Cockayne Syndrome

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--(BUSINESS WIRE)-- 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 surgeries1 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 pro 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 publication2 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 pro 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: . 1 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 View source version on businesswire.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 Source: AM-Pharma View this news release online at:

ROSWELL, Ga., Dec. 4, 2023 /PRNewswire/ -- Roivios Ltd., a medical device company pioneering a revolutionary treatment to reduce poor surgical outcomes associated with Acute Kidney Injury (AKI), today announces that the final patient has been enrolled in the BIPASS-AKI study for the JuxtaFlow Renal Assist Device (RAD). The Institute of Cardiovascular Diseases, Sremska Kamenica in Serbia was the highest enrolling site, led by principal investigator Prof Dr Milovan Petrovic, cardiac surgeon Prof Dr Lazar Velicki and urologist Dr Dimitrije Jeremic. Additional study sites include The American Heart Hospital in Bielsko Biala, Poland and The Institute for Cardiovascular Diseases Dedinje, Serbia. "When we began this feasibility trial, we anticipated the use of the JuxtaFlow RAD to be an exciting moment," said Prof. Petrovic. "We frequently perform cardiac surgery on patients with renal impairment and they are among our most complicated cases, so we are proud to have enrolled several patients into this study to contribute insights into this novel therapy in advance of its pivotal trial." Cardiac surgery-associated AKI (CSA-AKI) occurs in up to 73% of patients who have pre-existing renal insufficiency documented as part of their standard pre-surgical workup1. This type of AKI then impacts a patient's ability to recover from surgery, leading to a longer and more costly hospital stay, a higher risk of morbidity and mortality, and a more frequent need for chronic dialysis treatment2-5. The JuxtaFlow RAD is used in the hospital setting and is designed to enable the kidneys to function optimally and thereby improve overall patient outcomes. "The mission of Roivios is to give clinicians the tools to protect, preserve and improve kidney function. Cardiac surgery is a major stress on the kidneys, and today these patients have few options. Our team is inspired to design a system that would assist critical renal function during times of acute stress, employing an innovative solution that enhances the kidneys' own natural function to support recovery.", said John Erbey, PhD, Chief Executive Officer of Roivios. "We are incredibly excited to have completed the first step in providing this novel therapy for at-risk patients and serve as the bridge to their successful recovery. We look forward to sharing this BIPASS-AKI data shortly and then continuing to partner with hospitals, surgeons, and critical care teams around the world who share our vision for reducing this all-too-frequent adverse event of surgery." The BIPASS-AKI feasibility trial was being conducted pursuant to the regulations of both ALIMS in Serbia and URPL in Poland. Ten patients were enrolled between September and December. The JuxtaFlow RAD is not commercially available in any geography. The system is limited by United States law to Investigational Use Only and is not available for sale in the United States. For more information about the JuxtaFlow RAD system, please visit For more information about BIPASS-AKI, see Contact John Erbey, PhD, Chief Executive Officer [email protected] Shen W, Aguilar R, Montero AR, et al. Acute Kidney Injury and In-Hospital Mortality after Coronary Artery Bypass Graft versus Percutaneous Coronary Intervention: A Nationwide Study. Am J Nephrol. 2017;45(3):217-225. Bowdish ME, D'Agostino RS, Thourani VH, et al. STS Adult Cardiac Surgery Database: 2021 Update on Outcomes, Quality, and Research. Ann Thorac Surg. 2021;111(6):1770-1780. Robert AM, Kramer RS, Dacey LJ, et al. Cardiac surgery-associated acute kidney injury: a comparison of two consensus criteria. Ann Thorac Surg. 2010;90(6):1939-1943. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury prediction following elective cardiac surgery: AKICS Score. Kidney Int. 2007;72(5):624-631. Brown JR, Kramer RS, Coca SG, Parikh CR. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann Thorac Surg. 2010;90(4):1142-1148. About Roivios Roivios® is a medical device company pioneering a novel renal assist device designed to reduce or eliminate acute kidney injury (AKI) in patients who are at elevated risk. Initially focused on meeting an unmet need of cardiac surgery associated-acute kidney injury (CSA-AKI) in the coronary artery bypass and surgical valve population, our pioneering renal assist device has the potential to address a range of poor outcomes. Our first product, the JuxtaFlow Renal Assist Device, is the world's first negative pressure renal assist device, featuring a patented catheter and unique energy delivery system. SOURCE Roivios, ltd

