Light chain amyloidosis is not cancer, but cancer drugs are this rare disease’s standard of care. The patient need for new treatment options has sparked R&D efforts at biotech and big pharmaceutical companies. Protego Biopharma aims to stand apart from them with a potential first-in-class drug that targets the proteins driving the disease before they do most of their damage.
The San Diego-based startup doesn’t have Phase 1 data yet, but what it does have is the confidence of an investor syndicate that has committed a fresh $130 million to back plans to advance the drug to a pivotal clinical trial. Novartis Venture Fund and Forbion led Protego’s Series B financing announced Monday.
Light chain amyloidosis, or AL amyloidosis, begins in bone marrow, where abnormal plasma cells make misfolded proteins called light chains. Because of this misfolding, the body cannot recognize these proteins to properly clear them. Consequently, the proteins form clumps of amyloid around organs. The heart is the organ most affected by AL amyloidosis; cardiac failure is the most common cause of death from the disease.
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“[Misfolded proteins] will aggregate around the heart and kidneys and cause a mechanical effect, effectively stiffening those organs, crowding the tissue, and effectively stopping the organs from being able to function,” Protego CEO Brent Warner said. “So the core issue, the core problem in light chain amyloidosis is that there is too many of these bad light chains and even a small amount can be very toxic to organs.”
AL amyloidosis’s origin in plasma cells is similar to multiple myeloma, a cancer of plasma cells. That’s how multiple myeloma drugs became standard treatments for the disease. Protego does not aim to replace the combinations of plasma cell-targeting drugs currently used to treat AL amyloidosis, Warner said. But the startup is bringing a novel approach with its small molecule, PROT-001.
There are two key challenges for drugging misfolded light chains with a small molecule, Warner said. The first is that these proteins do not have a natural binding site for a drug. The second is that the genetic mutation that leads to the misfolding is different for each patient.
Protego’s scientific founders identified a cryptic binding site, a hidden pocket to which a molecule can bind, making the protein druggable, Warner said. The company designed PROT-001 to bind to this to the cryptic site as well as to account for the majority of patient sequences driving the disease. Binding to the light chain stabilizes it, returning that protein to a state the body recognizes and naturally clears from the body, Warner said. Over time, the protein buildup on the heart and other organs should be cleared away as well. Furthermore, the drug’s effect of immediately binding to light chains as they are produced by plasma cells should prevent further aggregation.
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Late-stage clinical research has not yielded much success in AL amyloidosis. Takeda Pharmaceutical’s ixazomib, brand name Ninlaro, an oral proteasome inhibitor approved for multiple myeloma, failed a Phase 3 test in Al amyloidosis in 2019. This past year, Prothena’s birtamimab and AstraZeneca’s anselamimab failed their respective Phase 3 trials in the disease.
The Prothena and AstraZeneca drugs are antibodies designed to bind to amyloid already accumulated on organs, reducing this protein buildup. Protego believes its small molecule can have a better clinical trial outcome because the way the drug works is upstream of amyloid aggregation and the damage that has already been caused, Warner said.
“Apoptosis (cell death) has likely already happened in a number of cells,” he explained. “So you can remove some of the aggregates, but you’re not removing the toxic light chain that’s still floating and available to continuously insult the cells.”
Protego’s protein-stabilizing approach is similar to that of tafamidis, a drug that Pfizer markets for the rare disease transthyretin amyloidosis (ATTR) under the brand names Vyndaqel and Vyndamax. Like AL amyloidosis, ATTR is caused by misfolded protein that leads to amyloid buildup on organs, particularly the heart. Tafamidis came from startup FoldRx Pharmaceuticals, which Pfizer acquired in 2010. Pfizer steered Vyndaqel and Vyndamax to FDA approvals and the drugs are currently blockbuster sellers as treatments for ATTR cardiomyopathy, though that field has expanded in the past year with new FDA-approved therapies for the disorder.
Protego was co-founded in 2017 by Jeffery Kelly, a professor of chemistry at Scripps Research. Kelly, an expert in protein folding, had previously co-founded FoldRx based on his research at Scripps. Warner said Protego builds on the work that led to tafamidis and the startup’s team includes many former FoldRx employees. Protego raised $51 million in Series A financing in 2021, but has disclosed little since then. Warner, who was most recently president of gene therapy at Poseida Therapeutics, was named CEO of Protego last year. He said the company maintained a low profile until it secured financing and was ready to move its lead program forward.
A placebo-controlled Phase 1 study is ongoing in Australia evaluating PROT-001 in more than 100 healthy volunteers. While the main goal is evaluating the molecule’s safety, secondary endpoints include measuring how the drug is distributed and its concentration in the body as well as confirmation it engaged its target. That confirmation will come from Protego’s proprietary AmyLite assay. Proceeding to pivotal testing with once-daily or twice-daily dosing will depend on the molecule’s half-life, which is also being measured in the Phase 1 study. Data from the Phase 1 test are expected early next year. Protego plans to begin the Phase 2/3 clinical trial in late 2026.
Joining the lead investors in Protego’s Series B round are new financial backers Omega Funds, Droia Ventures, YK Bioventures, and Digitalis Ventures. Earlier investors Vida Ventures, MPM BioImpact, Lightspeed Venture Partners, and Scripps Research also participated in the latest financing.
Photo by Protego Biopharma