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An article by Alan Reynolds and Nicholas Larkins in the March 2021 edition of The Journal of Precision Medicine

Introduction and Background

Osteoarthritis (OA) is the most prevalent joint disease, estimated to affect 250 million people worldwide with prevalence increasing due to aging populations and growing levels of obesity.1 The estimated global incident cases from the 2017 Global Burden of Diseases (GBD) study were almost 15 million with an age standardised incidence of 181.19 per 100,000, which was highest in the USA at 316.87 per 100,000.2

OA causes a substantial burden of disability, ranking third behind Alcohol Use and Unipolar Major Depression for Years Lost to Disability (YLDs) in the USA in 1996 totalling 434,000 YLDs, 5.9% of the total.3 Based on the 2010 GBD study, the combined incident case total of hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in Disability Adjusted Life Years.4 Mobility disability due to OA is greater than any other disease and OA of the knee contributes 83% of the total burden attributed to OA.1 The quality of life (QoL) of patients with OA is substantially reduced, not only with respect to physical function but across other domains, including mental health.5-7

The socioeconomic impact is significant. In the USA, annual total costs for 2013 were estimated at $139.8 – $161.8 billion (direct $115.3 billion and indirect $11.6 – $13.0 billion).8 The social cost of OA could be as high as 2.5%9 of Gross Domestic Product although a recent systematic review reported values between 0.25 and 0.5%.10 A study from Sweden found that patients with knee OA have double the risk of sick leave with 2% of all days off work resulting from the disease and an increased risk of receiving a disability pension.11 In a survey of five European countries involving 3750 subjects, the mean SF-12 score* was 40.53 (perfect health =100] and 21.5% reported depression. Among the one third who were employed, 7% reported absenteeism and 24% presenteeism.12

*SF-12 is a self-reported short form outcome measure assessing the impact of health on an individual’s everyday life. It is often used as a quality-of-life measure.

The economic and QoL impact of OA led the Osteoarthritis Research Society International (OARSI) to submit a white paper to the US Food and Drug Administration (FDA) in 2016, “Osteoarthritis: A Serious Disease”,13 which resulted in the publication of draft guidance in 2018 that stated the “FDA recognizes that OA can be a serious disease with an unmet medical need for therapies that modify the underlying pathophysiology of the disease and potentially change its natural course to prevent long-term disability.”14

In this article we will discuss the challenges in demonstrating disease modification in OA, illustrate this with examples of recently published clinical trials, and then describe the current status of APPA, a novel, patented potential Disease Modifying Osteoarthritic Drug (DMOAD). APPA is an oral combination of two synthetically produced isomers, originally of plant origin: 4-hydroxy-3-methoxyacetophenone (apocynin) and 2-hydroxy-4-methoxyacetophenone (paeonol).

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