Osteoarthritis is a common, complex musculoskeletal disorder with multiple genetic, constitutional and biomechanical risk factors. It is the most common form of joint disease and disability in older people and ranks amongst the top 5 causes of disability. Cellular pathways in OA operate more like webs than superhighways, there are multiple redundancies, or alternate routes, that may be activated in response to the inhibition of a single pathway as seen in commonly prescribed drugs such as NSAIDs. Furthermore, NSAIDs are associated with gastrointestinal, cardiovascular and renal complications, resulting in product withdrawals. FDA / NIHCE guidance states NSAIDs should be used at the lowest dose for the shortest period of time, in addition to co prescription of a proton pump inhibitor. Similarly, acetaminophen commonly used in OA hasrecently been described as offering no benefit by NIHCE. No licensed drugs exist that can halt the progression of OA.
APPA is an orally administered synthetic combination of two molecules, both of which are naturally occurring phytochemicals. There is a long history of traditional use of the two source plants for the treatment of a range of ailments, including inflammatory conditions. The transcription factor NFkB is persistently upregulated in chronic inflammatory conditions such as osteoarthritis (OA). As NFkB expression involves complex signalling pathways restoration of normal NFkB autoregulation and constitutive function is unlikely to be achieved by a single substance. Moreover profound NFkB inhibition causes severe adverse effects. The APPA combination targets multiple steps in the NFkB signalling pathway. APPA downregulates NFkB activation, nuclear translocation, DNA binding and inhibits ROS (reactive oxygen species) overexpressionenabling APPA to have a multimodal NFkB moderator activity that does not cause profound inhibition. APPA affects several other signal transduction pathways both at the gene and protein level. During the respiratory burst by neutrophils APPA is a strong scavenger of ROS upregulating the transcription factor NRf2, decreasing degranulation of neutrophils and inhibiting the production of neutrophil extracellular traps (NETs). In vivo animal models of OA have demonstrated that chronic administration of APPA relieves pain as effectively as the gold standard and limits cartilage degeneration in arthritic joints without the poor tolerability seen with NSAIDs. Administered as an unlicensed supplement in ~ 100 OA patients has demonstrated that APPA is well tolerated even in the long term.
NSAID related adverse events place a substantial clinical and economic burden on global healthcare systems. Direct, indirect and intangible costs in the USA, UK, Canada, France and Australia are estimated at 1-2.5% of GDP. 11% of preventable, drug related hospital admissions could be attributed to NSAIDs and adverse events are both dose and duration dependant. FDA guidance lists myocardial infarction, stroke, renal problems and GI bleeding as some of the serious adverse events. Patients at risk of GI, CV or renal complications, as well as patients on anticoagulant therapy, represent a substantial segment that currently have no safe, effective treatment option for OA. APPA’s efficacy and improved tolerability may result in improved adherence compared to NSAIDs helping ensure that the clinical benefits are realised.APPA promises an effective alternative to NSAIDs for patients at risk of GI, CV and renal complications plus OA patients taking anti coagulation therapy promising important long term clinical benefits for patients as well as long term direct and indirect cost savings for payers.