Mereo BioPharma’s phase two study of setrusubab misses primary goal

Mereo BioPharma Group’s Phase 2b dose-ranging “Asteroid” clinical study of setrusumab (BPS-804), an anti-sclerostin antibody,  in adults with Type I, III or IV osteogenesis imperfecta (OI), a rare bone disease with no approved treatments, failed to meet the primary endpoint and any of the three setrusumab dose levels.

As the company explained in a Monday press release, the primary endpoint of the Asteroid study was change in Trabecular Volumetric Bone Mineral Density (Tr vBMD) of the radius (wrist) over baseline after 12 months of treatment as measured by High Resolution peripheral Quantitative Computed Tomography (HR-pQCT). As a result of the unexpected high heterogeneity of the study patients’ trabecular bone baseline values at the wrist, and the primary endpoint was not met at any of the three setrusumab dose levels.

Mereo said HR-pQCT is a relatively new imaging technique that has not been used widely in clinical studies and was chosen in order to improve the understanding of the effect of setrusumab on the bone biology in OI patients, given it can measure both trabecular and cortical vBMD separately. It said that an increase in total vBMD at the wrist as measured by HR-pQCT (measuring cortical and trabecular together), a secondary endpoint of the study, was observed and reached statistical significance in the medium and high dose cohorts. Mean increases in total vBMD were 4.11% (p=0.004), 4.5% (p=0.028), and 0.58% (p=0.97) in the high, medium, and low dose cohorts, respectively. This suggests total vBMD increases were driven by the ability of setrusumab to increase cortical vBMD.

The study achieved its important secondary endpoint

The study achieved its important secondary endpoint of increase in areal Bone Mineral Density (BMD) at the lumbar spine at 6 and 12 months over baseline using two-dimensional dual-energy X-ray absorptiometry (DXA), a well-established measurement tool of BMD (cortical + trabecular bone), reaching statistical significance in the high and medium doses cohorts at both 6 and 12 months with a clear dose-dependent response, the company said.

Mean increases in areal BMD at the lumbar spine were 8.8% (p<0.001), 6.8 % (p<0.001), and 2.6% (p=0.057) in the high, medium, and low dose cohorts at 12 months, respectively. Moreover, increases in areal BMD were consistent across all OI subtypes (I, III or IV) represented in the study and improved with duration of treatment. Statistically significant changes in areal BMD were also observed by DXA at the femoral neck and total hip with mean increases of 3.1% (p=0.022) and 2.2% (P=0.011), respectively, at 12 months in the high dose cohort, Mereo said.

Although the ASTEROID study was not powered to show a difference in fracture rates, a trend of reduction in fractures was observed in the high dose cohort. Setrusumab was safe and well-tolerated in the study. There were no cardiac-related safety concerns observed in the study, the company said in the press release.

Dr. Denise Scots-Knight, Chief Executive Officer of Mereo, said: “The DXA data clearly differentiate setrusumab from other therapeutic agents in OI types I, III and IV, such as teriparatide, where a 4.7% increase was observed at the lumbar spine at 12 months and where the effect was significantly lower in types III & IV versus type I OI patients. Further, the DXA data also show a consistent improvement at 12 months in areal BMD at the lumbar spine compared to the open-label data set from the study that we first reported in May 2019 where a 3.5% change from baseline was observed seen at 6 months in the highest dose cohort.”

Dr. Scots-Knight said that the trend of decrease in fractures observed in the high dose cohort is also particularly encouraging. Dr Scots-Knight said that, based on the data, Mereo will be moving forward with the preparations for its pivotal pediatric study in children with OI as originally planned, which will be based on a primary endpoint of fracture rate over a 12-month period.“We believe setrusumab has the potential to become the first approved pharmacologic treatment for the OI patient community and would like to thank the investigators and patients for participating in the ASTEROID study, the largest ever completed interventional trial in adult OI,” Dr. Scots-Knight said.

Dr. Alastair MacKinnon, Chief Medical Officer of Mereo, said: “The technique of HR-pQCT is a relatively new and cutting-edge technology in bone research. We believe the HR-pQCT data from the ASTEROID study indicate a significant improvement in total vBMD that is driven by cortical changes, which differentiates setrusumab from existing bone-building agents. It is important to emphasize that it is not possible to build bone that does not already exist, which may be the case with some patients’ trabecular bone at the wrist in this study given the variable HR-pQCT measurements of Tr vBMD. The total vBMD data together with the statistically significant and dose dependent improvement in areal BMD as measured by DXA, a well-established bone measurement technique, support the further development of setrusumab in pediatric patients, where the unmet medical need is most apparent.”

Jay R. Shapiro, Former Director of the Bone and Osteogenesis Imperfecta Department at the Kennedy Krieger Institute said that the results from the Asteroid study underscore the ability of setrusumab to function as a strong bone-building agent and potentially serve as a new therapeutic option for patients living with OI. Shapiro said that the fracture rate reduction seen in the highest dose cohort with setrusumab is particularly encouraging and bodes well for future development in pediatric OI patients.

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