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.