A chance for the US regulator to show its teeth, at Amag’s expense

An advisory panel votes to pull Amag’s Makena from the market, but will the US regulator follow through?

The controversial preterm birth prevention drug Makena has already accounted for the bankruptcy of one company, K-V Pharmaceuticals, and after a US panel yesterday voted to pull it from the market it is threatening the prospects of its current maker, Amag.

That, however, relies on the US FDA following through on the recommendations of its advisors – a scenario not supported by the agency’s recent form. Add into the equation the fact that Makena is the standard of care in this setting, and that an influential US patient lobby tacitly backs it, and a swift withdrawal is by no means certain.

Opposition to such a move might be considerable, and Amag has singled out the fact that five of the six practising obstetricians on yesterday’s panel voted to keep Makena on the market. This might reflect concerns that without Makena there would be no other drug available, though overall the adcom’s vote was nine to seven in favour of withdrawal.

The view of doctors and patient groups will weigh heavy. One of the most prominent US charities working to reduce infant mortality, March of Dimes, backs the use of synthetic hormone injections, which in practice means 17-alpha-hydroxyprogesterone caproate, the active ingredient in Makena, generic versions and compounded equivalents.

No confirmation

Makena has a troubled history, and its latest problem stems from the failure of its confirmatory trial, Prolong. This had recruited 1,710 pregnant women with a history of preterm birth, but found no difference versus placebo on incidence of subsequent preterm birth before 35 weeks, or on neonatal mortality or morbidity.

Without the necessary clinical backing the adcom voted that the drug be withdrawn. As for March of Dimes, the charity has not made any recent public statements specifically about Makena, and had not responded to a request to state its position as Vantage went to press.

Back in 2011 March of Dimes welcomed the product’s US approval, which came on an accelerated basis, backed by the NCI-sponsored Meis study. But it later severed ties with Makena’s then-maker, K-V Pharmaceuticals, over the drug’s $1,500 price (K-V Pharmaceutical orders a beer in last-chance saloon, July 20, 2012).

K-V then collapsed under the weight of the furore and its precarious financial situation, but Makena lived on through Lumara Health, a company that emerged from the bankruptcy and was later acquired by Amag. Last year March of Dimes signed Amag up as a “strategic corporate partner”, under a deal to fund nine supportive pregnancy care sites.

Remarkably, given Makena’s disastrous launch, the drug sold over $300m last year, its 2017 peak coinciding with the end of a seven-year orphan exclusivity period. Amag, which had been halted yesterday, opened down 25% this morning, reflecting some risk that the FDA would now withdraw Makena’s approval.

However, it is not clear whether this will happen; several oncology drugs have been allowed to remain available under accelerated approval despite the failure of confirmatory trials, while in the case of Sarepta’s Exondys 51 the agency has apparently put little pressure on the sponsor even to run such a study.

Amag argues that over 75% of Prolong’s patient population had to be recruited outside the US, since US patients were unwilling to forgo the standard of care and enter a placebo-controlled trial. This could call the result into question, something that has also been pointed out by the Society for Maternal-Fetal Medicine.

A definitive view by patient groups will be pivotal to Makena’s future. In the meantime this saga is set to run on.

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