Ilofotase alfa

Trial will evaluate ilofotase alfa as a treatment to prevent renal damage in at-risk patients following open heart surgery Ilofotase alfa’s clinical record of renal protective effects supports therapeutic potential in underserved and high-need indication Utrecht, The Netherlands, January 16, 2024 – AM-Pharma B.V. today announced that the first patients have been treated in a Phase 2 clinical study evaluating the company’s proprietary recombinant alkaline phosphatase, ilofotase alfa, as a preventive treatment for cardiac surgery-associated renal damage (CSA-RD). With over 2 million open heart surgeries[1] performed worldwide every year, CSA-RD represents a critical surgical complication for which there is no specific pharmacological therapy. CSA-RD is defined as the long-term loss of renal function in cardiac surgery patients and arises from acute kidney injury (AKI) immediately following the surgery. CSA-AKI occurs in approximately 1 out of 3 patients undergoing open heart surgery and is the predominant risk factor for death post-surgery, with 2-5% of patients requiring renal replacement therapy as a result. Ilofotase alfa has a proven safety and tolerability profile and a strong record of renal protective effects as observed in previous clinical studies. Notably, prior Phase 2 and Phase 3 trials with ilofotase alfa demonstrated significant improvements in Major Adverse Kidney Events by day 90 (MAKE90) in sepsis-associated AKI. As recently reported in a publication[2] on the REVIVAL Phase 3 trial, MAKE90 events were reduced to 57.2% of patients in the ilofotase alfa group compared to 64.7% in the placebo group. “Previous clinical trials showed ilofotase alfa had significant reno-protective effects in sepsis-associated AKI patients. Given the role of AKI in long-term renal impairment in cardiac surgery patients, ilofotase alfa preventative treatment could have substantial clinical benefits on renal function and potentially save lives,” said Peter Pickkers, MD, PhD, Principal Investigator in the Phase 2 study and Professor of Experimental Intensive Care Medicine at Radboud University Nijmegen Medical Centre, The Netherlands. The multicenter, double-blind, randomized, placebo-controlled Phase 2 trial will evaluate the efficacy and safety of ilofotase alfa as a preventive treatment in 150 patients scheduled for cardiac surgery and at risk for CSA-RD. Treatment will be administered intravenously before and after surgery, with a follow-up period of 60 days. The primary endpoint will be the ratio between pre- and post-surgery creatinine levels. Important exploratory endpoints will be the incidence of Major Adverse Kidney Events (MAKE) and the incidence and severity of AKI post-surgery. The trial is planned to end in Q4 2024 with a data readout expected in early 2025. Ilofotase alfa was recently evaluated in a Phase 1b pilot study as enzyme replacement therapy in hypophosphatasia (HPP) patients. “With the initiation of the Phase 2 trial in CSA-RD following the positive results from the Phase 1b study in HPP we have achieved important progress toward establishing ilofotase alfa’s potential through our updated clinical development strategy. We are confident in our new trajectory and remain committed to delivering a therapeutic solution for patients in these two severe, high-need conditions,” said Juliane Bernholz, PhD, Chief Executive Officer of AM-Pharma. “The clinical centers we are working with show great enthusiasm for our approach with ilofotase alfa and we look forward to the data readout.” About ilofotase alfa Ilofotase alfa is a proprietary recombinant alkaline phosphatase, constructed from two human isoforms of alkaline phosphatase, that has been shown to be stable and highly active in multiple clinical trials. The recombinant enzyme displays exquisite activity towards dephosphorylating and detoxifying damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), ATP, ADP and other extracellular substrates that drive acute inflammation, coagulation and microvascular ischemia found in kidney following sepsis or ischemia-induced damage. Research has shown that ATP dephosphorylation has a double effect in protecting against kidney injury. When the pro-inflammatory