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What could be the first specific drug to treat osteogenesis imperfecta (OI), a rare genetic bone-growth disorder, fared pretty well in a phase II trial despite missing one of its primary endpoints, a researcher suggested.

Setrusumab, an investigational monoclonal antibody that inhibits sclerostin, failed to improve radial trabecular bone mineral density (BMD), prespecified as a primary outcome measure in the , at any of three doses, said Suzanne Jan de Beur, MD, of Johns Hopkins University in Baltimore, at the American Society for Bone and Mineral Research annual meeting, held online and in San Diego.

But the drug did show benefits in other outcomes:

• Radial bone strength by micro finite element analysis (co-primary endpoint)
• Lumbar spine BMD
• Total hip BMD
• Femoral neck BMD
• Bone turnover markers in serum

Setrusumab also appeared fairly safe in the study, with only two serious adverse events potentially related to the agent in the 112 adults treated. One patient suffered an anaphylactic reaction and another experienced headache and hydrocephalus, both leading to treatment discontinuation.

Based on these results, the drug's co-sponsors, London-based Mereo Biopharma and Ultragenyx Pharmaceutical in California, plan to pursue "a comprehensive late-stage program to continue development of UX143 [their codename for setrusumab] in pediatric and young adult patients across OI sub-types I, III and IV," following Jan de Beur's presentation.

Most OI cases are caused by loss-of-function defects in the COL1A1 or COL1A2 genes that encode type 1 collagen. These can have and are classified as types I to IV, with OI I the mildest and most common, type II the most severe, type III characterized by very early clinical manifestations (including prenatally), and type IV moderately severe. All types of OI are characterized by weak bone structure and extreme fracture risk, hence the informal name of "brittle bone disease." The incidence rate is roughly one in 10,000 births.

Lacking a specific, FDA-approved therapy, OI patients are typically treated off-label with bone-building agents such as bisphosphonates or teriparatide. One promising but as-yet-unproven therapeutic target in OI is sclerostin. Inhibiting it in osteoporosis, such as with romosozumab (Evenity), leads to both increased bone formation and decreased resorption. Mereo developed its own sclerostin inhibitor, setrusumab, and saw a commercial opportunity in OI as an orphan disease. It has since received FDA for setrusumab.

ASTEROID enrolled only adults (ages 18 and over) with types I, III, or IV, although Mereo and Ultragenyx do expect to seek pediatric indications as well. Patients were randomized initially in equal numbers to placebo or three doses of setrusumab (2, 8, and 20 mg/kg), given monthly by infusion for 12 months. Partway through, however, the placebo arm was quietly ended with all patients in that group switched to the 20 mg/kg dose. Mereo never explained the switch, nor did Jan de Beur in her presentation, which dealt only with the 75 patients randomized to the three active-drug doses who received the full 12 months of treatment.

There was a dose-response relationship of sorts seen for the failed co-primary endpoint, radial trabecular BMD. The low-dose group saw a mean decline of 20.0%, the mid-dose group a decline of 0.6%, and the high-dose group an increase of 0.7%.

Benefits from treatment were much more apparent in the other primary endpoint and secondary outcomes, with 20 mg/kg consistently outperforming the lower doses. For example, patients receiving this dosage had nearly 9% gain in lumbar spine BMD, versus about 6.5% with 8 mg/kg and 2% with 2 mg/kg. A similar pattern was seen for femoral neck BMD; there was no difference between the two higher doses for total hip BMD but the gains were significantly greater than for the lowest dose.

The micro finite element analysis for radial bone, a measure of bone strength, showed a 3% increase in failure load with the high dose, versus about 0.5% increase at 2 mg/kg; results were the same for radius stiffness.

Jan de Beur also said the drug at 20 mg/kg was highly effective in these measures across OI subtypes.

One intriguing finding was that biomarker effects (C-terminal telopeptide and procollagen 2 intact N-terminal propeptide) were relatively short lived, peaking in the first month of treatment and then slowly returning to baseline despite continued treatment -- yet BMD increases continued steadily through the full 12 months.

For reasons unknown, setrusumab appears to hold a competitive lead for the OI indication. Romosozumab maker Amgen only recently began a with OI, and the literature suggests it hasn't yet become a common drug to use off-label.

Study limitations included the lack of substantive placebo control and the small numbers of patients enrolled.

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