Esmo – Cachexia progress at last, but watch the diabetes
Despite the recent entry of big pharma, progress in cancer-related cachexia has been painfully slow. Now, at least judging by some doctors’ enthusiasm, there is a chance that this might change.
The source of the hope are pivotal data on one of the industry’s most advanced projects, Helsinn’s anamorelin, unveiled today at the Esmo congress. The results are not unequivocally positive, and diabetes is a worrying adverse event, but given the paucity of treatments for this common condition they might be enough to push anamorelin across the regulatory line.
Both the pivotal Romana 1 and 2 studies recruited patients with stage III/IV non-small cell lung cancer and cachexia, and had a similar double-blind design, measuring change in lean body mass and hand-grip strength versus placebo as the co-primary endpoints. Anamorelin succeeded in only the first endpoint.
Given anamorelin’s mechanism, of course, this makes perfect sense. The compound is a ghrelin receptor agonist, and the hormone ghrelin stimulates appetite, so mimicking its action should logically encourage patients to put on weight. Conversely, antagonising ghrelin receptors has been used as an investigational strategy for treating obesity.
But the appetite-stimulating approach has not previously succeeded in cachexia, and neither have such projects as GTx’s enobosarm and Ark Therapeutics’ imidapril (Therapeutic focus – Big pharma adds weight to thin cachexia pipeline, September 3, 2013).
First time in a decade
Indeed, Dr David Currow, from the Flinders University, Australia, who presented data from the two 12-week Romana 1 and 2 studies of anamorelin, said this was the “first time in over a decade” that a novel agent had succeeded in this condition.
In Romana 1 and 2, anamorelin produced body mass increases of 1.10kg and 0.75kg respectively, versus mass loss of 0.44kg and 0.96kg in the corresponding placebo arms. Each study hit statistical significance on this primary endpoint, Dr Curran said, and across the two trials combined the p value was below 0.0001.
However, change in hand-grip strength was not statistically different between anamorelin and placebo. Thus the obvious pessimistic view is that all Helsinn has shown is that anamorelin makes people put on weight, and that regulators will want to see a tough endpoint, like real improvement in muscle strength, hit before approving.
On the other hand, Dr Curran said 12 weeks was too soon to see an improvement in muscle strength. The filing process with regulatory agencies is now getting under way.
Adverse events, however, could throw another spanner in the works. 5.3% of anamorelin-treated patients in Romana 1 developed hyperglycaemia, while in Romana 2 4.2% got hyperglycaemia and 2.1% developed diabetes.
Dr Curran said this was not unexpected given the compound’s mechanism of action, and in fact hyperglycaemia had been looked for prospectively under the studies’ designs. But he admitted that standard anti-diabetics – including insulin – were needed to bring the diabetes under control.
An obvious and worrying comparison could be made, for instance, with the situation at Asco, where Clovis Oncology’s investors panicked after their company revealed that some patients treated with its NSCLC project CO-1686 developed a diabetic condition that had to be controlled with insulin.
At least, being a private company, Helsinn does not need to worry about short-term share price swings. And, even if the Romana data are somewhat equivocal, it cannot be denied that anamorelin has in a much shorter study beaten the last cachexia project to hit the headlines, GTx’s enobosarm.
This had been studied in two 84-day phase III studies, and showed a modest but statistically significant effect on lean body mass in one trial but not the other. It failed to improve stair climb power in either trial, and was deemed to have flunked the pivotal programme overall.
Helsinn will now be hoping that anamorelin has done enough to earn regulators’ favour. There was little doubt in the mind of the Esmo session’s moderator, Dr Giuseppe Curigliano, from the European Institute of Oncology in Italy, who said of the project: “This is a real breakthrough.”
|Romana 1||484 patients, vs placebo||NCT01387269|
|Romana 2||495 patients, vs placebo||NCT01387282|