8. Why does Clementia believe this drug may be effective for the treatment of MO? Research in a mouse model of MO (Multiple Osteochondromas) shows that palovarotene potently inhibits the formation of new
osteochondromas by decreasing signaling in the bone morphogenetic protein pathway (BMP pathway) in bone precursor cells. These
animals develop osteochondromas as they age, developing hundreds of osteochondromas on their ribs and limb bones by 6 weeks of age.
Treatment with palovarotene from a young age at doses equivalent to test doses in the MO‐Ped trial inhibited osteochondroma formation by 30-80% compared with mice not receiving palovarotene treatment. Additionally, Clementia has data from FOP (Fibrodysplasia Ossificans
Progressiva) patients treated with palovarotene that demonstrates substantial decreases in the amount of abnormal bone that is seen in
these FOP patients (up to 95% reduction in mean bone volume following flareup treatment). MO and FOP share the same disease process of excess bone morphogenetic protein signaling within cells resulting in chondrogenesis (cartilage formation) and further ossification (bone
formation). Together, these data showing efficacy in MO animals and FOP patients and the safety data from more than 800 human subjects who have been treated with palovarotene support the idea that palovarotene may be effective in patients with MO in the MO‐Ped Trial. As osteochondroma growth only occurs while the growth plate is active, palovarotene is likely only effective in preventing new OC formation and subsequent joint deformity, loss of function, need for surgery in pediatric MO patients. The objective of the MO‐Ped Trial is to assess palovarotene’s effect on osteochondroma formation, and these other related events that impact a subject’s physical function and
quality of life.
9. Do you expect any difference in palovarotene efficacy between males and females? No. While multiple studies have shown that male patients with MO tend to have more severe disease, it is not known why. The study is
designed in a way for us to determine if there is a difference in efficacy and safety between males and females.
10. Are there potential risks in administering palovarotene to children that are still growing? Experience with palovarotene from clinical trials in another rare bone disease, fibrodysplasia ossificans progressiva (FOP), has not shown
treatment‐related side effects on bone growth plates or height with weight‐adjusted doses of palovarotene and with higher doses (up to 20 mg) administered during episodes of soft tissue swelling (flareups). The MOPed Trial will include strict safety monitoring for any potential
skeletal effects associated with bone growth plates and linear growth.
The reason for caution is that the biological process by which palovarotene inhibits osteochondroma formation may also affect normal bone growth in children. Results from animal research showed that impaired growth may occur if palovarotene treatment is started at a very
young age. This effect is alleviated with lower doses or by beginning treatment at older ages.
The selection of ages for subjects in the MO-Ped Trial (2 to 14 years) takes into consideration the findings in animal models and provides an
optimal age range balancing the potential benefit of palovarotene treatment while minimizing potential risks. This targeted population,
coupled with the doses selected to be administered and the careful monitoring for potential adverse growth effects should help
minimize any potential risks.
All subjects will have X-rays of the hand/wrist area and knee along with linear and knee height measurements every 6 months to monitor
bone growth plate and growth. The growth of long bones of the legs (tibia and femur) will also be monitored. The bone thickness of the lumbar spine, hip and radius will be assRessed by dual X-ray absorptiometry (DXA) every 6 months. Dose modification or discontinuation
will be considered should adverse effects be identified.
11. Why is a placebo needed in the MO‐Ped Trial?
Our goal is to answer key questions about the true treatment effect of palovarotene for Multiple Osteochondromas (MO). It is by comparing
the efficacy and safety to a placebo group that we can carefully assess the efficacy and safety of the investigational drug. This is especially true for diseases where there have not been previous clinical trials to determine the natural course of disease progression. Therefore, the MO‐Ped Trial will be a “placebo‐ controlled, treatment‐ blind study”.