October 25, 2022

Moving Forward to Prevent Preterm Birth: What We Need to Do Now that the FDA Advisory Committee Votes to Withdraw MAKENA

Written by Phyllis Leppert

The Campion Fund stands for excellence in fundamental reproductive science. That this statement is vitally important hit home this past week as I reviewed the US Food and Drug Administration (FDA)’s hearing on MAKENA (17-hydroxyprogesterone caproate injection) held on October 17-19. It is abundantly clear that an understanding of the basic mechanism of progesterone in maintaining of pregnancy would have helped to provide a better appraisal of the inconclusive research used to promote this drug. An understanding of the complex process of birth would also have encouraged the development of more effective drugs to prevent preterm birth, rather than continuing to rely on this drug for so many years.

The FDA’s Obstetrics, Reproductive and Urology Advisory Committee held an emotionally charged meeting to discuss the FDA’s Center for Drug Evaluation and Research’s (CDER) Proposal to Withdraw Approval of MAKENA’s New Drug Application (1). MAKENA received accelerated approval in 2011 based on one clinical trial published in 2003 (2). MAKENA is hydroxyprogesterone caproate, a synthetic progesterone, given in weekly intramuscular injections starting between 16 to 20 weeks of pregnancy and continued to 37 weeks or birth to prevent preterm delivery in women with one or more previous spontaneous preterm births. In 2011 MAKENA was given accelerated approval because preterm birth is a serious public health problem in the United States, particularly among blacks.  Accelerated approval is an FDA process whereby a drug for a serious health condition can obtain approval while confirming clinical studies are conducted. At the time MAKENA was given accelerated approval concerns were raised  regarding the statistical analysis used in the 2003 study and the fact that the control group had a very high incidence of preterm birth. Furthermore, one site in the multisite study recruited a larger number of enrollees than the other sites raising further concerns. The study had not been designed for drug regulation and approval and had only one outcome, that of preterm birth defined as a birth prior to 37 weeks of gestation (1,2). Therefore, the FDA required a confirmatory study as a condition of approval. At this point, it is helpful to note that the European Medical Agency (EMA) has not approved MAKENA (2).

The confirmatory  trial was a multicenter, randomized, double-blind placebo- controlled study of women with a prior preterm birth and a singleton pregnancy- (no twins, triplets or other multiple fetuses) and was published in 2019. It evaluated how may pregnancies ended in a birth before 35 gestational weeks and neonatal morbidity and mortality. The study recruited the number of subjects required by the initial study design. There were 1138 pregnancies in the hydroxyprogesterone arm and 578 in the placebo arm. Statistical analysis revealed that there was no significant difference in preterm birth between the two groups.  Furthermore,  there was no significant statistical difference in a composite index of neonatal morbidity and mortality (3). The FDA advisory committee at that time concluded that 17- hydroxyprogesterone caproate should  be withdrawn from the market since it had no therapeutic benefit. The committee’s advice for many reasons, one being the demands of the COVID -19 pandemic, was not acted upon.

In the years 2019 to 2022 the reaction of clinicians to the confirmatory study was mixed and confusing. Professional organizations such as the American College of Obstetricians and Gynecologists (ACOG) continued to endorse the use of the drug. The Society for Maternal-Fetal Medicine (SMFM) endorsed MAKENA only for women who had risk factors similar to those outlined in the 2003 study (4). In 2021 a meta-analysis of published studies of progesterone, including injectable hydroxyprogesterone was published showing suggested efficacy (5). The manufacturer argued that MAKENA should be made available to blacks as they represent a very high-risk group and that there were fewer blacks enrolled in the confirmatory study as opposed to the 2003 study.

At the recent October hearing the FDA’s CDER scientists presented their carefully evaluated conclusions. MAKENA is not effective as a preventive treatment for preterm birth nor in improving neonatal outcomes (1). They also pointed out that side effects of the injections are blood clots and depression. The Advisory Committee heard from physicians and patient advocates who argued that the drug should be available to black pregnant individuals. The Advisory Committee rejected that reasoning. Giving a non- effective drug to anyone is wrong, they concluded. The committee members also expressed opinions that further studies of newer potential drugs would be a wise move.  The Advisory Committee’s opinion now goes to the FDA’s Commissioner, Dr. Robert Califf and the Chief Scientist, Dr. Namandjé Bumpus for the final decision in a few months.  It is expected that they will agree with the Advisory Committee’s findings.

It is indeed disheartening that physicians and other providers do not have a treatment for preterm birth. This means that scientists must continue to work on the discovery of new drugs. But here is the thing and it is good news: since 2003 numerous fundamental molecular studies have been published which have expanded our knowledge of the onset of human labor and birth.  Pregnancy and birth are a complex process that ensures that the uterus is quiescent and grows to allow for the development of the fetus. The uterus does not have organized muscle contractions during is gestation. At the onset of labor, the uterus must become a contractile organ that will allow for opening of the cervix so that birth can take place. Science has shown that here are multiple molecular cascades that allow the cervix to change from a stiff tissue that will hold the fetus in the uterus to a tissue that is soft and will open easily as the uterine muscle contracts.  Progesterone, initially from the corpus luteum of the ovary and then from the placenta does play an important role in this process. However, it is not just progesterone alone that regulates the birth process. The function of progesterone is highly controlled by complex alterations in progesterone receptor activity. At term these changes cause a decline in progesterone effectiveness allowing the increased function of factors leading to birth. Changes in estrogen, prostaglandins, initiation and repression factors, factors associated with the immune system which play a role in tissue remodeling, the extracellular matrix and mechanical factors as well as gene expression changes and physiological clocks all are involved in the process of birth. During this complex process the fetus placenta and mother all play  roles and provide the essential molecules necessary to initiate and complete birth. This process has many pathways and has redundancy. This is a good thing as it allows for the process to proceed even if one pathway is altered or does not function. Ongoing studies are investigating the racial and socioeconomic disparities in preterm birth and include studies on the environment as well as epigenetic factors. Science still has much to learn.  It does seem to make sense that if progesterone receptors change to allow a decline in progesterone function at a point in pregnancy when a preterm birth might occur, an injection of a synthetic progesterone would not be effective in preventing that untimely delivery.

