Study recruitment was temporarily stopped. Due to a lethal case at site 4401 (concerns patient 4401-001) a thorough investigation has been started by Akinion Pharmaceuticals to understand the cause of death and possible relationship to the study drug. After conducting an ad hoc safety meeting that involved several leading independent experts of AML disease and liver toxicology, a decision has been taken to put enrolment in the study on a halt until further clarifications of the case and recommendations of the Data Safety Monitoring Committee (DSMC) are available. No patients were being treated in the study at the time of recruitment interruption. The hold was removed upon receiving applicable approval(s) for Protocol Amendment 2 of 14 December 2012.

On 12 March 2014 Akinion Pharmaceuticals made a decision to temporarily interrupt the inclusion of new patients into the clinical study. The company had to solve a technical issue with the formulation of AKN-028. Study AKN001 was initiated late 2011. Seven patients were treated before the study recruitment was temporarily interrupted during summer of 2012. Several patients were treated with the dose of 360 mg BID before the discontinuation and several pharmacokinetic assessments were performed on these patients. The median systemic exposure (assessed as AUC) was 5877 nM hrs (n=7) during 2012. After reinitiation of the study 2013, the systemic exposure of the study medication has been disappointing. The median exposure at 360 mg BID was only 531 nM hrs during 2013 (n=10J, clearly below the exposure levels anticipated for therapeutic effects. The solubility of the study medication is highly pH dependent, and strongly favored by acidic conditions. Therefore, several actions have been introduced in a step-wise manner, aim ing to ensure acidic conditions in the stomach of the patients at the time of drug intake. These actions included; clarification that proton pump inhibitors such as omeprazole must be avoided, intake of drug together with food, and acidic drink (orang.e juice). These actions were successful in elevating the exposure level as shown by a median exposure of 2135 nM hrs for 2014 (n=4). However, this is significantly below the 2012 exposure levels. Importantly, both drug substance and drug product reached the respective specifications at all tested time points, showing that the present testing does not detect the subtle differences causing differential uptake. A thorough investigation has been started by Akinion Pharmaceuticals to understand what has caused a reduction in exposure. A decision has therefore been taken to temporarily discontinue recruitment of new patients into the study. Recruitment restarted with Protocol Amendment 4 of 28 November 2014.

On 4s of March 2015 Akinion Pharmaceuticals AB made a decision to halt recruitment into the clinical study AKN001 and to terminate all clinical work on drug candidate AKN-028 due to safety concerns. Clinical study AKN001was initiated in 2011. To date 25 patients have been treated with AKN-028. During the course of the study two patients have experienced liver events. ln August 2012 a patient died due to liver failure. The event was assessed as related to the AKN-028 treatment by an independent committee of experts in hepatology. lt was recommended to continue the study with shorter cycle lengths and more frequent monitoring of liver enzymes. ln February 2016 a patient developed rapid increases in ALT and AST enzymes after initiation of a second treatment cycle with AKN-028. The pattern of changes in laboratory values was of a similar kind as in the previous patient. The treatment was stopped immediately and the patient recovered fully. The reaction was assessed as related to AKN-028 with no contributing factors. Based on these two events with one fatal outcome in a small study population the risk-benefit balance was judged to be negative and that no further patients should be administered the drug.