Lilly's Forteo should be approved for treatment of osteoporosis in postmenopausal women but restricted either to high-risk patients or second-line use, FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended July 27.

Patients who may be considered for first-line teriparatide therapy comprise those "with very severe disease, or the patient who has a fracture who is at high risk for a second fracture in the near future," Acting Committee Chair Mark Molitch, MD, Northwestern University Medical School, said.

"I'm not sure that I would want to actually restrict [Forteo] to being a second-line therapy, although I think that's probably how I would use it for most patients," he added.

"I would be in favor of restricting it as a second-line drug because I think the efficacy and safety of the other first-line drugs is much better," committee member Deborah Grady, MD, University of California at San Francisco, commented.

While the panel unanimously voted for the approval of Forteo for the postmenopausal treatment indication based on efficacy, it was evenly split on whether to approve the injectable recombinant parathyroid hormone for increasing bone mineral density in osteoporotic men.

Out of the five (of 10) committee members who advocated approval in men, only two relegated the drug to first-line use, both with restrictions.

The committee's hesitation about the drug had to do primarily with risk-benefit considerations following a finding of dose-related osteosarcomas in a two-year rat carcinogenicity study; the finding led to the termination of Phase III trials for Forteo in December 1998.

In light of the risk, the committee questioned whether the results for men - which found BMD increases only in the lumbar spine and femoral neck, and not at other skeletal sites - were robust enough for approval. "I think with regard to men, I don't think we have enough clinical outcomes yet to conclude that it should be approved for that indication at this time," risk management consultant Eric Holmboe, MD, Yale University School of Medicine, said.

An FDA proposal to place a black box warning to communicate osteosarcoma concerns in labeling was met with mixed opinions from the committee; half of the committee preferred a bolded warning. The rodent finding "continues to trouble the FDA" the agency said in committee briefing materials.

However, the agency also stressed a clinical need for an anabolic, or bone-building, agent for osteoporosis. "There clearly is an unmet medical need for an anabolic agent," FDA medical reviewer Bruce Schneider, MD, told the committee.

"I think it's clear that we have taken the strategy of using anti-resorptive therapy...about as far as we could go...but our task now is to consider now whether in the case of teriparatide...the benefit-to-risk profile merits approval."

"The results of the pivotal controlled clinical trials...clearly established efficacy," Schneider continued. "Although we don't have head-to-head comparisons, it seems clear at least to me...that for both men and women the beneficial effects at the lumbar spine, including BMD effects and fracture prevention, appear to exceed those of any currently approved agent." In one study in women, Forteo produced a 12.2% increase in lumbar spine bone mineral density compared to 5.6% for Merck's Fosamax (alendronate).

The pivotal Phase III study in postmenopausal women treated 1,637 osteoporosis patients with placebo, 40 ug per day of Forteo, or 20 ug per day. Out of 105 patients with one or more vertebral fractures at the end of the study, 14.3% had received placebo, 5% Forteo 20 ug, and 4.4% Forteo 40 ug. For non-vertebral fractures, at least one occurred in 9.7% of placebo patients, 6.3% of patients in the 20 ug group, and 5.8% of patients in the 40 ug group.

Labeling should limit use to two years (the exposure time in trials) to enhance safety once Forteo is marketed, the committee agreed, and the drug should be contraindicated in more vulnerable populations such as children and Paget's disease patients (who are at higher risk for osteosarcoma).

The committee also urged rigorous postmarketing surveillance as well as additional studies in both animals and humans. The Forteo NDA was submitted in November 2000.

Lilly Forteo Osteoporosis Indication Approval Recommended With Restrictions

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