Precision Medicine in IMIDs - The Path to Improved Healthcare Outcomes
February 9, 2021 Justyna Lisowska
In the last few years, precision medicine has been successfully applied to the field of oncology, providing more targeted, effective therapeutics for previously uncurable medical conditions. However, while precision therapies are now established in clinical practice within oncology-related fields (e.g., immune-oncology), other therapeutic areas such as inflammatory diseases are yet to benefit from this novel medical approach.
What are the IMIDs?
Immune-mediated inflammatory diseases (IMIDs) consist of more than 100 (1) clinically unrelated, pathological conditions characterized by chronic, organ-targeted, or systemic inflammation resulting from the aberrant response of the human immune system to either external infectious factors, tissue micro-damage (auto-inflammatory disorders) or native antigens (autoimmune diseases). While the exact pathogenic mechanisms underlying such conditions (including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, systemic lupus erythematosus (SLE), asthma, multiple sclerosis (MS), or type-1 diabetes) remain to be elucidated, it is generally accepted that they share common molecular pathways triggered by a complex interplay between genetic and environmental factors. Indeed, genome-wide association studies (GWAS) have recently identified a wide array of immune-related genes associated with IMIDs revealing numerous loci shared between multiple inflammatory conditions (2-3).
Among environmental factors, lifestyle factors such as smoking, physical activity, stress, and diet as well as microbial exposure, hormones, medications (such as antibiotics or NSAIDs), or pollutants have been shown to increase the susceptibility to certain IMIDs and be responsible for their rising incidence in an industrialized world (4-9). Associated with fatigue, substantial pain, progressive organ or systemic failure, and concomitant depression and anxiety (10-11), IMIDs reduce patients’ quality of life (QoL) and can lead to their premature death. IMID patients also commonly develop multiple inflammatory disorders over time, which further exacerbates their physical condition and vitality- significantly impairing work-related productivity. High healthcare costs associated with long-term treatment (For IBD alone in Europe, €4.6–5.6 billion per year (12)) and other indirect costs (such as disability payments or early retirement) impose a substantial financial burden on the entire economy. It is thus evident that, with the rising incidence of IMIDs worldwide and their detrimental socio-economic impact, efforts need to be made to develop novel, effective therapies to treat these debilitating medical conditions.
The highly complex diagnosis of IMIDs
As different IMID conditions affect different body parts (joints, muscles, skin, digestive, respiratory and nervous system as well as other internal organs), despite having systemic consequences, they are often considered as organ-specific and thus, are diagnosed and treated by different specialists (e.g., rheumatologists, dermatologists, gastroenterologists or neurologists). Clinical diagnosis relies on the qualitative assessment of the affected organ(s) and collection of symptoms (tiredness, pain, depression) subjectively reported by patients and evaluated by organ/symptom-specific scores or metrics. However, since IMID symptoms vary widely across and within a particular disease, and perception of their severity may be different between patients, this approach does not reflect the full picture of the disease and cannot result in an accurate diagnosis and efficient treatment. Composite scores used for RA (DAS28), or Psoriasis (PASI), including biomarkers, lab test results, fatigue, and pain scores provide a more complete description of the burden of the disease but do not describe the underlying pathological mechanism which would enable the provision of effective medical treatment.
IMID treatment and the promise of biologics
The realization that these symptomatically unrelated conditions result from a dysregulation of the immune system and share common inflammatory pathways (13) has shifted the paradigm of IMID treatment. Instead of relieving the symptoms of each disease separately, the current clinical strategy involves targeting underlying molecular mechanisms orchestrated by specific pro-inflammatory cytokines (such as TNF-α, interleukin 1, 6, 17, 23, 18, 15 or Interferon-γ) and other immune-related mediators (CD20, CD80, CD86, Janus Kinases ex. Tyk2, JAK 1/2/3 or Toll-like receptors, etc.) allowing the same medication or treatment protocols to be applied to different IMID conditions. Initially developed as small molecules, these anti-inflammatory drugs, and other immune system regulating agents, have been gradually replaced by biologics since the 1990s. As reported by Walsh G (14) between 2014 and 2018, inflammatory conditions have become the 2nd most prominent indication (after cancer) for biologics approved by the FDA. The introduction of these new biological therapies has truly revolutionized the treatment of IMIDs. As highly efficacious therapies with an overall good tolerability, biologics have substantially improved patients’ well-being (15).
