One of the more active areas of drug research gets cells to eliminate proteins that drive disease. Cancer was the proving ground for this targeted protein degradation and the first degraders for oncology reached the market this year. The approach is expanding to immunology, but to date, diseases of the brain have been a formidable challenge.
While some small molecules can penetrate the blood-brain barrier, the relatively large size of the molecules used in protein degradation has kept such drugs from neurological applications. London-based Oyster Therapeutics has technology that gets its degraders across the protective barrier. With a lead therapeutic candidate designed to degrade pathological tau, the preclinical startup last week unveiled $60 million to fund research in Alzheimer’s disease and potentially other neurodegenerative disorders.
A protein degrader is a heterobifunctional molecule, meaning it’s comprised of one part that binds to the target protein and another part that binds to the enzyme that marks a protein for degradation by the cell. The dual function of a degrader makes for a molecule large in size relative to other small molecules, said Oyster CEO Rob Johnson. But for protein degraders destined for the brain, the first obstacles is actually the gut. The large size of a degrader makes it hard for the molecule to be absorbed by the intestine. The amount of drug that does get through still has to penetrate the blood-brain barrier. Johnson notes that many degrader programs in the biopharmaceutical industry have been shelved due to the inability to overcome the size problem of these molecules.
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Oyster addresses the size problem with a molecule that disassembles into two smaller molecules capable of passing through biological membranes, such as the intestinal wall and the blood-brain barrier, Johnson said. When those smaller molecules reach their destination inside a cell, such as a neuron, they reassemble to form the protein degrader that directs a disease-driving protein to the proteasome, a component of the cell that eliminates old or damaged proteins.
“It is chemistry that has been used in previously approved pharmaceuticals,” Johnson said of Oyster’s technology. “The human body has been exposed to these particular chemical groups. We’re just using them in a unique way.”
Tau is particularly suited for a degrader drug. This protein doesn’t have an active site where a classic small molecule inhibitor can bind, which opens the door to addressing it in other ways. One of those ways is RNA medicines. Biogen’s diranersen (formerly BIIB0880) is an antisense oligonucleotide designed to bind to the messenger RNA carrying the instructions for making tau. In May, the company reported preliminary Phase 2 results showing reduction in tau and cognitive benefit in patients with Alzheimer’s. However, this trial did not meet the main goal of showing a dose response according to a rating scale measurement at week 76. Biogen is scheduled to present new Phase 2 data for the drug this week during the Clinical Trials on Alzheimer’s Disease (CTAD) Conference in Boston.
Arrowhead Pharmaceuticals is in Phase 1/2 testing with ARO-MAPT, a small interfering RNA (siRNA) therapy designed to silence the gene that codes for tau. Last month, Arrowhead reported interim Phase 1/2 data showing its therapy reduced levels of tau in healthy volunteers. The trial is continuing and additional data are expected in 2027.
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Johnson acknowledged the RNA drug candidates going after tau, but said that they lower levels of all tau, including the healthy form of this protein. Healthy tau is important for neuron function and it’s found in high concentrations in the brain. The unhealthy, pathological form leads to insoluble aggregates found in the brains of Alzheimer’s patients. There’s a third form of tau, an intermediary type in which protein changes from healthy to pathological. Johnson said this form takes on a certain shape that Oyster’s drug can selectively target, leaving healthy tau untouched. .
An orally administered protein degrader would have other advantages. A small molecule is less expensive to manufacture compared to RNA medicines and is stable at room temperature, Johnson said. Oral dosing is also more convenient for patients compared to therapies administered by injection or infusion. Those properties will be important for making the drug accessible. It’s also important as the Alzheimer’s field pursues ways to treat patients earlier when they show biological signs of disease but no symptoms.
“What modality is going to win in that pre-symptomatic patient population?” Johnson said. “An injectable is going to be a tough sell. If you have a safe oral solution, that’s got to be the end goal, and that’s what we’re aiming for.”
SELFTAC, the platform technology that produced Oyster’s tau-targeting drug, could also apply to other neurological proteins. Johnson said the most obvious next target is misfolded versions of alpha-synuclein whose role in Parkinson’s disease has drawn interest from other neuroscience-focused biotechs. While Oyster has not disclosed a Parkinson’s program, Johnson acknowledged the startup is interested in the disease. He added that Oyster’s approach to degradation could be used to treat cancer.
Oyster was built on the research of medicinal chemist Harry Finch, the startup’s founder and chief scientific officer. Johnson said that during the Covid-19 pandemic, Finch spent his time studying how to overcome the size problem for protein degraders. In 2022, the startup raised £25m (about $33 million) in Series A funding co-led by Syncona and Oxford Science Enterprise (OSE).
With the new financing, Johnson said one of Oyster’s goals is bringing the tau degrader to the clinic, though he declined to specify a timeline. The cash is a Series A-2 financing that includes participation from new investor Eli Lilly, maker of Kisunla, an amyloid-targeting antibody drug for Alzheimer’s. 4BIO Capital led the latest Oyster financing with participation from additional new investors Actium Group, CE Ventures, and TOHO Ventures. Earlier investors Syncona, OSE, Mission BioCapital, and MGB Ventures also participated. Alongside the latest financing, Oyster revealed a change from its previous name, Kesmalea Therapeutics. Johnson joked that Oyster is easier to pronounce. But there’s also symbolism for the new moniker.
“An oyster can take a grain of sand and turn it into a beautiful pearl,” Johnson said. “Oysters also have a cleansing role and degrading is sort of cleansing the brain from pathologic forms of protein.”
Photo by Oyster Therapeutics