Nine members of the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee have voted to recommend that the FDA pursue withdrawal of approval for hydroxyprogesterone caproate injection (Makena, AMAG Pharmaceuticals) for the prevention of preterm birth in pregnant women, while 7 of the committee’s members voted to leave the product under accelerated approval and to require a new confirmatory trial.1

Hydroxyprogesterone caproate injection is a progestin indicated to reduce the risk of preterm birth in women pregnant with a single baby who have a history of singleton spontaneous preterm birth.

However, the advisory board voted unanimously that the most recent AMAG Pharmaceutical Meis study showed no benefit.

The PROLONG trial evaluating the drug was conducted as part of the approval commitment under the FDA’s “Subpart H” accelerated approval process. It included 1700 pregnant women and found that hydroxyprogesterone caproate, the synthetic version of the hormone progesterone, was no more effective than placebo in preventing premature birth or reducing the resulting problem.2

Adverse events of special interest, including miscarriage and stillbirth, were infrequent and similar between the treatment and placebo groups.2

The injection was approved by the FDA in February 2011 based on the Meis trial, which concluded that weekly shots of hydroxyprogesterone resulted in a substantial reduction in the rate of recurrent preterm delivery, defined as delivery before 37 completed weeks, among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.3

“For more than a decade, health care providers have relied on hydroxyprogesterone caproate to reduce preterm delivery in high-risk patients, which aligns with recently updated treatment recommendations of the American College of Obstetricians and Gynecologists, as well as the Society for Maternal-Fetal Medicine,” said Dr. Krop in a prepared statement.1

The advisory committee’s recommendation, while not binding, will be considered by the FDA.4

Among the concerns of some members on the advisory committee was that the drug’s withdrawal would leave no safe treatment options for pregnant women. The injection’s active ingredient, 17α hydroxyprogesterone caproate (also known as 17P), is currently the only approved treatment for pregnant women who have had a prior spontaneous preterm birth.1

Moreover, the drug can be ordered from compounding pharmacies that custom make it for about $20 a dose, so taking hydroxyprogesterone caproate injection off the market will not necessarily change medical practice, according to a report by the Philadelphia Inquirer.5

“We are disappointed with the nearly split vote on this key question, and we are committed to working with the FDA to identify feasible ways to generate additional efficacy data on Makena while retaining current access to the therapy for at-risk pregnant women,” said Julie Krop, MD, chief medical officer at AMAG said in a company press release.1

AMAG Pharmaceuticals stock trading was halted following the company’s announcement on the vote.6


REFERENCES
  1. AMAG Reports on FDA Advisory Committee Meeting for Makena (Hydroxyprogesterone Caproate Injection). Waltham, MA. AMAG Pharma website. Published October 29, 2019. https://www.amagpharma.com/news/amag-reports-on-fda-advisory-committee-meeting-for-makena-hydroxyprogesterone-caproate-injection/. Accessed October 30, 2019.
  2. AMAG Pharmaceuticals Announces Topline Results from the Prolong Trial Evaluating Makena. Published March 8, 2019. https://www.amagpharma.com/news/amag-pharmaceuticals-announces-topline-results-from-the-prolong-trial-evaluating-makena-hydroxyprogesterone-caproate-injection/#_ftn1. Accessed October 30, 2019.
  3. Meis P, Klebanoff M, Thom E, et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate. June 12, 200 New England Journal of Medicine. 2003; 348:2379-2385. DOI: 10.1056/NEJMoa035140. Accessed October 30, 2019.
  4. October 29, 2019: Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement. FDA website. Published October 29, 2019. https://www.fda.gov/advisory-committees/advisory-committee-calendar/october-29-2019-meeting-bone-reproductive-and-urologic-drugs-advisory-committee-meeting-announcement. Accessed October 30, 2019.
  5. McCullough, Marie. FDA advisors recommend yanking approval of preterm birth prevention drug after it flops in crucial study. Philadelphia Inquirer. Published October 29, 2019. https://www.inquirer.com/health/fda-advisors-makena-preterm-birth-20191029.html. Accessed October 30, 2019.
  6. AMAG Pharmaceuticals Stock Trading Halted Today; FDA Advisory Committee Meeting to Discuss the Results of the Makena PROLONG Trial. Published October 29, 2019. https://www.amagpharma.com/news/amag-pharmaceuticals-stock-trading-halted-today-fda-advisory-committee-meeting-to-discuss-the-results-of-the-makena-prolong-trial/. Accessed October 30, 2019.