Periodic Reporting for period 6 - NECESSITY (NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients)
Período documentado: 2024-01-01 hasta 2024-12-31
Primary Sjögren’s disease (SjD) is an autoimmune disease where the body's immune system mistakenly attacks and damages the glands that produce moisture (such a tears, saliva and other secretions). This can cause dryness in the mouth, eyes, lungs, skin, and genitalia. People with SjD may also experience joint pain, swelling, and extreme fatigue (tiredness). One in three patients with SjD can experience spread of inflammation beyond their moisture secretory glands and cause damage to other organs. Patients with SjD are at an increased risk for developing lymphoma, a type of cancer, frequently located in salivary glands. Although there are treatments available to manage symptoms (such as artificial tears, anti-inflammatory drugs, painkillers), however currently there is no cure for SjD. Patients often have a poor quality of life due to the debilitating symptoms like extreme fatigue and dryness, which can lead to social and professional isolation, anxiety, and depression.
As there is no currently available cure for this disease, some treatments exist to help with symptoms like dry eyes, swelling, and pain, but they are not always entirely effective. Consequently, there is a major unmet need for new and better treatments for SjD. The manifestation of SjD in patients can differ greatly in terms of their symptoms and the changes in these symptoms over time. This variation in underlying mechanisms behind the disease in SjD patients makes it challenging to design clinical studies that can effectively evaluate patients’ response to the new treatment. Currently, there are in existence two composite outcome measures (ESSDAI and ESSPRI) that aim to determine how well the treatment works for SjD, however the clinical trials using them had given mixed results.
The NECESSITY project is designed to firstly aim at to develop a new composite responder score to measure treatments efficacy for pSS, and secondly to identify biomarkers for patient that permit to stratify patients by their disease profile and to predict disease progression. Finally, these two aims need to be validated in large multicenter multinational clinical trial.
As there is no currently available cure for this disease, some treatments exist to help with symptoms like dry eyes, swelling, and pain, but they are not always entirely effective. Consequently, there is a major unmet need for new and better treatments for SjD. The manifestation of SjD in patients can differ greatly in terms of their symptoms and the changes in these symptoms over time. This variation in underlying mechanisms behind the disease in SjD patients makes it challenging to design clinical studies that can effectively evaluate patients’ response to the new treatment. Currently, there are in existence two composite outcome measures (ESSDAI and ESSPRI) that aim to determine how well the treatment works for SjD, however the clinical trials using them had given mixed results.
The NECESSITY project is designed to firstly aim at to develop a new composite responder score to measure treatments efficacy for pSS, and secondly to identify biomarkers for patient that permit to stratify patients by their disease profile and to predict disease progression. Finally, these two aims need to be validated in large multicenter multinational clinical trial.
Development of a composite responder index: Sjögren’s syndrome Tool for Assessing Response to treatment (STAR)
The strategy for developing composite responder index (STAR) was both data and expert-driven and was built on the idea that, although the overall outcome of the trial was negative, there may be some patients with similar distinct mechanistic pathways of SjD (subsets) in the population that responded positively to the treatment. The novel endpoint STAR allows for an extensive evaluation of the effectiveness of a drug on all aspects of the disease: systemic activity, patient reported symptoms, salivary gland function, ocular gland function and biological parameters. The consortium completed the development of STAR and published it in The Annals of Rheumatic Diseases in April 2022. Currently, follow-up analysis on the validation of STAR are ongoing on both previously available data sets from previous trials and newly completed indusrial trials for retrospective validation.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different distinct mechanistic pathways of SjD in patients will allow stratification of patients in clinical trials to evaluate efficacy of a new drug in meaningful populations. Tissue and blood samples from past studies are currently being analyzed to identify correlation between biomarkers and clinical phenotype (observable expression of the disease), disease progression, damage to the glands. We are also evaluating several stratification algorithms, with the use of novel technologies such as artificial intelligence based algorithms and various clustering approaches (based on symptoms, clinical and biological data). The stratification of methodology using clustering approaches done on French cohort called ASSESS was published in Arthritis and Rheumatology in 2024.
A preliminary list of candidate tissue and blood biomarkers has been identified, with a shortlist of tissue biomarkers being identified and made available for further evaluation by the bigger NECESSITY consortium.
Development of new tools to assess patient reported outcomes
The clinical presentation of SjD varies greatly across patients so there is a high interest in developing innovative tools to capture the potential effect of therapy on the many facets of disease. A web application called PEPSS was developed for patient self-reporting of pain, dryness and fatigue symptoms on a daily basis from their home (“ecological” environment) and is currently being used in the NECESSITY trial. Physical features have been selected, as proxy for fatigue, and will be assessed with the use of biosensors, data from which will be evaluated during the NECESSITY clinical trial.
