ASBMR 2020: Garetosmab and palovarotene show promise in FOP

[Author: Laura Cowen]

Results of two trials presented at the ASBMR 2020 Annual Meeting Virtual Event show promising new options for the treatment of fibrodysplasia ossificans progressiva (FOP).

The phase 2 LUMINA-1 trial investigated garetosmab, a human monoclonal antibody against Activin A, while the phase 3 MOVE trial looked at the selective retinoic acid receptor-γ agonist palovarotene. Both drugs had previously shown efficacy in animal models of FOP.

LUMINA-1 included 44 adults with FOP (mean age 27.6 years, 43% men) who were randomly assigned to receive intravenous garetosmab 10 mg/kg (n=20) or placebo (n=24) every 4 weeks for 28 weeks.

Marelise Eekhoff, from Amsterdam UMC in the Netherlands, reported that garetosmab treatment decreased heterotopic ossification (HO) total lesion activity, as measured by 18F-sodium fluoride positron emission tomography, by a nonsignificant 24.6% relative to placebo, and decreased total (new and existing) HO lesion volume, measured by whole-body low-dose computed tomography, by a nonsignificant 24.9%.

The total volume of new HO lesions and the rate and number of new HO lesions were each reduced significantly, by nearly 90%, with garetosmab versus placebo.

In addition, significantly fewer patients in the garetosmab group developed new HO than in the placebo group (15.0 vs 45.8%), and both patients and investigators reported significantly fewer flare-ups with garetosmab versus placebo, at respective reductions of 51% and 76%.

In terms of safety, Eekhoff said that individuals who received garetosmab treatment had an increased incidence of epistaxis, headache, acne, madarosis, and skin infections compared with those who received placebo.

She concluded that garetosmab “substantially reduces the formation of new HO lesions and flare-ups and demonstrates a favorable benefit/risk profile for adults with FOP.”

She added that the results support the hypothesis that “activin A is a key driver of HO in FOP.”

The single arm, open-label MOVE trial evaluated a chronic/episodic regimen for palovarotene, in which participants aged 4 years and older were given oral palovarotene 5 mg/day (adjusted for weight in skeletally immature participants) and palovarotene 20 mg/day for 4 weeks, followed by 10 mg/day for 8 weeks during flareups.

Robert Pignolo, from the Mayo Clinic, in Rochester, Minnesota, USA, reported that, at the preplanned 12-month assessment, the likelihood of achieving a 30% or greater reduction in square root-transformed annualized new HO volume was 4.9%, which fell within the cut-off for futility, set at a less than 5%.

However, he pointed out that post-hoc analyses of non-transformed data “would have exceeded the prespecified boundary for early efficacy.”

At 18 months, the researchers compared data for 97 patients (mean age 15.1 years, 52.6% male) from MOVE with that of 98 individuals (mean age 17.8 years; 55.1% male) from the non-interventional FOP Natural History Study (NHS).

In this analysis, there was no significant reduction in the square root-transformed annualized rate of new HO volume in palovarotene-treated versus untreated patients, but there was a significant 62% reduction when the non-transformed data were used. The mean annualized HO volume was 8821 mm3 among MOVE participants compared with 23,318 mm3 among NHS participants.

All of the MOVE patients reported least one adverse event (AE), which were categorized as mild, moderate, or severe in 32.3%, 45.5%, and 22.2%, respectively. Nearly all (97.0%) patients reported at least one retinoid-associated (eg mucocutaneous) AE.

Serious AEs occurred in 29.3%, including premature physeal closure (PPC) or epiphyseal disorder in 27.1% of 70 patients who were skeletally immature at baseline. Pignolo concluded: “Although prespecified futility criteria were met, subsequent post hoc analyses showed substantial efficacy suggesting that, despite the risk of PPC in a subset of [patients], [palovarotene] may be an important therapeutic option in FOP.”

FOP Drug trial summary

Trial name LUMINA-1 MOVE
Drug investigated
Mechanism of action
Activin A inhibitor
Retinoic acid receptor-γ agonist
Number of participants
Significant reductions in rate and number of new HO lesions and fewer flare-ups at 28 weeks versus placebo
Significant reduction in annualized new HO volume at 18 months (untransformed data)
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