Achieving long-term treatment responses in moderate/severe Crohn’s Disease

The advent of monoclonal antibody therapies revolutionized the treatment of Crohn’s Disease, but sustaining clinical response has proven a challenge. Time to ask patients’ immune systems to pick up the load?

“Whereas the monoclonal antibodies recognise only a single target, the antibody response to the Kinoid is polyclonal (multi-target). One might expect that the Kinoid would produce a broader therapeutic effect.”
-Guy-Charles Fanneau de la Horie

Crohn's Disease is an autoimmune chronic and progressive inflammatory disease of the gastro-intestinal tract.  It manifests itself via a range of debilitating symptoms, including severe diarrhea, abdominal pain, intestinal strictures and malnutrition. Most frequently diagnosed in young adulthood, in the vast majority of cases, patients receive long-term treatment which focuses on suppression of the immune response, although surgery is also employed.  According to Datamonitor, Crohn's Disease affects nearly 1 million people in the seven largest pharmaceutical markets.

Since the late 1990s, Crohn's patients failing traditional therapies have had an additional option: monoclonal antibodies (mAbs) to TNFα.  Two drugs are approved in Europe, infliximab and adalimumab, and have shown themselves to be highly efficacious in both inducing and maintaining remission, and further as very safe given their potency. 

Despite this success, they have one major flaw: in many patients, they stop working over time.  For example, in patients with initial response to infliximab, only 43% were still responding at one year¹ and adalimumab shows a similar profile².  For a life-long serious disease usually diagnosed in early adulthood, this issue is clearly a major problem, especially because, unlike some other inflammatory diseases, there is currently no safe and efficacious alternative to the anti-TNF mechanism.  Hence, patients' post-TNF options are poor: immuno-suppressants like azathioprine, corticosteroids and surgery.  Loss of response may also explain why gastroenterologists are reluctant to make wider early use of mAbs (the so-called top-down approach), despite a growing body of evidence³ that such a treatment model might change the natural course of the disease.

The reasons for the loss of response phenomenon are not fully understood.  One reason is certainly that many patients' immune systems react to the monoclonal antibody as a foreign entity and raise an immune response against it: patients with detectable antibody to the drug experience lower efficacy, including loss of response over time.  A second putative mechanism might be that, as the name implies, monoclonal antibodies recognize and bind to a single site (epitope) on the target.  If this epitope is absent or shielded, the monoclonal antibody will be ineffective.  This might explain why patients who do not respond to, or lose response to, a given TNF inhibitor frequently do respond to a second drug in the same class although this response is more likely to be transient.

Given the central role of TNF in this disease, but the clear shortcomings of the current products, we at Neovacs asked ourselves if there might not be a better way to target TNF to achieve superior, more durable, therapeutic outcomes.  Our focus as a Company is on using the patients' own immune systems to generate an antibody response to a pathogenic cytokine of interest.  To do this, we use our proprietary Kinoid technology (See figure 1), which takes the full length cytokine, couples it to a carrier protein and inactivates the cytokine.  The resultant compound is administered with an immune stimulant by intra-muscular injection.  We often hear people referring to this as a "vaccine", although from a regulatory and scientific perspective we think active immunotherapy is more accurate.  One key difference as compared to a traditional vaccine is that the Kinoid does not raise a T cell response to the cytokine, an important safety consideration.

Figure 1: Neovacs' Kinoid Technology

The characteristics of the antibodies produced by the TNF Kinoid are very different to the synthetic monoclonal antibodies used in the treatment of Crohn's Disease.  Relative to loss of response, we believe two differences are of critical importance.  First, the antibodies are generated by the patient him or herself, and the patient's immune system will not therefore respond to them as foreign and raise anti-drug antibodies against them.  Second, whereas the monoclonal antibodies recognize only a single target, the antibody response to the Kinoid is polyclonal (multi-target), as with any natural immune response to an antigen.  Consequently, one might hope and expect that the Kinoid would produce a broader therapeutic effect as well as one that was more sustained, since it is not reliant on a single target for its mechanism of action.

These hypotheses have received some confirmation from the recent top-line data from Neovacs' Phase I/II clinical trial of TNF-Kinoid in Crohn's.  The first objective of this study was to demonstrate safety, and the results here were very pleasing, with no treatment-related adverse events. Local and systemic tolerance was also very good.  Second, the Kinoid consistently produced anti-TNF antibodies at the higher doses tested: this confirms the ability of the Kinoid to "break natural tolerance" to TNF.

Importantly, patients treated with TNF-Kinoid showed promising evidence of clinical benefit.  Specifically, at week 12, 76% of patients showed a clinical response (defined as a drop in Crohn's Disease Activity Index (CDAI) of 70 points or better), and 43% were in clinical remission (CDAI of 150 or less).  These figures compare favorably with those achieved with mAbs, although one should note that this was a first small safety study.  Moreover, there is a correlation between observed clinical effect and antibody response as well as between the evolution of disease activity and the evolution of a biomarker for intestinal inflammation.  Finally, we do see responses to therapy in patients who have previously failed therapy with monoclonal antibodies to TNF: hence, this study supports both hypotheses of broad efficacy and that TNF treatment failures may be effectively treated with the Kinoid.

All told, we were very encouraged by the results of our Phase I/II study and gratified by the level of interest we have seen from the gastroenterology community.  This shows the continuing high level of unmet medical need in Crohn's Disease.  We are hopeful that the TNF-Kinoid will present a new option for patients, durably and broadly inducing and maintaining remission.  Consequently, Neovacs is in the process of initiating of double-blind, placebo-controlled Phase II study of TNF-Kinoid in Crohn's patients.

References:

1. Hanauer, the Lancet, 2002
2. Colombel, Gastroenterology, 2007
3. Colombel, NEJM, 2010