February 1, 2012
Marylyn Donahue, Special Projects Editor, Pharmaceutical Executive magazine
While going through menopause, I went to a weekly support group of 40 or so women, all of whom were at different points in their menopause—pre, post, and during. The women were treating their menopausal reactions in different ways—from trying to forget about it, to making changes in diet and exercise, to taking drugs or what was called hormone replacement therapies (HRT).
Hardly a clinical trial, our rag-tag group was, however, both invaluable and interesting. It offered support and an opportunity to hear and talk with other women who were going through the same phase in their lives. It was also a unique chance to see what methods worked for what women and how.
At the time, HRT was by far the preferred choice of treatment in the medial community. The drugs contained estrogen alone or a combination of estrogen with progesterone or progestin, a synthetic hormone with effects similar to those of progesterone. The women at the meeting were not so convinced. Some on the drugs experienced side effects as bad as their reactions to menopause; some did not, some didn't take drugs at all; some took just a low dose.
Many doctors, on the other hand, were so in favor of HRT for all menopausal women they suggested never going off them, (even after menopausal reactions such as hot flashes and mood changes stopped) pointing out the advantages of HRT in maintaining bone density.
(So enthusiastic about HRT, I even went to a new doctor in New York City who refused to treat me because I was not on HRT).
My concern at the time was in taking a drug for the rest of my life (or for however long) for a condition that was not an illness (menopause). And that there were not data at the time involving long-term risks.
Then in 2002, the tide turned when the results from a large government study, the Women's Health Initiative (WHI) were published. The WHI's large, randomized clinical trial included more than 16,000 healthy women, was sponsored by the National Institutes of Health (NIH), and raised serious safety issues in connection with HRT.
It remains today the best evidence of the risks and benefits of menopausal hormone replacement therapy. The trial showed that the overall risks of estrogen plus progestin outweigh the benefits. Among the risks observed after 5.6 years of follow-up were increased risks of breast cancer, heart disease, stroke and blood clots.
On March 1, 2004, after nearly seven years of follow-up, NIH stopped the estrogen-alone arm of the trial, concluding that estrogen alone does not appear to affect (either increase or decrease) heart disease, a key question of the study. But in addition, estrogen alone appeared to increase the risk of stroke and decrease the risk of hip fracture. No increase in breast cancer risk was observed during the study period.
One of the HRT drugs, PremPro, which Pfizer acquired with its purchase of Wyeth in 2009, was shown to increase risk of breast cancer. A similar drug, Premarin, has been tied to increased risk of uterine cancer, and both drugs have been linked to risks for stroke and certain blood clots. Pfizer has set aside more than $800 million to cover previous and potential settlements and judgments for lawsuits alleging injuries caused by hormone-replacement therapies.
Now Pfizer is preparing to seek U.S. regulatory approval to sell a new menopause drug that the company hopes could pose an alternative to their older problematic hormone-replacement therapies.
However, repeated delays in developing the new drug, Aprela, have raised questions about its potential. Some analysts and doctors question whether regulators will approve it, and Aprela's market potential could be limited by continued safety concerns about hormone-based drugs.
Earlier this month, health writer Peter Loftus at The Wall Street Journal interviewed Olivier Brandicourt, president and general manager of Pfizer's primary-care unit, who said the company expects to submit Aprela for Food and Drug Administration approval sometime this year, (see Loftus's story here: http://online.wsj.com/article/SB10001424052970204652904577193132452570386.html)
Brandicourt told Loftus that the drug has the potential to reduce menopausal symptoms such as hot flashes and to prevent bone-thinning osteoporosis, but with a better safety and tolerability profile than older hormone-replacement therapies.
Aprela contains an active ingredient found in the older drugs, known as conjugated estrogens, which are derived from the urine of pregnant horses. But Aprela combines conjugated estrogens in a single pill with another drug, bazedoxifene, which may mitigate the risks of conjugated estrogens alone.
Loftus points out that bazedoxifene is a selective estrogen receptor modulator, or SERM, the same category as Eli Lilly & Co.'s Evista, which is approved to prevent and treat osteoporosis. A SERM is designed to provide the benefits of estrogen while mitigating the negative effects of estrogen such as increased risk of uterine cancer. Pfizer, via Wyeth, licensed bazedoxifene from Ligand Pharmaceuticals Inc.
Aprela's development has taken longer than expected. The FDA declined several years ago to approve bazedoxifene as a stand-alone drug because regulators wanted more information about the incidence of strokes and certain blood clots in clinical testing.
"We think this is a market which is unsatisfied … and if you can bring a hormone therapy which doesn't have the traditional side effects, we can actually lead that marketplace," Brandicourt told reporters at a November meeting.
Adverse events among women taking Aprela in the clinical trial included back pain, headache, and inflammation of the nose and throat.
