BPS-804 (setrusumab) is a fully humanized monoclonal antibody designed to inhibit sclerostin, a mechanism of action that is believed to improve bone strength and, consequently, to have the potential to reduce fractures and improve quality of life for people with Osteogenesis Imperfecta (OI).
OI is a serious, inherited rare genetic disorder, commonly known as brittle bone disease, which is characterized by fragile bones that fracture easily, often starting from birth. OI is caused by a problem in the formation of type I collagen, the most abundant protein in our bodies. This means that people with OI experience a broad range of impacts: in addition to frequent fractures, people with OI often have skeletal deformities, constant chronic pain, respiratory insufficiency, dentition problems and early hearing loss. More broadly, its impact extends to fatigue and muscle weakness. In other words, OI is a multi-systemic condition that can affect people’s lives in a multitude of different ways. And each person’s experience is different.
Ingunn Westerheim, President of OIFE, shares her experiences of life with Osteogenesis Imperfecta in an April 2020 interview.
There are currently no FDA- or EU-approved treatments for OI. Current treatment is based on supportive care, using off-label, unapproved compounds to seek to improve bone density, treating fractures as they occur – an often all-too-frequent occurrence particularly in children with OI – and on maximizing mobility via physiotherapy, pain management and orthopaedic surgery.
The majority of cases of OI (up to 90%) are caused by a dominant mutation in the genes coding for – Type I collagen – which is a key component of healthy bone. As setrusumab aims to act on dual pathways for both bone formation and bone resorption, our clinical studies are seeking to understand if setrusumab can play a role in improving the health and quality of life for people with OI.
OI is recognized as an area of high unmet medical need. Setrusumab (BPS-804) has been designated an “Orphan Drug” in the USA and the EU, meaning it is officially acknowledged by the regulatory authorities to be targeting a rare and serious disease. Most recently, setrusumab has been granted Rare Pediatric Disease Designation by the FDA. This means that the FDA formally recognises the significant unmet medical need in children. In addition, setrusumab has also been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA), a programme aimed at enhancing support for the development of medicines that target an unmet medical need; as well as being accepted in the EMA’s Adaptive Pathways programme.
Setrusumab has been studied in adults with OI and, in 2019, we announced the results of our Phase 2b study for setrusumab in adults.
This was designed to evaluate whether setrusumab was able to create an increase in bone density measured by High-Resolution peripheral Quantitative Computed Tomography (HRpQCT), a relatively new imaging technique that allows the examination of the microarchitecture of the bone in a non-invasive manner.
The study in adults with OI enrolled 112 patients in the US and Europe into three blinded dose-ranging arms and an open-label arm at the top dose. The top-line 12-month data from the three blinded dose-ranging arms of the study were reported on 11 November 2019, with a further update in January 2020. These demonstrated setrusumab to have a dose-dependent bone-building activity measured by DXA scans as well as data showing a trend in fracture reduction when given at the highest dose in the study. The data also demonstrated such activity across all types of OI that were studied in the trial: Types I, III and IV.
Further the data published on 14 January 2020 showed setrusumab to have a positive impact on bone stiffness and strength as measured by Finite Element Analysis (FEA).
Setrusumab was demonstrated to be safe and well-tolerated in the patients participating in the Phase 2b adult study, as well as by the 83 subjects who have received it across the 4 Phase 1/2 studies completed to date.
This was the first time that HRpQCT had been used in an OI trial. More well-recognized techniques were also used for the secondary endpoints, which included the traditional and well-established DXA scan, measuring bone density; as well as fractures and quality of life, amongst other aspects of OI.
The trial did not show a statistically significant increase in the trabecular bone measured by the HRpQCT imaging, because of the high variability of the baseline bone in the studied patients, which fell far outside the values expected from the literature published to date. We will be sharing the findings about HRpQCT as a technique with the research community to continue to build understanding of the role of HRpQCT as a measurement in bone research.
Following the review of the data from the Company’s Phase 2b ASTEROID study with setrusumab in adults with OI, the FDA agreed on the design of a Phase 3 pediatric study in OI to be completed prior to the submission of a Biologics License Application (“BLA”) in the United States. This is in line with Mereo’s proposed pivotal pediatric study design that has already been agreed to in principle with the European Medicines Agency (“EMA”) to support the submission of a Marketing Authorisation Application (“MAA”) in the EU. The study will enrol approximately 160 children and adolescents ages 2 to <18 years with severe OI. Preparations to initiate the Phase 3 pivotal study are underway.
Bringing the patient perspective into our work
Nothing about us without usAlastair Kent OBE, AMBASSADOR, GENETIC INTEREST GROUP, UK
Mereo is committed to developing and making available therapies in collaboration with all stakeholders, most importantly, the people who we are seeking to serve. This means we are committed to ensuring that the patient voice is included in every step of the way; and we actively seek opportunities for having leadership from the OI community as part of our development programme for setrusumab.
Rare diseases, individually, each affect small numbers of people. This means that, individually, patients are rare but it also means that expertise and experience is rare, too. A primary care physician might never see one case of a given rare disease. Patients and their families, on the other hand, are often extremely well-informed – more often than not becoming experts in their condition. This means that their point of view and their experience is crucially important in all decision-making, because they have the lived experience and are able to point to what will make a real and meaningful difference in their lives.
The respect for and inclusion of the rare disease patients’ point of view is also recognized by Regulatory, Health Technology Assessment and Pricing & Reimbursement authorities, who are increasingly including patient representation in their evaluation and decision-making processes, both in the USA and in Europe. Mereo is committed to maximising those opportunities to include the patient voice, while respecting the independence of patient representatives and community leaders. Conflict of interest policies and procedures are in place to respect the different roles and responsibilities of all actors in such processes and Mereo adheres to these. We also make available all financial support that we provide to patient organizations via our transparency reporting.
Multi-stakeholder collaboration is a fundamental condition to achieving patient access to rare disease medicinesEURORDIS MULTI-STAKEHOLDER FORUM, FEBRUARY 2019
In addition to the formal external engagements, we also believe that it is important for all of our team members at Mereo to be able to feel and understand the potential benefits that our shared work is providing for patients. We are proud that organisations from the Osteogenesis Imperfecta community spend time with our broad company team in order to secure that we are always keeping the patient perspective in our minds.
OSTEOGENESIS IMPERFECTA COMMUNITY REPRESENTATION ORGANISATIONS
RARE DISEASE ORGANISATIONS
1. Shapiro J (2014) Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease.community
Academic Press. Chapter 2: p15-22
2. Glorieux et al (2017) BPS-804 Anti-Sclerostin Antibody in Adults With Moderate
Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial. JBMR 32: 1496-1504