If at first you don’t succeed try, try and try again. Unless you are Pain Therapeutics. The company’s supposedly abuse-proof opioid, Remoxy ER, has now surely reached the end of the road after a negative US FDA advisory panel vote yesterday – at the fourth time of asking.
With an unpromising pipeline, it could soon be the end for Pain Therapeutics too. At least the group’s partner, Durect, has non-pain projects to pivot to, including DUR-928, which is in mid-stage trials in liver diseases such as Nash and skin disorders like psoriasis (see tables below).
This helps explain why Durect opened down a mere 11% this morning, while Pain plummeted 74%, leaving it with a market cap of just $15m, not far off its cash levels of $11m. Also, Durect had less riding on the project as it only stood to receive royalties of 6-11.5% of net sales if Remoxy ER had reached the market.
To get around the problem of abuse, other companies are attempting to develop non-opioid pain relief drugs. But their path to market is not always smooth either, as Cara – a company that today reported seemingly positive data – might be about to find out.
The possibility of Remoxy ER getting approved looks very remote after yesterday’s 14-3 negative panel vote; the FDA is due to make a final decision for the treatment of chronic pain by August 7.
Remoxy ER contains oxycodone – the active ingredient in Purdue Pharma’s OxyContin – formulated into an extended-release gel designed to thwart attempts to cut, inject or snort it.
However, the true extent of the project’s resistance to abuse had been called into question. The latest of three FDA complete response letters, issued in September 2016, requested new studies exploring possible routes of abuse: injection, inhalation and snorting (Snippet roundup: Wins for Amgen, cuts for Novo and confusion over Cabometyx, September 30, 2016).
Ultimately, while panellists concluded that Remoxy ER was effective, and that Pain had addressed the potential for intranasal abuse, they were still concerned about the possibility of intravenous abuse, and concluded that the benefits did not outweigh the risks.
Pain is perhaps the victim of bad timing: with the US in the grip of an opioid crisis, regulators are no doubt wary of greenlighting anything that could add to the problem. Other controlled-release opioids have previously been approved, in the form of OxyContin ER and Xtampza ER – but FDA briefing documents released before the Remoxy ER panel noted that a third of would-be abusers were still able to inject or snort the supposedly abuse-resistant OxyContin ER.
The tide is turning towards non-opioid pain candidates; last week, Heron Therapeutics reported more positive data with its bupivacaine and Cox2 inhibitor combo HTX-011, this time in patients who had undergone total knee arthroplasty or breast augmentation. Heron made the most of its share price surge to raise $200m.
|Selected non-opioid pain projects|
|Korsuva||Kappa opioid agonist||Cara Therapeutics||NCT02542384|
|IV meloxicam||Cox2 inhibitor||Recro Pharma||NCT02678286|
|HTX-011||Local anaesthetic + Cox2 inhibitor||Heron Therapeutics||NCT03015532|
The markets also responded well to the data Cara revealed today for its lead non-opioid, Korsuva, in post-surgical pain. Cara was up 27% in early trade, suggesting that investors were willing to overlook Korsuva’s marginal benefit, the study’s adaptive design, and the precedent of Recro Pharma, which demonstrated a stronger improvement on a similar endpoint – but still got a US complete response letter.
The higher of two Korsuva doses, 1.0μg/kg, yielded a p value of 0.0315 for its primary endpoint, improvement in pain intensity 24 hours post-surgery versus placebo, which Cara said was statistically significant. The lower, 0.5μg/kg dose appeared to show an effect initially, but the 24-hour endpoint missed significance.
A year ago Recro’s IV meloxicam – another Cox2 inhibitor – yielded significant reductions in 24-hour pain intensity in a post-operative pain study, with p=0.0145 versus placebo. However, last month the FDA said it would not approve IV meloxicam because some secondary measures suggested an insufficient analgesic effect, casting doubts over the relevance of the primary measure used by Recro and Cara alike.
While Heron and Cara are on the up, the future looks bleak for Pain.
After Remoxy ER the company’s most advanced candidate is in Alzheimer’s, a sector littered with failures. And next up is another “abuse-deterrant” opioid, a fentanyl patch that might have an equally hard time with regulators.
|Pain Therapeutics’ remaining pipeline|
|PTI-125||Alzheimer’s||Beta amyloid A4 protein inhibitor||Phase I|
|Fenrock||Pain||Transdermal fentanyl patch||Preclinical|
|Source: company website.|
Durect’s chances of moving on from Remoxy ER look slightly better. The company has another chance to pick up a royalty stream soon – the once-monthly risperidone formulation RBP-7000, which it licensed to Indivior, is due an FDA decision by July 28 in schizophrenia.
And clues about the potential of Durect’s first epigenetic regulator project, DUR-928, should come this year, with phase II data due in primary sclerosing cholangitis and alcoholic hepatitis this year.
Still, the project has a long way to go. With just $44m in the bank Durect could have done with the royalty stream from Remoxy ER to fund DUR-928’s trials. But at least it is in better shape than Pain.
|Durect’s remaining pipeline|
|RBP-7000*||Schizophrenia||Once-monthly risperidone||Under review|
|Posimir**||Pain||Extended-release bupivacaine||Phase III (failed)|
|Oradur-methylphenidate ER||ADHD||Psychostimulant||Phase III|
|DUR-928 (oral and IV)||Liver disorders, acute organ injury, skin disorders||Epigenetic regulator||Phase II|
|*Licensed to Indivior; **licensed to Novartis. Source: company website.|