Aquinox Pharmaceuticals Inc. CEO David Main told investors during a conference call that it was "impossible to know the right answer" to the question of why the phase II trial called Flagship with AQX-1125 failed in chronic obstructive pulmonary disease (COPD), but he noted the very sick patients enrolled had "lots of exacerbations" and "lots of symptoms."

Shares of the company (NASDAQ:AQXP) closed Thursday at $2.13, down $4.42, or 67.5 percent.

"As part of the top line we received the [pharmacokinetic data]," Main said. "We know that the patients that were on the treatment arm [and] received the drug had the same plasma levels as the patients receiving the same dose of drug in prior trials. We got good drug exposure, so our expectation is that there is probably more likely something to do with the refractoriness of this disease" at the stage patients were tested, he said.

Last month, the lead candidate from the firm's SH2-containing inositol-5'-phosphatase-1 (SHIP-1) program narrowly missed statistical significance in the phase II trial called Leadership in bladder pain syndrome/interstitial cystitis (BPS/IC), but the data were good enough for Vancouver, British Columbia-based Aquinox to move ahead with development of AQX-1125 in that indication. Stephen Shrewsbury, chief medical officer (CMO), said at the time that "pain scores seemed pretty well matched between the groups. I think had the trial [enrolled] a few more patients or perhaps gone on for a few weeks longer we might have actually hit" the statistical significance bar.

Such was not the case for Flagship, though, which randomized 400 patients to get either AQX-1125 or placebo. AQX-1125 on top of standard of care did not improve COPD exacerbation symptoms, nor did it reduce the medically treated exacerbation rate as compared to placebo on top of standard-of-care therapy.

"We have examined the parameters of the trial and are confident that these results were not due to any observed imbalance in the treatment arms or due to the design or execution of the trial," CMO Shrewsbury said of the Flagship experiment. Patients treated with 200-mg oral, once-daily AQX-1125 (same dose and frequency as in the Leadership trial) for 12 weeks tracked their results by using a patient-reported outcomes tool called EXACT, a rough acronym for "the Exacerbations of Chronic Pulmonary Disease Tool," a diary with 14 items.

Patients in the Leadership study, too, were required to report daily on pain in an electronic or e-diary. The patients in that more successful trial were randomized following a screening period of nine to 21 days during which they had to demonstrate an average minimum pain score of five on a numerical rating scale (NRS) for short of zero to 10, with 10 being severe pain. They had to have at least a mean score of five over a minimum of seven for the last nine days prior to randomization. As with EXACT, the NRS scale is one of several standard endpoints used in trials; pain is the most common endpoint for current BPS/IC trials, too, with 21 of 48 current BPS/IC trials registered on clinicaltrials.gov listing pain as the primary endpoint, Shrewsbury noted.

Yet to report is the Kinship phase II trial with AQX-1125 for atopic dermatitis, with top-line results expected in the first quarter of next year.

The idea behind binding and activating SHIP-1 is to enhance the enzyme's inflammation reduction activity. SHIP-1 is mainly found in immune cells and functions by restoring balance after inflammatory responses, dialing down the activation state of immune cells, along with the recruitment and migration to sites of inflammation. SHIP-1 operates in the PI3 kinase pathway. In June, before either of the phase II trials reported data, Cowen and Co. analyst Ritu Baral expressed confidence. "We think Aquinox's SHIP-1 platform is the basis for a promising portfolio of the potential drugs for epithelial inflammatory diseases (e.g., COPD, BPS/IC)," since SHIP-1 plays a key role in the immune system. She predicted both experiments would succeed, and forecast $1.8 billion in COPD peak sales.

Of the Flagship trial, Shrewsbury said Aquinox "will complete secondary analyses, [but] these are unlikely to alter our conclusions, though they may help explain the absence of an effect in this population." CEO Main, asked if AQX-1125 is kaput in COPD, said "the better use of our resources and energies are on BPS/IC," adding that "we will continue to think about COPD and other respiratory diseases, but if we were to specifically talk about COPD, we would probably conclude that [in] a future trial we would want to think about earlier intervention in the disease." COPD, he said, "is not going to be on the near-term horizon."

Jefferies analyst Biren Amin wrote in a June research report that "an increase in the treatment period beyond six weeks in addition to sample size could increase the odds of success" in future BPS/IC experiments. Amin, during the conference call Thursday on Flagship, wanted to know if the company had collected biomarker data that might provide clues to the drug's activity in COPD. Shrewsbury said researchers had not, but "we will be selecting biopsy samples in our Kinship trial in atopic dermatitis and we'll obviously be discussing those at some point in the future."

Aquinox went public in the first quarter of last year, pricing its offering at $11, the midpoint of the proposed range, and bumping up the number of shares sold by half a million to 4.2 million for gross proceeds of about $46.2 million. (See BioWorld Today, March 10, 2014.)

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