LIKMEZ™ (metronidazole) Oral Suspension, the First and Only FDA-Approved Liquid Option for Patients with Adherence Hurdles such as Dysphagia, Difficulty Swallowing Kesin Pharma Launches Novel Formulation of Mainstay Anti-Infective, Metronidazole Kesin Pharma: Solutions for Better Health™ OLDSMAR, Fla.--(BUSINESS WIRE)-- Kesin Pharma Corporation, a pharmaceutical company focused on innovative Specialty brands and Unit Dose formulations, announced today that the U.S. Food and Drug Administration (FDA) has approved LIKMEZ™ (metronidazole) oral suspension, 500 mg/5 mL. Available now, LIKMEZ™ is the first and only FDA-approved ready-to-use oral liquid metronidazole in the U.S. market. LIKMEZ™ is a novel presentation of a mainstay antibiotic drug, reinvented to address common adherence issues. Kesin is the exclusive U.S. commercialization partner for LIKMEZ™ through its collaboration with Saptalis Pharmaceuticals, LLC, the developer and NDA holder of the product. LIKMEZ™ is a novel proprietary liquid formulation of metronidazole for patients who may struggle with dysphagia, difficulty swallowing, or high taste sensitivities. These potential compliance and persistency obstacles can lead to treatment discontinuation and inefficient treatment outcomes, including rebound infection. LIKMEZ™ is approved for the treatment of trichomoniasis and anaerobic bacterial infections in adults and amebiasis in adults and pediatric patients. LIKMEZ™ comes in a 200 mL bottle as a strawberry peppermint flavored suspension, with a 24-month shelf life and does not require refrigeration. Metronidazole has been shown to be carcinogenic in mice and rats, and the most common adverse reactions to metronidazole include nausea, headache, anorexia, vomiting, diarrhea, abdominal cramping, epigastric distress, and constipation. LIKMEZ™ addresses inherent risks associated with crushing tablets for those patients needing a liquid formulation and eliminates the potential inconsistences associated with extemporaneously compounding metronidazole prescriptions. Additionally, compounding can amplify the pronounced bitter, metallic taste of metronidazole tablets, which can also negatively influence patients’ adherence to therapy. “LIKMEZ™ is for patients and providers who need a liquid option for those faced with adherence obstacles due to taste sensitivities or difficulty swallowing. An increasing number of patients can benefit from a safe and efficacious product that can support medication adherence. We are very excited with our first brand launch which is part of our upcoming pipeline of novel products, designed to address unmet patient needs and bring value to the healthcare system,” said Narasimhan Mani, President & CEO of Kesin Pharma Corporation. “We are pleased with our partnership with Saptalis Pharmaceuticals, the NDA holder and manufacturer of LIKMEZ™. The timely approval of this NDA505(b)(2) presents a significant opportunity for Kesin Pharma to bring a value-added product to the market,” said Narasimhan Mani. LIKMEZ™ will be available through most full-line wholesalers and retail pharmacies. To learn more and view Full Prescribing Information, including complete BOXED WARNING and additional Safety Information see . About Kesin Pharma Kesin Pharma Corporation, based in Oldsmar, FL, is a specialty pharmaceutical company with deep experience and strong capabilities in commercial sales & marketing, distribution, and market access. Kesin’s mission is to provide unique healthcare solutions to patients through our portfolio of strategic, value-driven brand and unit-dose products. Kesin Pharma works closely with patients, payers, and provider partners to bring to market innovative pharmaceutical products to better address unfulfilled needs and enhance patient adherence and accessibility. For more information, visit . About Saptalis Pharmaceuticals, LLC Saptalis Pharmaceuticals, LLC is a rapidly growing pharmaceutical company specialized in development, manufacturing, and commercialization of generic and innovative products in liquid and semi-solid dosage forms. Located in the Hauppauge Industrial Park on Long Island, NY, USA, Saptalis has fully equipped Research & Development Laboratories and state of the art commercial scale manufacturing facility designed to meet FDA cGMP requirements. For more information, visit . Important Safety Information INDICATIONS AND USAGE LIKMEZ™ (metronidazole) is a nitroimidazole antimicrobial indicated for: Trichomoniasis in adults Amebiasis in adults and pediatric patients Anaerobic Bacterial Infections in adults To reduce the development of drug-resistant bacteria and maintain the effectiveness of LIKMEZ™ and other antibacterial drugs, LIKMEZ™ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. WARNING: POTENTIAL FOR CARCINOGENICITY Metronidazole has been shown to be carcinogenic in mice and rats. Avoid unnecessary use of LIKMEZ™. Reserve LIKMEZ™ for use in the following indications: trichomoniasis, amebiasis, and anaerobic bacterial infections. See full prescribing information for complete BOXED WARNING. CONTRAINDICATIONS Hypersensitivity Reactions: LIKMEZ is contraindicated in patients with known hypersensitivity to metronidazole or other nitroimidazole derivatives. Psychotic Reactions with Disulfiram: LIKMEZ is contraindicated in patients who have used disulfiram within the last two weeks. Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Interaction with Alcohol: LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least three days after LIKMEZ therapy. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Cockayne Syndrome: LIKMEZ is contraindicated in patients with Cockayne syndrome. WARNINGS AND PRECAUTIONS Potential for Carcinogenicity: Metronidazole has been shown to be carcinogenic in mice and rats. Reserve LIKMEZ for use in the following indications: trichomoniasis, amebiasis, and anaerobic bacterial infections. Central and Peripheral Nervous System Effects: Encephalopathy, aseptic meningitis, peripheral neuropathy (including optic neuropathy) and convulsive seizures have been reported with metronidazole. The appearance of abnormal neurological signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy. Fungal Superinfections: Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with LIKMEZ and requires treatment with an antifungal agent. Blood Dyscrasias: LIKMEZ is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. Total and differential leukocyte counts are recommended before and after therapy. Drug-Resistant Bacteria: Prescribing LIKMEZ in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Adverse Reactions The most serious adverse reactions in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole. In addition, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia have been reported. The most common adverse reactions reported: Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic: Erythematous rash and pruritus. Hematopoietic: Reversible neutropenia (leukopenia); reversible thrombocytopenia. Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T‑wave may be seen in electrocardiographic tracings. Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness”. Cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause-and-effect relationship has not been established. Crohn’s disease is not an approved indication for LIKMEZ. DRUG INTERACTIONS Disulfiram: Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. LIKMEZ is contraindicated in patients who have taken disulfiram within the last two weeks. Alcoholic Beverages: LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least 3 days after therapy with LIKMEZ. Use of LIKMEZ with alcohol or other products containing propylene glycol is associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) Warfarin and other Oral Anticoagulants: Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When LIKMEZ is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. Lithium: In patients stabilized on relatively high doses of lithium, short-term use of LIKMEZ has been associated with elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations for several days after beginning treatment with LIKMEZ to detect any increase that may precede clinical symptoms of lithium toxicity. Busulfan: Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer LIKMEZ concomitantly with busulfan unless the benefit outweighs the risk. Inhibitors of CYP450 Liver Enzymes: The simultaneous administration of LIKMEZ and drugs that decrease microsomal liver enzymes, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. Inducers of CYP450 Liver Enzymes: The simultaneous administration of LIKMEZ and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported. Drugs that Prolong the QT Interval: QT prolongation has been reported. Drug/Laboratory Test Interactions: Metronidazole may interfere with certain types of determinations of serum chemistry values. Values of zero may be observed. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary: Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Lactation Risk Summary: There are no data on the effects of metronidazole on milk production. Pediatric Use: The safety and effectiveness of LIKMEZ for the treatment of amebiasis have been established in pediatric patients. The safety and effectiveness of LIKMEZ for the treatment of trichomoniasis and anaerobic bacterial infections have not been established in pediatric patients. Geriatric Use: In elderly geriatric patients, monitoring for LIKMEZ associated adverse events is recommended. Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage. Renal Impairment: Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for LIKMEZ associated adverse events is recommended. Hepatic Impairment: Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment, reduce the dose of LIKMEZ by 50%. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for LIKMEZ associated adverse reactions. OVERDOSAGE There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy. In case of an overdose, patients should contact a physician, poison control center, or emergency room. Please see full Prescribing Information, including BOXED WARNING at LIKMEZ™ and the stylized LIKMEZ™ logo are registered trademarks of Saptalis Pharmaceuticals, LLC. LIKMEZ™ is marketed by Kesin Pharma Corporation. © 2023 Kesin Pharma Corporation. All rights reserved.