Project Description

Overview / Statement of Need

Osteoarthritis (OA) is a well-known cause of disability in the United States and around the world. It is characterized by degeneration of articular cartilage and other joint changes, and it commonly presents as joint pain with ambulation or other activities of daily living, depending on the joint(s) affected. According to analysis of data from 3 large US population‐based studies, it is estimated that almost 27 million Americans 25 years of age and older suffer from clinical OA, a number that has increased from estimates in the 1990s.6 Prevalence is much higher in women, as females comprise approximately 78% of adults with OA.7 Prevalence also increases with age; 43% of adults over the age of 65 years have OA. This age group is expected to increase from 15% of the US population to 24% in the next 40 years.8 It should be noted that exact figures for incidence and prevalence are difficult to obtain due to differences in study designs and definitions of OA.

The financial cost of OA is staggering; according to data from the Medical Expenditures Panel Survey (MEPS) performed by the Agency for Healthcare Research and Quality, direct medical costs are over $65 billion annually.7 Another study found that privately insured adults with symptomatic OA had 4-times greater healthcare costs than matched controls.9 Perhaps more alarming is the effect on productivity. MEPS estimated OA-related earnings losses at over $71 billion for a 6-year period.7 In 2010 alone it was estimated that aggregate absenteeism costs due to OA were over $10 billion.10

In addition to the significant economic impact, OA also causes significant physical, social, and psychological burdens on individuals. Activity restrictions, reduced productivity, social interference, and mental health effects have all been reported.11–16 OA has also been associated in multiple studies with greater all-cause and cardiovascular mortality, which is not associated with nonsteroidal anti-inflammatory drug (NSAID) use or obesity, with walking disability being the main risk factor.17–19 Research continues to support weight loss and physical activity for improvements in pain, disability, and quality of life (QoL), but because physical activity and weight loss are critical to the management of OA and comorbid cardiometabolic conditions, difficulty walking can have negative effects across the board.

In the end, a glaring lack of effective treatments remains.20 As the prevalence of this debilitating disease continues to increase, there is an enormous need for novel treatment and pain management strategies and incorporation of them into clinical practice.

This program will begin by outlining standards of care and current treatment guidelines for moderate-to-severe OA and bringing attention to the significant unmet needs for these patients. It will also describe the pain pathway and elements in bone and cartilage homeosynthesis pathways that are currently being targeted for treatment, and it will highlight safety and efficacy data for novel agents currently in development. Lastly, the program will revisit supportive evidence for the role of nonpharmacologic treatments such as exercise, as clinicians can play a role in improving adherence and thus improving outcomes.

Gap 1. Untreated and undertreated pain due to OA have an enormous impact on patient quality of life.

The current standard of care for OA is inadequate. Treatment guidelines exist, but the space has become stale, and disability from OA remains high. No new effective interventions for the safe treatment of OA-related pain have been approved despite decades of research. Despite its enormous prevalence, the exact pathogenesis is incompletely understood,1 contributing to a profound lack of effective treatments. Additionally, there are no available agents that modify the disease, leaving clinicians only with pharmacologic options that treat pain and inflammation.

Existing guidelines recommend oral and topical selective and nonselective NSAIDs for hip, knee, and hand OA, with significant exceptions based on comorbidities, and long-term use is not recommended.2,21,22 There is insufficient evidence to support recommendation for use of acetaminophen/paracetamol. Support for intra-articular corticosteroids and hyaluronic acid has fluctuated over the years, and is generally considered weaker or inconclusive. These typically only provide short-term relief, and are not recommended for regular use.2,21–23 Opioids are conditionally not recommended in the treatment of OA,2 but continue to be prescribed.24

Gap 2. Clinicians may be unaware of recent developments in OA treatment research.

Because the OA treatment approach has remained relatively unchanged for many years, clinicians may be unaware of newer treatments on the horizon. This activity will inform the clinician of ongoing research into novel approaches to OA-related pain, including those targeting nerve growth factor (NGF) and other disease-modifying agents. Particularly of note are the trial data …

NGF’s role in nociceptive and neuropathic pain has been extensively studied. It is produced in response to noxious stimuli and subsequently promotes growth and differentiation of sensory and sympathetic ganglia, and incites inflammation after binding to mast cells.27 Increased NGF expression in subchondral bone likely contributes to pain in OA.28 NGF-Abs are thought to sequester free NGF without affecting other inflammatory processes or bone healing.27 These agents, namely tanezumab and fasinumab, have demonstrated efficacy in randomized, placebo-controlled, phase 2 or 3 clinical trials in patients with moderate-to-severe pain due to lower limb OA, as measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores.

NGF-Abs have been in the research pipeline for years. Due to reports of osteonecrosis in phase 2 and 3 trials, which were considered to be unexpected adverse events, the US Food and Drug Administration (FDA) initiated a partial hold on all trials. Most cases were ultimately adjudicated as normal or rapid progression of OA, which was deemed associated with increasing doses of NGF-Abs, as well as concomitant use of NSAIDs.29 After the hold was lifted, clinical trials moved forward with new safety strategies, including prohibiting the concomitant use of NSAIDs, excluding patients at risk for rapidly progressive OA and who are not candidates for arthroplasty, and evaluating lower doses.30 Because of the safety signals seen early in the development of NGF-Abs, there may be a lingering negative perception of this drug class. It will be important to provide prescribing clinicians up-to-date efficacy and safety data, as these agents may prove to be beneficial for their patients with moderate-to-severe and difficult-to-treat OA.

This educational program will address previous safety concerns associated with NGF-Abs and will also introduce more recent safety and efficacy data. In addition, it will review other novel agents in development, highlighting how the previously unchanged treatment patterns in OA may soon be changing.