Nowadays it can be difficult to find people with OI who have not yet received some kind of treatment. Also people can’t be withheld existing treatments, so usually trials compare a new substance against a standard treatment like bisphosphonates instead of using a blind placebo as control. The end points of most studies are usually fracture rate or changes in bone mineral density (BMD), while important especially adults also seek alleviation of things like pain, fatigue and general improvement in quality of life – increasingly these are now also endpoints of studies.

ULTRAGENYX LED COSMIC & ORBIT STUDY (SETRUSUMAB)

Stan Krolczyc from the company Ultragenyx presented an update on clinical trials in OI with setrusumab. Bone growth is a tightly regulated process, sclerostin is a substance in the human body that slows down bone growth so we don’t get too much bone. Setrusumab is an antibody that inhibits the function of sclerostin. It is thought it can thereby stimulate bone formation. Increased bone formation could then lead to less fractures.

Two studies were presented, (a third one, the Asteroid study in adults is already completed). Orbit is a Phase II/III study in children and young adults aged 5-<26. Cosmic is a Phase III study in children aged 2-<7. Both trials are fully enrolled at this point and limited to OI types I, III and IV. Intermediate results from the Orbit study show a clear increase in BMD (on average +22% after a year) for the setrusumab group. At the same time this increase in BMD was coupled to a 67% reduction in (large) fractures. Even though the group was relatively small (19 patients) an age effect was also visible; with the youngest participants having the largest BMD gains. The BMD gain of the 18-25 year olds was similar to what was observed in the Asteroid study for adults.

EVENITY Ph3 STUDY (ROMOSOZUMAB)

Romosozumab is another sclerostin antibody, it has already been approved as a drug (Evenity) to treat osteoporosis in women in many countries, including the EU (in some countries in men as well). Large studies into its safety, efficacy and side effects have already been performed. It works by stimulating bone growth, but it also slows down bone resorption somewhat.

Diala El-Maouche from the company Amgen shared results of studies in OI. In OI-mouse models, effectiveness has been shown. A Phase I study in OI looked at different dosages in children and teens and studied the pharmacokinetics. No severe severe side effects were observed. The protocol for a future Phase III trial was shown. Children aged 5-17 with OI types I, III or IV who are ambulatory will be studied with bisphosphonate treatment in the control group. Subjects will be 1:1 randomized between romosozumab and the control group and receive 12 monthly doses in the treatment arm. Over 50 treatment centers in some 20 countries will probably take part. Fractures and lumbar BMD will be the endpoints.

THE TOPAZ TRIAL (TERIPARATIDE AND ZOLENDRONATE)

The TOPaZ trial is currently underway, and Stuart Ralston gave us an update. This trial studies the combined effect of parathyroid hormone (teriparatide) followed by zoledronic acid (zoledronate), both of which have shown to be effective. It is hoped that the gain achieved by teriparatide can be maintained by zoledronate. TOPaZ is one of the largest trials in OI to date, 350 participants were recruited at 29 sites (25 in the UK) and 1:1 divided between a therapy arm of 175 people who get 2 years of teriparatide followed by 0 – 6 years of zoledronate, and a control group of 175 people who get 2-8 years of standard of care therapy of any kind, (except for anabolic drugs).

The study was hindered initially by a lack of funding for the teriparatide and then by the COVID pandemic but still managed to recruit enough patients in the end. The primary endpoint will be the number of patients with new fractures confirmed by imaging. Secondary endpoints will be the total number of confirmed new fractures, the number of patient-reported fractures, bone pain, health related quality of life, BMD and side effects. The results are expected to become available by July 2025.

THE MOI-A TRIAL (REPURPOSING OF LOSARTAN)

The next clinical trial was the MOI-A trial presented by Nick Bishop. TGF-β is a substance present around the cells in what is called the extracellular matrix. It can bind to the surface of various cells that then respond to it, for instance by breaking down bone. But it also functions in other tissues in the body such as muscles. In OI TGF-β is overactive. An antibody to TGF-β called Fresolimumab was shown to improve the bones of OI mice, especially at low dosage.

A first study in people also seems to indicate this but only included very few people. As Fresolimumab was not available to the researchers an alternative inhibitor of TGF-β was sought and found in Losartan. This is a blood pressure drug that has been on the market for many years. MOI-A is part of the REMEDi4ALL project that aims to repurpose drugs. A study has been designed in which 30 people will receive Losartan, things like safety, bone turnover, TGF-β levels, pain, fatigue, muscle power, well-being and BMD will be endpoints in this study.

BOOSTB4 (STEM CELLS)

A very different trial is the BOOSTB4 Phase I/II trial where healthy mesenchymal stem cells (MSCs) are used to try to improve the outcome in children with severe forms of OI. Cecilia Götherström presented this work. MSCs are harvested and cultured in a medium and then injected in the blood. When they reach the bone, they engraft and give rise to cells that produce normal collagen.

Three groups were compared. In the postnatal group 15 children were given 4 doses of MSCs at 4-month intervals after birth. In the prenatal group 3 children received the first dose already in the womb and the 3 further doses after birth at 4-month intervals. The third group are the controls. Patients came from 7 countries and travelled to Sweden for stem cell therapy, the follow up period is 10 years. 70 of the 72 stem cell treatments have been given now. No safety issues have been encountered. The first preliminary results show a 76% reduction in fracture rate. Next step will be (fundraising for) a pivotal clinical trial to prove efficacy.

STUDY PROPOSAL

Where most trials focus on the more common forms of OI and exclude the rare ones, Heike Hoyer-Kuhn presented a study proposal to look at the possibility to treat the very rare OI type XV with romosozumab. OI type XV is caused by mutations in the WNT1 gene that disturb the function of the osteoblast. Treatment with a drug like romosozumab that stimulates the osteoblast function could thus make sense.

LANGUAGE DISCRIMINATION IN CROSS BORDER CLINICAL TRIALS

The final presentation was not on an OI specific clinical trial, but rather asked attention for the problem that sometimes the ability to speak a certain language is part of the inclusion criteria for a clinical trial. This is discriminating and unethical. Especially in the case of rare diseases larger studies can only be done when they are international. Things like travel from abroad and long stays can be further obstacles while patients can sometimes really benefit from taking part in a study. Begonya Nafria presented on a project that aims to come up with recommendations on how to fight language discrimination in cross border clinical trials.

This article has first been published in OIFE Magazine 1-2025