LONDON – AM-Pharma BV has raised €116 million (US$130.7 million) in a series E round to fund phase III development of its recombinant alkaline phosphatase, Recap, in the treatment of sepsis-associated acute kidney injury (SA-AKI).

The new money will support the largest trial to date in SA-AKI, recruiting 1,400 patients at more than 100 sites in 12 countries.

Bunnick, the Netherlands-based AM-Pharma had to look to investors after Pfizer Inc. declined to exercise an option it was granted in 2015 to acquire the company for $600 million, citing "internal strategic reasons." (See BioWorld, May 12, 2015.)

Pfizer's decision was taken last year when Recap failed to reach the primary endpoint in the phase II trial, of showing short-term improvement in kidney function as measured by creatinine clearance in the first seven days post-treatment.

Despite that, the 301-patient study did show a significant, progressive and sustained improvement in renal function over 28 days. There was a relative reduction in mortality of more than 40% in the treatment group, compared to placebo. All-cause mortality at day 28 was 14.4% in the Recap group, compared to 26.7% in the placebo group (p=00.02). The effect persisted to day 90. (See BioWorld, March 12, 2018.)

AM-Pharma chose creatinine clearance as the endpoint on the basis of earlier studies, and for want of an alternative biomarker. However, there is now increasing recognition that this measure is of limited precision in estimating kidney function, especially in the context of the dysregulated immune response sparked by sepsis.

"The primary endpoint in phase II of a biomarker was to establish the most effective dose," said Erik van den Berg, AM-Pharma's CEO. "For registration, we will be looking at hard clinical endpoints," he told BioWorld.

The series E attracted new investors LSP and Andera Partners who co-led the round. Founding investor Forbion followed on, as did other existing investors Ysios Capital, Kurma Partners, ID Invest Partners, BB Pureos Bioventures and Gilde Healthcare. The round brings the amount raised by AM-Pharma since its formation in 2001 to €195 million.

Recap has FDA fast track designation in SA-AKI, and van den Berg said discussions with both the FDA and EMA indicate it will be possible to get marketing approval on the basis of a single phase III trial. "It will be pretty similar to the confirmatory part of the phase II," van den Berg said. Details of the exact design will be announced next year.

There are no approved drugs for AKI, which is managed with dialysis and supportive care. Figures quoted by AM-Pharma show hospital-acquired AKI affects around 3 million patients annually in the U.S., Japan and Europe, occurring in 40% to 60% of critical care admissions. It is associated with mortality in around 700,000 patients per year and annual care costs in the U.S. are $10 billion.

Van den Berg said the fact there are no treatments can mean AKI is undiagnosed, but with sepsis accounting for around half of cases, he said he is confident the trial will be quick to recruit.

Martijin Kleijwegt, managing partner at LSP, said the firm has been following AM-Pharma's progress for some time and the phase II data are promising. Recap has the potential to become the first drug and a "blockbuster first-line therapy" for treating SA-AKI, he said.

Recap exerts its detoxifying effects through dephosphorylation of bacterial endotoxins and proinflammatory mediators such as adenosine triphosphate (ATP). Inactivating ATP, and the resulting formation of adenosine, further reduces inflammation through the adenosine A2a receptor pathway.

AM-Pharma originally was developing a bovine form of alkaline phosphatase, but dropped that after an initial phase II, in favor of the recombinant product. That is based on combining the properties of the intestinal isoform of the enzyme, which is the most active of the four human isoforms, with its placental counterpart, which has the longest half-life, resulting in a highly stable biologically active product.

In addition to SA-AKI, AM-Pharma has explored the use of Recap for other indications, including ulcerative colitis, necrotizing enterocolitis and hypophosphatasia. Those programs are still active, but van den Berg said the new funding will all be dedicated to bringing phase III development in SA-AKI to a conclusion.

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