LUXEMBOURG and ZUG, Switzerland – March 26, 2021 – Covis Group S.à r.l. (“Covis”) announced today that the updated results of EPPPIC (Evaluating Progestogens for Preventing Preterm birth International Collaborative), found that both 17-OHPC and vaginal progesterone reduced the relative risk of early preterm birth in high-risk singleton pregnancies before 34 weeks, while current evidence for oral progesterone is insufficient to support use.
The EPPPIC study represents a systematic review of randomized trials evaluating vaginal progesterone, intra-muscular 17-alpha-hydroxyprogesterone caproate (17-OHPC), and oral progesterone in women at risk of preterm birth. Funded by the Patient-Centered Outcomes Research Institute, the final results of the study were published in The Lancet.
The publication presents the results of a meta-analysis of individual participant data from five trials examining injectable 17-alpha hydroxyprogesterone (17-OHPC), also referred to as MakenaÒ or generic alternatives. 17-OHPC is the only FDA-approved treatment indicated to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.
“The EPPPIC meta-analysis reported an overall reduction of the relative risk of early preterm birth following the use of 17-OHPC in women with a singleton gestation with a prior spontaneous preterm birth and found a consistent pattern of neonatal benefits with no safety signals related to pregnancy loss. In my opinion, this is strong evidence to support efforts to maintain access to 17-OHPC while conducting further clinical trials to assess the treatment benefits in our patients in the U.S.,” states Sean C. Blackwell, MD, professor and chair of the Department of Obstetrics, Gynecology, and Reproductive Sciences at McGovern Medical School-UTHealth, Houston, Texas; chair of the PROLONG publications committee; and a member of the EPPPIC authorship group.
The findings show that 17-OHPC and vaginal progesterone both reduced birth before 34 weeks, by 17 percent and 22 percent respectively, with favorable reductions at <28 weeks and <37 weeks. The analysis also indicated potential reductions in serious neonatal complications and incidence of low birthweight infants for both 17-OHPC and vaginal progesterone. Vaginal progesterone is not FDA-approved for prevention of preterm birth.
Importantly, a study limitation is that researchers could not reliably differentiate in trial data between women with varying risk profiles – women who experienced preterm birth due to early induction of labor vs. women who experienced spontaneous preterm birth – and as a result, analyzed them as one, “history of a prior preterm birth.”
In addition, the analysis of women with both a history of preterm birth and either a short or non-short cervix was limited to studies that measured cervical length, which does not include the original study that led to FDA approval of 17-OHPC in 2011 (Meis et al.). The only study included in the EPPPIC analysis of women with both prior preterm birth and non-short cervix was the 17-OHPC confirmatory study required by FDA, called PROLONG, which did not require the measurement of cervical length.
“While the EPPPIC analysis found that the effects of 17-OHPC and vaginal progesterone did not differ by short cervical length or history of prior preterm birth, the limitations in available data from the underlying studies make it difficult to generalize about risk reduction in these subgroups,” said Anita F. Das, PhD, member of the EPPPIC authorship group, a statistician for the PROLONG study, and a member of the PROLONG publications committee. “As such, we do not have sufficient information from this analysis to draw definitive conclusions about the subgroups of women with a spontaneous prior preterm birth—or with both a prior preterm birth and a short or non-short cervix.”
The EPPPIC analysis is relevant as part of the FDA’s ongoing consideration of 17-OHPC. FDA published a notice proposing to withdraw its approval of 17-OHPC in October 2020, after the PROLONG study reaffirmed 17-OHPC’s maternal and fetal safety profile, but failed to verify clinical benefit in a different population of women than those studied in the original Meis trial. Since then, the sponsor has filed a request for a hearing and extensive information supporting its view that 17-OHPC should continue to remain available to patients and providers.
“Given the prevalence and severity of preterm birth in the U.S., we are committed to further study of 17-OHPC. As described in our response to the FDA and request for a hearing to maintain Makena as a treatment option for indicated patients, we are seeking the opportunity to discuss data-driven next steps, including further evaluating real-world data,” said Covis CEO Michael Porter.
Covis Pharma completed the acquisition of AMAG Pharmaceuticals, Inc., the application holder of Makena, in November 2020. At this time, Makena remains approved and available and the product label remains unchanged.
Covis is headquartered in Luxembourg with operations in Zug, Switzerland and is a global specialty pharmaceutical company that markets therapeutic solutions for patients with life-threatening conditions and chronic illnesses. Additional information is available at www.covispharma.com.