Just revealed in briefing documents which were released in advance of a scheduled Thursday meeting of the FDA’s Advisory Committee for Reproductive Health Drugs, which will be considering whether to recommend denosumab for approval, are significant concerns that denosumab, the investigational biologic drug for osteoporosis, may increase risk of serious infections through its activity against an important immune system modulator.
The agency has also expressed concerns that the drug, provisionally trade-named Prolia, could delay fracture healing as well as increase the risk for infections. In addition, the the even worse news is that there is some evidence that suggests that Prolia could also promote tumor development and cancer progression.
Denosumab is a monoclonal antibody to RANKL, the receptor activator of nuclear factor-B ligand. The molecule appears to help drive osteoclast (the cells that normally re-absorb bone) development and activation, as well as playing a vital role in the body’s defenses against infection.
Amgen, the manufacture of Prolia, filed last December for FDA approval of denosumab for preventing and treating osteoporosis in postmenopausal women, in women undergoing hormone ablation for breast cancer, and in men on androgen-deprivation therapy to treat prostate cancer.
There has been much discussion that denosumab is actually superior to the current standard of care, Zometa. Two of the registration trials for denosumab were published by the New England Journal of Medicine as early online releases. Those randomized, placebo-controlled studies showed that the drug was as effective and could be the best bisphosphonate drug for osteoporosis.
The studies included more than 7,800 postmenopausal women with osteoporosis and close to 1,500 men with prostate cancer.
Amgen also reported no indications of increased rates of serious infections, cancers, or most other serious adverse events, except for an increased incidence of eczema. The drug also has an extremely convenient dosing regimen — subcutaneous injection every six months. Many clinicians believe this is a big advantage for denosumab, considering that compliance with daily oral medications for osteoporosis is notoriously poor.
But the drug’s risk profile, especially with regard to infections and cancers in women being treated for postmenopausal osteoporosis, appears to be the FDA’s chief concern going into the advisory committee meeting.
After reviewing the pooled data from the clinical studies in postmenopausal osteoporosis submitted by Amgen (including phase I and II trials), the FDA found hints of potential problems. “Overall, subjects in the denosumab group had a slightly increased incidence of serious infections,” according to the briefing document. “There were more serious infections of the skin, ear, abdominal system and urinary tract. Also, endocarditis, infected arthritis and skin ulcers occurred more commonly in denosumab subjects. There were three denosumab subjects in phase I studies who developed pneumonia requiring hospitalization following a single dose of denosumab.”
The document also noted that while Amgen did not perform carcinogenicity studies in animals because denosumab is not active in normal mice or rats, the clinical data showed a modest increase in certain malignancies in the human subjects. “Three subjects receiving a high dose of denosumab in