Societal Relevance

University of Groningen: As postdoc at the RUG, Klaas Poelstra discovered the role of the enzyme alkaline phosphatase in tissues to detoxify LPS in 1997 (ref 1-4) and he patented the therapeutic use of this enzyme to treat sepsis and other LPS-mediated diseases (patent 1). This patent and publications, as well as subsequent patents and publications were the driving force for a number of start-up companies, pre-clinical development programs and therapeutic compounds that are now tested in multiple clinical Phase I, II and III trials in many academic centers and hospitals around the world.

AM-Pharma: Patent 1 formed in 2001 the basis for the start-up company PharmAAware (press release 1), now called AM-Pharma (www.am-pharma.com ). In subsequent years this company obtained over 60 million Euro for further preclinical development of alkaline phosphatase preparations and for Phase I and II clinical trials in several academic centers around the world in patients with sepsis, ulcerative colitis and sepsis-induced acute kidney disease. These phase II trials were finished with positive results in different patient groups (press release 2,3,4). In 2020, the company raised 163 million Euro to support a phase III clinical trial (REVIVAL trial) in patients with sepsis-induced acute kidney diseases using their Recombinant Alkaline Phosphatase (Recap) enzyme (press release 5). In November 2020 the first patient was enrolled in this trial (press release 6). The target enrolment is 1,600 patients at ICUs in Europe, United Kingdom and North America. In January 2021 Am-Pharma announced the financing and start of an extra COVID-10 cohort in this Phase III trial (press release 7). 

Alloksys & AMRIF: Additional publications (ref 5,6) and patents (patents 2,3) on the therapeutic use of alkaline phosphatase formed the basis for the start-up company Alloksys Life Sciences (www.alloksys.com), and its sister company AMRIF (www.amrif.eu). These companies explore the use of this enzyme in several other acute and chronic inflammatory disease applications respectively. In 2017, among others the first patient was recruited in the global clinical phase 2b/3 study of Alloksys (APPIRED III) in cardiothoracic surgery to test their rescuing alkaline phosphatase enzyme (RESCAP) in 9 clinical centers around the world (press release 8). Solid organ transplantation studies and burn wound trauma trials are also ongoing.  In 2020 Alloksys received a fast-tract approval for RESCAP intervention using RESCAP in critically ill SARS-COV2 infected patients admitted to ICU’s in 4 hospitals in and outside the Netherlands (press release 9).

BiOrion: The research line on drug targeting has yielded several innovative drug carriers and cell-specific therapeutic proteins for the treatment of liver fibrosis (ref 7-10, patent 4,5), which has led to the start-up company BiOrion Technologies BV in 2003 (www.biorion.com). Klaas Poelstra was co-founder and the first chief scientific officer of this company until 2012. The lead product, representing a bi-cyclic PDGF-receptor-targeted construct, was further developed in a pre-clinical trajectory for the imaging and treatment of liver fibrosis and colon carcinoma.  In 2020, a consortium was created to support the start of a phase I clinical trial in NASH patients for the diagnosis of liver fibrosis using BOT501i  (Heptoscan) in Uppsala (press releases 10,11). In September 2020, the first patient was enrolled in Sweden.

Selected references:

1. Poelstra K, Bakker WW, Klok PA, Hardonk MJ, Meijer DK. A physiologic function for alkaline phosphatase: Endotoxin detoxification. Lab Invest 1997; 76 (3): 319-327.
2. Poelstra K, Bakker WW, Klok PA, Kamps JA, Hardonk MJ, Meijer DK. Dephosphorylation of endotoxin by alkaline phosphatase in vivo. Am J Pathol 1997; 151(4): 1163-1169.
3. Bentala H, Verweij WR, Huizinga-Van der Vlag A, van Loenen-Weemaes AM, Meijer DK, Poelstra K. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock 2002; 18(6): 561-566.
4. Verweij WR, Bentala H, Huizinga-van der Vlag A, Miek van Loenen-Weemaes A, Kooi K, Meijer DK, Poelstra K. Protection against an escherichia coli-induced sepsis by alkaline phosphatase in mice. Shock 2004; 22(2): 174-179.
5. Tuin A, Huizinga-Van der Vlag A, van Loenen-Weemaes AM, Meijer DK, Poelstra K. On the role and fate of LPS-dephosphorylating activity in the rat liver. Am J Physiol Gastrointest Liver Physiol 2006; 290(2): G377-85.
6. Tuin A, Poelstra K, de Jager-Krikken A, Bok L, Raaben W, Velders MP, Dijkstra G. Role of alkaline phosphatase in colitis in man and rats. Gut 2009; 58(3): 379-387.
7. Bansal R, Prakash J, Post E, Beljaars L, Schuppan D, Poelstra K. Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 2011; 54(2): 586-596.
8. Bansal R, Prakash J, de Ruijter M, Beljaars L, Poelstra K. Peptide-modified albumin carrier explored as a novel strategy for a cell-specific delivery of interferon gamma to treat liver fibrosis. Mol Pharm 2011; 8(5): 1899-1909.
9. Bansal R, Prakash J, De Ruiter M, Poelstra K. Targeted recombinant fusion proteins of IFNgamma and mimetic IFNgamma with PDGFbetaR bicyclic peptide inhibits liver fibrogenesis in vivo. PLoS One 2014; 9(2): e89878.
10. Bansal R, Prakash J, De Ruiter M, Poelstra K. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo. J Control Release 2014; 179: 18-24.

