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Hope that a cancer drug can stop FOP, one of the rarest diseases in the world

STOPFOP are trialling the cancer drug saracatinib, which has shown promise in stopping muscle and tissue from turning to bone in FOP patients 

The ACVR1 gene. Image by By Pleiotrope own work public domain via Wikipedia
The ACVR1 gene. Image by By Pleiotrope (public domain via Wikipedia )

 

Fibrodyplasia ossificans progressiva (FOP) is a rare and devastating disease in which muscles, tendons and ligaments slowly turn to bone. People with FOP gradually get ‘locked in’ their bodies, making it difficult to move and breathe. It’s caused by a mutation in a single gene, called ACVR1, which encodes for the protein kinase ALK2. The mutation causes ALK2 to become overactive, causing muscles and connective tissues to turn into bone. There is no drug to treat this disease.

The project STOPFOP was launched to trial an experimental drug from AstraZeneca called saracatinib, originally developed as a cancer drug. The project team has shown that it blocks the activity of ALK2 kinase in mice, preventing ectopic bone formation and keeping the joints mobile. We know enough about the drug’s safety and efficacy thanks to trials in humans with cancer as well as healthy volunteers, so researchers are now proceeding to trial the drug on people suffering from FOP.

The drug is taken orally, as a once-daily dose. The first patient is now progressing through the STOPFOP study, with the randomised control trial period due to be completed within six months. Success will be measured by the ability of saracatinib to show less increase in bone formation outside the skeleton.

Every little helps

“We hope to stop the formation of bone, which will hopefully preserve the movement they have,” says Marelise Eekhoff of Amsterdam UMC, referring to the patients enrolled in the trial. “A 100% effect given the complexity of the clinical picture is almost impossible. We have given the definition of success as at least more than 50% reduction in bone formation outside the skeleton compared to controls. But in this disease even any effect would be useful.”

“Of course a negative result, also tells us more about the way FOP works.”

Despite the fact that FOP is extremely rare, close relationships between doctors who treat people with FOP and their patients, as well as their involvement in patient organisations, makes it relatively easy to find recruits for the study, according to Clemens Stockklausner of the Garmisch-Partenkirchen Medical Center in Germany. “The patient population itself is very motivated. Although FOP is a very rare disease, there are often patients willing to participate because the disease is devastating and STOPFOP it is the only study that is open to inclusion.”

“If this treatment is indeed as effective as we think, FOP disease can be treated and possibly stopped at a young age. Since people with FOP are born with only a big toe malformation, this would mean that they would be able to live their lives just like people without FOP. In addition, we hope to be able to perform surgery on older patients to free them from their contractures while being treated with this drug.”

COVID-19, an unforeseen obstacle

“The biggest problem now is COVID-19, which makes traveling difficult for these patients and of which patients are rightly afraid. For the time being, vaccinations are only administered intramuscularly, and are therefore not possible in this disease.” This means that it will take much longer for the study to be completed, says Richard Keen of the Royal National Orthopaedic Hospital in London. “We have taken measures to keep the study running as safely as possible, but the lockdown has thrown a spanner in the works. In addition, patients are also more afraid to meet other people.”

The project has been able to use a type of imaging called 18F-NaF-PET/CT in the study, thanks to recent demonstrations that it can be used to measure both the activity of the disease present and the degree of activity. According to Alex Bullock of the Nuffield Department of Clinical Medicine at the University of Oxford, IMI offered a unique opportunity to reuse a drug developed for other purposes, to which little attention would otherwise be paid. If they can prove safety and effectiveness, the drug will be quickly available to patients on the market. He adds that the STOPFOP study may have a broader impact of demonstrating the potential of kinase drug repurposing strategies in healthcare in general.

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