Beyond monoclonals for severe autoimmune diseases

By Guy-Charles Fanneau de la Horie, DVM, Chief Executive Officer, Neovacs SA

<br /> Autoimmune diseases such as rheumatoid arthritis (RA), Crohn’s 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 very distressing to disabling to life-threatening. In addition to the personal impact, these diseases represent a significant public health and societal burden; as one example, an individual with Crohn’s disease has an 80% lifetime risk of requiring surgery.

Treatment for these diseases has historically focused 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 still progresses leading to, for example, irreversible joint damage in RA.  Second, the disease-modifying therapies have very significant off-target side effects.  It is estimated that up to half of the pathological effects of lupus are attributable to the therapies versus directly to the disease itself.

Over the last twelve years, the advent of targeted biologic therapies, especially inhibitors of TNFα, a pro-inflammatory cytokine, has 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 they have demonstrated both steroid-sparing 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 infections.  Five TNF inhibitors are currently marketed, with apparently similar efficacy in RA, although not all appear efficacious in CD.  The first of this class was introduced in 1998 and today is the most successful category of biologic drugs, with sales in 2009 of over $18bn, 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 40-60%.  The analysts Datamonitor estimate that 90% of Crohn’s patients have failed a TNF inhibitor after three years.  Such figures clearly represent a major medical challenge in the treatment of chronic diseases typically diagnosed in young or middle-aged adults.
•    Current TNF inhibitors typically require frequent injections, once per week or biweekly.  This represents both a compliance challenge and is potentially a burden on caregivers or the healthcare system.
•    These drugs are expensive, typically $15,000 to $20,000 per patient/year.

Products from Neovacs Kinoid platform, using a whole cytokine coupled to a carrier protein as an immunogen, are being developed to treat severe autoimmune diseases such are rheumatoid arthritis and lupus. 

As a consequence of these and other concerns, the current generation of TNF inhibitors are typically held in reserve for the most severely ill patients (for example, in Europe and the US, 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 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 these diseases are of great interest to the biopharmaceutical industry.  There are significant efforts in hand to expand significantly the options open to patients and their physicians, which can be divided into three categories:

•    Small molecule immune modulating drugs
•    Passive immunotherapy biologics to other targets
•    Active immunotherapies

With regard to small molecule product candidates, a number of companies have compounds in clinical development, in particular tyrosine kinase inhibitors, a drug class with products already marketed in cancer indications. Small molecule drugs have advantages, including low costs of manufacture and the convenience of oral administration.  However, they lack the specificity of biologics, increasing the risk of off-target adverse effects, especially in chronic use.  Further, a daily or twice-daily pill may represent a compliance challenge, notably in younger patients and those not experiencing any current disease activity.

There are a number of passive immunotherapies to non-TNF targets, either approved or in development, including ones targeting cytokines such as Il-6, and others inhibiting B or T cell activity.  Most often these drugs are used in patients who have failed, or are intolerant of, 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 and frequency of administration.  In addition, obviously there is not the safety experience with these newer agents, 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.  One 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.  The TNF inhibitors have established that antibody to TNF is 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.  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 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.  Finally, passive immunotherapies rely completely on the drug administered for their therapeutic effect, requiring gram quantities per patient per year.  By contrast, with active immunotherapy it is the patient generating the antibody and hence only milligram quantities per patient per year are required, with obvious implications for cost of goods.

In conclusion, 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, with clinical trials in hand in CD, RA, Type 1 diabetes and lupus.