Activin A blockade with garetosmab suppresses heterotopic ossification in adults with the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP), according to findings from the phase III OPTIMA trial that served as the basis for its Food and Drug Administration (FDA) approval.
OPTIMA met its primary endpoint, with the total number of new heterotopic bone lesions at week 56 being significantly lower with garetosmab vs placebo: one in the 3-mg/kg garetosmab group and two in the 10-mg/kg group vs 19 in the placebo group (3 mg/kg vs placebo: rate ratio [RR], 0.06, 95 percent confidence interval [CI], 0.00–0.73; 10 mg/kg vs placebo: RR, 0.10, 95 percent CI, 0.01–0.76; p=0.027 and p=0.026, respectively). [Lancet 2026;doi:10.1016/S0140-6736(26)01599-0]
The difference “corresponds to a 94-percent and 90-percent rate reduction in the number of new heterotopic bone lesions in the garetosmab 3-mg/kg group and 10-mg/kg groups, respectively, vs placebo,” noted lead investigator Dr Riccardo Papa from IRCCS Istituto Giannina Gaslini, Genova, Italy, and colleagues.
Additionally, garetosmab 10 mg/kg was associated with a significantly lower number of clinician-assessed flare-ups at week 56 compared with placebo (RR, 0.12, 95 percent CI, 0.03–0.42; p=0.0010). Other outcomes, including the proportion of participants with new heterotopic bone lesions and total volume of new heterotopic bone lesions, did not significantly differ between garetosmab and placebo.
In terms of safety, “both doses of garetosmab were well tolerated, although it appeared that the lower dose had a more favourable safety profile,” noted Papa and colleagues.
Adverse events (AEs) of special interest occurred in 17 percent of participants in the 10-mg/kg group and 5 percent in the placebo group, and all these events were considered related to treatment. Serious AEs were reported in 5 percent of participants in the 3-mg/kg group (pneumonia), 9 percent in the 10-mg/kg group (abscess, cellulitis), and 10 percent in the placebo group (peritonsillar abscess, ovarian cyst). Ovarian cyst led to early study discontinuation, which was the only case of study dropout that occurred through week 56. There were no deaths reported.
“Dose dependence was most apparent with skin and soft tissue infections (SSTIs), particularly acne and abscesses, with SSTIs occurring in 47 percent and 65 percent of participants receiving garetosmab 3 and 10 mg/kg, respectively, compared with 33 percent of those receiving placebo,” said Papa and colleagues.
“The only notable bleeding event was epistaxis, which was mild to moderate in severity, with similar rates seen in the garetosmab 10-mg/kg and placebo groups,” they added.
These findings, according to Papa and colleagues, provide evidence of garetosmab’s potential to be an efficacious and generally well tolerated disease-modifying therapy for FOP. This holds important implications, given that the current treatment landscape for FOP is marked by unmet need, with most therapeutic agents being only palliative in nature and do not stop progression of disease, they added.
From avoiding harm to disease modification
In an accompanying editorial, Prof Ernestina Schipani from the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, US, echoed the authors and described the evidence presented in OPTIMA as “compelling.” [Lancet 2026;408:1530-1531]
“OPTIMA marks a decisive transition from managing FOP primarily by avoiding harm to directly suppressing a genetically defined pathogenic signal. Preventing even a single lesion in a functionally critical location could preserve shoulder movement, jaw opening, walking ability, or chest-wall mobility. If sustained, near-complete suppression of new heterotopic ossification could fundamentally alter the natural history of FOP, particularly when treatment is initiated before extensive ankylosis develops,” Schipani wrote.
“For the first time, people with FOP might be offered not merely mitigation of an apparently inevitable decline, but a realistic prospect of preventing much of the future accumulation of heterotopic bone,” she added.
Nevertheless, Schipani highlighted an important safety consideration with garetosmab, with SSTI rates increasing from 33 percent with placebo to 47 percent with garetosmab 3 mg/kg and 65 percent with 10 mg/kg. “This apparent dose-response relationship is clinically relevant because suppression of new heterotopic bone lesions was broadly similar with the two doses, whereas the higher dose appeared more effective in reducing clinician-assessed flare-ups,” she said.
“For a treatment that might be continued throughout life, identifying the lowest dose that provides durable control of both heterotopic bone formation and disease activity will be central to optimizing the balance between benefit and risk,” Schipani added.
Finally, “the findings cannot be assumed to apply to people with more advanced disease or to individuals carrying uncommon ACVR1 variants. In addition, preventing new lesions cannot reverse mature heterotopic bone or restore function that has already been lost,” Schipani said.
OPTIMA population
OPTIMA was conducted at 18 study sites across 16 countries and regions. A total of 63 adults with FOP (mean age 26.6 years, 60 percent female, 67 percent White) participated in the trial and were randomly assigned to receive garetosmab at 3 mg/kg (n=19) or 10 mg/kg (n=23) or placebo (n=21). Treatment was administered intravenously once a month.
All participants had clinical or radiological evidence of ongoing FOP disease activity within 1 year before screening, and 95 percent carried the R206H variant. Those who had a Cumulative Analogue Joint Involvement Scale score >19 were excluded.
FDA approval
In August 2026, the US FDA approved garetosmab for reducing the formation of new heterotopic bone lesions and clinician-assessed disease flare-ups in adults with FOP. [https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-treatment-fibrodysplasia-ossificans-progressiva]
Garetosmab is the second drug approved for patients with FOP.