biogen’s Leqembi and Eli Lilly’s donanemab, and lower concentrations of the drug in the blood could lessen the risk of amyloid-related imaging abnormalities (ARIA). Possibly the greatest barrier to the use of anti-amyloid antibodies like Leqembi and donanemab, ARIA “is thought to be due to the binding of antibody in blood to the plaques that adhere to blood vessels,” Reiman said. This causes an inflammatory response that leads to leaky blood vessels, and possibly ARIA. “So, the Brainshuttle strategy could enhance the antibody therapy’s ability to remove amyloid plaques in the brain, do so with lower doses and blood concentrations, and have a lower ARIA risk.”

In Brainshuttle AD, Roche reported a “low incidence of ARIA despite robust amyloid lowering,” with two cases of ARIA in the 1.8 mg/kg cohort.

Kulic said the trial results represent a proof-of-concept for the Brainshuttle platform, as the amyloid lowering seen is “quite impressive and happens at a much lower dose than what is usually used with standard antibodies.”

Mayank Mamtani, head of healthcare research at B. Riley Securities, went an adjective further, calling the efficacy data “mind-blowing.”

“They basically are able to do what the Biogen and Eli Lilly antibodies take 18 months [to do]; they were able to do the same in seven months in very rapid beta-amyloid clearance,” he told BioSpace.

Nature’s Challenge

Roche is not alone on its quest to cross the blood-brain barrier. Headed by former Genentech head of neuroscience Ryan Watts, Denali Therapeutics is leveraging its proprietary BBB platform against MPS II (Hunter syndrome), Parkinson’s disease, frontotemporal dementia and more.

Watts attributed the challenges posed by the BBB to the brilliance of evolution. “The blood-brain barrier evolved to protect the nervous system and to create a unique microenvironment for electrochemical signaling,” he told BioSpace. “The fact that we can process and communicate so rapidly—that sort of electrochemical signaling—is because of the microenvironment that’s formed by the blood-brain barrier.” But as a result, “the vast majority of medicines as originally invented don’t get across the blood-brain barrier in therapeutic concentrations,” he said.

Watts emphasized the importance of the BBB as a traffic controller, determining what does and doesn’t penetrate its shield. Denali doesn’t want to mess with this system but rather aims to “hitch a ride” with natural transporters, including the iron transporter or a neutral amino acid transport like CD98.

“There are certain nutrients that need to get into the brain at high concentrations. Can we basically utilize these natural transporters in a way that doesn’t disrupt the normal transport in order to get large molecules across the blood-brain barrier?” Watts asked.

Denali also has programs focused on small molecules. With these, Watts explained, “It’s about the chemistry. They diffuse through a membrane, so it’s a very different biology.”

The ‘Ultimate Fantasy’

Another, very different type of treatment that companies are looking to sneak past the BBB is gene therapy. With its one-and-done potential, Mamtani said gene therapies will always be interesting, but said important questions to ask around candidate therapies include, “Can you get it to the right organ? Can it have the right expression in the tissue that you’re trying to get to, and then will that convert into a symptom benefit? I feel like we’re still maybe in the early innings with [gene therapy]. Not that we’re not in the early innings with Brainshuttle.”

One of the biggest remaining barriers to gene therapy is delivery, and this is particularly true when it comes to the brain. There is one FDA-approved gene therapy that has shown the ability to successfully cross the BBB, said Al Sandrock, president and CEO of Voyager Therapeutics: the spinal muscular atrophy treatment Zolgensma, which travels via an adeno-associated virus (AAV) vector. “But it can only be used in infants up to age two,” Sandrock told BioSpace. “My belief is that’s because the blood-brain barrier matures during infancy to the point where . . . the same exact gene therapy doesn’t cross in older children.”

Voyager is developing AAV capsids that Sandrock believes can cross the BBB more efficiently than AAV9, which he called “the very best of the neurotropic capsids.” The company discovered that making certain changes on the surface of AAVs gets them across the BBB “up to 1,000-fold better” than AAV9, he said, adding that the approach should improve both efficacy and safety.

Voyager began with AAV9 and AAV5, to which Sandrock said there are fewer naturally occurring antibodies than for other vectors. The company’s scientists created mutations—either amino acid substitutions or peptide insertions—on certain loops without breaking the virus. Voyager then conducted next-gen sequencing in nonhuman primates to identify which of the resulting variants could successfully cross the BBB. “We look not only to see if the virus got there but that they express the messenger RNA, their payload, as well,” Sandrock explained.

Internal programs using these novel AAV capsids, as well as ones being run by Pfizer, Novartis, Neurocrine and Sangamo using the capsids, could enter the clinic as early as 2025, he said.

Voyager researchers also made an inadvertent discovery. “We had some very promising capsids and our team said, ‘well, how do they get across the blood-brain barrier?’” Sandrock recounted. It turned out they had identified three previously undescribed receptors unique from the transferrin receptor. Now, Voyager is researching whether it can make ligands against these receptors in the hopes of transporting either nucleic acids or proteins across the BBB without the use of AAV. 

Mamtani sees a future where both of these approaches—Brainshuttle and gene therapy—may combine to treat neurodegenerative diseases. 

“Maybe we’ll do gene therapy with Brainshuttle one day,” Mamtani said. “That’s kind of the ultimate fantasy science . . . but I feel like we might be a few years away from that.” 

Heather McKenzie is a senior editor at BioSpace. You can reach her at [email protected]. Follow her on LinkedIn.