Periodic Reporting for period 4 - NECESSITY (NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients)
Período documentado: 2022-01-01 hasta 2022-12-31
Primary Sjögren’s syndrome (pSS) 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, skin, and genitalia. People with pSS may also experience joint pain, swelling, and extreme fatigue (tiredness). One in three patients with pSS can experience spread of inflammation beyond their moisture secretory glands and cause damage to other organs. Patients with pSS are at an increased risk for developing lymphoma, a type of cancer, frequently located in these patient’s 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 pSS. 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.
Although pSS is the most common systemic autoimmune disease after rheumatoid arthritis, no cure is available for it. Some treatments exist to help with symptoms like dry eyes, parotid swelling, and pain, but they are not always entirely effective. Consequently, there is a major unmet need for new and better treatments for pSS. The manifestation of pSS 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 pSS 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 pSS, however the clinical trials using them had given mixed results and none of these score evaluate all aspects of the disease.
The NECESSITY project is firstly aiming to develop a new composite responder index 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.
Although pSS is the most common systemic autoimmune disease after rheumatoid arthritis, no cure is available for it. Some treatments exist to help with symptoms like dry eyes, parotid swelling, and pain, but they are not always entirely effective. Consequently, there is a major unmet need for new and better treatments for pSS. The manifestation of pSS 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 pSS 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 pSS, however the clinical trials using them had given mixed results and none of these score evaluate all aspects of the disease.
The NECESSITY project is firstly aiming to develop a new composite responder index 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 some previous trials was negative, there may be some patients with similar distinct mechanistic pathways of pSS (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, the top one journal of rheumatology, in April 2022. Follow-up analysis are currently ongoing.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different distinct mechanistic pathways of pSS 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. The stratification of patients made on blood transcriptomic data (complete set of all the RNA molecules expressed in blood) from three cohorts from NECESSITY (ASSESS in France, UKPSS in UK and Bergen in Norway) has been published in Arthritis Rheumatology in June 2022.
A preliminary list of candidate tissue and blood biomarkers has been identified for further analyses.
Development of new tools to assess patient reported outcomes
The clinical presentation of pSS 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 clinical 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 pSS patients and validating the novel responder index (STAR), the identified biomarkers and various tools the project has developed. The first center opened in April 2022, and 11 sites in France, Spain, Sweden and Greece opened in 2022. More sites will open in 2023. In 2022, 21 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 pSS patients. The EMA has published a Letter for Support for STAR in March 2022. In October 2022, the consortium has obtained a positive response from the Food and Drug Administration to hold a Critical Path Innovation Meeting in Q1 2023 to discuss STAR. Discussions with OMERACT for endorsing STAR have begun in 2022.
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 some previous trials was negative, there may be some patients with similar distinct mechanistic pathways of pSS (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, the top one journal of rheumatology, in April 2022. Follow-up analysis are currently ongoing.
Identification of biomarkers for patient stratification and predictive of disease progression
Biomarkers defining different distinct mechanistic pathways of pSS 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. The stratification of patients made on blood transcriptomic data (complete set of all the RNA molecules expressed in blood) from three cohorts from NECESSITY (ASSESS in France, UKPSS in UK and Bergen in Norway) has been published in Arthritis Rheumatology in June 2022.
A preliminary list of candidate tissue and blood biomarkers has been identified for further analyses.
Development of new tools to assess patient reported outcomes
The clinical presentation of pSS 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 clinical 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 pSS patients and validating the novel responder index (STAR), the identified biomarkers and various tools the project has developed. The first center opened in April 2022, and 11 sites in France, Spain, Sweden and Greece opened in 2022. More sites will open in 2023. In 2022, 21 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 pSS patients. The EMA has published a Letter for Support for STAR in March 2022. In October 2022, the consortium has obtained a positive response from the Food and Drug Administration to hold a Critical Path Innovation Meeting in Q1 2023 to discuss STAR. Discussions with OMERACT for endorsing STAR have begun in 2022.
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 pSS and bringing new therapies to patients.