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AM-Pharma's Recap misses primary endpoint but cuts mortality in phase II AKI trial


By Nuala Moran
Staff Writer

LONDON - Despite missing the primary endpoint, AM-Pharma NV's recombinant alkaline phosphatase (Recap) has demonstrated a 40 percent reduction in mortality vs. placebo in a phase II 301-patient study in sepsis-associated acute kidney injury (AKI).

The data were presented at the conference on Advances in Critical Care Nephrology in San Diego on Friday, and are now being scrutinized by Pfizer Inc., which has an option to acquire AM-Pharma on completion of the phase II trial.

In the trial, patients in the treatment arm were given Recap as part of standard of care on admission to an intensive care unit.

Treated patients showed a significant, progressive and sustained improvement in renal function in the 28 days of the trial. Overall, there was a significant and dose-dependent reduction in mortality in the treatment group compared to placebo.

However, Recap did not improve kidney function in the first seven days of treatment, as measured by creatinine clearance, meaning the study failed to meet the primary endpoint.

"We missed the primary endpoint, but sometimes you get something better in return," said Erik van den Berg, CEO of AM-Pharma. "The hard clinical endpoints are what the trial should be judged on, and mortality is the hardest endpoint there is," he told BioWorld.

Improvement in renal function in the first seven days of treatment was chosen as the primary endpoint on the basis of findings from earlier trials, van den Berg said. "We do see an improvement in renal function; just not in the first seven days."

For Peter Pikkers, chair of experimental intensive care medicine at Radboud University Medical Center, Nijmegen, the Netherlands, principal investigator, who presented the data on Friday, the significant improvement demonstrated in survival and kidney function "are very encouraging and strongly support further development of Recap."

AKI is a common complication of sepsis in ICU. Worldwide, hospital-acquired AKI affects 3 million patients per annum. There are 700,000 deaths as a result, according to data cited by AM-Pharma.

AM-Pharma has FDA fast track designation for Recap in that indication. Van den Berg said the Bunnik, the Netherlands-based company is now seeking a meeting with the agency to discuss the results.

Meanwhile, Pfizer is reviewing the data, but van den Berg said he does not know when to expect a decision.

In a deal struck in May 2015, Pfizer took an option to acquire AM-Pharma for $600 million once the results of the AKI trial were known. At that point, the pharma company made a down payment of $87.5 million in return for a minority equity stake.

If it decides to go ahead, Pfizer will get rights to Recap in other indications, including ulcerative colitis and hypophosphatasia. Should Pfizer exercise the option, Recap has to reach market for AM-Pharma shareholders to get the full $600 million. (See BioWorld Today, May 12, 2015.)

Van den Berg said it is "too early to speculate" on what the alternate plan will be if Pfizer decides not to go ahead.

The phase II trial used an adaptive design in which data from the first 120 patients were evaluated to select the most effective dose of Recap. Following that, the rest of the patients were recruited into two arms, receiving either the optimal dose of Recap identified in the first stage of the trial, or placebo. AM-Pharma said the 301-patient trial is the largest interventional clinical study in AKI to date.

Even though it failed to meet the primary endpoint, van den Berg is "delighted" with the outcome of the trial. "There was an improvement in AKI over the study period, the [results] support data from our other studies and there was a significant improvement in mortality. There is a clear path forward," he said.

In the treatment of AKI, Recap works by dephosphorylating pro-inflammatory substances, including lipopolysaccharides and extracellular adenosine triphosphate, that are released as a result of gram-negative sepsis.

Van den Berg agreed the heterogeneity of sepsis patients, and the systemic impact of the condition, means it is not possible to single out the effect on AKI as the sole source of reduced mortality.

As he noted, the mode of action of Recap is that it scavenges circulating and localized pro-inflammatory factors. In the case of multi-organ failure, that mechanism could contribute to wider improvements. "The 40 percent improvement in mortality is hard to dissect. But the only real difference in the trial is drug vs. placebo, so it must be a drug effect," van den Berg said.