Gentle chain amyloidosis is just not most cancers, however most cancers medication are this uncommon illness’s commonplace of care. The affected person want for brand new therapy choices has sparked R&D efforts at biotech and large pharmaceutical firms. Protego Biopharma goals to face aside from them with a possible first-in-class drug that targets the proteins driving the illness earlier than they do most of their injury.
The San Diego-based startup doesn’t have Section 1 knowledge but, however what it does have is the arrogance of an investor syndicate that has dedicated a recent $130 million to again plans to advance the drug to a pivotal scientific trial. Novartis Enterprise Fund and Forbion led Protego’s Collection B financing introduced Monday.
Gentle chain amyloidosis, or AL amyloidosis, begins in bone marrow, the place irregular plasma cells make misfolded proteins known as gentle chains. Due to this misfolding, the physique can’t acknowledge these proteins to correctly clear them. Consequently, the proteins kind clumps of amyloid round organs. The guts is the organ most affected by AL amyloidosis; cardiac failure is the most typical reason for loss of life from the illness.
“[Misfolded proteins] will mixture across the coronary heart and kidneys and trigger a mechanical impact, successfully stiffening these organs, crowding the tissue, and successfully stopping the organs from having the ability to operate,” Protego CEO Brent Warner mentioned. “So the core subject, the core drawback in gentle chain amyloidosis is that there’s too many of those dangerous gentle chains and even a small quantity will be very poisonous to organs.”
AL amyloidosis’s origin in plasma cells is just like a number of myeloma, a most cancers of plasma cells. That’s how a number of myeloma medication grew to become commonplace therapies for the illness. Protego doesn’t goal to exchange the mixtures of plasma cell-targeting medication at present used to deal with AL amyloidosis, Warner mentioned. However the startup is bringing a novel method with its small molecule, PROT-001.
There are two key challenges for drugging misfolded gentle chains with a small molecule, Warner mentioned. The primary is that these proteins don’t have a pure binding web site for a drug. The second is that the genetic mutation that results in the misfolding is completely different for every affected person.
Protego’s scientific founders recognized a cryptic binding web site, a hidden pocket to which a molecule can bind, making the protein druggable, Warner mentioned. The corporate designed PROT-001 to bind to this to the cryptic web site in addition to to account for almost all of affected person sequences driving the illness. Binding to the sunshine chain stabilizes it, returning that protein to a state the physique acknowledges and naturally clears from the physique, Warner mentioned. Over time, the protein buildup on the center and different organs is cleared ought to be cleared away as effectively. Moreover, the drug’s impact of instantly binding to gentle chains as they’re produced by plasma cells ought to forestall additional aggregation.
Late- stage scientific analysis has not yielded a lot success in AL amyloidosis. Takeda Pharmaceutical’s ixazomib, model identify Ninlaro, an oral proteasome inhibitor accredited for a number of myeloma, failed a Section 3 take a look at in Al amyloidosis in 2019. This previous 12 months, Prothena’s birtamimab and AstraZeneca’s anselamimab failed their respective Section 3 trials within the illness.
The Prothena and AstraZeneca medication are antibodies designed to bind to amyloid already gathered on organs, decreasing this protein buildup. Protego believes its small molecule can have a greater scientific trial end result as a result of the best way the drug works is upstream of amyloid aggregation and the injury that has already been brought about, Warner mentioned.
“Apoptosis (cell loss of life) has doubtless already occurred in quite a lot of cells,” he defined. “So you’ll be able to take away a number of the aggregates, however you’re not eradicating the poisonous gentle chain that’s nonetheless floating and out there to repeatedly insult the cells.”
Protego’s protein-stabilizing method is just like that of tafamidis, a drug that Pfizer markets for the uncommon illness transthyretin amyloidosis (ATTR) underneath the model names Vyndaqel and Vyndamax. Like AL amyloidosis, ATTR is brought on by misfolded protein that results in amyloid buildup on organs, notably the center. Tafamidis got here from startup FoldRx Prescription drugs, which Pfizer acquired in 2010. Pfizer steered Vyndaqel and Vyndamax to FDA approvals and the medication are at present blockbuster sellers as therapies for ATTR cardiomyopathy, although that area has expanded previously 12 months with new FDA-approved therapies for the dysfunction.
Protego was co-founded in 2017 by Jeffery Kelly, a professor of chemistry at Scripps Analysis. Kelly, an skilled in protein folding, had beforehand co-founded FoldRx based mostly on his analysis at Scripps. Warner mentioned Protego builds on the work that led to tafamidis and the startup’s staff contains many former FoldRx workers. Protego raised $51 million in Collection A financing in 2023, however has disclosed little since then. Warner, who was most lately president of gene remedy at Poseida Therapeutics, was named CEO of Protego final 12 months. He mentioned the corporate maintained a low profile till it secured financing and was prepared to maneuver its lead program ahead.
A placebo-controlled Section 1 examine is ongoing in Australia evaluating PROT-001 in additional than 100 wholesome volunteers. Whereas the primary purpose is evaluating the molecule’s security, secondary endpoints embody measuring how the drug is distributed and its focus within the physique in addition to affirmation it engaged its goal. That affirmation will come from Protego’s proprietary AmyLite assay. Continuing to pivotal testing with once-daily or twice-daily dosing will rely on the molecule’s half-life, which can be being measured within the Section 1 examine. Information from the Section 1 examine are anticipated early subsequent 12 months. Protego plans to start the Section 2/3 scientific trial in late 2026.
Becoming a member of the lead traders in Protego’s Collection B spherical are new monetary backers Omega Funds, Droia Ventures, YK Bioventures, and Digitalis Ventures. Earlier traders Vida Ventures, MPM BioImpact, Lightspeed Enterprise Companions, and Scripps Analysis additionally participated within the newest financing.
Picture by Protego Biopharma
