Periodic Reporting for period 5 - STOPFOP (Saracatinib Trial tO Prevent FOP)
Berichtszeitraum: 2023-11-01 bis 2025-05-31
Fibrodysplasia ossificans progressiva (FOP) is a genetic chronic and devastating disease characterized by extensive bone formation within mucles, tendons and ligament. It causes severe contractures and early death. There are no approved medications yet.
The aim of the STOPFOP trial is to see if the investigative drug AZD0530, also known as Saracatinib, could be used to treat FOP. In people with FOP, a mutation occurs in the gene ACVR1 that encodes for the protein kinase ALK2. As a result, ALK2 becomes overactive causing muscles and connective tissues (e.g. tendons) to slowly turn into bone, which severely limits mobility and even breathing. Scientific research by the STOPFOP team has shown that AZD0530 blocks the activity of the pathogenic ALK2 kinase. The team has demonstrated in FOP-mice that the drug was effective in preventing ectopic bone formation which led to preserved mobility of joints.
AZD0530 is an investigative drug that has been developed by AstraZeneca initially as a potential treatment for patients with cancer. It has been tested for safety and efficacy in humans with cancer and healthy volunteers. Over 600 people have used the drug, which means researchers are familiar with the effects and safety profile of the drug. The drug is taken orally, as a once-daily dose.
The aim of the STOPFOP trial is to see if the investigative drug AZD0530, also known as Saracatinib, could be used to treat FOP. In people with FOP, a mutation occurs in the gene ACVR1 that encodes for the protein kinase ALK2. As a result, ALK2 becomes overactive causing muscles and connective tissues (e.g. tendons) to slowly turn into bone, which severely limits mobility and even breathing. Scientific research by the STOPFOP team has shown that AZD0530 blocks the activity of the pathogenic ALK2 kinase. The team has demonstrated in FOP-mice that the drug was effective in preventing ectopic bone formation which led to preserved mobility of joints.
AZD0530 is an investigative drug that has been developed by AstraZeneca initially as a potential treatment for patients with cancer. It has been tested for safety and efficacy in humans with cancer and healthy volunteers. Over 600 people have used the drug, which means researchers are familiar with the effects and safety profile of the drug. The drug is taken orally, as a once-daily dose.
The following is a very concise summary of the work performed split out per area of work
1. Management: All boards were established with regular meeting times (in person and/or digitally) and clear goals. A management plan was made to coordinate the different partners in our group.
2. Study protocols: All documents for ethical and regulatory approval were prepared. These have been fully approved in the Netherlands and in Germany. Approval in the UK has not been achieved and mitigation measures were applied (see point 4 below). We made several small changes to the protocol to better streamline processes and to increase safety and conform for included patients.
3. Data collection and planning: A data management plan was created and completed. An electronic data reporting/questionnaire collection form was created. Regular reports are sent to the Data Safety Board.
4. Randomized controlled trial (RCT): After initial delays due to COVID19, the RCT phase of our the STOPFOP clinical trial has been successfully completed. More specifically, 17 patients have enrolled in the study: 11 in VUMC Amsterdam, the Netherlands and 6 in Garmisch partenkirchen (GAP), Germany. All patients finished the RCT and started the open label phase. The London site (RNOH) was unable to open. British patients have therefore travelled to Amsterdam to participate in the study via the VUMC site, which was a manageable journey for them. No serious side effects occurred during the RCT.
5. Open label extension (OLE): All participants who completed the RCT phase progressed to the OLE phase of the study, as foreseen in the DoA. The OLE study was successfully completed too. No serious side effects occurred during the RCT and overall, the participants of the study experienced benefits from the repurposed drug. However, further analysis of the data is required before drawing conclusions and make them public.
6. Prolonged extension open-label study (beyond the STOPFOP project): A prolonged extension study was designed for those patients who completed the study and wanted to continue due to the benefit from the repurposed drug experienced. All 17 patients that completed the OLE phase of the study continued to the prolonged OLE phase (GAP 6; VUMC 11). The OLE part of the study has been continued after the completion of the IMI2 STOPFOP project, as it was beyond the project’s scope.
7. Sustainability plan: Contact with EMA was made for orphan drug designation and all relevant documents have been prepared. Further progress on this subject may take place after the end of the project.
8. Dissemination and communication: Dissemination and exploitation plans have been drawn up and regularly updated. A logo and website were created that has been frequently visited. The project has been presented and discussed internationally on a very regular basis at scientific conferences, FOP patient meetings and educational events. A peer reviewed article has been published on the original design of the study: https://pubmed.ncbi.nlm.nih.gov/35650602/(öffnet in neuem Fenster).
9. Ethics: An independent ethics advisor has been involved throughout the lifetime of the project who supported and guided the it. This advisor has regularly checked the status of the project and provided reports with recommendations.
1. Management: All boards were established with regular meeting times (in person and/or digitally) and clear goals. A management plan was made to coordinate the different partners in our group.
