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Human Foot X-ray Image showing bones and soft tissue.
Fibrodysplasia ossificans progressiva is caused by genetic mutations that lead to abnormal formation of bone outside of the normal skeleton in soft tissue.
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Rare Musculoskeletal Condition Treatment Shows Promise in Phase 2 Trial

Drug candidate indirectly blocks mutant ACVR1 gene activation and prevents formation of new bone lesions

Vanderbilt University Medical Center
Published:Sep 28, 2023
|3 min read
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A multisite, international, Phase 2 trial evaluating the investigational drug, garetosmab, has shown that it reduced soft-tissue flare-ups significantly and prevented new areas of abnormal bone formation in patients with fibrodysplasia ossificans progressiva (FOP). Kathryn Dahir, MD, professor of medicine in the Division of Endocrinology and Diabetes, served as the principal investigator at Vanderbilt University Medical Center for the randomized, double-blinded, placebo-controlled trial to study the efficacy and safety of garetosmab—a human monoclonal antibody. 

Garetosmab binds to activin A, a protein associated with growth, and blocks its ability to activate the FOP-mutant ACVR1 gene. The findings, published recently in Nature Medicine, give hope to individuals with the rare disease (FOP) that affects 1 out of 1 million individuals in the United States.

What happens in fibrodysplasia ossificans progressiva?

FOP is caused by mutations in the ACVR1 gene which lead to abnormal formation of bone outside of the normal skeleton in soft tissue including muscles, tendons, and ligaments throughout the body. 

“Garetosmab decreased total lesion activity by nearly 25 percent, including new and existing lesions, as compared to placebo, and showed a remarkable 90 percent decrease in the number of new bone lesions. The prevention of new, heterotopic bone is of critical importance to the treatment of FOP,” said Dahir. “Patient-reported soft tissue flare-ups—with symptoms such as fever, pain, swelling, and stiffness—were also reduced by half. As flare-ups often precede the formation of new lesions, we are encouraged that this investigational drug may help prevent the progression of FOP.

“The loss of mobility created by the abnormal bone growth is cumulative and steadily limits the ability of persons with FOP to perform even the most basic activities. It’s time for these patients and their families to feel hope with the possibility of a treatment that can make a real difference in their lives. I’m grateful to the patients and their families who participated in the trial, and we look forward to continuing to gather evidence on the safety and efficacy of this treatment,” said Dahir.

Proceedings of the trial

In the trial, 44 adults enrolled in the multicenter study who were diagnosed with FOP received garetosmab or a placebo every four weeks and were evaluated for new bone lesions by using the whole-body positron emission tomography (PET) with sodium fluoride and low-dose computed tomography (CT) scans at baseline, eight, 28, and 56 weeks. 

At 28 weeks, all subjects began an open-label period in which both patients and researchers knew which treatment was being administered. Patients in the placebo group could choose to begin receiving garetosmab.

Brentwood, TN, resident Sharon Kantanie, who was diagnosed with FOP at age six, was one of the participants in the drug trial at VUMC. When the study shifted to the open-label period she learned she had received garetosmab from the beginning. Kantanie primarily experienced minor dermatological side effects. She is happy the results have been published and that further investigation of the drug’s efficacy and safety is now in progress.

“There are really no words to adequately explain FOP’s effects on a person and the disease’s impact on their family and caregivers,” Kantanie said. “To move closer to an effective treatment is a wonderful thing. And to have that treatment provided earlier in life would be amazing so people with FOP and their families won’t have to go through the extremes and painful progression of this disease as we’ve experienced.”

There were five deaths during the trial—a relatively high number for a small study. After a pause to investigate, the deaths were determined to be unlikely related to the drug intervention. It was concluded that the deaths were most likely associated with the severity of the participant’s baseline disease or preexisting comorbidities and were consistent with known causes of death and life expectancy for patients with FOP. 

Researchers from 11 institutions across the United States, as well as Italy, England, France, Poland, Spain, Canada, and the Netherlands participated in the study. 

Dahir is currently one of three US principal investigators in a Phase 3, adult OPTIMA trial to further assess the benefits and risks of garetosmab for individuals with FOP and to validate the Phase 2 results. A pediatric trial is imminent.

- This press release was originally published on the Vanderbilt University Medical Center website