Clinical trial: Investigating Denosumab in children with OI

Interview with Dr. Jörg Oliver Semler, Paediatrician, OIFE Medical Advisory Board (MAB)

How did the project of investigating denosumab in children start?

Regarding the use of denosumab in OI there are a few projects which have to be separated. At the beginning there were a few case studies and a small clinical trial which was performed in Cologne on our own initiative due to scientific interest. Some years later the pharma company Amgen initiated an international multicenter trial with the aim to approve denosumab for the treatment of children with OI.

In 2012 we realized that our usually used bisphosphonate treatment was not effective in 4 of our children. Bone resorption markers in the urine responded not in the same way as in other children. Therefore, we tried to find the reason and did genetic testing, elucidating the genetic cause of OI type VI. In this special group of patients an increased bone resorption and not an impaired production of collagen is the reason of the fragile bones. After looking more detailed into the pathophysiology we decided that the osteoclastic antibody denosumab would be a suitable treatment and might be more effective than bisphosphonates. That’s why we treated those patients with denosumab and the patients had a benefit compared to the previous bisphosphonate treatment.

Denosumab is an antibody which inactivates osteoclast directly compared to bisphosphonates, which bind to the bone and get effective only after being resorbed by osteoclasts. Both agents lead to a reduced bone resorption but denosumab will vanish (degrade) after some months and can be administered directly under the skin. After we had seen that denosumab is effective in OI type 6 we did a small trial in 10 patients with “normal OI” and showed that the treatment was a bit more effective than bisphosphonates during 1 year of treatment. This trial aimed to assess the safety of denosumab and therefore the trial was not blinded or randomized. The trial was sponsored by a funding of 300.000 € by the medical faculty Cologne. The results have been published in a medical scientific journal.

What happened next?

After we had shown that denosumab was safe in 10 children with classical OI the pharma company “Amgen” decided to do a big trial to get denosumab approved in children with OI. They performed an international, multicenter, non blinded clinical trial in 130 OI-children, 2-18 years of age and they treated the children 3 years with denosumab. Because no other drug is approved in OI they had not to do a blinded or a placebo controlled trial because there is no official alternative treatment. The children received denosumab every 6 months and no bisphosphonates in addition. Primary outcome was bone mineral density measured with DXA at the lumbar spine. The trial was sponsored by the pharmaceutical company Amgen. After patients completed the 3 year study, they were given the possibility to enroll in an extension trial where treatment with denosumab will be continued. This extension trial will probably be continued till a decision about the approval of denosumab for the treatment of children with OI will be made by the FDA/EMA. Currently there are some patients who have already completed the 3 years of the “main study” and have already enrolled in the “extension study” and other patients are still treated in the main study, because they have not completed the first 3 years.

Did you have patient involvement in the project?

In our first small clinical trial the German OI society was involved in the planning of the trial. Regarding the Amgen sponsored trials (ongoing trail and extension trial) there was not much contact between the company and the patient organizations. OIF and OIFE have been informed about the trial but were not involved in the planning. But from a company’s point of view the most important questions regarding study design and treatment were raised by the authorities (FDA) and they requested to take bone density (DXA) as primary outcome parameter.

What has been the findings so far?

As mentioned above our small trial showed a higher increase of bone mineral density during one year of treatment compared to bisphosphonates. As complication we saw severe fluctuations of the calcium levels in the blood during and after treatment with denosumab. During the first few weeks after injection it is necessary to take additional calcium. In contrast at the end of the treatment period bone resorption increases and calcium is extracted from the bone and is high in blood and urine. What the clinical consequences of this fluctuation calcium levels will be has to be followed up in the future. At the moment no results of the international trial sponsored by Amgen are available because not all patients have completed the 3 years of treatment and an analysis will only be performed at the end.

And what about adults?

In adults no trials about the effect of denosumab are currently performed to my knowledge. From adults with osteoporosis we know a good effect on bone mineral density during treatment. We also know about relevant problems after pausing or ending the treatment. An increased “rebound” bone resorption has been reported, leading to new vertebral fractures. If this is the same in adults with OI and how severe this rebound is, when it will start and how it could be prevented has not been investigated at the moment. In children treated with denosumab due to other bone diseases a severe rebound has been reported in the literature.

Clinical studies in adults with OI and denosumab are definitely needed but nobody is performing these at the moment because they are highly expensive and difficult to perform. Benefits of a treatment with denosumab for adults might be an easier administration (injection under the skin versus intravenously) and the degradation after some months reducing the hypothetical risk of long term side effects.

What is the most important take home message for clinical work?

Currently we have no proof that denosumab is better than bisphosphonates and special concerns exist regarding the rebound after ending the treatment. Therefore, I cannot recommend using denosumab outside a clinical trial at the moment.

Any other messages for the readers of OIFE Magazine?

In case you or your child receive denosumab outside a clinical trial I would highly recommend checking the calcium levels in blood and in urine regularly because this parameter is influenced the most. Before results from the Amgen trial are available no additional children should be treated with denosumab, because we do not understand the effect of the drug completely. On the other side these trials are the only possibility to investigate new drugs and to improve treatment of people with OI in the future.