Aprela® — the making of a new pregnant mare’s urine drug

Part 1 of a Special Report by Jane Allin

October 3, 2013 looms as the harbinger of foreboding news for PMU mares and their foals.

This is the day that the U.S. Food and Drug Administration (FDA) will make a decision whether or not to approve Ligand Pharmaceutical’s dual-acting drug Aprela® for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis in women who have not undergone a hysterectomy. The drug was developed by Ligand in partnership with Pfizer.

Aprela® is a combination of Premarin® and bazedoxifene, a selective estrogen receptor modulator or SERM also known as Viviant®. Of particular note is that Viviant® has failed to receive approval from the FDA as a result of increased risks of stroke and thromboembolic events although it has been approved for use in other countries (i.e. EU and Japan) under different trade names. What’s more, Pfizer/Wyeth’s struggle to gain approval of Aprela® has been a long drawn-out process with introduction to the marketplace originally slated for 2008.

Some analysts have largely written off Aprela® primarily for safety reasons but also from an efficacy perspective relative to that of conventional HT (Premarin®). Both efficacy and safety were evaluated in multicenter, randomized, double-blind, placebo- and active-controlled, phase III studies referred to as the SMART trials.(1)  Despite the fact that Aprela® reduced the hot flash frequency and severity compared to the placebo, HT reduced  the incidence of these symptoms to a much greater extent.(2)

And, given that the drug is targeting the osteoporosis component as its marketing attribute, results from bone mineral density (BMD) measuring increases in lumbar spine and total hip BMD indicate that the combination of bazedoxifene (BZD) and conjugate equine estrogens (CEE) were significantly lower (~ 0.8% over baseline) than those observed for HT (~ 2.22% over baseline).(3)  Hence, in spite of the fact that Aprela® is more effective than a placebo, there is no advantage whatsoever over conventional HT which consistently shows a better efficacy profile for both menopausal systems and bone density. This is an interesting observation particularly since the dosage of CCEs in Aprela® is identical to that in Premarin®.

In any case, it is really not the efficacy that is of concern but more so the safety aspect and the continued abuse of the pregnant mares and their foals. Pfizer claims that preliminary, and very limited (1-year), studies of Aprela® have not shown to prove deleterious to the overall health of women in terms of carcinogenic effects. That said these studies are insufficient in evaluating longer-term safety effects of the combination drug. Specifically, the studies did not evaluate adverse events (AEs) such as cancers that occur relatively infrequently which are considered primary risk factors with conventional HT.(4)

Consequently, in addition to reduced efficacy compared to Premarin®, there is no guarantee that Aprela® provides a better long-term safety profile than standard HT.

One can only hope that the prediction of Dr. Hyun Ji Noh and Sophie Wang, two analysts from Beacon VP Investments, rings true:

“After reviewing Aprela’s clinical trial results and relevant scientific literature, we believe Aprela will fail to receive FDA approval and, consequently, Ligand’s stock will underperform in the near term….We believe that the FDA will likely continue applying stringent safety criteria to potential menopause drugs, leading us to conclude that Aprela is unlikely to obtain FDA approval.”(5)

While there may be those that disagree with this conjecture there are signs that the FDA is setting higher safety standards for therapies to treat menopausal symptoms.

“Recently, the FDA approved the first non-hormonal therapy, Brisdell, for the treatment of hot flashes. The approval was considered somewhat surprising given the poor efficacy of Brisdelle compared to HT. Overall, this suggests that the FDA prioritizes safety over efficacy in menopausal therapeutics, which further decreases the likelihood of Aprela being approved. In addition, Pfizer previously sought an extended label for its drug Pristiq to cover hot flashes, but received a complete response letter requesting additional studies on the safety of the drug. Generally, the FDA has set a high bar for safety of alternative menopausal therapy and, in our opinion, Aprela does not clear this bar.”(6)

Brisdelle™, manufactured by Noven Pharmaceuticals, is a low-dose (7.5 mg/day) version of paroxetine (paroxetine mesylate). This is in the same group of drugs such as Paxil (paroxetine hydrochloride) and Pexeva (paroxetine mesylate) – serotonin reuptake inhibitors (SSRIs) used to treat a number of psychiatric disorders but in higher doses than Brisdell™.(7) Noven also manufactures Pexeva™.

