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Saracatinib Trial tO Prevent FOP

Periodic Reporting for period 2 - STOPFOP (Saracatinib Trial tO Prevent FOP)

Reporting period: 2020-05-01 to 2021-04-30

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 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 is pending. We made several small changes to the protocol to better streamlime processes and to increase safety and conform for included patients.
3. Randomized controlled trial: After inital delays due to COVID19, the RCT phase of our project is well underway with 5 included patients and more interest than open spots available.
4. Open label extension): Several of the participants that started with the RCT phase of the study have now gone on to the open label-phase of the study.
5. Data collection and planning: A data management plan was created and is updated upon need. An electronic data reporting/questionnaire collection form was created. Regular reports are sent to the Data Safety Board.
6. Sustainability plan: Contact with EMA was made for orphan drug designation and all documents are prepared. We have established contact with parties interested in further development of the study drug.
7. Dissemination and Communication: Dissemination and exploitation plans were made and will be updated regularly. A logo and website were created. The project was presented and discussed at a combination of scientific congresses, patient assemblies and educational events.
8. Ethics: An independent ethics advisor was found who has supported and guided the project. This advisor regularly checks the current status of the project.
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 occuring 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 will have 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. Co