A new drug offers a glimmer of promise for a rare genetic condition – FOP – which causes uncontrolled explosions of bone, reports The New York Times.
It was Jordyn Bugarin’s grandmother who first suspected what was wrong. In a television documentary that aired on American TV in 2006, she watched as a child showed off a shortened, misshapen big toe just like Jordyn’s.
According to the narrator, this was one of the early signs of fibrodysplasia ossificans progressiva, or FOP, a rare genetic disorder that slowly turns muscle, tendons and connective tissue into bone. To the woman watching, it was a revelation: “That’s what Jordyn has,” she told her family.
The mutated gene that causes FOP was discovered only 20 years ago, and until recently there was no approved treatment. Now, there are three, and for patients like Bugarin (22), they offer the first real hope that this terrible disease can be slowed.
In August, the Food and Drug Administration approved garetosmab (brand name: Pasatru), a monoclonal antibody made by Regeneron. The drug reduces new abnormal bone formation by 90% in FOP patients, making it the most effective treatment yet.
Two other drugs have been approved: zilurgisertib (brand name: Atebrioz), which inhibits ALK2, a protein that tells the body how to grow bones; and palovarotene (brand name: Sohonos), which overrides the body’s signals to grow more bone. But in some cases, the drugs have serious side effects and aren’t as effective as researchers had hoped.
Worldwide, there are about 900 confirmed cases of FOP, roughly one in 2m births. People with the disease experience runaway bone growth, usually after even mild injury.
By the time they are adults, most are immobilised by so-called second skeletons. Most are in wheelchairs by their late 20s, and the median age at death is about 40.
“It’s a devastating condition,” said Frederick Kaplan, a professor of molecular orthopaedics at the University of Pennsylvania and one of the foremost experts on the disease.
Kaplan, with his colleague Eileen Shore, is responsible for the discovery of the mutated gene that causes FOP called ACVR1. The gene produces a mutated cell receptor that responds to activin A, a protein produced when the body is injured.
In people with FOP, the mutation causes a switch to remain permanently on, triggering a transformation of soft tissue into bone. Garetosmab binds to activin A, preventing it from activating the mutated receptor.
Regeneron scientists were developing garetosmab for other purposes when they began testing what might happen if activin A were blocked, said Susan Rhee, the lead researcher in the company’s clinical trials.
Why pursue a treatment for an ultra-rare disease when very few patients stand to benefit? The research has implications that stretch beyond the disease, Rhee said, including furthering understanding of inflammation, bone formation and skeletal muscle biology.
“There’s a huge scientific engine that is looking at how we can apply these learnings to other disease areas,” she added.
The treatment can be administered across a range of care settings, including at home, which is especially useful to FOP. patients with limited mobility. A trial investigating the efficacy and safety of the treatment in children and adolescents – who could most benefit from early administration of the drug – is due to begin later this year.
Long accustomed to the prospect of diminished life spans and mobility, people with FOP are finally allowing themselves to hope for more.
Laura Rossano (37), was diagnosed with FOP at the age of five. By the time doctors figured out what was wrong with her, she was unable to move her neck or lift her arms above her head.
Still, she lived a relatively normal life until about eighth grade, when her body locked up overnight. “It was a summer I wish to never live again,” she recalled.
Rossano was not a participant in the garetosmab trial, nor has she taken the drug. She was hesitant to participate in the trial because of past bad experiences, but recently decided that she would try the drug.
Ashley Kurpiel (44), was the first American participant in Regeneron’s trial of garetosmab, which spanned 16 countries. Diagnosed at three, she is now bedbound and has not been able to stand up in three years.
“My hope is that we’ll turn this horrible nightmare disease into nothing more than an inconvenience,” said Kaplan, the disease expert. “And I can hang a sign on my door that says ‘Gone Fishing’.”
Bugarin was luckier than some FOP patients. She enjoyed a typical teenage life: She drove, managed her high school sports teams and was involved in campus life.
At 17, her left hip started flaring up and turned to bone. Then it was her left knee, then her right hip, then her shoulders, then her elbows – all within 18 months.
She can no longer drive or sit down and has difficulty walking. Her legs are stuck straight, and her arms are locked. She participated in the garetosmab trial anyway.
So did Kurpiel. At 44, she has lived longer than doctors expected – and continues to make the most of it. “I knew this would be my life,” she said. “I didn’t do these drug trials for me. I did it for the next generation.”
See more from MedicalBrief archives:
SA film tells the stories of one of the rarest conditions in medicine
FDA approves rare bone disorder drug
More support needed for genetic tests to diagnose rare diseases in children