By David Lee, M.D., Ph.D., Global Therapeutic Area Head, Immunology, Janssen
One of the greatest advancements in treating immune-mediated inflammatory diseases (IMIDs) over the last 20 years has been the advent of targeted biologic injectable therapies that target cytokines — the soluble proteins that act as intercellular mediators of the immune system. In the case of autoimmune diseases, inflammatory cytokines are persistently and excessively secreted from immune cells, driving inflammation. This is why many therapies used to treat IMIDs include monoclonal antibodies (mAbs) to help neutralize inflammatory cytokines.
There is a growing list of IMIDs that can be treated by biologics, including Crohn’s disease (CD) and ulcerative colitis (UC), as well as psoriatic disease and rheumatoid arthritis. It is estimated that this heterogenous group of diseases affects between 5% and 7% of the population worldwide, with many patients who do not respond to treatment or fail treatment after a few years. Multiple IMIDs often exist within the same patient, or because of genetic predisposition, within the patient’s family.
Despite Advances, There Remains Immense Unmet Need
While there are no cures for most IMIDs, biologic therapies like mAbs have had success in helping patients achieve relief — albeit typically partial — from their disease symptoms. Further, some therapies have shown disease modification — interrupting irreversible damage that can worsen if left untreated. However, the intrinsic properties of such therapies can have a range of limitations, including causing patients to develop antibodies that neutralize the treatment’s therapeutic effect and therefore limit durability of treatment responses. There is also concern that the long half-lives inherent to mAb therapies can negatively affect immune function, making patients more susceptible during times of infection. Risk profiles for mAb therapies can vary greatly and reactions are not always predictable within patient populations. Further, these therapies must be injected either subcutaneously or intravenously, an undesirable feature for many patients.
Millions of eligible patients are not receiving advanced therapies; a significant reason for the avoidance of these therapies is patients dislike of injections. I can attest to the need for better oral treatments from my own experiences as a practicing rheumatologist — many times I have seen patients who could have clearly benefitted from advanced therapies, but they just could not bring themselves to receive an injectable medicine on a regular basis.
Durable remission rates for most IMIDs remain well below 50%, thus the need for more treatment options available to patients suffering from IMIDs remains high. These needs can be variable across diseases and among patients and providers. Safety and effectiveness are paramount, as IMIDs are often lifelong diseases requiring chronic administration of medicine. Durability is also a predominant consideration, as many cytokine inhibitor drugs have attrition rates of greater than 50% over a two-year period, and a major issue here is their waning effectiveness.
Shifting The Treatment Landscape
Developing therapeutic alternatives that offer patients greater convenience, freedom, and flexibility can significantly improve medication adherence. These can be some of the benefits of taking a pill rather than requiring an injection that needs to be administered at home or in their healthcare provider’s office.
Oral cytokine inhibitors hold significant promise as next-generation options for treating IMIDs, offering the potential for improved safety, durability, and adherence by addressing barriers to the use of advanced biologic therapies for many patients. Current oral therapies for IMIDs are known to cause side effects in some instances due to their immunosuppressive properties or they can have other tolerability or adverse event profiles that limit their use. When these adverse events do occur, the long duration of activity of these therapies means that it can potentially take days for those symptoms to subside.
Small molecule oral cytokine inhibitors hold potential for the selectivity and efficacy demonstrated by mAbs or other injectable biologics while offering potential increases in durability as well as shorter half-lives in the event of adverse events. Due to the daily dosing regimen of oral medicines, patients are able to quickly stop the medicine’s activity and mitigate side effects. Another consideration for patients is the potential convenience that an oral medication can offer, such as eliminating travel to medical facilities for injections.
Bringing New Therapies Over The Finish Line
Research is ongoing to address some of the major hurdles in developing effective oral cytokine inhibitor therapies. Foremost, it must inhibit the interaction of the cytokine with its receptor. As these protein-to-protein interactions have large surface areas, this is a major challenge for small molecules. Next, it must be bioavailable, which is easier to accomplish when the therapy is administered intravenously or subcutaneously. An oral therapeutic must survive the harsh environment of the stomach and intestine, must have the capacity for absorption through the intestine and to enter the bloodstream, and then must effectively penetrate the target tissues.
Despite these challenges, some theorize that orals have the potential for increased efficacy, as they would be able to penetrate tissue in a way that the physical size of mAbs may prevent. Developing effective oral cytokine inhibitors thus presents a difficult, yet not insurmountable, challenge that has not yet been solved. An immense investment and ongoing innovation are needed to develop these medications and ensure that they can effectively treat the populations that need them most. This includes collaboration across a wide array of stakeholders, including researchers, suppliers, manufacturers, and, of course, patients and healthcare professionals.
Promising Results Could Lead To Enhanced Options For Patients
These advancements are just the beginning of a wave of innovation likely to take place over the next decade in striving to make these much-needed therapies a reality and ensuring that patients have effective, safe, and durable options that offer the potential for remission — restoration of health to lead a life not burdened by their IMID.
Though injectable biologics will likely remain an important treatment choice for patients, the expansion of therapeutic options is critical. Together with our scientists, partners, and researchers, we are on the cusp of new opportunities and alternatives for patients with IMIDs.
About The Author:
David M. Lee, M.D., Ph.D., is Global Immunology Therapeutic Area Head for the Janssen Pharmaceutical Companies of Johnson & Johnson, leading and developing a team focused on end-to-end pipeline and a portfolio of treatments for immune-mediated diseases. Lee’s passion for developing new medicines is rooted in his experiences treating patients as a practicing rheumatologist. You can follow him on LinkedIn here.