Market and opportunity
Each year, approximately 700,000 deaths in Europe, the US and Japan are associated with AKI. Annually, hospital-acquired AKI affects approximately 2 million patients in the Western World (Europe, the US and Japan) and the incidence is rising. The disease occurs in as many as 4% of hospital admissions and up to 40% of admissions to intensive care units.
Despite the significant unmet medical need in AKI, especially sepsis-associated AKI, no pharmacological treatment is available and only a limited number of candidate medicines is in clinical development. The multi-factorial pathogenesis of the disease probably necessitates a multi-factorial intervention to allow protection, thereby limiting the number of potentially effective treatment options.
AM-Pharma’s proprietary human AP (recAP) has a dual mechanism of action via dephosphorylation of both lipopolysaccharides (LPS) and extracellular ATP. Currently, AKI patients only receive supportive care, such as temporary renal function replacement (dialysis), that give the kidneys time to heal. As such recAP could become the first pharmacological treatment for these critically ill AKI patients.
Background information on AKI’s market opportunity:
Knotnerus DDW 2014 Developing the first treatment for AKI.pdf
AM-Pharma completed Phase I and Phase II proof-of-concept clinical trials with intravenous administration of bovine Alkaline Phosphatase and demonstrated that the enzyme is safe and efficacious in restoring kidney function in patients suffering from AKI. In addition, in a Phase I study in healthy volunteers recombinant human Alkaline Phosphatase showed a good safety profile with favorable pharmacological properties. The effect of recAP on sepsis-associated AKI is currently being investigated in a 50-center Phase II trial in the US and Europe.
Bovine AP Phase I trials
AM-Pharma conducted two Phase I studies in a total of 103 subjects (67 healthy volunteers and 36 patients with severe sepsis). The results demonstrated that the enzyme had a good safety profile for the administered doses.
Background information and study results: Pickkers et al, Eur J Clin Pharmacol.2009
Bovine AP Phase II (APSEP)
The first Phase II clinical study was a double-blind, 2:1 randomized, placebo-controlled multicenter trial. It focused on a 24-hour treatment regime in 36 patients with sepsis. A subgroup of sixteen patients (11 active and 5 placebo) with AKI showed an improvement in kidney function. Results showed that 80% of patients who received placebo treatment required renal replacement therapy (dialysis) versus 36% of the patients who received bovine Alkaline Phosphatase.
Background information and study results: Heemskerk et al, Critical Care Medicine 2009
Bovine AP Phase II (APREN)
The second Phase II study concerned a double-blind, randomized, placebo-controlled multi-center trial in 36 patients with both sepsis and AKI with48-hour bovine AP administration .
This study showed a statistically significant improvement in the primary composite efficacy endpoint of renal creatinine clearance. Positive results were also obtained for a number of secondary parameters, e.g. length of hospital or Intensive Care Unit stay, and for a series of systemic inflammatory markers, including Lipopolysaccharide-binding protein (LBP), C-reactive protein (CRP) and IL-6. Further positive results were seen with urinary markers specific for kidney injury e.g. Kidney Injury Molecule (KIM-1), and Interleukin-18 (IL-18).
Background information and study results:
Pickkers et al, Critical Care 2012
Ireland, Nature Reviews 2012
Recombinant human AP Phase I study
AM-Pharma completed a Phase I study in 51 healthy volunteers. The trial demonstrated a good safety and tolerability profile, and showed favorable pharmacological properties and enzyme activity in serum – a key indicator of the drug’s therapeutic potential.
Recombinant human AP Phase II study (STOP-AKI)
The company has recently started a large therapeutic AKI trial. This adaptive Phase IIa/b trial will investigate the effect of recAP in patients with sepsis-associated AKI in 50 sites in the US and in Europe.
The primary objective of the trial is to establish proof-of-concept and to determine the most effective dose of recAP for treating AKI by measuring kidney function, and to confirm the favorable safety data observed in previous trials.
The adaptive Phase II trial involves two-stages and will recruit a total of 290 patients. The first four-arm stage, with 120 patients, will identify the most effective of three different doses of recAP. In the second stage 170 additional patients will be recruited in two arms of 85 patients, which will receive either the best dose of recAP as identified in stage one, or placebo.
Background information on the adaptive trial design:
AM-Pharma starts adaptive phase II trial of recAP in AKI
BioCentury 2015 Adapting for speed.pdf