FDA, Regulatory

Glass half empty: Achaogen receives split vote from FDA experts on lead antibiotic, shares plunge

An FDA advisory committee has handed down a split vote — yes for one indication and no for another — on Achaogen’s lead antibiotic, ruffling the high expectations it set up going in.

Investors weren’t happy, sending Achaogen stocks down close to 29% in after-hours trading.

The split decision carries interesting implications for other antibiotic makers. In a first, Achaogen $AKAO submitted an NDA with a request to use the Limited Population Antibacterial Drug (LPAD) pathway in reviewing the drug, plazomicin, for the treatment of bloodstream infections (BSI) due to Carbapenem-resistant Enterobacteriaceae. That happens to be the indication that the adcomm voted down; all 15 of them voted yes when it came to treating patients with complicated urinary tract infections (cUTI).

Packaged into the 2016 21th Century Cures Act, the LPAD regulatory pathway allows for acceptance of greater uncertainty or higher risk in patients with serious diseases (and an unmet need) provided that substance evidence of effectiveness is presented.

A large part of what seems to have doomed Achaogen’s plans for the BSI indication was a smaller-than-expected sample size that complicated statistical analysis. Early in the meeting, an FDA clinical reviewer pointed out that the biotech had to amend protocols for a Phase III study (ACHN-490-007) because they could only enroll 37 patients out of the 286 planned. That resulted in statistical limitations in concluding that plazomicin had superior efficacy compared to colistin in the comparator arm, even though numerical trends pointed to that conclusion.

The reviewer went on to suggest looking at the data through the lens of noninferiority, which the data would allow for, but cautioned that such assessments are complicated by design features the FDA agreed to back when Achaogen was planning a superiority trial. Among those features: prior or concomitant antibacterial therapy, as well as laxer criteria for patients regarding bacteria culture in their bodies. That additional uncertainty regarding baseline status for patients didn’t help, either.

After discussing the statistical plan and clarifying how best to balance the LPAD consideration with benefit-risk assessments, 11 committee members voted against plazomicin in BSI, mostly concerned that the study was underpowered to support conclusions of efficacy. The other four disagreed, citing the limited use and unmet need.

For cUTI, on the other hand, committee members had no problem unanimously endorsing plazomicin based on a study that showed its was noninferior to meropenem, even considering a larger margin of 15% (versus a conventional 10%) the FDA sanctioned.

Achaogen CEO Blake Wise had this to say in a short statement:

We are encouraged by the Committee’s unanimous vote in favor of plazomicin for complicated urinary tract infections (cUTI). The discussion underscored the real-world challenges that healthcare providers face every day given limited or inadequate treatment options for certain pathogens. Regarding bloodstream infections, the Limited-Population Antibacterial Drug pathway, or LPAD, is a novel approach that enables the FDA to consider the benefits and risks for the sickest patients who have few or no available treatment options, and to approve antibiotics like plazomicin that we believe, have the potential to address these limited patient populations.

South San Francisco-based Achaogen is one of a handful of biotechs in late-stage development with new antibiotics in an era of rising drug resistance to the mainstays in the field. Whether it will become a trailblazer or a cautionary tale will become clear by its PDUFA date of June 25.


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