Author: Inês Abrunhosa Amaral, Research Analyst, Scientific & Advisory Services
Immune-mediated inflammatory diseases are a group of highly heterogeneous and multifactorial diseases, which include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), the spondyloarthritis (SpA) disease spectrum, cutaneous inflammatory conditions (including psoriasis and atopic dermatitis), inflammatory bowel disease (IBD), and asthma and autoimmune neurological diseases such as multiple sclerosis (MS). Precision medicine (PM), and more specifically biomarker-directed therapies, are needed here to identify and target the norms and the differences among IMIDs.
The diagnosis of patients with an immune-mediated inflammatory disease (IMID) is often delayed for up to 3 months since the onset of symptoms, causing subsequent delays to the initiation of treatment resulting in disease progression and poorer prognoses.
Multiple related factors can lead to an increase in the time from symptom onset to diagnosis:
- Disease related: variability of clinical and imaging manifestations,
- Physician-related: insufficient primary care physician knowledge,
- Testing-related: lack of specific testing; and
- System-related: unavailability of diagnostics facilities and specialized centers and physicians.
To overcome these barriers, we should prioritize enhancing physician and testing components. This involves implementing physician education programs for primary care providers, enabling them to promptly recognize patients at the onset of disease and symptoms. Additionally, we should streamline the process of requesting specific tests during the patient journey. These efforts will result in earlier diagnoses, improved access to targeted therapies, and better patient outcomes.
After diagnosis, many patients do not get started on the appropriate treatment. Untreated or inadequately treated IMIDs naturally progress, causing severe tissue damage and disability, resulting in a reduced quality of life and increased mortality. In addition, IMIDs are associated with emergency room visits, hospitalizations, and surgeries, all of which substantially elevate both short-term and long-term healthcare costs. There are a few reasons why IMID patients may not receive the right treatment at the right time, with one of the most significant factors being the process of trial and error as physicians experiment with different targeted therapies (i.e. synthetic or biological disease-modifying drugs (DMDs)). The conventional approach of following a pre-determined path for treatment experimentation does not align with the precision medicine approach, which is needed for these patients when considering the highly diverse disease phenotypes associated with IMIDs.
Biologic agents, or biologic DMDs, have revolutionized the treatment of IMIDs. However, 30% to 40% of patients still do not respond to therapy. The reasons behind this are complex and include:
- alternative inflammatory pathways to the one targeted by the specific biologic therapy,
- development of neutralizing antidrug antibodies, and
- pharmacodynamic or pharmacokinetic reasons.
The burden of this issue significantly affects patients, clinicians, and healthcare systems alike. To address it, Diaceutics proposes implementing a precision medicine approach throughout the patient journey. This involves enhancing physician awareness, optimizing existing diagnostic tools, and creating new tests that consider the intricate molecular landscape of these patients. Additionally, treatment developers should consistently enhance their offerings, while ensuring that the ongoing exploration of new disease pathways is taken into account.
A key problem is that IMID patients, who are often diagnosed very late after the onset of their symptoms, can present mixed phenotypes. This can be due to the high degree of variability associated with the disease, but can also be caused by the patient accumulating more than one condition within the spectrum of IMIDs. The complexity of the situation, associated with the diagnosis being mainly based on a clinical evaluation of symptoms and not on specific biomarker testing, can further delay diagnosis and therefore hinder patient access to the right treatment which positively affects their disease outcome.
Our concern here is both the total lack of, as well as delayed patient access to the proper targeted treatment. Instead of going down a precision medicine route, the current therapeutic avenue for IMIDs is based on a conventional trial and error approach, often starting with broad spectrum options like nonsteroidal anti-inflammatories (NSAIDs), corticosteroids, such as prednisone and cortisone, or conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, followed by biological DMARDs. When entering the biological DMARDs, most patients will be prescribed tumor necrosis factor (TNF) inhibitors, without any prior molecular study, with many patients failing to achieve optimal response - approximately 30-40% will end up being non-responders and discontinuing treatment, perpetuating the trial and error and fail-first treatment approach which results in uncontrolled diseases, aggravating tissue damage and increasing the chance of a poor prognosis.
Diaceutics recommendations:
1: Primary care physicians
- Stay aware of IMIDs and their early symptoms and manifestations in your patients.
- Direct patients under suspicion of an IMID diagnosis as early as possible to specialized care.
- Recognize the importance of comprehensive testing.
2: Treating specialists
- Incorporate a precision medicine mindset into treatment practices.
- Keep up to date with research, innovative diagnostics techniques, and targeted therapies.
- Incorporate technologies such as PrismRA into clinical practice to decrease time spent in the trial-and-error process.
3: Diagnostics
- Continue developing support tools and testing to guide appropriate treatment strategies.
- Develop stratification methods to identify which patients will benefit most from each treatment.
4: Pharma
- Include testing within new clinical trials to increase the efficacy of targeted treatments.
- Incorporate a precision medicine, patient-centered approach, as current targeted treatments are targeted to a molecular target, not specific to one patient or group of patients.
Current and future development of precision medicine in IMIDs
The diagnosis of IMIDs is complex since it is normal for patients to concurrently bear several inflammatory diseases with overlapping phenotypes. The current clinical diagnosis of IMIDs is further complicated due to the lack of disease-specific biomarkers.
