Home > Rheumatology > Anti-TGF-beta therapy promising in osteogenesis imperfecta

Anti-TGF-beta therapy promising in osteogenesis imperfecta

Journal of Clinical Investigation
Reuters Health - 24/02/2022 - In adults with osteogenesis imperfecta (OI), a single administration of fresolimumab, a pan-anti-TGF-beta neutralizing antibody, improved bone mass and turnover in a phase 1 study.

Currently, there is no specific therapy for OI.

"We were surprised by the size of the effect on bone mass in the spine of some of the patients with moderate OI," Dr. Brendan Lee of Baylor College of Medicine in Houston told Reuters Health by email. "As this was a phase 1a study that focused on evaluating safety, we did not expect dramatic changes in bone mass. In some of the subjects with moderately severe forms of OI, we saw increases of 6%-8% in bone density at the spine at three-to-six months after a single injection."

However, he noted, "This was not seen in all subjects and it will be important to perform follow up repeat studies to determine the range of effect."

"We would expect (fresolimumab) to also work in children, but we need to focus further on safety and side effects, as TGF-beta has different effects during development," he added. "However, we hope that because of the unique aspects of targeting the bone remodeling unit, the longer duration in between doses may improve safety."

Preclinical studies have shown that excessive TGF-b signaling is a driver of pathogenesis in OI, Dr. Lee and colleagues note in the Journal of Clinical Investigation. For the current study, they analyzed TGF-beta signaling in children with OI and translated this discovery by conducting a phase 1 trial of TGF-beta inhibition in adult patients.

First, they analyzed bone samples from 10 children with OI and four control children without OI using genetic technologies to identify key dysregulated pathways, and various assays to evaluate changes at the protein level.

SMAD phosphorylation was the most significantly upregulated gene ontology molecular event. Gene set enrichment analysis identified the TGF-pathway as the top activated signaling pathway in OI. Ingenuity pathway analysis showed that TGF-beta1 was the most significant activated upstream regulator mediating the global changes in OI bone.

Next, the team conducted the phase 1 study with a single administration of fresolimumab in eight adults (ages 25-55; about half, women) with moderate-severe OI. Half of the participants received a single 1mg/kg dose and half received a single 4 mg/kg dose.

With the 1mg/kg dose, two participants with OI type IV showed robust increases in lumbar spine areal bone mineral density (LS aBMD) at six months post-treatment.

In the 4 mg/kg cohort, LS aBMD was assessed at days 90 and 180. Two participants with OI type IV had robust increases in aBMD by day 90.

Overall, fresolimumab was well-tolerated and associated with increase in LS aBMD in participants with OI type IV, while those with more severe OI type III and VIII had unchanged or decreased LS aBMD.

"Anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover," the authors conclude.

Dr. Lee noted, "We are completing a pilot repeat dosing phase I study in the Brittle Bone Disorders Consortium of the NIH Rare Diseases Clinical Research Network. Sanofi, which provided the medication for our study, plans to build on our data to continue clinical development of this approach and if successful, it may lead to the first FDA-approved treatment for OI. Also, it may lead the way to targeting TGF-beta in bone for other genetic diseases."

Dr. Frank Rauch of McGill University and Shriners Hospital for Children in Montreal commented on the study in an email to Reuters Health, "The findings in bone samples from children with OI show for the first time that TGF-beta signaling is increased in the bone tissue of humans with OI. The paper also describes the first data on anti-TGF-beta antibody treatment in humans with OI."

However, he said, "This is a small phase 1 trial, so it is too early to judge whether the treatment has a clinically meaningful benefit. The data from this paper are the necessary first step towards larger studies that investigate the efficacy of this treatment."

"The potential concern with anti-TGF-beta treatment is that TGF-beta is expressed in many tissues," he added. "It is therefore theoretically possible that the treatment has 'off-target' effects. The initial results look promising with regard to safety, but more safety data are needed."

SOURCE: https://bit.ly/3JThNTO Journal of Clinical Investigation, online February 3, 2022.

By Marilynn Larkin

Posted on