All of this extensive information regarding the process of pregnancy and birth is exceedingly good news as it means that as scientists learn more, potential drug therapies will be discovered.  It is important that we continue to fund the basic scientific work that will uncover these potential treatments.  A number of reviews discuss these studies (6, 7, 8, 9, 10, 11). There is hope.

To create awareness of our current knowledge and to stimulate further research, The Campion Fund is partnering with Franco DeMayo, PhD of NIEHS to hold a meeting on the Basic Science of Gestation and Parturition on February 17, 2023 that will provide a venue for discussion of this important topic in reproductive science. Speakers addressing the science of the birth process will be Carole Mendelson, Liping Feng, Mala Mahendroo, Kristin Myers, Sarah England and Ramkumar Menon. Additional sessions will discuss early pregnancy. Make a note of this meeting and plan to attend. A summary of the proceedings will be published in Biology of Reproduction, an important leading journal.

References and Further Reading

  • Carome, MA. Presentation at the FDA’s October 17-19. 2022 Hearing on the Center for Drug Evaluation and Research’s Proposal to Withdraw approval of MAKENA (Hydroxyprogesterone Caproate Injection) New Drug Application 021945 https://www.fda.gov/media/162305/download
  • Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85. doi: 10.1056/NEJMoa035140. Erratum in: N Engl J Med. 2003 Sep 25;349(13):1299. PMID: 12802023.
  • Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, Chauhan SP, Hughes BL, Louis JM, Manuck TA, Miller HS, Das AF, Saade GR, Nielsen P, Baker J, Yuzko OM, Reznichenko GI, Reznichenko NY, Pekarev O, Tatarova N, Gudeman J, Birch R, Jozwiakowski MJ, Duncan M, Williams L, Krop J. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. Am J Perinatol. 2020 Jan;37(2):127-136. doi: 10.1055/s-0039-3400227. Epub 2019 Oct 25. PMID: 31652479.
  • Norman JE. Progesterone and preterm birth. Int J Gynaecol Obstet. 2020 Jul;150(1):24-30. doi: 10.1002/ijgo.13187. Erratum in: Int J Gynaecol Obstet. 2020 Dec;151(3):487. PMID: 32524598; PMCID: PMC8453855.
  • Stewart, Lesley orcid.org/0000-0003-0287-4724 and Simmonds, Mark Crawford orcid.org/0000-0002-1999-8515 (2021) Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) : meta-analysis of individual participant data from randomised controlled trials. The Lancet. pp. 1183-1194. ISSN 0140-6736 https://doi.org/10.1016/S0140-6736(21)00217-8
  • Rokas A, Mesiano S, Tamam O, LaBella A, Zhang G, Muglia L. Developing a theoretical evolutionary framework to solve the mystery of parturition initiation. Elife. 2020 Dec 31;9:e58343. doi: 10.7554/eLife.58343. PMID: 33380346; PMCID: PMC7775106.
  •  Mesiano S. Progesterone withdrawal and parturition. J Steroid Biochem Mol Biol. 2022 Sep 9;224:106177. doi: 10.1016/j.jsbmb.2022.106177. Epub ahead of print. PMID: 36096351.
  • Mendelson CR, Gao L, Montalbano AP. Multifactorial Regulation of Myometrial Contractility During Pregnancy and Parturition. Front Endocrinol (Lausanne). 2019 Oct 25;10:714. doi: 10.3389/fendo.2019.00714. PMID: 31708868; PMCID: PMC6823183.
  • Menon R, Bonney EA, Condon J, Mesiano S, Taylor RN. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum Reprod Update. 2016 Sep;22(5):535-60. doi: 10.1093/humupd/dmw022. Epub 2016 Jun 30. PMID: 27363410; PMCID: PMC5001499.
  • Nallasamy S, Palacios HH, Setlem R, Colon Caraballo M, Li K, Cao E, Shankaran M, Hellerstein M, Mahendroo M. Transcriptome and proteome dynamics of cervical remodeling in the mouse during pregnancy. Biol Reprod. 2021 Nov 15;105(5):1257-1271. doi: 10.1093/biolre/ioab144. PMID: 34309663; PMCID: PMC8599062.
  • Vink J, Myers K. Cervical alterations in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2018 Oct;52:88-102. doi: 10.1016/j.bpobgyn.2018.03.007. Epub 2018 Apr 11. PMID: 30314740; PMCID: PMC6282836
  • Koullali B, Westervelt AR, Myers KM, House MD. Prevention of preterm birth: Novel interventions for the cervix. Semin Perinatol. 2017 Dec;41(8):505-510. doi: 10.1053/j.semperi.2017.08.009. Epub 2017 Oct 5. PMID: 28988725; PMCID: PMC5711549.