Patents (source: Espacenet):

1. Poelstra K, Bakker WW, Hardonk MJ, Meijer DKF. Pharmaceutical composition comprising phosphatase or a derivative thereof. International patent application nr. PCT/NL94/00189 (refiling of PCT/NL93/00171, priority date August 1993). Patent is filed in Australia (1999), in the USA (2001), Japan and Europe.
2. Poelstra K, Brands R. The LPS-binding moiety of alkaline phosphatase as a diagnostic tool in patients with sepsis. International patent application nr. PCT/NL98/00722. Priority date: Dec. 21, 1998. Regional applications in Europe, USA, Japan, Australia, Canada.
3. Brands R, Poelstra K. Use of alkaline phosphatase for the detoxification of LPS present at mucosal barriers. International patent application nr. PCT/NL2005/000084 Priority date: Febr. 4, 2004.
4. Poelstra K, Beljaars L, Schuppan D, Meijer DKF. Peptide-based carrier devices for stellate cells and other cell-types involved in chronic inflammatory and fibrotic disorders. International patent application nr. PCT/NL98/00579. Priority date: Oct. 8, Patent pending in Europe and Japan. Patent filed in Australia (2004), USA (2005), Hong Kong (2005) and Canada (2005).
5. Poelstra, R. Bansal,  J. Prakash, L. Beljaars.   “Interferon analogs”  EP09181049   RUG/STW Patent application. Priority date: Dec 31, 2009

 Press Releases:

1. Wetenschappelijke vondst groeit uit tot nieuw bedrijf. Press release RUG, 22 okt 2001.
2. Dutch Biopharmaceutical Company AM-Pharma announces positive results in its double-blind, placebo controlled Phase IIa Sepsis trial with Alkaline Phosphatase, 20th October 2006; Am-Pharma Media Centre.
3. AM-Pharma announces positive results of Phase IIa clinical trial with Alkaline Phosphatase for ulcerative colitis, 9th July 2007; Am-Pharma Media Centre
4. AM-Pharma announces Phase II study results of RECAP in sepsis-associated acute kidney injury, 9th March 2018; Am-Pharma Media Centre.
5. AM-Pharma Increases Funding to €163m for Phase-III Trial of recAP in SA-AKI, 31st March 2020; Am-Pharma Media Centre.
6. AM-Pharma Announces Enrollment of the First Patient in REVIVAL Phase III Pivotal Trial in Patients with Sepsis-Associated Acute Kidney Injury, 12th November 2020; Am-Pharma Media Centre.
7. AM-Pharma Announces Enrollment and Financing of COVID-19 Cohort in Phase III REVIVAL Trial, 7 January, 2021; Am-Pharma Media Center.
8. APPIRED III Clinical study kicked off with first patient recruited, 16 November 2017; Alloksys New blog.
9. COVID19 RESCAP intervention. Participating hospitals and sister company Alloksys receive fast track approval, May 30, 2020; Amrif Home page.
10. BiOrion Technologies, Zealand Pharma and Akademiska Sjukhuset Uppsala receive a EUROSTARS grant for their € 1.8 M fibrosis imaging program BONIFIB, September 26, 2017; BiOrion Press release.

11.BiOrion concluded investment by a consortium of investors including Pharma         Connect Capital, March 4, 2019; Biorion.com/news.