Index heads for another dubious pivotal trial

Six years after failing phase III cobitolimod underwhelms in phase II, but Index ploughs on into a fresh pivotal study.

Trial Results

A common pitfall for overzealous biotech companies is to continue developing a drug after a clinical readout suggests that it would be wiser to stop. Index Pharmaceuticals, a Stockholm-listed micro cap, appears to have taken this a stage further with its ulcerative colitis lead project, cobitolimod.

Six years ago cobitolimod crashed in a pivotal study, but Index ploughed on, designing and running a new phase II test, which yesterday yielded a result that can at best be called equivocal. Index’s view? The new “study confirms the successful topline results and supports the strategy going forward”.

The latest study, Conduct, had been designed as a dose-optimisation trial using a slightly different endpoint to the failed phase III test, Collect. Conduct had been toplined as showing an “outstanding combination of efficacy and safety” last August, but it was only yesterday that Index revealed its statistical analysis.

Conduct tested four cobitolimod doses, three of which were higher than the one that had failed in Collect. And it recruited ulcerative colitis specifically of the left-side variety, signifying a relatively severe disease and hopefully resulting in a more uniform dataset than Collect, which did not make this distinction.

It seems that only the double 250mg dose showed any relevant activity; this was the joint highest tested.

Low bar

But Index revealed that it had set a remarkably low bar for success in Conduct, determining that one-sided p values below 0.1 would be deemed statistically significant. The industry standard is a two-sided p value, which is roughly twice as hard to hit, and a tougher, 0.05 threshold for significance.

The high dose cleared the bar, with a one-sided p of 0.0247, though apparently none of the other three managed to meet even the low threshold used. Various undisclosed secondary endpoints were also said to be significant at the one-sided p<0.1 level, but given such a low goal it is impossible to gauge their clinical relevance.

Just how low a bar this was can be seen by the two-sided p value that the high dose achieved: 0.0495, just scraping below 0.05. What is more, Index said it did not carry out any correction for multiple analyses of the various doses, arguing that Conduct was an exploratory study, and was powered in accordance with regulatory guidelines for such studies.

And it does not even seem that there was a dose-response relationship: the lowest dose performed numerically better than the joint-highest, four times 125mg, for instance.

Summary of cobitolimod trials in ulcerative colitis (UC)
Study N Disease/dose Primary endpoint/result Secondary endpoints/results
Collect 131 Refractory UC 12wk clinical remission (CAI ≤4) Mucosal healing Patient-reported outcomes
2 x 30mg Fail: 44.4% vs 46.5% in placebo Fail: 34.6% vs 18.6%; nominal p = 0.09  32.1% vs 14.0% at wk 4, nominal p = 0.020
Conduct 213 Left-sided UC 6wk clinical remission (modified Mayo subscores) Included patient-reported symptoms, endoscopy & QoL measures
2 x 250mg 21.4% vs 6.8%; one-sided p=0.0247 Some said to be significant at one-sided p<0.10
4 x 125mg Fail: 9.5% vs 6.8% None said to be active
2 x 125mg Fail: 4.7% vs 6.8%
2 x 30mg Fail: 12.5% vs 6.8%
Source: company presentation &

Unfortunately for Index, when the available evidence is taken together the result in Conduct seems to be down to luck; its stock was down 4% in afternoon trading today.

Cobitolimod is an oligonucleotide against TLR9, and according to EvaluatePharma is the most advanced industry asset blocking this target. Significant work has gone into TLRs (toll-like receptors) without huge success; some companies are pursuing the opposite mechanism, agonising TLRs including TLR9, for oncology use.

At best Conduct suggests that even higher doses should be tested, especially given what is said to be good safety. Undeterred, Index plans to start enrolling subjects into a new phase III study of the double 250mg dose this year.

Its chief executive, Peter Zerhouni, told Vantage he had not yet decided whether a higher dose should also be tested, and argued that running yet another phase II study instead would take almost as long as a phase III and delay time to market.

This is true, but without a more convincing efficacy signal caveat emptor applies.

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