Clinical Trials

Date: 2015-09-30

Type of information: Publication of results in a medical journal

phase: preclinical

Announcement: publication of results in the British Journal of Pharmacology

Company: AM-Pharma (The Netherlands)

Product: recAP - recombinant alkaline phosphatase

Action mechanism:

• enzyme. recAP (recombinant Alkaline Phosphatase) is a proprietary recombinant human alkaline phosphatase constructed from two naturally occurring human isoforms of the AP enzyme. This hybrid is highly stable and active, and has been optimised for treating inflammatory conditions. It is being developed as an injectable for the treatment of acute kidney injury and hypophosphatasia, and an oral formulation for ulcerative colitis.

Disease: hypophosphatasia

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country:

Trial details:

Latest news:

• • On September 30 2015, AM-Pharma, a biopharmaceutical company focused on the development of recAP (recombinant human Alkaline Phosphatase), announces the publication of two papers on recAP for the potential treatment of Acute Kidney Injury (AKI). The first, published in the British Journal of Pharmacology (BJP), describes recAP's likely mode of action to protect against tissue damage during renal inflammation. The second, published in the International Journal of Pharmaceutics, covers the biodistribution and pharmacokinetics of recAP in relevant animal models. The first author of both papers was Esther Peters (Department of Intensive Care Medicine, and Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands). In the BJP paper, the investigators used in vitro models to show that recAP attenuated lipopolysaccharide (LPS)-induced and adenosine triphosphate (ATP)-mediated inflammation in human peritubular epithelial cells (kidney barrier cells). As such, the investigators concluded that recAP's anti-inflammatory mode of action in this model, likely results from its dephosphorylating enzymatic activity of LPS and ATP. Additionally, kidney function (measured as glomerular filtration rate) was improved, as demonstrated by FITC sinistrin clearance, in rats exposed to an LPS-challenge and receiving recAP versus placebo.
• In the second paper, the researchers firstly investigated biodistribution of recAP in rat and minipig models to support dose selection for clinical trials. The investigators used rats with LPS-induced AKI and observed distribution of recAP throughout the body. They observed that the liver was the primary site of accumulation, where recAP is cleared from the body.
• The research also included pharmacokinetic studies in rats and minipigs to measure plasma concentrations of recAP after single and multiple doses. recAP exhibits a linear-dose exposure relationship and clearance in a biphasic manner. Repeated dosing in both models was well tolerated. • On December 2, 2014, AM-Pharma announced that preclinical data on recAP, to treat the ultra rare disease hypophosphatasia, have been published in the journal Bone. The senior investigator of the study is Dr. José Luis Millán, of Sandford-Burnham Medical Research Institute, La Jolla, CA, USA, and world-leading researcher in Hypophosphatasia. In the study, mice with severe hypophosphatasia, due to a genetic defect (knock-out) in one of the genes encoding for alkaline phosphatase, were administered daily subcutaneous injections of recAP at doses of 1, 8 or 16mg/kg, from birth up to 53 days. This resulted in normal lifespans and body weights of the mice, whilst untreated mice died after 20 days. A combination of imaging techniques showed improved mineralisation in both cortical (compact) and trabecular (spongy) bone, as well as in secondary ossification centres in the longer bones. In the highest dose group, recAP showed improved molar tooth development and function. Furthermore, seizures, which are commonly associated with severe hypophosphatasia, were absent in treated mice and there was neither evidence of craniosynostosis (premature ossification of the skull), nor ectopic calcification (bone deposits in soft tissues).
• • On November 13, 2014, AM-Pharma has presented further preclinical data on its drug candidate recAP, at the American Society of Nephrology (ASN) meeting Kidney Week in Philadelphia, PA, USA. The research was conducted by Professor Bruce A. Molitoris, MD FASN, and his team at the Indiana University School of Medicine, Indianapolis, IN, USA. RecAP is currently in clinical development for Acute Kidney Injury (AKI). The research presented in the ASN poster used two-photon microscopy fluorescence imaging to monitor kidney function in rat models of Ischemia-Reperfusion Injury-induced AKI. At 24 hours post-AKI induction, the study quantified both plasma creatinine (PCr) levels and Glomerular Filtration Rate (GFR).
• The results show in Sprague-Dawley rats that clamping of the renal pedicle and contralateral nephrectomy induced a significant rise in PCr from ~0.4 ml/dL prior to AKI induction to 3.2 ± 0.59 mg/dL after 24 h. Treatment results showed that over a wide dose range (50-2000 U/kg) a single intravenous administration of recAP significantly reduced PCr (1.7 ± 0.65 mg/dl at 500 U/kg) (p<0.01). Similarly, in Munich-Wistar Frömter rats, PCr rose from t 0.38 ± 0.04 mg/dL to to 2.28 ± 0.64 mg/dL post-AKI and a single dose of 1000 U/kg recAP limited PCr to 0.82 ± 0.15 mg/dL (p<0.003). Also, control AKI rats demonstrated a GFR of 0.09 ± 0.09 ml/min, compared to 0.75 ± 0.29 ml/min in recAP treated rats (p<0.003).

 

Is general: Yes