Autoimmune diseases such as rheumatoid arthritis (RA), Crohn disease (CD), and psoriasis are a major source of morbidity and mortality, affecting substantial numbers of people across age and gender groups. Over 3% of the population suffers from a severe autoimmune disorder, with an impact on health and well-being that ranges from the distressing to disabling to life-threatening.
In addition to the personal impact, these diseases represent a significant public health and societal burden—an individual with CD disease has an 80% lifetime risk of requiring bowel resection surgery, while rheumatoid arthritis produces progressive disability, with many patients unable to work after several years of active disease.
Treatment for these diseases has historically focused first on symptomatic therapy, such as anti-inflammatories, and second on disease-modifying drugs, typically broad-spectrum immunosuppressants, including corticosteroids and folate inhibitors.
This classical approach has two major shortcomings: first, while treating symptoms, the disease would still progress leading to, for example, often irreversible joint damage in RA. Second, the disease-modifying therapies have significant off-target side effects. As a result, in CD patients, therapy frequently needs to be interrupted to avoid serious side effects, leading to a flare up in disease activity, while it is estimated that up to one-half of the pathological effects of lupus disease are attributable to the therapies, as opposed to directly to the disease itself.
Over the last 10 to 12 years, the advent of targeted biologic therapies and, in particular, inhibitors of TNFα, a pro-inflammatory cytokine, have transformed the treatment of many of these diseases. In RA, this class of drugs has shown the ability to arrest and even, in some cases, reverse disease progression, and in CD these drugs have demonstrated both a steroid-sparing quality and the ability to induce mucosal healing.
For such powerful drugs, they are also relatively safe, with the most significant concern being the potential reactivation of latent mycobacterial infection. Five TNF inhibitors are currently marketed, with apparently similar efficacy in RA, although not all have been able to demonstrate efficacy in CD. The first of this class was introduced in 1998 and today this is the most successful category of biologic drugs, with sales in 2009 of over $18 billion, a double-digit percentage increase on 2008.
For all the success of these drugs, they also have significant drawbacks and as a consequence there remain significant unmet medical needs.
The major shortcomings include:
- In many patients, current drugs lose efficacy over time, often because the patient’s immune system generates anti-drug antibodies. In a recent large Danish study, drug adherence at year 2 in RA patients ranged from 40 to 60%. Datamonitor estimates that 90% of CD3 patients have failed a TNF inhibitor after three years. Such figures clearly represent a major medical challenge in the treatment of chronic diseases usually diagnosed in young or middle-aged adults.
- Current TNF inhibitors typically require frequent injections. This represents both a compliance challenge and a potential burden on caregivers or the healthcare system if the patient does not self-administer.
- These drugs are expensive, typically $15,000 to $20,000 per patient/year.
As a consequence of these and other concerns, the current generation of TNF inhibitors are often held in reserve for the most severely ill patients (for example, in Europe and the U.S., under 20% of CD patients with moderate-to-severe disease receive a TNF inhibitor), notwithstanding a growing body of evidence that shows, in both RA and CD, that early use can alter the course of the disease long-term.