Two randomized, double-blind, placebo-controlled studies with a total population of 1,175 menopausal women experiencing moderate to severe hot flashes were used to evaluate the efficacy and safety of Brisdell™.(8) Briefly, the results show that Brisdell™ reduced both the frequency and severity of hot flashes compared to a placebo. The mechanism by which hiot flashes are reduced is unknown.
 
Brisdell™ carries with it the same risks and side effects as the higher-dosage anti-depressants but is well tolerated for the most part. Risks include; an increased risk of suicide in children and young adults, increased risk of bleeding in addition to serotonin syndrome (confusion, rapid heart rate, and high blood pressure).(9)

“The approval of Brisdelle™ is significant because it meaningfully expands the therapeutic options for the 24 million women in the U.S. affected by moderate to severe VMS, two-thirds of whom are not currently treating these often debilitating symptoms,” said Joel Lippman, M.D., FACOG, Noven’s Executive Vice President – Product Development and Chief Medical Officer. “Noven has long focused on developing and offering therapies to address women’s menopausal health concerns, and we are pleased to address the diverse needs of this population.” (10)

What is worthy of note about the FDA approval of Brisdell™ is that in June of 2012 Noven announced that it had submitted a NDA for low-dose mesylate salt of paroxetine (LDMP) to the FDA seeking approval for the treatment of vasomotor symptoms associated with menopause. Yet, on March 4, 2013, the FDA’s Reproductive Health Drugs Advisory Committee voted that the overall risk/benefit profiles of LDMP were not acceptable to support approval. The committee voted 7 to 7 that it was effective in treating moderate to severe VMS (vasomotor symptoms) associated with menopause however 10 to 4 that there was not sufficient evidence of its effectiveness to decrease the frequency of VMS events. Tuesday’s Horse covered this in an article in March 2013.(11)

This is the same drug now trademarked Brisdell™. Noven’s continued commitment to their product paid off.

“As conveyed during Noven’s presentation, we believe our clinical trial data support LDMP as a safe, effective nonhormonal treatment option offering clinical benefit to menopausal women,” said Joel S. Lippman, M.D., Noven’s Executive Vice President – Product Development and Chief Medical Officer. “While we are disappointed in today’s outcome, we appreciate the discussion and will work closely with the FDA as it completes its ongoing evaluation.”(12)

The FDA is not bound by the recommendations of its advisory committees, such that ongoing reviews of New Drug Applications (NDA) continue until the scheduled Prescription Drug User Fee Act (PDUFA) action date which was June 28, 2013 for LDMP, the same day the FDA granted approval. It is refreshing to see that the FDA chose to override the Reproductive Health Drugs Advisory Committee to provide a safe alternative to the ravages of conventional HT manufactured from CEEs.

Nonetheless there are those that continue to promote and defend the atrocities associated with the PMU industry – those who profit from the exploitation of both women and horses alike.

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Read PART 2 of this Special Report by JANE ALLIN, “And now a word from a PMU industry sponsor“, Friday, Sept. 27.

© Int’l Fund for Horses

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RELATED READING

Our Website

What is a PMU horse? Mares are kept pregnant cycle after cycle and “milked” for their estrogen rich urine to make drugs like Premarin® and Aprela®.

Millions of foals over the decades have been cast off by this industry, and sent to slaughter auctions. Many mares have met a similar fate when they could no longer get pregnant. But that is just the beginning of the story of this cycle of abuse and death.

— Find out more in our Fact Sheet >>

Tuesday’s Horse

— Read more here on Tuesday’s Horse about PMU Horses