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

[a] dose-finding study died of a new malignancy,” the staff review found. Those individuals received 100-mg doses, whereas 60 mg was used in the phase III studies and would likely be the recommended dose upon approval.

Pooled data from all the postmenopausal osteoporosis trials suggested “a slightly increased incidence” of breast, pancreatic, gastrointestinal, and reproductive-tract tumors. Twice as many women discontinued denosumab versus placebo because of breast cancer, the reviewers noted — 0.5% (20 cases) of patients receiving denosumab versus 0.3% (10 cases) of the placebo group.

The review found certain data thAT indicated that denosumab may produce unhealthy changes in bone structure.
According to the briefing document, both osteoclasts (cells that normally re-absorb bone) and osteoblasts (cells that normally recreate new bone) were suppressed relative to patients taking placebo and alendronate. Markers of bone dynamics such as activation frequency, bone formation rates, and mineralizing surface were also much lower in denosumab-treated patients.

This raises a concern that with long term use, suppression of bone remodeling may lead to complications such as delayed fracture healing, osteonecrosis of the jaw, or atypical fracture,” the document said.

Neither of the two New England Journal of Medicine reports this week, however, gave any indication of clinical bone problems associated with denosumab. Authors of those studies said they found no signs of delayed bone healing after fracture and there were no cases of jaw osteonecrosis, a rare but frightening side effect of bisphosphonate drugs. The FDA document confirmed that no actual cases of jaw osteonecrosis were seen in any of the osteoporosis or hormone ablation trials.

But one case was reported in another trial sponsored by Amgen in patients with multiple myeloma and metastatic cancer. Also, the clinical data alleviated concerns about possible adverse cardiovascular events, such as promotion of atherosclerosis, that were hypothesized on the basis of its anti-RANKL mechanism.

Deaths were no more frequent in denosumab groups versus placebo in the trials.

In light of the safety worries that still remain with the drug, the advisory committee will be asked to comment on whether a risk evaluation and mitigation strategy should be required as a condition of denosumab’s approval. The FDA is not bound to follow its advisory committee’s recommendations, but it usually does.

This is very disappointing news as many of us thought that denosumab would be both easily approved by the FDA and would also prove itself to be a much better drug than Zometa.

Joel T Nowak, M.A., M.S.W.