Makena Might Stay On Market Despite Failed Confirmatory Trial In Pre-Term Birth

Subgroup analyses by AMAG may support ongoing use, but the once-controversial Makena seems unlikely to be pulled from the US market in any event since compounded progesterone is the only alternative therapy.

AMAG Pharmaceuticals Inc.'s Makena (hydroxyprogesterone caproate injection) failed to achieve both co-primary endpoints in the PROLONG confirmatory study required by the US FDA when it granted the product accelerated approval in 2011, but that doesn't necessarily mean the pre-term birth drug will need to be withdrawn.

While PROLONG was meant to confirm FDA's accelerated approval decision for Makena, it's unclear whether the agency will require AMAG to stop selling the drug and an authorized generic. In fact, the drug – already seeing sales decline due to competition from generics that launched last year – may well remain on the market.

AMAG said on March 8 that it is reviewing the PROLONG data in hopes that subgroup analyses will confirm a benefit for some patients.

Makena has been plagued by controversy for more than a decade as the drug's original developers struggled to win FDA approval for their proprietary formulation of progesterone – a hormone that obstetricians have long used in compounded forms to prevent pre-term births. (Also see "KV's Gestiva Reemerges With New Name, Makena, And A Long-Sought FDA Approval" - Pink Sheet, 7 Feb, 2011.)

But KV Pharmaceutical, the initial sponsor, stumbled out of the gate, pricing Makena at $1,500 per dose – a list price that generated public and political backlash – then cutting the cost to $690, which was still far higher than the $20-$100 prices per dose that compounders charged for progesterone used to prevent pre-term births.

In the face of the outcry, FDA declined to stop compounders from continuing to provide lower-cost progesterone, a surprising decision given that the agency was essentially acknowledging that pricing issues were driving its enforcement discretion, and a key impetus for Makena's approval in the first place was concerns about the safety and efficacy of the compounded products. (Also see "FDA Steps Into Makena Pricing Dispute In The Name Of "Access"" - Pink Sheet, 4 Apr, 2011.)

FDA May Have Vested Interest In Makena

The worst-case scenario for Makena after the failed trial is that the FDA will require AMAG to stop marketing the product, but that's not a certainty, given that some other drugs granted accelerated approval have not been taken off the market.

For example, AstraZeneca PLC’s lung cancer drug Iressa was allowed to stay on the market after a failed confirmatory trial, and it eventually received a full approval for a selected population (EGFR-positive).

Cowen analyst Ken Cacciatore suggested that Makena's approval wouldn't be pulled because FDA has a vested interest in keeping manufacturing of progesterone for prevention of pre-term birth under the agency's watchful eye rather than have all at-risk pregnant women treated with compounded progesterone.

"Recall, at the time of the Makena approval, the clinician community had become convinced (over years of off-label use) that compounded 17a-hydroprogesterone caproate injection utilized in pregnant women at risk of pre-term birth could have vastly improved outcomes," Cacciatore wrote in a March 8 note.

"FDA was presented with a very difficult choice: accept fairly limited clinical data (albeit via sponsorship from the NIH) or continue to allow pregnant women to receive an injection from fairly unregulated sources," he continued. "The agency clearly accepted the limited clinical data and granted approval for Makena as we believe (and speculate) that the true goal was to bring the manufacturing under FDA compliance."

Demographic Differences Could Have Doomed Confirmatory Trial

PROLONG enrolled 1,700 women – 75% of whom were from outside of the US – with a history of pre-term delivery of a single baby. Makena did not achieve statistical significance on either of the co-primary endpoints relating to pre-term deliveries and neonatal mortality.

The incidence of pre-term delivery at less than 35 weeks was 11% in the Makena-treated group and 11.5% in the placebo group (p=0.72), while the percentage of patients who met criteria for the pre-specified neonatal morbidity and mortality composite index was 5.4% in the Makena arm of PROLONG and 5.2% in the placebo arm (p=0.84).

AMAG said adverse event profiles were comparable for Makena and placebo with adverse events of special interest described as infrequent and similar, including miscarriage and stillbirth.

AMAG Chief Medical Officer Julie Krop suggested in a statement from the company that the demographic differences between the clinical trial used to support Makena's 2011 approval and the newly reported confirmatory study explain the lack of a significant benefit of the drug in PROLONG.

Because Makena has become the standard of care for preventing pre-term labor in the US, Krop said US doctors were reluctant to enroll their patients in a clinical trial in which they might receive a placebo. That led to 75% of women enrolled in PROLONG coming from outside the US, largely in Eastern Europe.

African Americans, Longer Endpoint Seemed To Drive Initial Trial's Success

SVB Leerink analyst Ami Fadia pointed out in a March 8 note that the women in the Meis trial, which supported Makena's approval, were largely African-American.

"We agree this could be part of the reason, given that in the Meis trial at 35 weeks the benefit in non-black women was much smaller than in black women," Fadia said. "Further, a change to a week 35 endpoint from the previous week 37 endpoint could also have made it harder to demonstrate benefit, as the treatment benefit in non-black women from the Meis trial was only evident from week 35 onwards."

As such, Krop said, "we plan to conduct additional sub-group analyses of the PROLONG data, particularly focusing on patients at the highest risk of preterm delivery and the subset of patients enrolled in the US. We will work closely with our publications committee to further assess the data, submit the findings to the FDA, and prepare the data for peer reviewed publication."

Fadia cited Centers for Disease Control data that show pre-term birth rates are 4.5% higher for non-Hispanic black women than for non-Hispanic white women, noting that socioeconomic status, severity of disease and other factors besides genetics may explain the difference.

The Fall And Rise And Fall Again Of Sales

After FDA reallowed compounding of the product, KV blamed the cheaper versions of the hormone for its lackluster Makena sales, leading the company to file for Chapter 11 bankruptcy.

Rebranding as Lumara Health Inc., the company eventually began to improve revenue, and sales really picked up after AMAG bought the firm and began making additional strategic material health acquisitions. (Also see "AMAG Spends $700 Million To Better Sell Makena" - Pink Sheet, 29 Jun, 2015.)

Makena sales more than doubled under AMAG from $165.8m in 2014 to a peak of $387.2m in 2017, declining to $322.8m in 2018 after generics began to hit the market. Even so, the drug provided 69% of the company's $474m in 2018 revenue, so it remains an important product even as its sales decline.