Positive phase III results in two pivotal trials of naloxegol, an opioid-induced constipation (OIC) therapy under development by Nektar Therapeutics and AstraZeneca, mean that the drug ought to become the second oral OIC therapy to reach market after a 2014 launch. While its chances of gaining US approval have increased, it is likely to be pipped to the post by Sucampo and Takeda’s Amitiza, already filed in the US with a PDUFA date of January 2013.
However, the FDA recently expressed doubts over the safety of Relistor, which like naloxegol is a mu-opioid antagonist OIC drug, requesting an additional trial from its developers Salix and Progenics. Nektar insists that naloxegol is safe, but if the agency extends its concern to all mu antagonists Amitiza – a chloride channel agonist – could gain an extended period of market exclusivity.
Top-line results from the Kodiac-04 study showed that significantly more patients responded to naloxegol at two dose levels, 12.5mg and 25mg once-daily, than to placebo. In the Kodiac-05 trial, the 25mg dose demonstrated a statistically significant result for response compared with placebo, but the 12.5mg dose did not.
In both trials, response – the primary endpoint – was defined as having at least three spontaneous bowel movements per week, with an increase over baseline of at least one per week, for at least nine out of 12 weeks, and at least three out of the last four weeks. This endpoint is considered more robust than those used in the trials of Amitiza or oral Relistor, and was requested by the FDA (Event – Naloxegol set to provide a Kodiac moment for Nektar, September 7, 2012).
Data from Kodiac-07, a 12-week safety extension of Kodiac-04, were also positive. Serious adverse events including major cardiovascular events were no more common in the treatment arms than with placebo in all three trials, AstraZeneca said. Rates of adverse events were lower in Kodiac-07 than in Kodiac-04 and -05.
A long-term safety trial, Kodiac-08, is expected to be completed by the first quarter of 2013.
NDA and MAA submissions for naloxegol are planned for the third quarter of 2013, but Nektar admits that approval could be delayed. Last week, Salix Pharmaceuticals said that the FDA was worried about a risk of cardiovascular events associated with the long-term use of mu-opioid antagonists in patients taking opioids for chronic pain. The agency, which sent Salix and Progenics a complete response letter for Relistor in the summer, has now requested that they conduct a very large, chronic administration trial (Progenics and Salix suffer as FDA blocks constipation drug, July 31, 2012).
In a conference call today, Howard Robin, Nektar’s president and CEO, said the company was aware that the FDA was exploring whether there is evidence of a cardiovascular risk related to mu-opioid antagonists. He said that Nektar had not seen any cardiovascular risk signal in the Kodiac studies, and it was “very very happy with the safety profile of naloxegol”.
Nevertheless, last week's admission that naloxegol could theoretically be subject to an FDA request for further trials caused Nektar's share price to fall by 7% on November 8. The stock has yet to recover.
The real win for Nektar does not come with the approval of naloxegol, but thereafter: the company intends to coformulate the drug with opioids, creating a single-pill opioid painkiller that does not cause constipation. The sales potential for these co-formulations – which are known as the NKTR-119 programmes and are also licensed to Astra – is estimated to reach nearly $1bn by 2025, more than double the peak expectations for naloxegol itself.
First, though, naloxegol must meet the FDA’s requirements. Results from Kodiac-08, which at a year’s duration has twice as long a timeframe as Kodiac-04 and-05, will be necessary to give a clearer picture of naloxegol’s chronic safety, and thus its approvability.
|Summary of Kodiac trials of naloxegol|
|Trial name||Number of patients||Study detail||Trial ID|
|Kodiac-04||630||12-week, placebo-controlled efficacy study||NCT01309841|
|Kodiac-05||630||12-week, placebo-controlled efficacy study||NCT01323790|
|Kodiac-07||633||12-week extension study||NCT01395524|
|Kodiac-08||1,135||Open-label, long-term safety study vs usual care comparator||NCT01336205|
To contact the writer of this story email Elizabeth Cairns in London at email@example.com