What could be the first specific drug to treat osteogenesis imperfecta (OI), a rare genetic disorder of bone growth, performed quite well in a phase II trial despite missing one of its criteria. main assessment, one researcher suggested.
Setrusumab, an investigational monoclonal antibody that inhibits sclerostin, failed to improve radial trabecular bone mineral density (BMD), predefined as a primary endpoint in the ASTEROID trial, at one of three doses, has said Suzanne Jan de Beur, MD, of Johns Hopkins University of Baltimore, at the American Society for Bone and Mineral Research annual meeting, held online and in San Diego.
But the drug has shown benefits in other results:
- Radial bone resistance by finite element analysis (co-main criterion)
- BMD of the lumbar spine
- Total hip BMD
- BMD femoral neck
- Serum bone remodeling markers
Setrusumab also appeared to be fairly safe in the study, with only two serious adverse events potentially related to the agent in the 112 adults treated. One patient experienced an anaphylactic reaction and another presented with headache and hydrocephalus, both of which resulted in discontinuation of treatment.
Based on these results, the drug’s co-sponsors, London-based Mereo Biopharma and California-based Ultragenyx Pharmaceutical, plan to pursue “a comprehensive late-stage program to further develop UX143. [their codename for setrusumab] in pediatric and young adult patients with OI subtypes I, III and IV “, they announced following Jan de Beur’s presentation.
Most cases of OI are caused by loss of function defects in the COL1A1 Where COL1A2 genes that code for type 1 collagen. These can have different clinical presentations 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 prenatal) and moderately severe type IV. All types of OI are characterized by poor bone structure and the risk of extreme fracture, hence the informal name of “fragile bone disease”. The incidence rate is approximately one in 10,000 births.
In the absence of specific treatment approved by the FDA, patients with OI are usually treated off-label with bone-strengthening agents such as bisphosphonates or teriparatide. A promising but not yet proven therapeutic target in OI is sclerostin. Its inhibition in osteoporosis, as with romosozumab (Evenity), results in 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 orphan drug designation from the FDA for setrusumab.
ASTEROID has only recruited adults (aged 18 years and older) with Type I, III or IV, although Mereo and Ultragenyx also expect to seek pediatric indications. Patients were initially randomized in equal numbers to receive placebo or three doses of setrusumab (2, 8 and 20 mg / kg), administered monthly by infusion for 12 months. Halfway through, however, the placebo arm was quietly finished, with all patients in that group upgraded to the 20 mg / kg dose. Mereo never explained the change, nor did Jan de Beur in his presentation, which only looked at the 75 patients randomized to the three doses of active drug who received the full 12 months of treatment.
There was some sort of dose-response relationship observed for the failed co-primary endpoint, radial trabecular BMD. The low dose group experienced an average decrease of 20.0%, the medium dose group a decrease of 0.6%, and the high dose group an increase of 0.7%.
The benefits of treatment were much more apparent for the other primary endpoint and secondary outcomes, with 20 mg / kg consistently outperforming the lower doses. For example, patients receiving this dosage had an almost 9% gain in lumbar spine BMD, compared to approximately 6.5% with 8 mg / kg and 2% with 2 mg / kg. A similar pattern was observed for BMD of the femoral neck; there was no difference between the two highest doses for total hip BMD, but the gains were significantly greater than for the lowest dose.
Micro finite element analysis for radial bone, a measure of bone strength, showed a 3% increase in breaking load with the high dose, compared to an increase of about 0.5% at 2 mg / kg; the results were the same for spoke stiffness.
Jan de Beur also stated that the 20 mg / kg drug was very effective in these measures across OI subtypes.
One intriguing finding was that the effects of the biomarkers (C-terminal telopeptide and intact N-terminal propeptide of procollagen 2) were relatively short-lived, peaking in the first month of treatment, then slowly returning to baseline despite continued treatment. treatment – but increases in BMD continued steadily throughout treatment. the full 12 months.
For unknown reasons, setrusumab appears to have a competitive advantage in the OI indication. The manufacturer of romosozumab Amgen only recently started a phase I trial in children and adolescents with OI, and the literature suggests that it has not yet become a mainstream drug for off-label use.
Limitations of the study included the lack of substantial placebo control and the small number of patients enrolled.
The study was sponsored by Ultragenyx and Mereo BioPharma. Some of the co-authors are employees of the company.