How PRX002 works
Parkinson’s disease is a progressive neurodegenerative disorder that results in the death of nerve cells in the brain that control movement. One potential cause of nerve cell death in some patients is the buildup of a protein called alpha-synuclein. In Parkinson’s, alpha-synuclein can fold incorrectly or be shortened, for example, due to a mutation in the gene encoding it. The misfolded proteins aggregate as toxic clumps, called Lewy bodies, in the brain; this helps kill surrounding nerve cells. Scientists also believe that alpha-synuclein may be a factor in disease propagation, as it can trigger the aggregation of alpha-synuclein and other proteins in neighboring cells, leading to further cell death.
PRX002 is a type of disease-modifying immunotherapy, as it aims to harness the body’s immune system to remove the toxic alpha-synuclein — possibly preventing or slowing alpha-synuclein-related neurodegeneration. The antibody interacts preferentially with the misfolded form of alpha-synuclein. The immune system uses antibodies designed to act against different antigens — or substances not normally found in the body —associated with abnormalities or infections to identify targets to be destroyed or removed.
When PRX002 is administered, it stimulates a passive immunity to alpha-synuclein; the immune system quickly raises a response against alpha-synuclein, triggered by the external antibodies, and removes the toxic protein. This is a transient immune response, and once PRX002 is no longer present the body, the response ends.
PRX002 in clinical trials
The first-in-human, single ascending dose, Phase 1 clinical trial (NCT02095171) assessed the safety of PRX002 compared to placebo in 40 healthy volunteers. This single-center, randomized, double-blind, placebo-controlled study placed participants into one of five dose-level cohorts, given either PRX002 at doses of 0.3, 1, 3, 10, or 30 mg/kg of body weight, or placebo, as a 60-minute infusion into the bloodstream. The 16-week study included a 12-week follow-up period after administration of a single dose of treatment.
Results, published in the journal Movement Disorders, suggested that PRX002 was safe and well tolerated. It also reduced blood levels of alpha-synuclein, supporting PRX002’s continued development as a Parkinson’s therapy.
This was followed by a randomized, double-blind, placebo-controlled, multiple ascending dose Phase 1b clinical trial (NCT02157714) of PRX002 in 80 Parkinson’s patients. This six-month trial evaluated the safety, tolerability, properties and immune system response of multiple ascending doses of PRX002, administered by intravenous infusion once every 28 days. Patients were randomly assigned to one of six dose groups of PRX002 (0.3, 1, 3, 10, 30, or 60 mg/kg of body weight) or to a placebo.
Prothena presented the study’s topline results in April 2017 at the 13th International Conference on Alzheimer’s and Parkinson’s Diseases in Vienna. They showed that levels of free alpha-synuclein in the blood fell by up to 97 percent after a single dose of PRX002. The treatment was also found to be safe and well-tolerated, without any major adverse events, and no dose-limiting toxicities. PRX002 was shown to have acceptable pharmacokinetic parameters, which measures how a drug is absorbed, distributed throughout, and expelled by the body.
A Phase 2 randomized and double-blind clinical trial (NCT03100149), led by Roche, is now evaluating PRX002’s effectiveness at a low (1500 mg/kg) and a high (4500 mg/kg for those with a body weight of 65 kg or more; 3500 mg/kg for those who weigh less) dose against placebo in about 300 people with early Parkinson’s (two years or less since diagnosis).
The study will run for one year, and be followed by a 52-week blinded extension study in which all patients will receive either the previous low- or high-treatment dose. PRX002 will again be given by intravenous infusion once a month. This trial, now recruiting eligible patients in the United States, France, Germany, Spai, and Austria, has as its primary goal changes in motor skills, as measured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Total Score at 52 weeks. Secondary measures include clinical and patient impressions of improvement and safety. The study should be completed by June 2021.
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