GOUT: THE MOST COMMON INFLAMMATORY ARTHRITIS IN THE UNITED STATES
Affects an estimated 14 million adults in the United States.
An estimated approximately 5% of the gout population is considered to have chronic refractory disease. Patients with other severe forms of gout may also benefit from new therapies.
Cause
Uncontrolled gout occurs when urate-lowering therapies (ULTs) fail to lower serum uric acid (sUA) levels below the gout guideline goal of 6 mg/dL at the maximum medically appropriate dosage or when gout does not improve clinically with oral ULTs. Uncontrolled gout is also reported to involve urate crystal deposition and associated inflammation in joints, soft tissues and organs. Currently available ULTs can be effective in treating gout. However, low adherence, under dosing and disease progression that cause high patient burden require, we believe, new, effective and safe therapies to treat these underserved uncontrolled gout patients.
Uncontrolled Gout
The risk of gout increases with age, and it is thus more common in ageing populations. Gout results from sustained elevation of serum urate levels (hyperuricaemia). Urate levels may increase due to diet, genetic predisposition and environmental factors leading to the deposition of monosodium urate crystals, which triggers recurrent episodes of pronounced acute inflammation, known as gout flares. Gout leads to substantial morbidity, severe pain, reduced quality of life, decreased physical function, increased healthcare costs, and lost economic productivity. In addition, in some patients deposits of monosodium urate crystals under the skin form Tophi on joints, tendons and other soft tissue, which can cause inflammation, pain and deformation. Furthermore, gout is strongly associated with a number of comorbidities, including hypertension, cardiovascular disease, renal impairment, diabetes, obesity, hyperlipidaemia and frequently in a combination known as the metabolic syndrome.
PRX-115
A recombinant PEGylated uricase enzyme, chemically modified enzyme in development for the potential treatment of uncontrolled gout.PRX-115 is our recombinant PEGylated uricase (urate oxidase) – a chemically modified enzyme under development for the potential treatment of patients with uncontrolled gout. The uricase enzyme, that does not exist naturally in humans, converts uric acid to allantoin, which is easily eliminated through urine . This recombinant enzyme, expressed via our ProCellEx system, is designed to lower uric acid levels and improve clinical manifestation of the disease while having low immunogenicity and increased half-life of the drug in the blood.
Pre-clinical data demonstrates long half-life, reduced immunogenic risk and high specific activity which supports the potential of PRX-115 to be a safe and effective treatment for patients with uncontrolled gout. One-month multiple dosing toxicity studies in two species and 6-month multiple dosing toxicity study in one specie were conducted to support single and multiple dose studies in humans.
Clinical Development
PRX-115 is being studied in a phase I First in Human (FIH) single ascending dose clinical trial to evaluate its safety, pharmacokinetics, pharmacodynamics and immunogenicity in patients with elevated uric acid levels.
It is a double blind, placebo-controlled study where 56 randomized subjects were enrolled across seven cohorts, 42 subjects were treated with PRX–115 and 14 subjects were treated with placebo.
Key preliminary results are as follows:
Exposure to PRX–115 increased in a dose–dependent manner
PRX–115 rapidly reduced plasma uric acid concentrations to below 6.0 mg/dL over time following a single administration. The effect of PRX–115 on plasma uric acid concentrations and the duration of response was found to be dose dependent
PRX–115 was well-tolerated
After a review of the initial positive top–line results from the seven cohorts, the FIH study is being expanded to an additional cohort to analyze a higher dose and, in parallel, preparations for a phase II clinical trial of PRX-115 have commenced.
