Circassia's Harris Deeply Frustrated By Phase III Cat Allergy Flop

The UK biotech’s potential revolutionary approach to allergies has failed to achieve its primary endpoint in a Phase III study, halting much of its research in the allergy area and casting a shadow over UK innovation.

Circassia Pharmaceuticals PLC’s cat allergy product, Cat-SPIRE, has failed to reach its primary endpoint in a pivotal Phase III study, disappointing investors who saw the company’s share price fall by more than 60% on June 20, the day of the announcement, and casting a pall over the UK biotech sector that had heralded the potential of the Oxford-based company.

The cat allergy vaccine was the company’s lead product and Circassia has been strongly backed by leading European biotech-focused investors such as Woodford Investment Management and Imperial Innovations. Circassia went public in March 2014 raising a substantial £200m, followed by an offering in June 2015 that raised £275m. (Also see "Circassia puts money where mouth is; IPO floats at top price" - Scrip, 13 Mar, 2014.)

The company presented top-line results on June 20 of the cat-SPIRE Phase III study, showing there was a high placebo response rate, in 40-60% of patients, preventing a treatment effect being shown. A placebo effect of around 20-30% was expected. It appears there was a dramatic improvement in allergy symptoms and a reduction in rescue medication use in all arms of the study.

“A high placebo response is not only disappointing but hard to understand; it’s deeply frustrating,” Circassia's CEO Steve Harris told Scrip. Initial suggestions of possible factors that could have confounded the results, such as the subjects reporting high baseline disease activity, are thought unlikely. “We have to be careful not to clutch at straws, and it’s unlikely that patients across countries and across different sites would have acted in some way to influence the study results.”

But the failed Cat-SPIRE study may have wider implications. “The scientific community will have to look closely at this carefully controlled study. How can they come up with new medicines with such a response?” Harris asked. A previous Phase IIb study conducted by the company with a potential ragweed allergy therapy also failed to show a significant benefit. But Harris noted in that study there was a treatment effect, albeit one that was non-significant. (Also see "Circassia Uses Adaptive Design For Phase III And Advances Commercial Plans " - Scrip, 16 Mar, 2016.)

Harris said Circassia would now rapidly analyze the full dataset of the Cat-SPIRE study and review its implications, but in the meantime it would halt research on most other allergy products in its pipeline. The company will stop a registration study for a grass allergy treatment that it recently started, and will halt preparations for a dose-ranging study of its ragweed allergy therapy.

But a Phase II study of its birch allergy product that is nearing completion will continue, and the company will decide over the coming weeks what to do about a Phase IIb study of its house dust mite allergy product that is well advanced.

Redundancies do not appear to be on the current agenda. The company outsources much of R&D, and the relatively small internal team of around 90 researchers will be refocused on other products, Harris said.

Missed Primary Endpoint

The Phase III study compared four- and eight-dose courses of its Cat-SPIRE product that contains a mix of synthesized short allergenic peptides, with placebo. The primary endpoint was the difference in the “mean combined score”, consisting of a combined total rhinoconjunctivitis symptom score (TRSS) and rescue medication use, a year after dosing started. The 1,245 subjects in the study were enrolled in more than 100 centers in North America, Europe and Russia, and had to have moderate to severe allergy symptoms and a cat living in their homes.

The study found the Combined Score versus baseline declined by 58.2% in the 4 x 6nmol doses group, and by 59.8% in the 8-dose group, while the Score declined by 58.5% in the placebo-treated patients. With regard to the secondary endpoint, the effect on TRSS alone, after one year this had declined from 14.5 to 5.7 points in the 4-dose group, from 14.2 to 5.5 in the 8-dose group, and from 14.5 to 5.9 in the placebo-treated group.

Over the past several years, Circassia has broadened its business strategy within the respiratory sector, including developing commercial operations in the US and Germany to market its NIOX asthma management products, and signing up distribution partners elsewhere, partly to prepare the ground for its allergy products.

The UK company acquired the respiratory biotech Aerocrine AB for around £88m and Prosonix Ltd. for up to £100m in 2015 to broaden its approach to asthma products. (Also see " Circassia paying £188m for two asthma firms, but it's still an allergy specialist " - Scrip, 15 May, 2015.) A generic, directly substitutable version of GlaxoSmithKline PLC’s Flixotide pMDI (fluticasone) has been developed and approved in the UK, and out-licensed to Mylan Pharmaceuticals Inc., and Circassia also has substitutable versions of Seretide pMDI (fluticasone plus salmeterol) and Serevent pMDI (salmeterol) in development. A fixed dose triple combination of an inhaled steroid, a long-acting beta-agonist and a long-acting muscarinic antagonist is also in development.