Prempro Osteoporosis Use In Older Women May Be Limited To Second-Line

Wyeth is considering revising Prempro 's indication to more clearly define the hormone therapy as second-line osteoporosis prevention for older women.

"We're actually discussing the possibility of requiring that other agents actually be used first" in older women, Senior VP-Clinical Research Joseph Camardo, MD, told an FDA advisory committee Oct. 7. Wyeth is considering the change based on the Women's Health Initiative Memory Study, which showed twice the rate of dementia in older patients taking Prempro (¹ (Also see "Wyeth Prempro Gets Dementia Warning; FDA Considering HRT Class Labeling" - Pink Sheet, 2 Jun, 2003.), p. 21).

"In the older women, there seems to be a different risk/benefit implied by the results of that study," Camardo said. "So we're discussing actually in that case maybe we should" make the recommendation to consider other agents "a little bit stronger."

FDA convened the meeting to discuss the implications of the Women's Health Initiative study for the use of estrogen/progestin hormone therapy for the prevention and treatment of postmenopausal osteoporosis (see ² (Also see "Hormone Therapy Osteoporosis Approval Hurdle Unchanged By WHI, FDA Says" - Pink Sheet, 13 Oct, 2003.)).

The current osteoporosis indication for Prempro and Premarin , which was revised based on the safety findings in the Women's Health Initiative, walks a fine line between recommending first-line use and suggesting that patients initially fail on non-estrogen products (³ (Also see "Hormone Therapy Class Labeling Uses Wyeth Template; Appeals Due By March" - Pink Sheet, 13 Jan, 2003.), p. 21).

"When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medicines should be carefully considered," the indication says.

FDA Division of Metabolic & Endocrine Drug Products Director David Orloff, MD, said that, while the agency "hedged" the revised indication, it interprets the label change as essentially limiting hormone therapy to second-line use for osteoporosis.

"The way we've structured these indications falls short of using the term 'second-line therapy,' but logic directs that the intent here is that the only primary indication for the use of this product at this point is for...vasomotor symptoms," Orloff said.

Wyeth's Camardo presented a slightly different interpretation, saying that the phrasing is "just short of requiring that an alternative agent be tried and shown to fail."

"We thought about it...and came to the conclusion that there are some cases where it wouldn't really make sense for us to recommend that another product be tried and failed first," Camardo said. "We thought it was sufficient to recommend choosing among the options...which is usually not said about products, it's assumed."

Wyeth's consideration of changing the indication for older women is in keeping with the company's post-WHI message that the use of hormone therapy should not assume that all patient subgroups have the same benefit/risk profiles.

"Practitioners really do need to determine the use of hormone therapy for an individual based on all the evidence available and the goal of treatment," Camardo told the advisory committee.

"The decision to use estrogen/progestin for osteoporosis and menopause, particularly in younger women, cannot just be based on the WHI study," he maintained.

While WHI was designed to assess the potential risks and benefits of long-term use of Prempro therapy, "it wasn't really designed to answer a question that physicians face all the time, which is how to use estrogen/progestin in women closer to menopause who have bone loss," Camardo argued.

The absence of prospective data from WHI on the risks of estrogen/progestin use in younger women during the early years after menopause should refer the decision back to the individual patient and her physician, he said.

In Wyeth's HOPE study, and other menopause studies of estrogen/progestin, the women were within five years of menopause, he noted. "That's because you try to enroll women in the study in whom we can demonstrate a benefit on vasomotor symptoms." The HOPE study group "is approximately 10 years younger than the average age of the WHI population," 53 years old versus 63 years old.

Wyeth's argument was challenged by WHI Acting Director Jacques Rossouw, MD. "The data that we have in WHI is actually the best data available at this point," even for the younger, symptomatic patient population, he maintained.

"If we are focusing on the younger patient who is symptomatic, to fall back and say we don't really have good data in that group, and we're still back to the 'seat of the pants' clinical judgment, is an unsatisfactory situation," Rossouw said.

Wyeth comments offer a glimpse into the company's view of WHI and how the company may be positioning Prempro against other osteoporosis agents.

Camardo maintained that since there are a "handful" of available therapies with various risk profiles, a "variety of therapies is essential to assure that treatments can be tailored to the individual woman."

For example, bisphosphonates (Merck's Fosamax , Aventis/Procter & Gamble's Actonel and Roche/ GSK's Boniva ), have "limited data in non-osteoporotic women" and some gastrointestinal side effects, he said.

Lilly's selective estrogen receptor modulator Evista "has been shown to prevent hip fracture" and cause hot flushes in 20% of women, "so it's really not an appropriate therapy for women with menopausal symptoms," Camardo maintained.

The WHI data confirmed Prempro's efficacy in increasing bone mineral density and demonstrated an ability to reduce non-vertebral fractures, even in women who do not yet have osteoporosis.

WHI's Jane Cauley, University of Pittsburgh, gave an update of the osteoporosis data based on 5.6 years of follow-up (versus 5.2 years in the original report). The fracture results were published in the Oct. 1 issue of the Journal of the American Medical Association.

WHI found "consistently higher bone mineral density measurements" in the Prempro group, so that after three years of treatment, the lumbar spine increased over 6.5% in the estrogen/progestin group, compared to about 1.2% in the placebo group.

There was a somewhat smaller difference in BMD at the hip.

In fracture risk, the updated WHI data showed a 24% reduction in the risk of total fractures in patients taking Prempro, a 35% reduction in hip fractures, a 28% reduction in wrist and lower arm fractures and a 31% reduction in clinical vertebral fractures.

All age groups favored estrogen/progestin, and "there was no evidence that the effect of E+P on fracture differed across age group," Cauley said. WHI also found no differences across several other subgroup analyses.

Prempro reduced fractures equally well in women at low risk of fracture and in those at high risk. In addition, the risk of total fractures did not vary between women with and without prior hormone therapy use.

Cauley confirmed WHI's initial conclusions that despite a benefit in bone mineral density and fracture risk, estrogen/progestin therapy "cannot be recommended for the prevention or the treatment of osteoporosis in asymptomatic women."

"Before the combination of estrogen and progestin is considered for the purpose of fracture prevention, women should be fully informed about the potential adverse effects," she concluded.

Chairman Michael McClung, MD, Oregon Osteoporosis Center, noted that because of WHI, the risk-benefit profile of estrogen therapies is better known than it is for other osteoporosis therapies.

"No other osteoporosis non-estrogen alternative, be it a SERM or bisphosphonate, has that kind of information," McClung noted. "And so while we are more confident about the risks associated with longer-term estrogen use, I personally am less confident about the risk profile of long-term use of these other agents."

Most committee members agreed with FDA's labeling changes as they relate to osteoporosis prevention.

Noting that WHI was not prospectively designed as an osteoporosis study, committee consultant Henry Bone, MD, Michigan Bone & Mineral Clinic, said that FDA "has done a good job of incorporating this information...into the current labeling."

"It's going to be difficult to improve on this very much without having more precise estimates...that we would derive in a purpose-built trial," Bone said. "I think we're getting to the point where we're pushing it pretty hard to say more than what has been said, with the possibility of some nuances."