ATP is dephosphorylated, the resulting adenosine further reduces inflammation through the activation of the immunosuppressive adenosine A2a receptor pathway. In hypophosphatasia, ilofotase alfa addresses elevated levels of pyridoxal-5′-phosphate (PLP), inorganic pyrophosphates (PPi), two disease-related biomarkers that are related to bone mineralization and pain sensation, for example. About cardiac surgery-associated renal damage (CSA-RD) CSA-RD is a clinical complication that arises from acute kidney injury (AKI) following open heart surgery performed with the use of a cardiopulmonary bypass (CPB) pump. Apart from sepsis, this type of surgery is the most frequent cause of AKI. CSA-AKI occurs in about 1 in 3 patients undergoing this surgical procedure.[3] Pre-operative and intra-operative measures can be taken to reduce the risk of AKI, and post-operative management strategies may also help mitigate further damage.[4] However, there is currently no pharmacological therapy to prevent AKI, and the kidney injury can result in long-term renal impairment and the need for renal replacement therapy (RRT) such as dialysis. Notably, mortality can be up to 50% in CSA-AKI patients who require RRT post-operatively. About AM-Pharma AM-Pharma strives to develop medicines for patients confronted with severe medical conditions. Our proprietary asset, ilofotase alfa, is being developed for the treatment of patients with acute kidney injury (AKI) and has been granted FDA fast-track status. We also develop ilofotase alfa in the severe rare disease hypophosphatasia where ilofotase alfa has orphan drug status in the US and EU. With approximately 1,000 subjects evaluated to date in clinical trials, ilofotase alfa has a proven safety profile and a demonstrated kidney benefit. We are a dedicated team driven to bring treatment options to severely ill patients, their families and acute care professionals. Find out more about us online at: www.am-pharma.com. Contacts Investors: Juliane Bernholz, Chief Executive Officer j.bernholz@am-pharma.com Media: Trophic Communications Gretchen Schweitzer or Priscillia Perrin +31 6 52 33 15 79 am-pharma@trophic.eu [1] https://www.nhlbi.nih.gov/health/heart-surgery [2] Pickkers P et al., Intensive Care Med., 2024 [3] Andújar A et al., Front. Nephrol., 2023 [4] Ostermann M et al., J Clin Med., 2021

• Ilofotase alfa demonstrates pharmacologically relevant effect on disease specific biomarkers and a positive safety profile in adult patients with hypophosphatasia; • Data to be presented by Lothar Seefried, MD, at the American Society for Bone and Mineral Research’s Symposium on Rare Bone Diseases on Thursday, October 12, 2023 Utrecht, The Netherlands, October 11, 2023 – AM-Pharma B.V. today announced positive clinical results from the Phase 1b study evaluating the company’s proprietary recombinant alkaline phosphatase, ilofotase alfa, as potential enzyme replacement therapy in adult hypophosphatasia (HPP) patients. HPP is an inherited metabolic disease, characterized by low activity of tissue non-specific alkaline phosphatase (TNAP), caused by mutations at the ALPL gene. This low activity leads to accumulation of inorganic pyrophosphate (PPi), a strong inhibitor of mineralization, as well as pyridoxal-5’-phosphate (PLP), an important cofactor for enzymes. The disease can range widely in severity, however most adults with HPP suffer from recurrent fractures, muscle weakness, joint diseases and pain.[1] In the open-label pilot trial, a total of 12 patients were randomly assigned to one of two treatment arms and received a single intravenous dose of either 0.8 mg/kg or 3.2 mg/kg. Patients were followed for 10 days after dosing to evaluate changes in the biochemical fingerprint of HPP, safety and tolerability. The primary objectives for the study were changes in serum levels of PLP and PPi as compared to baseline. For PLP, the maximum proportional reduction was 35% in the 0.8 mg/kg cohort and 66% in the 3.2 mg/kg cohort. The mean time to return to 90% of baseline was 55 hours in the low-dose cohort and 168 hours in the high-dose cohort. The maximal proportional reduction for PPi was 36% in the 0.8 mg/kg cohort and 77% in the 3.2 mg/kg cohort. The mean time to return to 