Ten days after disappointing investors in what appeared a messy mistake in the European phase III trial of Xilonix in symptomatic, advanced colorectal cancer, Xbiotech Inc. turned its story around by reporting that the interleukin-1 alpha ligand inhibitor met the primary study endpoint of response rate compared to placebo.

The company plans to move immediately to filings in the EU, with a registration package expected to be submitted in the first quarter of 2016 or thereabouts, according to John Simard, the company's president and CEO.

The company's shares (NASDAQ:XBIT) opened 20 percent higher Monday morning and climbed nearly 94 percent before closing at $13.03 for a gain of $4.42, or 51.3 percent.

Patients enrolled in the double-blind, placebo-controlled study had refractory, metastatic colorectal cancer and exhibited cancer-associated symptoms such as fatigue, pain, elevated inflammatory markers, weight loss and reduced physical ability at baseline. Patients were randomized 2:1 to Xilonix or placebo, respectively.

On Nov. 23, Xbiotech reported that data cleaning from the EMA study revealed that 25 patients dropped off prior to dosing with drug or placebo. Another 14 patients erroneously received placebo or study drug, and 33 additional patients completed the study but failed to receive scheduled DEXA scans, to complete the European Organization of Research and Evaluation of Cancer instrument (EORTC-QLQ-C30) questionnaire properly, or both. In short, the irregularities compromised data from 72 of the 333 patients enrolled in the study.

The Austin, Texas-based biotech said the study was oversampled to accommodate loss of patients due to disease progression prior to evaluation but not to accommodate the unexpected data loss, resulting in reduced statistical power to demonstrate the proposed effect. Simard noted at the time that Xbiotech had not received all patient samples and data, with the ongoing analysis expected to be completed in approximately 10 days.

The loss of data, while disappointing, "will not necessarily delay the scheduled unblinding or final analysis of the data," he said at the time.

In reporting details from the analysis, Xbiotech said 33 percent of the 207 patients randomized to Xilonix met responder criteria compared to just 19 percent of the 102 patients in the placebo arm (p=0.009), and those findings suggested a conservative assessment. Based on the modified intent to treat analysis plan, patients with missing endpoint data and those who received Xilonix instead of placebo were deemed non-responders off the top, according to the company, while those who failed to receive Xilonix or placebo altogether were excluded from the analysis.

The company plans to provide the entire dataset to the EMA.

'A NEW WAY TO LOOK AT ADVANCED CANCER PATIENTS'

The phase III, designed with input from European regulators, assessed patients for anti-tumor response using a co-primary objective response rate: a composite measure consisting of change in lean body mass, change in quality of life and change in patient-reported symptoms from screening to week eight. X-ray imaging was used to quantify change in lean body mass and health status was assessed based on patient-reported outcomes using the EORTC-QLQ-C30. Patients with conserved or improved lean body mass and EORTC-QLQ-C30 performance over the treatment period were considered responders.

Responder analysis – which Xbiotech has been developing as a surrogate measure of anti-cancer activity – was determined after just four cycles, or eight weeks, of therapy. After completing assessment of the primary endpoint at eight weeks, patients were eligible to cross over to an open label extension of Xilonix.

A candidate from Xbiotech's True Human therapeutic antibody platform, Xilonix blocks inflammation believed to support tumor growth, dispersion through the body and disease symptoms. In the phase III EMA trial, the company postulated that control or reversal of symptoms related to disease was considered sufficient evidence of anti-cancer activity and a better prognosticator than progression-free survival (PFS) to warrant approval. The study represents the first use of this type of responder analysis in a controlled study in an anti-cancer agent, according to Simard.

"This is such a novel study from several different points of view," Simard told BioWorld Today. "Firstly, it is the only attempt to develop a new surrogate endpoint for a cancer therapy that's been successful, that I know of. What we're really getting at with these endpoints is a new way to look at advanced cancer patients to get a good handle on whether a treatment is helping them or not. You can always do that with survival, of course – that's the bottom line – but when you want to find out sooner whether a therapy is helping people, conventional radiology really proves to be of limited value in metastatic cancer."

Despite its optimism about the use of symptomatic response as a surrogate endpoint, the company is conducting a separate global phase III study of Xilonix in metastatic colorectal cancer for review by the FDA, which authorized fast track designation. The ongoing study, dubbed XCITE, expects to enroll 600 patients who failed previous treatment, including flouropyrimidines, oxaliplatin and irinotecan, who are being randomized 2:1 to Xilonix or placebo plus best supportive care. Unlike the EMA trial, symptoms at baseline are not required for entry, and patients will continue on study until they show evidence of radiographic progression. The primary endpoint is overall survival – the FDA's gold standard for drug approval – with secondary endpoints of objective response rate and PFS as well as change in lean body mass as measured by DEXA and improvement in patient-reported quality of life using the EORTC-QLQ-C30.

With its more conventional design, using 18-month patient follow-up, the FDA-directed study will also take longer. The first readout is expected toward the end of 2016, Simard said.

Xbiotech, which raised $76 million in April in its IPO, has already witnessed the vagaries of the public markets. The company priced its IPO at $19 and shares spiked within days to $32.50 before gradually falling back. The low point of $7.17 came Nov. 30, following disclosure of the phase III EMA data glitch. (See BioWorld Today, April 16, 2015.)

With the EMA phase III now deemed a success, the company expects to begin working with a contract sales organization in Europe as a cost-effective way to prepare for a potential product launch.

"We didn't want to make a big investment in a sales organization ahead of results," Simard explained, but he voiced confidence in the company's ability to take Xilonix to market.

"What this study does for us as a company is symbolize our ability to go the full distance with a molecule," he said. "We brought this from the bench. We developed our own manufacturing program and have taken this through phase III on our own. It shows folks that we can bring products all the way through the pipeline, which we intend to do."

The commercial goal, once revenue is flowing, is to transition to a company-owned sales force, which Simard called "quite manageable for this kind of indication."

The IPO provided the company with a runway through 2017, according to Simard, but Xbiotech is completing a major manufacturing facility in Austin and ramping up head count, which may require another financing round.

Xilonix also presents applications in other indications, since it blocks a common step in the inflammatory cascade, and the company is pursuing additional therapies, including an antibody candidate against Staphylococcus aureus.

"We have an extraordinary emerging opportunity in infectious disease because of the way we can clone antibodies from donors," Simard said. "Our study to treat Staph aureus is moving along, and we intend to finish that program by the middle of next year and advance that into a pivotal program thereafter."