ABOUT IMMUNOBIOGRAM® RA
INMUNOBIOGRAM® (IMBG) is an In Vitro Diagnostic immunoassay that combines a biotechnological KIT and a software for data interpretation.
IMBG is a service provided by BH that will help physicians to adapt the immunosuppressive drugs (IS) in patients with Rheumatoid Arthritis (RA), allowing to select for each patient the most adequate IS and doses to reach clinical remission and reduce the side effects of treatment.
IMBG offers a personalized comparative evaluation of patient sensitivity/resistance profile to a panel of IS most commonly used in RA in clinical practice, allowing to predict and monitor patients‘ response to IS and supporting clinicians to take informed decisions to optimize the immunosuppressive therapy.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes chronic inflammation of the synovial membrane of multiple joints, generating swelling, pain and stiffness, and that can lead to a progressive cartilage and bone destruction resulting in severe joint deformities and disability. The disease can have also systemic manifestations.
The clinical evolution of RA is fluctuating with periods of exacerbation and remission; the prognose differs a lot from one patient to another and in some cases can be rapidly progressive.
The treatment paradigm of RA has changed a lot in the last years due to new concepts in the diagnosis and in the treatment goals, and since more successful treatment options are now available. The main goal of disease-modifying anti-rheumatic drugs (DMARD) treatment is to achieve remission.
Currently the mainstay of RA treatment includes conventional synthetic drugs (csDMARDS), biological, and novel potential small molecule DMARDs (called tsDMARDS, targeted synthetic DMARDs), which have allowed a significant progress to attenuate disease activity and decrease joint deformity. But even with a medical treatment, 40% of patients will develop some type of functional disability after 10 years of evolution.
Patients with early arthritis should be treated as soon as possible (ideally within 3 months after onset of symptoms) in order to reduce and even prevent the risk of joint damage and disability. DMARDs have been shown to slow disease progression in RA. However, there is a wide variation in patient clinical response to current therapies. Among the DMARDs, Methotrexate (MTX) monotherapy should be part of the first treatment strategy (unless contraindicated), with or without Glucocorticoids (GC) as bridging therapy for most patients.
However, it fails to control the disease activity in 30-40% of patients (Rau R 2010).
The optimum treatment goal is remission, or at least low disease activity in patients irresponsive to earlier treatments. Until the desired treatment target is reached, drug therapy should be reviewed at least every 3 to 6 months.
Due to the heterogeneity of patients´ clinical evolution and treatment response, it is important to adjust the treatment at a patient basis. EULAR recommends “a regular monitoring of disease activity, treatment adverse events and comorbidities to guide decisions on choice and changes in treatment strategies to reach this target”.
The availability of diagnostic tools that allow to evaluate for each patient the clinical efficacy of the drugs before administration can help clinicians to take treatment informed decisions to prevent delays in the use of the more effective treatments for each patient and to avoid the risk of unnecessary adverse events and costs.
IMBG can support clinicians to individualize immunosuppressive treatment based on the patients´ immune profile of response to the disease-modifying antirheumatic drugs (DMARDs) tested.
IMBG is being studied in Rheumatoid Arthritis under a comprehensive clinical plan program, which includes an already running first proof of concept clinical study in 100 patients (BH-Pilot Study 2018 in Rheumatoid Arthritis) and a it is planned to be followed by a subsequent validation study
BH-Pilot Study 2018 in Rheumatoid Arthritis aims to evaluate the feasibility and potential clinical utility of a specifically-developed IMBG for Rheumatoid Arthritis. This first-in-clinic study is being done in collaboration with the Rheumatology Unit of “Reina Sofía” Hospital (Córdoba) and “Maimonides Institute of Biomedical Research” (IMBIC).
It will include 100 Rheumatoid Arthritis patients classified in the following categories:
- Naïve patients
- Chronic patients under treatment with DMARDs with low disease activity
- Chronic patients under treatment with DMARDs with high disease activity
We expect BH- Pilot Study 2018 in Rheumatoid Arthritis to be a clinical study that will demonstrate:
1) IMBG -RA will be feasible in patients with Rheumatoid Arthritis at various disease stages and clinical scenarios
2) IMBG-RA will offer an in vitro potency evaluation of Immunosuppressant drugs (IS) that will correlate with sensitivity grades of the patient to a panel of IMs
3) A significant proportion of patients with non-controlled RA will show low-sensitivity patterns in IMBG -RA to the medication they are taking
BH-Pilot 2015 in renal transplant was a clinical study performed in 2015-2016 in “La Paz” and “Puerta de Hierro” University Hospitals (Madrid) as a proof of concept study in patients with a renal transplantation. The study included 70 renal transplanted patients at least 1 year after the transplant (immunosuppression maintenance period).
The study outcomes indicated a positive proof of concept for IMBG that can be summarized in the following points:
1) Immunobiogram provided an individualized patient response pattern to immunosuppressive medication.
