In another blow to Prothena’s neurodegenerative disease portfolio, anti-amyloid candidate PRX012 has run into the same problem that larger peers Biogen and Eli Lilly have battled: high rates of swelling in the brain.
Following the May failure of AL amyloidosis drug birtamimab, Prothena is facing more bad news for its Alzheimer’s porfolio. Like Biogen and Eli Lilly have seen with their approved anti-amyloid antibodies, Prothena’s anti-amyloid beta therapy PRX012 elicited high rates of amyloid-related imaging abnormality edema (ARIA-E), or swelling in the brain, in the Phase I ASCENT trials.
While the trio of studies showed proof of concept for PRX012 with dose dependent reductions in amyloid plaque observed, the results revealed “a non-competitive ARIA-E profile,” Prothena said in a Wednesday afternoon release.
Both ARIA-E and ARIA-H, or small brain bleeds, became key concerns as Biogen and Eisai’s Leqembi and Lilly’s Kisunla reached the market.
Heading into the readout, Jefferies analyst Michael Yee was “cautious at best given [the] high bar from current drugs Leqembi and [Kisunla],” according to a June note. Prothena’s shares have declined 61% year to date, with a slight dip as the markets opened Thursday. The stock is sitting at $8.30.
The news marks the second stumble for Prothena this year after birtamimab failed to improve all-cause mortality in patients with AL amyloidosis in a Phase III trial. The failure pushed Prothena into crisis mode, with the board promising to slash spending and consider business options that are in the best interest of shareholders. Birtamimab was discontinued.
In June, Prothena announced a restructuring that saw a 63% reduction in its workforce to support the wholly owned programs.
Next Steps
Prothena said the ASCENT studies, which featured those with early symptomatic Alzheimer’s, showed higher rates of ARIA-E as compared to approved amyloid drugs. Therefore, PRX012 is “less appropriate” for the patients in the ASCENT program, who were at the early stages of their disease.
Overall rates of ARIA ranged from 16% in the low dose group to 42% in the highest dose, compared to 7% in the placebo arm. ARIA-E had the highest percentage, ranging from 12% to 42%.
The biotech will now seek a partner for the program and turn its attention to a preclinical wholly owned Aβ-transferrin receptor antibody surrogate, PRX123.
“Prothena believes this approach may represent an opportunity to significantly lower the risk of ARIA and quickly reduce amyloid plaque with a once-monthly subcutaneous administration,” the company said in a statement.
Yee noted in June that Prothena had already indicated a desire to partner the PRX012 program given the high cost of capital. But the mixed results in the Phase I trial put the program’s future up in the air.
PRX012 was one of Prothena’s two wholly owned programs besides PRX123. The rest of the biotech’s portfolio includes multiple neurodegenerative programs with Bristol Myers Squibb, a Parkinson’s disease program with Roche and an ATTR amyloidosis therapy with Novo Nordisk. The latter two are in the Big Pharmas’ hands to initiate Phase III development.
