TNF-Kinoid
Therapies targeting TNF have already demonstrated efficacy across a wide range of inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondulitis, psoriasis and Crohn’s disease. In 2009, sales of drugs targeting TNF exceeded $18bn.
Although powerful, current anti-TNFα therapies also have significant drawbacks, making new treatment approaches sorely needed. The most problematic aspect of monoclonal antibody (mAb) therapies is the frequent development of treatment resistance as they are used long-term to treat chronic diseases. Datamonitor estimated in 2007 that there were over 126,000 patients resistant to current TNFα therapies in rheumatoid arthritis alone. Anti-TNFα treatments also have a cumbersome dosing regimen of frequent IV infusions or SC injections.
The TNF-Kinoid is a promising approach to address the shortcomings of the monoclonal antibodies
The TNF Kinoid is the only active immunotherapy targeting TNF in clinical development today, and may offer a therapeutic alternative to patients who have lost response to monoclonal antibody products. Neovacs’ active immunization avoids treatment resistance by eliciting a natural immune response through the production of polyclonal antibodies against multiple epitopes of TNFα. Importantly, since the antibodies are elicited from the patient’s immune system itself, they will not generate an immune response themselves, even in patients that have developed resistance to mAb treatments. The polyclonal nature of the response to the Kinoid should allow the antibodies to overcome resistance developed against a particular antibody. It is well established that over 50% of patients that have lost response to a given anti-TNF antibody do respond to a second, albeit with a higher probability of developing resistance to this second product also.
Furthermore, patients only need 3 or 4 maintenance doses per year, another key benefit for patient compliance and healthcare costs.
Rheumatoid arthritis : a chronic and disabling disease, more common in women than men
Rheumatoid arthritis (RA) is an auto-immune, inflammatory disease in which the immune system attacks the synovial membrane and/or the joint capsule. RA is a chronic disease and a patient can expect to be treated for it for the rest of his or her life. Ease of administration, safety and tolerance and efficacy over the long term are the key attributes for a therapy.
In RA, the inflammatory response leads to progressive destruction of the joint's muscles, tendons and ligaments. This produces pain, swelling, severe, progressive joint deformation and functional impairment leading to mobility and dexterity problems. Rheumatoid arthritis is often graded according to the disease severity. It is estimated that 50% of RA patients have a mild (and often undiagnosed) condition, 30% suffer from moderate disease and 20% have severe disease. The prevalence of RA is estimated at between 0.3% and 1% of the general population. Although RA can affect all ages (including children), around 70% of RA patients are women. Disease onset generally occurs between the ages of 30 and 50.
Phase IIa study of the TNF-Kinoid in RA
A Phase IIa study of TNF-Kinoid is being conducted in patients who have failed a TNF inhibitor. The study is double blind, placebo controlled and will recruit 48 subjects. The primary objective is to select the dose levels and dosing schedule to be tested in a subsequent Phase IIb. The treatment’s safety and clinical efficacy are secondary endpoints.
The results from the trial are expected in mid-2011.
Crohn’s Disease: A continuing high unmet medical need
Crohn’s Disease is one of a family of Inflammatory Bowel Diseases (IBD). It is a chronic and progressive inflammatory disease of the gastro-intestinal tract associated with an autoimmune pathology. Crohn’s manifests itself via a range of debilitating symptoms, including severe diarrhea, abdominal pain and cramping, intestinal strictures and fistulae and malnutrition. It is most frequently diagnosed in young adulthood, thus requiring treatments that have efficacy over the long term. In the vast majority of cases, patients receive long-term treatment which focuses on suppression of the immune response, including monoclonal antibodies; although surgery is also part of the therapeutic arsenal. The central role of TNF in the pathology of this disease has been confirmed by the clinical efficacy of monoclonal antibodies targeting TNF. Nonetheless, current medical options are limited, and in particular there is a need for drugs that can durably induce and maintain remission, a development eagerly awaited by both physicians and patients. According to Datamonitor, Crohn’s Disease affects nearly 1 million people in the seven largest pharmaceutical markets.
On 8 December 2010, Neovacs announced the final results of its Phase I/II study in Crohn’s patients.
The TNF-K-001 study was conducted in 21 patients and produced the following encouraging findings :
- the drug candidate has an excellent safety profile in all subjects.
- an immune response to the drug as intended, and
- a high clinical response rate, with clinical remission (absence of symptoms) in almost half the patients.
In terms of immune response, in 17 of the 21 treated patients, TNF-Kinoid induced the production of anti-TNF antibodies. Of the three patients receiving the lowest dose (60 mcg), only one mounted an immune response to TNF. In both the 180 and 360 mcg dose levels, 8 of the 9 patients in each group (89%) produced anti-TNF antibodies.
In terms of clinical response (at study week 12 and after 3 administrations of the drug), 76% of the patients showed a significant clinical improvement (defined as a 70-point drop in the CDAI) and 43% of these patients were in clinical remission (i.e. the absence of symptoms, as evidenced by a CDAI at or below 150).
Tables : Source Neovacs
Based on this study, it has been decided that the 60 mcg dose is too low; the 180 mcg was selected for the Phase II study that is underway.
Early 2011 : Phase II testing of the TNF-Kinoid in Crohn’s Disease starts
The double-blind, randomized, placebo-controlled TNF-K-005 study will recruit between 66 and 132 patients with moderate to severe Crohn’s Disease (having a Crohn’s Disease Activity Index, CDAI, of between 220 and 450) and who have failed treatment with a TNF inhibitor.
The primary endpoint of the study is to measure the efficacy of the TNF-Kinoid in inducing clinical remission, defined as a CDAI of 150 or less. Other measures of clinical activity to be measured include clinical response, defined as a decline in CDAI of 100 points or more as compared to the value at study entry, mucosal healing measured by colonoscopy, and relevant biomarkers.