2. Study protocols: All documents for ethical and regulatory approval were prepared. These have been fully approved in the Netherlands and in Germany. Approval in the UK has not been achieved and mitigation measures were applied (see point 4 below). We made several small changes to the protocol to better streamline processes and to increase safety and conform for included patients.
3. Data collection and planning: A data management plan was created and completed. An electronic data reporting/questionnaire collection form was created. Regular reports are sent to the Data Safety Board.
4. Randomized controlled trial (RCT): After initial delays due to COVID19, the RCT phase of our the STOPFOP clinical trial has been successfully completed. More specifically, 17 patients have enrolled in the study: 11 in VUMC Amsterdam, the Netherlands and 6 in Garmisch partenkirchen (GAP), Germany. All patients finished the RCT and started the open label phase. The London site (RNOH) was unable to open. British patients have therefore travelled to Amsterdam to participate in the study via the VUMC site, which was a manageable journey for them. No serious side effects occurred during the RCT.
5. Open label extension (OLE): All participants who completed the RCT phase progressed to the OLE phase of the study, as foreseen in the DoA. The OLE study was successfully completed too. No serious side effects occurred during the RCT and overall, the participants of the study experienced benefits from the repurposed drug. However, further analysis of the data is required before drawing conclusions and make them public.
6. Prolonged extension open-label study (beyond the STOPFOP project): A prolonged extension study was designed for those patients who completed the study and wanted to continue due to the benefit from the repurposed drug experienced. All 17 patients that completed the OLE phase of the study continued to the prolonged OLE phase (GAP 6; VUMC 11). The OLE part of the study has been continued after the completion of the IMI2 STOPFOP project, as it was beyond the project’s scope.
7. Sustainability plan: Contact with EMA was made for orphan drug designation and all relevant documents have been prepared. Further progress on this subject may take place after the end of the project.
8. Dissemination and communication: Dissemination and exploitation plans have been drawn up and regularly updated. A logo and website were created that has been frequently visited. The project has been presented and discussed internationally on a very regular basis at scientific conferences, FOP patient meetings and educational events. A peer reviewed article has been published on the original design of the study: https://pubmed.ncbi.nlm.nih.gov/35650602/(öffnet in neuem Fenster).
9. Ethics: An independent ethics advisor has been involved throughout the lifetime of the project who supported and guided the it. This advisor has regularly checked the status of the project and provided reports with recommendations.
Rare diseases collectively affect over 7% of the general population and present a major challenge for healthcare systems and society. The majority are inherited rare diseases occurring as chronic monogenic conditions that present in early life and cause severely debilitating symptoms and reduced life expectancy.
The condition of FOP shares all of these characteristics. In their third decade of life, many FOP patients become dependent on full time carers; locked elbow joints can prevent individuals dressing themselves, while locked jaws can hinder unaided eating or drinking. Individuals lacking mobility risk dangerous falls and may require regular medication to manage painful inflammatory episodes. Like many rare diseases, the impact of FOP therefore extends beyond patients to their wider family and social networks, friends and the general healthcare system. A successful trial repurposing saracatinib in FOP will establish a path to overcome this severe disease burden and meet this significant unmet medical need.
The STOPFOP study has been designed to offer a broader impact to report on the potential of drug repurposing strategies in general in healthcare. The disease FOP presents a highly tractable drug repurposing opportunity with strong genetic validation of the target ALK2. It therefore represents a highly suitable test case to demonstrate how to select a repurposing project.
The understanding and management of bone growth and disease is an important area of research, particularly with a rapidly aging population with wild-type ALK2. Heterotopic ossification (HO) is a frequent complication of hip surgery and of gunshot trauma.
Innovative models for drug discovery are urgently required to reduce costs and the time to approval.
The assessment of the impact of the STOPFOP trial will be possible when the full analysis of the trial’s data is completed.
The condition of FOP shares all of these characteristics. In their third decade of life, many FOP patients become dependent on full time carers; locked elbow joints can prevent individuals dressing themselves, while locked jaws can hinder unaided eating or drinking. Individuals lacking mobility risk dangerous falls and may require regular medication to manage painful inflammatory episodes. Like many rare diseases, the impact of FOP therefore extends beyond patients to their wider family and social networks, friends and the general healthcare system. A successful trial repurposing saracatinib in FOP will establish a path to overcome this severe disease burden and meet this significant unmet medical need.
The STOPFOP study has been designed to offer a broader impact to report on the potential of drug repurposing strategies in general in healthcare. The disease FOP presents a highly tractable drug repurposing opportunity with strong genetic validation of the target ALK2. It therefore represents a highly suitable test case to demonstrate how to select a repurposing project.
The understanding and management of bone growth and disease is an important area of research, particularly with a rapidly aging population with wild-type ALK2. Heterotopic ossification (HO) is a frequent complication of hip surgery and of gunshot trauma.
Innovative models for drug discovery are urgently required to reduce costs and the time to approval.
The assessment of the impact of the STOPFOP trial will be possible when the full analysis of the trial’s data is completed.