2) Sensitivity ranges could be determined in each patient for each of the drugs and doses tested.
3) Significantly associated low-sensitivity patterns to IS in IMBG have been observed in patients with high risk immunological-profile and who present worse clinical evolution.
4) Patients with a low-risk profile showed better sensitivity scores to IS in IMBG compared with other patients.
The classification of immunoassay profiles could be reproduced accurately by a neural network and thus completely automatized.
The outcomes of the study indicated that in renal transplantation IMBG enables to measure the sensitivity/resistance profile of patients to immunosuppressant medication, and it can detect patients with bad prognosis due to IS low sensitivity.
TRANSBIO study in Renal Transplantation is an ongoing, international study (conducted in 10 Europe and USA hospitals) that will allow to confirm the results of the PoC study in Renal Transplantation, and that will also allow to test IMBG reproducibility. Final results are expected in September 2019.
Regarding Rheumatoid Arthritis, once the feasibility and robustness of IMBG in this disease have been demonstrated with the BH-Pilot Study 2018, a subsequent validation study is planned to be carried out at international level.
Final results of BH-Pilot Study 2018 IN RHEUMATOID ARTHRITIS are planned to be presented 2019/2020 in EULAR Annual European Congress of Rheumatology and in ACR/ARHP American College of Rheumatology Annual Meeting
It is planned to publish a paper with the results of RA BH-Pilot Study 2018
The clinical program has been designed to cover the essential aspects of the technology that provides the data needed to use the IMBG in a reliable way in clinical practice. It is very important to consider that the IMBG will not directly guide physician prescription. This means that the tool does not ambition to tell the doctor what medicine should be used; we offer efficacy/potency information to be added to other variables, which altogether combined, will drive the clinical decision.
Clinical decisions will have always to be made taking into account other important patient variables (like immunological patients´ profile, baseline disease activity, clinical evolution and treatment side effects) to help physicians to make more precise therapeutic decisions.
The IMBG is being currently clinically tested in patients with early disease (2010 classification criteria for RA from American College of Rheumatology (ACR). The objective is to test if IMBG can be used to identify the patients´ sensitivity/resistance profile to first line treatments for RA before treatment is begun and to advise over the treatment adequacy after 3/6 months of follow-up when remission is not achieved. One important goal is to demonstrate if IMBG can be used to identify and monitor patients with a higher probability of resistance to methotrexate to allow physicians to take a quicker treatment change orientation to achieve remission.
It is also being tested in patients with a chronic AR when they are treated with the IMS tested, to facilitate therapeutic decisions.
The immunosuppressive drugs tested by IMBG in rheumatoid arthritis are the following:
The recipients where IMSs are included for the exposure in channels to PBCMs in IMBG are prepared by Biohope following a standardized method.
Biological DMARDs aren´t currently tested with the IMBG due that they are monoclonal antibodies with a larger molecular size, what hamper the passive diffusion process in the hydrogel through the IMBG channels to create a concentration gradient. An adaptation in the diffusion process is being developed to adjust IMBG to the physicochemical features of these compounds is currently ongoing. For the Rheumatoid Arthritis indication, we have added JAK inhibitors, which demonstrates that such adaptations to other products are possible.
Biohope expects to achieve CE marking Self-Certification in 2021, when the company will accomplish all the needed legal requirements. We also have a QA team fully dedicated to the development of the technical file regarding our Kit, which will be produced according to the ISO13485 standard, already in place. ®
We expect IMBG will be available for RA in 2021.
A pharmacoeconomic model will be developed to estimate the potential impact of IMBG in clinical outcomes and cost savings in the follow-up of patients with RA. Direct medical costs in RA are mainly driven by pharmacological treatment and disease activity. The availability of IMBG can largely contribute to adequate the drug regimen for each patient to the individualized profile of sensitivity/resistance to DMARDs as shown in IMBG and can have a great potential for better clinical outcomes and cost savings.
Kirkham BW, Corkill MM, Davison SC, Panayi GS. Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses. J Rheumatol
Radner H, Smolen JS, Aletaha D. Remission in rheumatoid arthritis: benefit over low disease activity in patient reported outcomes and costs. Arthritis Res Ther 2014; 16: R56.
Bernard Combe, Robert Landewe, Claire I Daien, Charlotte Hua, Daniel Aletaha, Jose María Álvaro-Gracia. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis 2017;76:948–959. doi:10.1136/annrheumdis-2016-210602
Smolen, J.S. et. al. 2016 EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update Ann Rheum Dis 76(6):960-977
Schipper, L.G.; van Hulst, L.T.; Grol, R.; van Riel, P.L.; Hulscher, M.E.; Fransen, J. Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome Rheumatology 2010, 49(11):2154-64 doi: 10.1093/rheumatology/keq195. Epub 2010 Jul 29.
Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations
for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009;68:1086–93.