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Posts: 160
Reply with quote  #1 
I was waiting for this to be available because I thought it would be safer than Zometa (not that my insurance would approve it-)
But it seems there are questions about safety here as well---not the least that would give me pause is this........
"Pooled data from all the postmenopausal osteoporosis trials suggested "a slightly increased incidence" of breast, pancreatic, gastrointestinal, and reproductive-tract tumors."

From MedPage Today:
FDA Questions Denosumab Safety in Advisory Meeting Documents
By John Gever, Senior Editor, MedPage Today
Published: August 11, 2009

FDA staff has expressed 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 believes the drug -- provisionally trade-named Prolia -- could delay fracture healing as well. Some evidence suggests it could also promote tumor development and progression.

The concerns were revealed in briefing documents released in advance of a Thursday meeting of the agency's Advisory Committee for Reproductive Health Drugs, which will consider whether to recommend denosumab for approval.

Denosumab is a monoclonal antibody to RANKL, the receptor activator of nuclear factor-?B ligand. The molecule appears to help drive osteoclast development and activation, as well as playing a vital role in the body's defenses against infection.

If NF-?B is the immune system's "master switch," as it has been called -- controlling B- and T-cell differentiation and dendritic cell development -- then RANKL is the finger that flips the switch.

The drug's manufacturer, Amgen, 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 for prostate cancer.

Just this week, 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 as the best bisphosphonate drugs for osteoporosis.

The studies included more than 7,800 postmenopausal women with osteoporosis and close to 1,500 men with prostate cancer.

They also reported no indications of increased rates of serious infections, cancers, or most other serious adverse events, except for an increased incidence of eczema. (See Denosumab a Winner in Phase III Osteoporosis Trials)

The drug also boasts 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 pooling data from the clinical studies in postmenopausal osteoporosis submitted by Amgen (including phase I and II trials), agency staff 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.

Certain data also indicated that denosumab may produce unhealthy changes in bone structure, the review found.

According to the briefing document, both osteoclasts and osteoblasts 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.

And, 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 agency is not bound to follow its advisory committee's recommendations, but it usually does.


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Goddess Forever
Posts: 2,525
Reply with quote  #2 
Thanks for posting this, I was hoping for more safety on this one too.

~ There are lies, damned lies and statistics ~

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Posts: 7,476
Reply with quote  #3 
Thank you for posting this.
Muffy, my insurance covers the Zometa as Reclast...
Zometa is 4mgs and Reclast is 5 mgs
My onc gives me the Zometa every six months and because I am medium level osteopenic (can't spell tonight) insurance covers it as bone builder.




Chief of Research
Posts: 1,129
Reply with quote  #4 

Denosumab Still in  the Running



As I always say: No  so fast!


After  reviewing safety and efficacy data from 30 clinical studies (12,000+ patients), the FDA Advisory Committee for Reproductive Health Drugs (ACRHD) unanimously recommended approval of denosumab (Prolia) for the treatment of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer, although the panelists suggested that the drug be only used by patients who face the greatest risk of fractures.  In addition, , the panel ruled against using the drug as a preventive measure for women with low bone density.


But in a separate 12-3 vote the FDA ACRHD voted against approval for the treatment or prevention of bone loss in women with breast cancer undergoing hormone ablation until additional safety data are available, based on  three deaths in the dose-finding trial due new malignancies, which the Committee viewed as at least suggesting some potential for tumor progression in patients with (pre)existing cancer (specific carcinogenicity studies could not be performed, as denosumab is not active in any rodent species).


But in fact, things are not so clear re the issue of safety in breast cancer populations, and it appears the reporting media did not critically review  the FDA ACRHD report and findings themselves (which I did). So several things have been missed in the popular media reporting on denosumab. 


First, on the very same day as  the FDA ACRHD report was published, two of the registration trials, both RCTs, for denosumab were also published in the New England Journal of Medicine / NEJM (early online release). And in 7800+ postmenopausal women there was no increased rate of malignancies, nor of serious infections or most other serious adverse events. 


Second, note that the three deaths cited by the ACRHD were among 12,000 treated patients, and that furthermore, it is important to note that despite these, deaths were no more frequent in the denosumab groups versus placebo in any of the trials.


Finally, and most  critically, the deaths were exclusively in individuals who received 100-mg dosing, whereas 60 mg was used in all the more robust phase III studies none of which raised any adverse safety signals, and I am absolutely  confidant that 60mg will be the recommended dose upon approval, and that Amgen will not even seek approval for the 100mg dosing that the FDA committee has voiced its concern about. 


Amazingly, and regrettably, all  this was missed  in  any reporting, popular or professional, so at this  juncture, it appears to me that the FDA, which is not obligated to follow any guidance issued by the Advisory Committee for Reproductive Health Drugs (ACRHD), will turn over the safety evaluation of denosumab to the more mature Oncologic Drugs Advisory Committee (ODAC), and given the methodological problems I discussed above that were exhibited in, and hence compromise, the ACRHD  report,  I still am anticipating positive FDA approval in October.


Constantine Kaniklidis

Breast Cancer Watch

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