Downfalls of current treatment
Unfortunately, a significant proportion of patients administered biologics fail to respond or eventually relapse after initially successful treatment. Also, some commonly prescribed biological drugs increase the risk of opportunistic infections or malignancies (16) as a consequence of the weakened immune system. They have also been shown to cause other side effects such as heart failure and demyelinating diseases as well as off-target effects and immunogenicity (17 - 19). All these factors pose a serious societal concern, considering the substantial cost of biologic therapies. For example, as reported in the retrospective study from 2016, the cost of treatment with anti-TNF biologics in the US is between $24,000 and the $26,000 per patient per year (20).
The reduction in efficacy of biologics over time may result from the progressive nature of these diseases involving other molecular players at the later stage. For instance, it has been shown that the level of IL-6, considered as a pathological factor in systemic sclerosis (SSc), gradually diminishes in favour of IL-13 as the disease evolves, reducing the effectiveness of tocilizumab (an anti-IL-6 receptor antibody) at the fibrotic stage of the disease (21). The difference in response to currently employed biological therapies also suggests that these pathologies might be more heterogeneous than we initially thought. In fact, in addition to age and gender-related differences in immune response, individual biological factors such as microbiota, genetic heritage as well as tissue-specific microenvironment can affect a patients’ responsiveness to certain therapeutics. As summarized by Baker and Isaacs, inhibition of the IL-17 family of cytokines, associated with RA, Psoriasis, PsA, ankylosing spondylitis (AS) and IBD, results in very different therapeutic outcomes depending on the disease (16). Similarly, in patients suffering from SSc, characterized by fibrotic changes in the skin and lungs, IL-6 inhibition seems to have a much stronger effect on pulmonary lesions (21). These examples demonstrate that the presence of a certain cytokine in the body does not necessarily imply its dominant pathogenic function. Its activity and level of involvement may vary depending on the affected organ and disease stage thus, targeting the same molecular pathway at different hierarchical levels can lead to different outcomes (16).
The need for a precision medicine approach
The above examples also confirm that although common inflammatory pathways may drive the pathophysiology of IMIDs, the existence of specific mechanistic patterns within phenotypically identical conditions play a role in differentiating the drug response, making a particular therapy efficient for just a subset of patients with a specific disease endotype. Understanding such biological mechanisms of diseases, through a multi-biomarker approach, would allow to better diagnose and stratify patents. Moreover, mapping disease endotypes with suitable drug endotypes (underlying mechanism induced by a therapeutic agent) would enable the determination of more targeted treatments with a higher level of efficacy and lower toxicity (22-23). The concept of endotypes, fundamental to precision medicine, has already been successfully exploited for the treatment of cancer (24) and should now pave the way for IMIDs. In addition to diagnostic molecular signatures, prognostic and predictive biomarkers would also be of high importance to better prognosticate disease course to identify the right treatment, and accurately predict drug response. Understanding the specific genetic aberrations, epigenetic changes and identification of other predictive biomarkers could also help initiate innovative master protocols in IMID clinical trials design. Already proven as effective in oncology, these trial designs have been rarely applied to the field of IMIDs (25). Master protocols would allow to investigate multiple treatments within a single disease population (umbrella trials) or test a specific medical intervention across different IMID conditions sharing the same disease endotype (basket trial), making clinical trials less risky, more efficient, and more likely to succeed (read more).
All this can be achieved by applying a multi-level, integrated analytical approach incorporating high-dimensional, multi-omics (genomic, epigenomic, metabolomic, microbiome or exposome) data from different tissues and/or technologies. The analysis of 97 articles from high-impact clinical journals, documented by MJ. Grayling, et al., indicates that only a very small percentage of clinical studies in the field of IMID have already collected such data (25). Exploring a large amount of heterogeneous, multimodal, and disparate data requires reliable, scalable IT infrastructure, advanced computational algorithms (e.g., machine learning) and analytical tools to draw actionable insights. In addition, improved collaboration between academic, industrial, and regulatory bodies as well as infrastructural changes facilitating secure data sharing within and across organizations would ease the transition to more personalized medicine. Such solutions already exist, and biopharmaceutical companies can embrace them to accelerate the development of precision therapies and change the fate of IMID patients for the better.