90% of baseline was 9.3 hours in the low-dose cohort and 53 hours in the high-dose cohort. In addition, ilofotase alfa was well-tolerated with pharmacokinetics consistent with observations from previous clinical studies. “The pronounced effect on all HPP disease relevant biomarkers together with a positive safety and tolerability profile, consistent with previous clinical studies with ilofotase alfa, supports its further development as a treatment option for adult HPP patients who are currently underserved,” said Juliane Bernholz, PhD, Chief Executive Officer of AM-Pharma. The full dataset will be presented at the American Society for Bone and Mineral Research – Rare Bone Disease Alliance (ASBMR-RBDA) Symposium at the Vancouver Convention Centre in Vancouver, BC, Canada. The presentation by Lothar Seefried, MD, from the University of Wuerzburg, lead investigator of the trial, is scheduled for 3:00 pm PDT on Thursday, October 12, 2023, in session III: Latest in Clinical trials. “Considering the wide range of clinical manifestations of HPP, there’s an unequivocal need to expand therapeutic opportunities for these patients,” added Lothar Seefried, MD. “The encouraging early results confirming dose-dependent reductions of PLP and PPi levels upon treatment with ilofotase alfa underline the compound’s therapeutic potential in that indication and I’m looking forward to evaluating ilofotase alfa in next stage clinical studies.” About ilofotase alfa Ilofotase alfa is a proprietary recombinant alkaline phosphatase, constructed from two human isoforms of alkaline phosphatase, that has been shown to be stable and highly active in multiple clinical trials. The recombinant enzyme displays exquisite activity towards dephosphorylating and detoxifying damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), ATP, ADP and other extracellular substrates that drive acute inflammation, coagulation and microvascular ischemia found in kidney following sepsis or ischemia-induced damage. Research has shown that ATP dephosphorylation has a double effect in protecting against kidney injury. When the pro-inflammatory ATP is dephosphorylated, the resulting adenosine further reduces inflammation through the activation of the immunosuppressive adenosine A2a receptor pathway. In hypophosphatasia, ilofotase alfa addresses elevated levels of pyridoxal-5′-phosphate (PLP), inorganic pyrophosphates (PPi), two disease related biomarkers that are related to, for example, bone mineralization and pain sensation. About hypophosphatasia HPP is a rare inherited disease characterized by a deficiency in alkaline phosphatase which is essential for bone mineralization and general functions. HPP patients of all ages can exhibit a wide variety of symptoms that worsen overtime, including bone injury, severe muscle pain and weakness. The disease can also lead to life-threatening complications in infants. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted AM-Pharma Orphan Drug Designation (ODD) for ilofotase alfa in HPP. In preclinical models, ilofotase alfa was able to achieve improved overall survival of severe disease, as well as restoration of phenotypes associated with HPP. About AM-Pharma AM-Pharma strives to develop medicines for patients confronted with severe medical conditions. Our proprietary asset, ilofotase alfa, is being developed for the treatment of patients with acute kidney injury and has been granted FDA fast-track status. We also develop ilofotase alfa in the severe rare disease hypophosphatasia where ilofotase alfa has orphan drug status in the US and EU. With approximately 1,000 subjects evaluated to date in clinical trials, ilofotase alfa has a proven safety profile and a demonstrated kidney benefit. We are a dedicated team driven to bring treatment options to severely ill patients, their families and acute care professionals. Find out more about us online at: www.am-pharma.com. [1] Tournis, S., Yavropoulou, M. P., Polyzos, S. A., & Doulgeraki, A. (2021). Hypophosphatasia. Journal of Clinical Medicine, 10(23), 5676. CONTACTS Investors: Juliane Bernholz, Chief Executive Officer j.bernholz@am-pharma.com Media: Trophic Communications Eva Mulder or Priscillia Perrin +31 6 52 33 15 79 am-pharma@trophic.eu