Biologic Drug for Parkinson’s Disease?

June 18, 2018

In phase Ib trial, investigational mAb targets aggregated alpha-synuclein

An investigational biologic agent appeared safe and well tolerated and led to marked reductions of alpha-synuclein in serum of Parkinson's disease (PD) patients, a phase Ib clinical trial found.

All dose levels of PRX002/RG7935, a monoclonal antibody targeting aggregated alpha-synuclein, met the study's primary safety and tolerability objective in patients with mild to moderate idiopathic PD, reported Joseph Jankovic, MD, of Baylor College of Medicine in Houston, and colleagues.

Single and multiple doses of the drug resulted in "robust binding of peripheral alpha-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated alpha-synuclein in the brain," they wrote in JAMA Neurology.

"This is the first demonstration of an anti-alpha-synuclein antibody immunotherapy in patients with PD," Jankovic told MedPage Today. "Robust target engagement led to a mean reduction of up to 97% in serum free alpha-synuclein levels."

Aggregated alpha-synuclein protein in the central and peripheral nervous systems is associated pathologically with PD, but the mechanisms underlying alpha-synuclein toxicity are unknown. PRX002 is a humanized monoclonal antibody designed to target aggregated forms of alpha-synuclein, inhibiting neuron-to-neuron transfer of presumed pathogenic forms of alpha-synuclein and potentially slowing disease progression.

An earlier single ascending-dose phase I trial in healthy adults showed that PRX002 was safe and well tolerated up to 30 mg/kg and led to dose-dependent reductions in free serum alpha-synuclein. In the current multiple ascending-dose phase Ib study, researchers evaluated the safety and tolerability of PRX002 at doses up to 60 mg/kg in patients with PD.

For this trial, the team evaluated patients ages 40 to 80 with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3) at eight U.S. study centers from July 2014 to September 2016. Patients were randomly assigned to placebo or three intravenous infusions of PRX002 at doses of 0.3, 1, 3, 10, 30, or 60 mg/kg every 4 weeks for a 24-week period.

A total of 80 patients participated; most were male (80%) and white (97.5%), and their median age was 58. PRX002 appeared safe and well tolerated with no serious or severe drug-related treatment-emergent adverse events reported. No antidrug antibodies were detected, and serum PRX002 levels increased in an approximately dose-proportional manner, with the average terminal elimination half-life similar across all doses at 10.2 days.

Rapid dose- and time-dependent average reductions from baseline in free serum alpha-synuclein levels of up to 97% occurred after a single infusion at the highest dose, with similar reductions after two additional infusions. The average cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts.

PRX002 did not lead to any change in disease progression, but "that will require a long-term study," Jankovic said. "The 2-year PASADENA Phase II study may provide a signal."

But as PRX002 moves into efficacy trials, "progress within the synuclein basic science field needs to follow suit," wrote Malu Tansey, PhD of the Emory University School of Medicine in Atlanta, and co-authors in an accompanying editorial.

The rationale for this trial, and others like it, rests on much-debated preclinical research, Tansey and colleagues observed.

"The entire premise of the current PRX002 clinical trial is based on the notion that extracellular or aggregated alpha-synuclein is capable of cell-to-cell transmission and thus capable of propagating the disease process and resultant neurodegeneration. This phenomenon is documented to occur in model systems, but whether it occurs in humans is, to our knowledge, completely unknown at this point."

Little clinical evidence that directly proves this prion hypothesis of PD exists, the editorial added: "The question remains: to what extent does this process reflect the role of alpha-synuclein in the causal mechanisms of Parkinson disease?"

If PRX002 proves to be effective and safe in the long-term, any patient with early PD could be a candidate, Jankovic said. "In the future, once we develop specific and sensitive biomarkers of prodromic PD, we could potentially target those pre-symptomatic individuals -- for example, those with [rapid-eye-movement sleep behavior disorder] or loss of smell -- who are at a high risk for developing PD."

The study was sponsored by Prothena Biosciences and F. Hoffmann-La Roche.

Jankovic reported a relationship with Prothena Biosciences; several co-authors are employees of Prothena, and others reported relationships with F. Hoffmann-La Roche, Genentech, vTv Therapeutics, and QUEST Research Institute.

Tansey reported relationships with INmune Bio, Above and Beyond, Hygieia Sciences, and UCB, and serving on the the Michael J. Fox Foundation for Parkinson's Research science advisory board.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College and Dorothy Caputo, MA, BSN, RN, Nurse Planner

https://www.medpagetoday.com/neurology/parkinsonsdisease/73555