Verona’s transformation clears its first hurdle

The transformation of Verona Pharma from a UK laggard to a credible biotech continued today, with the company claiming success in its most important binary event of 2018 – a chronic obstructive pulmonary disease study of RPL554 against placebo.

Even without knowing all the numbers there is cause for optimism. But smart investors should ask how clinically relevant the phase IIb data are, given that subjects were required to forgo LABAs – standard treatment for COPD – and that the trial was run largely in European countries that do not have advanced standards of care.

These are not mere insignificant details; positive readout of the phase IIb RLP554 study in question is to serve as the trigger for further phase II trials to begin later this year. Those, eventually, could lead to a typically large pivotal programme that presumably would have to be financed by a partner.

Good news

The good news is that all four RPL554 doses tested beat placebo in terms of the primary endpoint, peak FEV1 change from baseline to week four, Verona said today.

The obvious question is how this relates to a real-world setting. The phase IIb trial’s enrolment criteria asked patients to withdraw from LABAs (long-acting beta agonists, including such commonly used drugs as formoterol and salmeterol) for the duration of treatment; those on short-acting agents had to forgo these for eight hours before RPL554 was administered.

Though the trial was in maintenance rather than acute COPD exacerbations it could be argued that it did not test RPL554 against standard of care. The reason Verona was able to do this was likely because 31 of 49 recruiting hospitals were in Bulgaria, the Czech Republic, Poland or Romania, where access to drugs considered standard in the West is relatively poor.

Another niggle is the lack of a dose response, though with 403 enrolees this trial was surely too small to detect a difference. All four nebulised RPL554 doses (0.75-6.0mg) showed a significant FEV1 increase from baseline versus placebo, but there was no visible difference either between them or between weeks one and four.

For now such questions have not unduly troubled investors, who today sent Verona stock up 20%. This is Verona’s second positive catalyst in a month, after RPL554 showed efficacy in a small pharmacokinetic study in cystic fibrosis.

Better than thought

On a call with analysts today Verona management said the data showed RPL554 to be “even more potent than we had thought ... even at the lowest dose”. However, the group accepted that this meant that it would now have to study administration below 0.75mg to find the lowest effective dose.

The company called the data clinically and statistically significant. Baseline FEV1 values were not given, but RPL554 was said to have raised these by 200ml, adjusting for placebo. In comparison, the US label for Foradil (formoterol) for COPD cites an FEV1 increase of some 350ml above placebo after 12 weeks’ treatment.

As for the lack of an active comparator, Verona accepted that RPL554 would most likely have to be used on top of other agents, and to be fair earlier phase IIa data in combination with either salbutamol or Spiriva do support this. The next key trial to start this year will be as a LABA add-on for 12 weeks (Interview – Verona investors still holding their breath, July 26, 2017).

Verona said a pivotal trial of RPL554 in the maintenance setting would begin next year. It will be up to others to determine whether the mid-stage data, and RPL554’s vanishingly short patent life – the composition-of-matter patent expires in 2020 – make this a worthy investment.

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