Change of direction for Prothena

DUBLIN—Prothena Corp. is changing tack on its pipeline in the wake of PRX003, a monoclonal antibody being advanced in psoriasis, failing to provide a sufficiently significant clinical benefit in a Phase 1b study to support further advancement. The compound targets CD146, a cell adhesion molecule found on the surface of T helper 17 cells, which are known to play a role in inflammatory responses and pathogenic autoimmune diseases.

Administering PRX003 led to dose- and time-dependent occupancy and downregulation of CD146 on Th17, similar to what was seen in a prior Phase 1a study. The pharmacodynamic effects of the drug did not result in meaningful clinical benefit for patients, though, as measured by responses in the Psoriasis Area and Severity Index 75. Skin biopsy data also showed insufficient reduction in the measurements of Th17 cell infiltration and other inflammatory markers. While the primary objectives of the study in question were reached, Prothena had set the bar for advancing the program into mid-stage development at the demonstration of “a well-defined relationship between biological activity and meaningful clinical effects, and these prerequisites were not met,” the press release noted.

The study—a double-blind, placebo-controlled multiple ascending dose study meant to evaluate PRX003’s safety, tolerability and pharmacokinetics—enrolled 33 individuals with psoriasis. Skin biopsies revealed no clinically meaningful or dose-dependent changes in the RNA transcript levels of genes linked to Th17-mediated inflammation, including IL-17A, IL-17F, IL-6, TNFα and IFNγ. The compound was found to be generally safe and well tolerated, even at the highest dose level, but the data showed that “near-complete downregulation of CD146 is insufficient to inhibit Th17 cell infiltration and associated inflammation to the degree necessary to achieve meaningful clinical benefit in patients with psoriasis.”

“As an organization guided by science and data-driven decision-making, we will only advance programs into mid- or late-stage clinical development that have the potential to offer clear and differentiated clinical benefits to patients,” Dr. Gene Kinney, president and CEO of Prothena, explained in a press release. “While we are disappointed that these data do not support moving PRX003 into mid-stage development at this time, we continue to focus on advancing NEOD001 (Phase 2b and Phase 3), PRX002 (Phase 2) and PRX004 (expected to enter Phase 1 by mid-2018), as well as our active discovery programs for new clinical candidates.”

Those three candidates are also monoclonal antibodies, though all are being advanced against different indications.

NEOD001, as noted on Prothena’s website, “targets the circulating soluble and deposited aggregated amyloid that accumulates in patients with AL amyloidosis and can cause organ damage and failure.” AL amyloidosis, or primary systemic amyloidosis, results when plasma cells from bone marrow overproduce light chain proteins that misfold and form chains, proteins that in turn build up in the bloodstream, deposit on organs and eventually interrupt normal function to the point of organ failure. Contrary to current treatment approaches, which seek to reduce amyloid production by targeting plasma cells, NEOD001 targets the accumulated amyloid, and its proposed mechanism of action is “to neutralize soluble aggregates and clear insoluble aggregates from organs,” per the website. NEOD001 has received orphan drug designation from the FDA and EMA.

At present, Prothena has two studies underway involving this antibody: PRONTO, a global Phase 2b, double-blind, placebo-controlled study assessing NEOD001 in previously treated individuals with AL amyloidosis and persistent cardiac dysfunction; and the VITAL Amyloidosis study, a Phase 3 global, double-blind, placebo-controlled study assessing NEOD001 in newly diagnosed, treatment-naïve patients with AL amyloidosis and cardiac dysfunction.

As for PRX002, it targets α-synuclein, the protein whose misfolded aggregates are implicated in Parkinson’s disease. Prothena is developing the compound in collaboration with Roche as a potentially disease-modifying therapy that could slow or reduce the neurodegeneration caused by the misfolding or transmission of α-synuclein. Prothena announced the launch of a Phase 2 study of PRX002 in individuals with early Parkinson’s disease on July 5.

PRX004, for its part, targets and clears misfolded (toxic) forms of the TTR amyloid protein found in transthyretin-mediated amyloidosis (ATTR amyloidosis), a rare, progressive disease characterized by the deposition of aggregates of misfolded amyloid.