In OIFE Magazine 2-2021 we published an interview with Brendan Lee, M.D. Ph.D., Baylor College of Medicine, Houston, Texas about research on the potential therapy Fresolimumab (TGFb).

Who are you and what is your relationship to OI?

I am a pediatrician and clinical geneticist who has engaged in basic, translational, and clinical research in skeletal dysplasias for over 25 years. Our group has been focused in identifying the first recessively inherited OI genes, understanding how mutations in these genes cause OI using cell and mouse models, and testing new therapies in OI as part of the National Institutes of Health (NIH) Brittle Bone Disorders Consortium (BBDC). The OI Foundation (OIF) has been a primary partner in all these activities. I have had the honor of serving on the OIF Medical Advisory Committee as well as chairing previous research meetings of the OIF.

Can you tell us about the research project on Fresolimumab?

The project’s goal was to identify common mechanisms of how mutations in collagen and collagen processing enzymes cause brittle bone and then translate this into a potential “targeted” therapy more effective in OI. We hypothesized a therapy focused on the underlying changes in OI might be more beneficial, than therapies that only increase bone mass. We discovered that an important growth factor called TGFb (beta) is elevated in OI bones and that by reducing this level, we may have beneficial effects not only in OI bones but also soft tissues like the lung.

Who came up with the idea and when did it start?

The idea came to us when we observed a lung picture in an OI mouse model that was reminiscent of other situations where TGFb was elevated. We then went on to test this in OI mouse models (COL1A2 mouse model and the CRTAP mouse model). We have now moved this preclinical study into a clinical trial as part of the BBDC, studying the safety of an anti-TGFb antibody called Fresolimumab. The aim of the study is to test the safety of Fresolimumab in OI type III and IV patients. We are also studying the effects on bone and other tissues. The antibody has been studied by Sanofi (and previously Genzyme) as a treatment of cancer and fibrotic disease. We are using it at a much lower interval than previous studies as bone turns over more slowly than soft tissues and cancers. This increases the safety profile of the drug.

Screenshot from dr. Nagamani’s presentation at OIF Investigator Meeting

And how is it progressing?

The study is in two parts. The first part or stage A is a single dose study. We have completed that, and we are now in the second part which is Stage B. Here we are doing repeated injections either every 3 or 6 months. We follow bone mass by DEXA scan and safety measures. In Stage B, we will also evaluate quality of life, mobility and pulmonary function. We are about to submit the paper describing Stage A results. The drug has had significant effects on increasing bone mass in some but not all patients even after a single dose at the 3 and 6 month time points. This was a very impressive result. It was also very well tolerated.

We have now recruited subjects for Stage B, the repeated dose study. Unfortunately, COVID19 has affected our ability to recruit as patients have not been able to safely travel as needed for the study. We hope the study will encourage companies like Sanofi to pursue clinical studies of efficacy (or phase 3 studies) that may lead to FDA or EMA approval.

Who is sponsoring the project?

The study is sponsored by the National Institutes of Health first as research grants to my group for the preclinical study and now as part of the Brittle Bone Disorders Consortium (BBDC) of the Rare Diseases Clinical Research Network (RDCRN). Sanofi, who is the maker of the antibody used in our trial, donated the antibody to the study and provided data to help with our regulatory applications. They do not participate in the performance, design, or interpretation of the study. This is purely what we call an “Investigator-initiated study”. The OIF also supports the project as they support all the activities of the BBDC.

What is the difference between Fresolimumab and other antibodies being investigated in OI?

Fresolimumab blocks the growth factor TGFb. Setrusumab and romozosumab blocks another protein call sclerostin. There are many different antibodies that each block specific proteins. Denosumab is another antibody that blocks RANKL, a growth factor that stimulates bone resorbing cells. This is also being studied in OI.