What looked on the face of it like decent mid-stage data from Achieve Life Sciences were not enough to stop the company’s stock sinking for a second day. Shares opened 10% lower this morning, after sinking 25% yesterday.
The company believes that its smoking cessation candidate cytisinicline has shown enough promise to justify going into phase III. But worries about the project’s patentability, Achieve’s capital structure and the company’s cash position probably all contributed to the selloff.
Some investors also questioned a high placebo response seen in the phase II Orca-1 trial, which tested four dosing regimens of cytisinicline: declining titration schedules starting at 1.5mg and 3mg, and 1.5mg and 3mg three times per day.
The primary endpoint was patients’ self-reported reduction in daily smoking. Over the 25-day treatment period and across all four dosing arms patients on cytisinicline reported a 74-80% median reduction in the number of cigarettes smoked, compared with a 62% drop in the placebo arms.
The high number with placebo might be explained by the self-reported nature of this endpoint, which could be open to abuse. The trial also looked at expired carbon monoxide, a biochemical measure of smoking activity and therefore a more objective endpoint; across the groups this declined by a median of 71-80% with cytisinicline, versus 38% with placebo.
The discrepancy between the two sets of results suggests a relative under-reporting of cigarettes smoked by patients in the placebo group, according to Achieve.
3mg three times daily
On the primary endpoint, only three of the four dosing arms met statistical significance, but this might not matter: Achieve plans to take forward just one of the successful doses, 3mg three-times daily, which it said was the “clear winner” in terms of performance.
The company will discuss the Orca-1 data with the US FDA in the next few weeks, and hopes to start its phase III programme in the second half of 2019. This will comprise two trials, the sizes of which are still to be determined. They had originally been set to enrol up to 2,300 patients in total, but Achieve said on a conference call yesterday that it might revise statistical powering assumptions based on the latest data.
The primary outcome in phase III will be the continuous abstinence rate over 5-8 weeks, confirmed by expired carbon monoxide levels – this is the endpoint preferred by regulators, according to Achieve.
On this measure the 3mg three-times-daily dose showed 30% of patients abstaining, versus 8% in those receiving placebo, with a p value of 0.005. Achieve’s chief executive, Rick Stewart, claimed that the study had not been designed to show this level of smoking abstinence.
Still, these results make cytisinicline look slightly less efficacious than an approved anti-smoking drug, Pfizer's Chantix, which according to its label has shown continuous abstinence rates through 9-12 weeks of 40-51% – although the usual caution about cross-trial comparisons applies.
And Chantix has its own issues, having been linked with suicidal ideation. Adverse events with cytisinicline looked more benign, with the most common being abnormal dreams, insomnia, upper respiratory tract infections and nausea, all seen in 6% of patients in the 3mg three-times-daily arm.
The hope is that cytisinicline, an alkaloid produced from the seeds of the laburnum plant, could be safer than Chantix, which was still a $1bn drug last year despite its side effects.
But Chantix is set to come off patent next year, which could eat into cytisinicline’s potential market. And Achieve has intellectual property issues itself: being a natural product, cytisinicline is not eligible for a composition-of-matter patent.
Achieve is trying to get around this, and was recently granted a patent covering a novel salt form of cytisinicline. The company has also pointed out that it would receive five years’ data exclusivity protection on FDA approval, while an EU green light would secure 10 years.
Cytisinicline has long been available in eastern Europe, at the 1.5mg downward titration dose, where it is also known as Tabex, but Achieve plans to pursue approval in the EU. It hopes that the 3mg three-times-daily dose could differentiate its product.
Other worries for the company include its capital structure. A high number of outstanding warrants leaves current shareholders at risk of being diluted.
If Achieve can get cytisinicline approved it might address a huge market: there are nearly 40 million smokers in the US and over a billion worldwide. Whether the company can get this far is another matter. The group had just $13.9m at the end of March, which will not be enough to fund its phase III trials.
Achieve has said it is looking for a partner; it will have to hope the Orca-1 data are enough to tempt a suitor, as a fundraising looks out of the question for now.