Background Analysis: US FDA Advisory Committee to Review Findings of the Postapproval Confirmatory Trial for Makena (hydroxyprogesterone caproate injection) - OCT 29, 2019 (BRUDAC)

Announcement

The US FDA has scheduled a meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) on Tuesday, October 29, 2019 to discuss a supplemental new drug application (sNDA 021945/S-023) for Makena (hydroxyprogesterone caproate injection, 250 mg/mL), manufactured by AMAG Pharmaceuticals (AMAG). The sNDA includes results of a postapproval confirmatory trial for Makena, named the PROLONG trial. AMAG has disclosed that this trial did not demonstrate a statistically significant difference between the treatment and placebo arms for the co-primary endpoints of reducing the risk of recurrent preterm birth or improving neonatal mortality and morbidity. The BRUDAC will be asked to consider the trial findings and the sNDA in the context of AMAG’s confirmatory study obligation.

Regulatory Background

In 2011, Makena received approval under the accelerated approval (AA) pathway for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Makena was shown in the preapproval clinical trial, referred to as the Meis trial, to reduce the proportion of women who delivered at less than 37 weeks gestation, a surrogate endpoint that FDA determined was reasonably likely to predict a clinical benefit of preterm birth prevention, such as improved neonatal mortality and morbidity. As required with AA, AMAG conducted a postapproval confirmatory trial to verify and describe clinical benefit, named PROLONG, and submitted these data to the FDA in an sNDA.

On March 8, 2019 AMAG reported top-line results of the PROLONG trial. The company reported that the trial did not demonstrate a statistically significant difference between the treatment and placebo arms for the co-primary endpoints: the incidence of preterm delivery at less than 35 weeks (Makena-treated group 11.0% vs. placebo 11.5%, p=.72) and the percentage of patients who met criteria for the pre-specified neonatal morbidity and mortality composite index (Makena-treated group 5.4% vs 5.2%, p=.84). The company says the adverse event (AE) profile between the two arms was comparable, and AEs of special interest, including miscarriage and stillbirth, were infrequent and similar between the treatment and placebo groups. Trial results have not yet been posted to ClinicalTrials.Gov (Trial ID: NCT01004029).

In their March 2019 press release, the company noted that more than 75% of the trial population (Total N=1700) was enrolled outside of the US, mostly in Eastern European countries. The company explained that US physicians were reluctant to enroll patients in a placebo-controlled trial after Makena was FDA-approved and established as US standard of care. AMAG’s Chief Medical Officer said that, in light of the trial findings and inconsistency with prior clinical trial evidence, they planned to conduct subgroup analyses of patients at the highest risk of preterm delivery and patients enrolled in the US. The Chair of the PROLONG Publications Committee noted that the PROLONG trial population was significantly different than that of the preapproval trial with respect to race, socioeconomic status, and severity of disease.

On August 7, 2019, in a Form 8-K filing to the US Securities and Exchange Commission, AMAG stated that the FDA has noted that they consider the post-hoc subgroup analysis informative for hypothesis generation only and did not consider it adequate to support efficacy for any subgroup. Below is an excerpt from the Form 8-K filing that pertains to the sNDA and upcoming BRUDAC meeting.

The PROLONG trial was conducted as part of an approval commitment under the FDA’s “Subpart H” accelerated approval process to confirm the efficacy of the Meis trial. The PROLONG trial results did not demonstrate a statistically significant difference between the treatment and placebo arms for the co-primary endpoints. Since the results of the PROLONG study were negative, the FDA could withdraw the approval of Makena, require us to generate or conduct additional clinical trials or update the approved labeling to include information on the PROLONG study, including the possibility of restrictions to the current indication or the insertion of new warnings or precautions. Although the usual regulatory process for a Subpart H approved product with a failed confirmatory trial is for the FDA to issue a Notice of Opportunity for Hearing to initiate the process to withdraw accelerated approval, the FDA indicated that it believed that an Advisory Committee is the preferred next step to inform regulatory decision-making for Makena. In addition, certain medical professional organizations and other societies could change their guidelines to physicians. The FDA has noted that it considered post-hoc subset analysis informative for hypothesis generation only and did not consider it adequate to support efficacy for any subgroup. The FDA further noted that it will not opine on the safety of Makena while the FDA review is ongoing.

At the upcoming BRUDAC meeting, the committee will consider the findings of the PROLONG trial and the sNDA in the context of AMAG’s confirmatory study obligation.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: AMAG Pharmaceuticals Drug Name: hydroxyprogesterone caproate injection Drug Class: hormone Indication: reducing the risk of recurrent preterm birth or improving neonatal mortality and morbidity

For more information about SAC Tracker reports and other benefits for our subscribers, click here.

DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.