AstraZeneca ($AZN) has wrapped another Phase III study of its opioid-induced constipation drug naloxegol (NKTR-118), trumpeting the successful outcome of a 52-week safety study and laying out a timeline to head to regulators with a new drug application. But a dark cloud has hovered over this program ever since last fall, when Salix and its partner Progenics ($PGNX) acknowledged that they were handed a rejection for an expanded use of Relistor, in the same class of drugs for OIC, as regulators demanded an expensive new cardiovascular safety study to make sure it didn't pose a threat to patients.
AstraZeneca, which in-licensed the drug from Nektar Therapeutics, recruited more than 800 patients for the yearlong study. The 534 patients in the naloxegol arm experienced various symptoms like abdominal pain, nausea and headaches at a higher rate than the arm receiving the standard of care. And investigators highlighted a "low number of major adverse cardiovascular events."
"These high-level results are similar to the safety results seen in the Phase III studies previously reported and provide further confidence in the data we've seen to date for naloxegol," said Briggs Morrison, the executive vice president of global medicines development at AstraZeneca. "We have now completed our core Phase III program and we are pleased to advance naloxegol toward a regulatory submission later this year." Applications are being readied for Europe and the U.S. and the company says they should be filed in the third quarter, pending a pre-NDA meeting with the FDA. AstraZeneca licensed the drug in a $1.5 billion deal with Nektar.
For AstraZeneca, which has failed repeatedly at mounting a successful Phase III program, the positive outcome of a program with four late-stage studies marks a key win for an R&D group undergoing a top-to-bottom reorganization. But analysts have been fretting over the implications of the FDA's rejection of Relistor last summer. Salix subsequently acknowledged that the CRL outlined agency concerns that people coming off therapy could be exposed to a higher risk of cardiovascular events and regulators demanded a new study ahead of an approval. Several analysts fretted that the same fate could await AstraZeneca and Nektar, forcing execs to downplay the threat of a CRL.
"We're aware that the FDA is exploring whether there's evidence of a cardiovascular risk associated, related to opioid withdraw from mu-opioid antagonist, and I know that AZ remains confident that the program is designed to properly evaluate that," Nektar CEO Howard Robin told analysts last November. "I think we've seen essentially very little of no incidences of withdrawal. And as I said, anything that we might have seen has been very mild. We don't see any cardiovascular risk signal in these studies."
Last November Adam Feuerstein at TheStreet also raised red flags, noting that investigators had "unlocked" the database in one of the Phase III efficacy trials, retrieved data on a patient that had been assessed as "non-retrievable" and then locked it again. That sort of event can be frowned on by regulators likely to be wary of any possibility of tampering, especially when only one of the doses in the study proved effective.
- here's the press release