Garetosmab, an inhibitor of activin A, reduces heterotopic ossification and flare-ups in adults with fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial
Bibliographic record
Abstract
ABSTRACT Background Fibrodysplasia ossificans progressiva (FOP), an ultra-rare disorder caused by mutations in the gene encoding activin A receptor type 1 ( ACVR1) , is characterized by painful flare-ups and cumulative heterotopic ossification (HO). Garetosmab, a fully-human monoclonal antibody blocking activin A, prevents HO in FOP mice. Methods LUMINA-1 ( NCT03188666 ) was a phase 2, multi-center, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and effects on HO of intravenous (IV) garetosmab 10 mg/kg every 4 weeks (Q4W). Adult patients with FOP were randomized to garetosmab or placebo for 28 weeks (Period_1), followed by an open-label period (Period_2). After Period_2, patients were allowed to stay on garetosmab in an open-label extension. For Period_1, primary endpoints were HO total lesion activity (HO-TLA) by 18 F-sodium fluoride positron emission tomography ( 18 F-NaF PET) and HO total lesion volume by computed tomography (CT). The Period_2 primary endpoint compared the number of new lesions in Period_2 versus Period_1. The safety primary endpoint was incidence and severity of TEAEs through the end of the Period 1 at week 28. Findings Patients (n=44) were randomized to garetosmab (n=20) or placebo (n=24). In Period_1, there was a trend for garetosmab to decrease HO-TLA versus placebo (24.6%; P =0.07), primarily driven by near complete prevention of new lesions (97% decrease by 18 F-NaF PET, post-hoc P =0.009; 90% relative reduction by CT, post-hoc P =0.017); flare-ups were significantly reduced ( P =0.0005). For placebo patients transitioning to garetosmab in Period_2, no patients developed new HO lesions (0% in Period_2 versus 40.9% in Period_1; P =0.0027) by CT. All 44 patients met primary safety endpoint of at least one TEAE during Period 1. Garetosmab was associated with more adverse events than placebo: mild recurrent epistaxis, madarosis, and skin/soft tissue infections. Overall, the AEs were predominantly mild in severity, with no effect on patients’ ability to receive garetosmab. Five deaths (5/44; 11.4%) occurred either in Period_2 or the open-label extension. The deaths were associated with baseline disease severity in some, preexisting comorbidities in others and occurred following 8-16 doses (median: 15) of garetosmab in the open label/follow-up periods. Interpretation Garetosmab reduced flare-ups and prevented new HO lesions in FOP patients. Although side effects were mild to moderate, there were a relatively high number of deaths for a small study; the deaths were not related to epistaxis and considered unlikely to be related to garetosmab. Funding Regeneron Pharmaceuticals, Inc.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".