5:59 PM
Jun 29, 2018
 |  BioCentury  |  Regulation

Not a test

Why Achaogen’s LPAD miss has limited readthrough to others using the pathway

Antibiotics developers shouldn’t read too much into FDA’s rejection of the first drug to be reviewed under a new limited-use pathway that is supposed to make it easier to develop treatments for rare and resistant infections.

That’s because Achaogen Inc.’s Zemdri plazomicin doesn’t make a good test case for whether the limited population pathway for antibacterial and antifungal drugs (LPAD) pathway will be able to accomplish its goals.

On June 25, FDA granted full approval for Zemdri in complicated urinary tract infections (cUTIs) proven or strongly suspected to be caused by susceptible microorganisms. But it issued a complete response letter for use of the drug in bloodstream infections caused by susceptible microorganisms, an indication the company had sought under the LPAD pathway.

At least three factors suggest Zemdri is not the prototype for the pathway. First, the program wasn’t prospectively designed to take advantage of LPAD. Then, problems with enrollment rendered the company unable to execute on its original trial design and forced it to make several modifications. The resulting data were ambiguous, which made it impossible to tell if the apparent mortality benefit was real.

Achaogen plans to discuss with FDA potential next steps for a bloodstream indication. In the meantime, it is likely Zemdri will see off-label use for the indication (see Sidebar: “Accessing Alternatives”).

Sidebar: Accessing alternatives

Achaogen’s registrational trial testing the next-generation aminoglycoside antibiotic in bloodstream infections caused by carbapenem-resistant Enterobacteriaceae (CRE) concluded before LPAD was legally enacted, thus it was not designed with it in mind. In addition, unforeseeable difficulties with enrollment caused the company to make multiple midstream changes to its protocol and analysis plan.

Achaogen changed endpoints and added a non-randomized cohort. It still ended up stopping the trial early due to poor accrual, eliminating the ability to conduct the planned superiority analysis.

In briefing documents released ahead of a May 2 advisory committee meeting, FDA reviewers said it could be appropriate to instead look at the results as evidence for non-inferiority. But the non-inferiority analysis was compromised by aspects of the protocol from the original superiority design, including the extent to which patients could receive prior antibiotic therapy.

As a result, questions about how to interpret Zemdri’s...

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