After diagnosis, IMID patients often need to go through a trial-and-error process to determine the most effective treatment from a wide selection of immune modulators. Unfortunately, a substantial number of patients still fail to respond or eventually relapse from initial effective treatment. The need for a clinical shift towards a more targeted therapeutic approach is clear for IMID patients; indeed, many efforts have been evidenced. A considerable number of targeted therapies, either approved (table 1) or still in clinical development, have been introduced to accelerate the realization of precision medicine in IMIDs. Those targeted therapies include biological and synthetic Disease Modifying Drugs (DMDs) that target either the major players or major pathways within one’s immune system.
However, the lack of proper and timely testing to guide treatment selection takes patients through months to even years of trials with expensive, ineffective, or toxic drugs without knowing whether it is the best choice for treating their unique IMIDs conditions. Recently (Sept 7th 2023), PrismRAÒ test, an AI-assisted predictive molecular signature test from Scipher Medicine, has received local coverage determination (LCD) from Medicare to guide TNF inhibitor’s (TNFi) treatment decision within RA patients. The LCD identifies evidence supporting the clinical utility of PrismRAÒ with three (3) times more accuracy in predicting remissions within RA patients received PrismRA guided therapy selection. Further studies are needed to guide single or combination therapies for specific sub-groups of IMIDs patients.
Unique challenges associated with PM in IMIDs
1. Patient identification: A major challenge for developing a PM therapeutic approach in IMIDs is the lack of proper testing for patient identification and a need for disease-specific biomarkers. While there are biomarkers used in IMID diagnosis and monitoring, there is a lack of highly specific and sensitive biomarkers for early detection, accurate prognosis, and treatment response prediction. This can hinder timely and precise intervention.
- There is a need for more disease-specific biomarkers and the development of testing algorithms for targeted treatments.
- We believe an early engagement and early partnership establishment between Rx and Dx could ultimately affect the probability of the success of the clinical uptake of the new targeted therapy. The establishment of a diagnostic partnership involves multi-stakeholders and is a multi-step process, which requires decisions towards diagnostic strategy determination, partner evaluation/selection, partner engagement and product life cycle management to be made by pharma.
Diaceutics can help in establishing the optimal diagnostics partner for clinical and commercial success.
2. Treatment management: There is a very significant and complex gap between IMID patients and an effective targeted treatment. Their access to these treatments can be hindered by the misinterpretation of symptoms, lack of awareness of the condition by the primary care physician, or delayed access to medical care. Alongside the failure of optimal response, the lengthy trial and error odyssey, often based on a fail-first treatment approach, has a significant impact not only on the disease progression and tissue damage but also a major psychological impact on patients. These patients are often prescribed non-specific treatments (such as NSAIDs or corticosteroids) by primary care physicians, which can hide their specific symptom manifestations, further delaying diagnosis, access to specialist care, and ideal treatment. We recommend:
- Both primary care physicians and treating specialists to rethink their approach to IMIDs, incorporating a Precision Medicine patient-centered approach in their clinical practice. Patients should be directed to treating specialists as early as possible, and broad use of NSAIDs or corticosteroids should be reduced, as they can influence the response of patients to biologic DMDs later in the patient journey.
- The uptake of specific testing approaches, and the use of technologies like PrismRA to minimize exposure of patients to ineffective treatment options.
Diaceutics can provide Physician Engagement strategies and Educational programs to help increase awareness of specific conditions among primary care physicians, as well as update treating specialists on the latest tools and precision treatment advances and best practices.
3. Clinical trial: Innovative IMID clinical trial setups are required to ultimately improve therapy decisions and patient outcomes for patients with IMIDs.
- Resistance builds up and loss of efficacy to specific drugs is one of the major barriers in IMID’s treatment. Biomarker-driven treatment selection models (basket or umbrella) that enable the study of novel targeted therapies in refractory patients, as well as novel combinations or sequences of existing therapies are increasingly adopted in IMID clinical trials. We anticipate that patient identification will be a barrier here to delay and ultimately increase the cost of the trials.
Diaceutics recommends: a timely patient alert selected by multiple biomarker tests from labs involved in our DXRX Network to increase the efficiency and success rates of trials via matching the right patients to the right treatment.
4. Clinical implementation: The complexity of the pathophysiology and evolutional progress underlying each of the IMID patients creates a very complex patient journey for IMIDs.
- Confusion and complications are common during the clinical implementation of each precision medicine treatment.
Diaceutics recommends: A deep-dive market analysis of key testing challenges and opportunities to build a differentiated strategy, alongside tactical plans in support of the commercialization of the therapy.
Addressing these challenges requires collaboration among the key stakeholders within precision medicine; researchers, clinicians, pharmaceutical and diagnostic companies, and patients.
Diaceutics are specialists in navigating complex precision medicine strategies, discover how we can support your precision medicine strategy in IMID and beyond. Contact us here
Current targeted therapies approved for IMIDs (FDA approved in the US):
References:
- https://www.nature.com/articles/s41577-021-00603-1
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2600039/
- https://academic.oup.com/cei/article/193/1/3/6411900
- https://www.sciencedirect.com/science/article/abs/pii/S0378111915011671
- https://pubmed.ncbi.nlm.nih.gov/34441297/
- https://pubmed.ncbi.nlm.nih.gov/35248489/
- https://www.sciphermedicine.com/solutions/
- https://www.sciphermedicine.com/scipher-medicine-receives-medicare-coverage-for-prismra-test-in-rheumatoid-arthritis-patients/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984588/
- https://www.ncbi.nlm.nih.gov/books/NBK532898/
- https://clinicaltrials.gov/study/NCT02265744
- https://clinicaltrials.gov/study/NCT05662241
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386864/
