[guest author: David Miles]*

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. OA causes a substantial burden of disability, ranking third behind alcohol use and depression and the socioeconomic impact is significant, estimated at 2.5% of Gross Domestic Product in developed nations.

The economic and quality of life (QoL) impact of OA led the Osteoarthritis Research Society International (OARSI) to submit a white paper to the U.S. Food and Drug Administration (FDA) in 2016, “Osteoarthritis: A Serious Disease” which resulted in the publication of draft guidance in 2018 that stated the “FDA recognizes that OA can be a serious disease with an unmet medical need for therapies that modify the underlying pathophysiology of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.”

Pathophysiology of OA

OA has historically been considered to result from ‘wear and tear,’ leading to cartilage loss and reduction in the joint space resulting in pain and damage to the bone. Research over the past decades has established that OA involves the whole joint with not only loss of cartilage, but also changes in the bone, synovium, tendons, ligaments and muscles. It is now recognised that the disease process is more complex than originally assumed.

Current Treatment of OA

Despite the importance of OA on patient QoL, the human cost of pain and disability caused, and economic costs, treatment options are limited. Unlike rheumatoid arthritis, no interventions have been approved that alter the course of the disease - the holy grail of OA treatment.

The primary reason subjects visit physicians with OA is because of pain, often in multiple joints. Oral pain killers such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are widely recommended, but use of NSAIDs is limited due to toxicity and should be used at the lowest dose and for the shortest possible time. Recent evidence however has questioned the efficacy of paracetamol in OA. Topical NSAIDs are recommended as effective, but without the safety concerns associated with the oral forms. In the event that pain relief is insufficient then opioids are an option with the associated concerns over long term use.

A number of injectable treatments are prescribed (for example, corticosteroids) although repeated injections of corticosteroids may be associated with additional joint damage and inadequate pain relief leading to joint replacement.

Notwithstanding these interventions, there remains a high unmet need for effective analgesics for patients with osteoarthritis and, in particular, treatments that slow, halt or even reverse the slowly progressing joint damage.

The Challenge in Finding a Disease Modifying Osteoarthritis Drug (DMOAD) for OA

Following submission of the OARSI white paper to the FDA in 2016, the agency published draft industry guidance. The document laid out the considerations for approval of a drug as a disease modifying osteoarthritis drug (DMOAD) including the validation of biomarkers associated with clinical benefits such as reduction in pain, improvement in function or delay or avoidance of joint replacement. The FDA goes on to comment that such validation has not yet been achieved.

Surrogate Endpoints and Biomarkers

The imaging standard used to measure changes in the joint in OA clinical trials has been minimum joint space width (mJSW) measured on X-rays, which equates to cartilage loss. This has a number of drawbacks, including the contribution of other structures to changes in JSW as well as issues with alignment, positioning and sensitivity to change in a disease that progresses slowly in the majority of patients. Magnetic Resonance Imaging (MRI) is now being seen as a more sensitive and reliable method to measure joint changes in OA.

In OA, biomarkers have a number of potential roles which include stratification of patient subgroups, measurement of disease activity and response to treatment. However, none of the biomarkers to date have been approved for use by a regulator though some show great promise as predictors of disease progression.

Current DMOAD Candidates

The increasing understanding of the complex pathways involved in OA has resulted in novel potential therapeutic targets being proposed with development of interventions designed to modify disease progression. These may be broadly classified into agents that:

• target cartilage turnover;
• target bone metabolism; or
• inhibit the inflammatory pathways that drive cartilage and bone loss.

In small, early clinical trials, phase one, several new drugs have shown promise, however, whilst some disease modifying effect has been demonstrated, the pain endpoints at the next stage, phase two, have not been met. This is important as the FDA requires both a disease modifying effect and an improvement in pain to secure marketing authorisation.

Given the multiple pathways involved in OA it is unlikely that targeting a single molecule by a specific mechanism will be effective at combating this condition. As with other chronic disorders, the future of OA treatment may lie in combination therapy, such as APPA, a novel treatment in development by AKL Research and Development, a privately held UK based pharmaceutical development company. APPA, currently in phase two, is a combination of two synergistic isomers that modulate the pathways involved in inflammation and joint damage through effects on intracellular signalling molecules, NF-kB and Nrf2.

Discussion and Conclusions

Addressing the substantial unmet needs in the treatment of OA, both for reduction of pain and for reducing the progression of disease, starts with an understanding the nature of OA as a heterogenous disease with a number of different pathways to joint damage. Personalised medicine has long been an aspirational goal of OA treatment and the scientific and clinical community and pharmaceutical companies have devoted much time, effort and money to achieve that target, but many obstacles remain.

OA is usually a slowly progressing disease so demonstrating reduction in the rate of damage is challenging. A premise of current investigational DMOADs is that effects on structural changes will lead to improvements in clinical endpoints such as pain and function. This assumption has been challenged recently as analysis of data from the Osteoarthritis Initiative led to the conclusion that cartilage loss on its own resulted in only limited worsening of pain.

Are we nearly there yet? No, but we now know the route and the journey has started and we have every reason to be optimistic.

*CEO of AKL Research and Development