June 1, 2010 (Vol. 30, No. 11)
Guy-Charles Fanneau de la Horie, DVM
Active Immunotherapy Holds Promise for Treatment of Autoimmune Diseases
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.
The fact that there remains a significant unmet medical need in these diseases, together with the commercial success of existing therapies, means that they are targets of great interest to the biopharmaceutical industry.
There are significant efforts on hand to expand the options open to patients and their physicians, which can be divided into three categories: small molecule immune modulating drugs, passive immunotherapy biologics to targets other than TNFα, and active immunotherapies to the cytokine of interest.
With regard to small molecule product candidates, a number of companies have compounds in clinical development, in particular different tyrosine kinase inhibitors, a class of drug with a number of products already licensed in cancer indications.
Small molecule drugs offer potential benefits, including low manufacturing costs and the convenience of oral administration. However, they lack the specificity of biologics and this increases the risk of off-target adverse events, especially in chronic use. Further, a daily or twice-daily pill may represent a compliance challenge, especially in younger patients and those not experiencing any current disease activity.
There are a number of passive immunotherapies to nonTNF targets, either approved or in development, including drugs targeting specific cytokines such as Il-6, Il-17, and Il-23, and others inhibiting B- or T-cell activity. Most often these drugs are used in patients who have failed or are otherwise intolerant to TNF inhibitors.
While providing valuable options to this population, these drugs typically have many of the disadvantages of the TNF inhibitors, notably cost, the risk of drug resistance emerging over time, and frequency of administration. In addition, obviously there is not the safety experience with these newer agents that there is with antiTNF, and some of them have some relatively significant, if rare, safety concerns.
The third category, active immunotherapy, holds out the promise of addressing the shortcomings of the TNF inhibitors without requiring a new therapeutic pathway.
This approach involves the administration of the target cytokine by intramuscular injection, formulated in such a way as to break immune tolerance to the cytokine, a self protein that would not normally be immunogenic. TNF inhibitors have established that TNF antibodies are efficacious in treating multiple autoimmune diseases; under this modality, instead of administering synthetically produced antibody, the therapeutic stimulates the patient’s own immune system to generate endogenous antibodies.
The advantages of this potentially elegant therapeutic approach are many. First, since the antibodies it produces are from the patient’s own immune system, they will not stimulate the generation of resistance. Indeed, since they are polyclonal, recognizing multiple epitopes on the target cytokine unlike current passive immunotherapy approaches, they might be expected to have both broader and longer efficacy.
Further, while the immune response to the active immunotherapies is transient, testing to date indicates that re-treatment will only be required every 3–4 months, a significant reduction in the compliance and patient/caregiver burden as opposed to current approaches.
Finally, as their name suggests, passive immunotherapies rely completely on the drug administered for their therapeutic effect, requiring gram quantities per patient per year. By contrast, since with active immunotherapy it is the patient generating the antibody, only milligram quantities per patient per year are required, which has obvious cost implications.
Biotechnology has transformed the treatment of severe autoimmune diseases, and continued innovation holds great promise for patients afflicted with these serious and debilitating conditions. The evidence is growing that an approach using active immunotherapy principles will have a key role to play in the future. Neovacs has ongoing clinical trials for Crohn disease, rheumatoid arthritis, and lupus.