Prolia ( Denosumab ) binds to RANKL, a transmembrane or soluble protein essential for the formation, function, andsurvival of osteoclasts, the cells responsible for bone resorption.
Prolia prevents RANKL from activatingits receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL /RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption andincreasing bone mass and strength in both cortical and trabecular bone.
The target population for osteoporosis treatment or prevention is postmenopausal women who might use this therapy for many years, including subjects who may have an impaired immune system function due to age, comorbid conditions, or concomitant medications. It is biologically plausible that the RANKL inhibitor Denosumab could increase the risk of infection as RANKL is expressed on activated T and B lymphocytes and in the lymph nodes and T and B lymphocytes are responsible for foreign antigen recognition.
Pharmacology/toxicology studies have raised some questions about immune suppression. However, Study 20010124 ( Phase 1 ) and Study 20010223 ( Phase 2 ) examined T & B cell counts and natural killer cells, white blood cell and lymphocyte counts. These studies did not identify any clinically significant changes in these parameters.
The overall incidence of serious adverse events ( SAEs ) of infection in the Primary PMO studies was higher in Denosumab than placebo subjects with 4.4% of Denosumab and 3.6% of placebo subjects developing a serious infection during the Primary PMO trials. There was no difference in the number of overall infections ( serious + non-serious adverse events ).
Opportunistic infections were not more common in the Denosumab group.
When serious adverse events were examined in detail, infections related to bacteria and unspecified pathogens occurred at higher incidence in Denosumab subjects compared with placebo. Specifically, serious bacterial infections occurred in 0.7% of Denosumab subjects as compared to 0.4% of placebo subjects and serious infections due to an unspecified pathogen occurred in 3.7% of Denosumab subjects and 3.1% of placebo subjects.
Denosumab subjects appeared to have a higher incidence of bacterial, streptococcal, abdominal, ear, and urinary tract infections.
As Denosumab may be used in an elderly population with a waning immune system, events of infection were reviewed by age groups of greater than or equal to 75 years and greater than or equal to 80 years.
A review of AEs and SAEs of infection in older subjects did not identify any unusual trends in regards to infection.
Infections of particular concern are: pneumonia, endocarditis, serious skin infections, gastrointestinal infections, urinary tract infections, infective arthritis, ear infections.
No carcinogenicity studies were performed due to lack of an appropriate animal model because Denosumab is not pharmacologically active in rodent species.
When individual studies of subjects with osteoporosis and low bone mass were reviewed, an imbalance in the number of Denosumab subjects developing a new malignancy was noted. In particular, 3 subjects from the dose-finding Study 20010223 in the Denosumab 100 mg Q6 months cohort died of a new malignancy.
The incidence of malignant female reproductive neoplasms in Denosumab subjects was 2-fold higher than placebo ( 21 vs. 9 subjects ); malignant gastrointestinal neoplasms were also reported more frequently in Denosumab subjects ( 35 vs. 24 ); malignant breast neoplasms were slightly more frequent in Denosumab subjects ( 35 vs. 30 ).
Although not commonly reported, malignant endocrine neoplasms were reported for Denosumab at a rate that was greater than 3-fold higher than placebo ( 7 vs. 2 ).
There were 3 Denosumab subjects who developed haematopoietic neoplasms, while none occurred in the placebo group.
The only malignancy that occurred more often in the placebo group was malignant respiratory neoplasms, at a rate of 15 Denosumab and 24 placebo subjects.
In summary, several malignancies occur at a higher incidence in Denosumab subjects. The finding of an increased incidence of certain gastrointestinal, reproductive and endocrine malignancies is important to the benefit-risk assessment for this product, particularly for the osteoporosis prevention indication.
Dermatologic adverse events
Analysis for skin and soft tissue disorder includes data from two pivotal studies ( 20030216 and 20040132 ) for postmenopausal women. Subjects with malignancy on hormone ablative therapies may have different background skin conditions. Therefore, this analysis does not include the hormone ablation therapy population.
There were a total of 7534 subjects ( 3769 in placebo and 3765 in Denosumab [ Prolia ] ) in the combined safety population of subjects who received greater than 1 dose of an investigational product.
There were more subjects in the Denosumab group ( 616, 16% ) with adverse events related to skin and soft tissue disorders compared to placebo ( 507, 13% ) This imbalance was mainly due to imbalance observed in Dermal and Epidermal conditions ( 450 vs. 343 events in placebo vs. Denosumab ).
Overall, subjects in the Denosumab group were more likely to develop skin and soft tissue related adverse events. There were more bullous conditions, photosensitivity conditions, pruritic conditions, skin rashes, dermatitis and eczema related adverse events in the Denosumab group compared to placebo.
Source: FDA, 2009