Did AstraZeneca constipation drug fail key trial?
The Big Pharma company and its partner Nektar added data to a phase III study of naloxegol that could have improperly changed results.
Did you catch the statistical jujitsu that AstraZeneca (AZN) and Nektar Therapeutics (NKTR) buried in Monday's press release announcing "positive" results from two pivotal trials of the opioid constipation drug naloxegol?
One of those studies -- dubbed KODIAC-05 -- might have failed.
Here's the key statement about the conduct of the KODIAC-05 study that AstraZeneca and Nektar hidden deep in Monday's announcement:
After initial locking of the database for KODIAC-05, data associated with one patient that was previously assessed as non-retrievable was found to be retrievable. These data were added to the database and the database was again locked and underwent a final analysis.
Once a clinical trial database is locked, it should stay locked. Locking and unlocking a database raises the risk that data can be improperly manipulated. AstraZeneca insists proper procedures were followed and the naloxegol analysis presented Monday is accurate. But it's also plausible to believe AstraZeneca found no statistically significant difference in response rates between naloxegol at either the 12.5 mg or 25 mg dose compared to placebo. (AstraZeneca admits the 12.5 mg dose of naloxegol showed no benefit.)
Faced with a failed phase III trial of its critically important opioid constipation drug, AstraZeneca may have sought to retrieve additional data from the "non-retrievable" patient. "Retrieved" data found. Database unlocked. "Retrieved" data added. Database locked a second time. Trial analyzed (again). Winner!
Before you ask, yes, data from a single patient could make a difference in the outcome of the KODIAC-05 trial. Look at the results announced Monday: The 12.5 mg dose of naloxegol failed badly with a probability value (or p-value) of 0.202 while the 25 mg dose barely squeaked into victory lane with a p-value of 0.021. (The trial required a p-value less than 0.025 to reach statistical significance.)
Think about it another way: If the retrieved data from the single patient had no material impact on the outcome of the KODIAC-05 study, then AstraZeneca would have had no reason to disclose anything about its data-retrieval expedition.
Yet, the company did.
Again, AstraZeneca and Nektar claim both naloxegol studies -- KODIAC-04 and KODIAC-05 -- achieved their primary endpoints of increasing bowel movements compared to placebo in patients taking opioids for non-cancer pain. But very little actual data from the studies was disclosed Monday, making it impossible to verify the claims independently. We may not find out the truth about the studies' real outcomes until naloxegol works its way through the FDA review process.
"The topline results announced today reflect an analysis of a dataset that includes all the accessible patient records," said AstraZeneca spokesman Esra Erkal-Paler. "Ultimately, that's the only analysis that matters and that is why we only report the result based on the most accurate and complete dataset. Any earlier analyses would have been based on an incomplete dataset and we therefore would not consider them meaningful."
Referring to the post-database lockup addition of the single-patient data, Erkal-Paler added, "Although unusual, this is not unprecedented and entirely appropriate under the circumstances to ensure data from all patients who took part in the trial are included where possible."
Nektar held a conference call on Monday morning to trumpet the naloxegol results to investors but refused to answer follow-up questions. Nektar says its contract with AstraZeneca forbids the company from discussing the naloxdegol data with journalists.
AstraZeneca and Nektar are in trouble if only one of the two naloxegol phase III studies was actually successful. FDA and its regulatory counterparts in Europe will not look kindly on an opioid constipation drug with one positive and one negative phase III trial.
Investors didn't buy the naloxegol good news story that both companies tried to sell Monday. Nektar shares fell 14% to $7.04, partly because the company lacks long-term data to satisfy new concerns FDA has raised about the heart safety of opioid constipation drugs like naloxegol.
But Nektar's stock price also tanked initially because some investors picked up on the controversy surrounding the KODIAC-05 study. The stock, however, has pared some of its losses in midday trading Tuesday.
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