Implementation of the NECESSITY clinical trial
The objectives of the NECESSITY clinical trial are multiple and include assessing the efficacy of two drug combinations on SjD patients and validating the novel responder index (STAR), the identified biomarkers and various tools the project has developed. The first center opened in February 2022, and in total 31 sites in France, Spain, Italy, The Netherlands, Norway, Sweden, UK and Greece were open by 2024. From the beginning of randomizations in 2022 to end of 2024, 180 patients were randomized in the trial.
Stakeholder engagement
Reaching consensus with key stakeholders (regulatory agencies, payers, and patients) is critical to ensure that the tools the project is developing will be widely used in future clinical trials and lead to approval of new drugs for SjD patients. The EMA has published a Letter for Support for STAR in March 2022. In February of 2023, the consortium participated Critical Path Innovation Meeting with the Food and Drug Administration to discuss STAR. This meeting yielded a summary document from the FDA, describing the strengths of the STAR endpoint and bringing forward some reservations for the consideration of the consortium.
The strategy for developing composite responder index (STAR) was both data and expert-driven and was built on the idea that, although the overall outcome of the trial was negative, there may be some patients with similar distinct mechanistic pathways of SjD (subsets) in the population that responded positively to the treatment. The novel endpoint STAR allows for an extensive evaluation of the effectiveness of a drug on all aspects of the disease: systemic activity, patient reported symptoms, salivary gland function, ocular gland function and biological parameters. The consortium completed the development of STAR and published it in The Annals of Rheumatic Diseases in April 2022. Currently, follow-up analysis on the validation of STAR are ongoing on both previously available data sets from previous trials and newly completed indusrial trials for retrospective validation.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different distinct mechanistic pathways of SjD in patients will allow stratification of patients in clinical trials to evaluate efficacy of a new drug in meaningful populations. Tissue and blood samples from past studies are currently being analyzed to identify correlation between biomarkers and clinical phenotype (observable expression of the disease), disease progression, damage to the glands. We are also evaluating several stratification algorithms, with the use of novel technologies such as artificial intelligence based algorithms and various clustering approaches (based on symptoms, clinical and biological data). The stratification of methodology using clustering approaches done on French cohort called ASSESS was published in Arthritis and Rheumatology in 2024.
A preliminary list of candidate tissue and blood biomarkers has been identified, with a shortlist of tissue biomarkers being identified and made available for further evaluation by the bigger NECESSITY consortium.
Development of new tools to assess patient reported outcomes
The clinical presentation of SjD varies greatly across patients so there is a high interest in developing innovative tools to capture the potential effect of therapy on the many facets of disease. A web application called PEPSS was developed for patient self-reporting of pain, dryness and fatigue symptoms on a daily basis from their home (“ecological” environment) and is currently being used in the NECESSITY trial. Physical features have been selected, as proxy for fatigue, and will be assessed with the use of biosensors, data from which will be evaluated during the NECESSITY clinical trial.
Implementation of the NECESSITY clinical trial
The objectives of the NECESSITY clinical trial are multiple and include assessing the efficacy of two drug combinations on SjD patients and validating the novel responder index (STAR), the identified biomarkers and various tools the project has developed. The first center opened in February 2022, and in total 31 sites in France, Spain, Italy, The Netherlands, Norway, Sweden, UK and Greece were open by 2024. From the beginning of randomizations in 2022 to end of 2024, 180 patients were randomized in the trial.
Stakeholder engagement
Reaching consensus with key stakeholders (regulatory agencies, payers, and patients) is critical to ensure that the tools the project is developing will be widely used in future clinical trials and lead to approval of new drugs for SjD patients. The EMA has published a Letter for Support for STAR in March 2022. In February of 2023, the consortium participated Critical Path Innovation Meeting with the Food and Drug Administration to discuss STAR. This meeting yielded a summary document from the FDA, describing the strengths of the STAR endpoint and bringing forward some reservations for the consideration of the consortium.
To date, there are no approved disease-modifying therapies for pSS patients. Most clinical trials have been unsuccessful in identifying a drug that has shown to improve patient symptoms. These negative results can be explained either by an inefficient drug or by known limitations in current measures. The NECESSITY consortium has provided Sjögren community with a new tool (STAR) that is more sensitive and evaluates the effect of a drug on all aspects of the disease compared to currently available measures (ESSDAI and ESSPRI). We expect that this will lead to increasing the success rate of clinical trials in SjD and bringing new therapies to patients.