Clinical Trials

Date: 2017-07-11

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the 26th Biennial Congress of the International Society on Thrombosis and Hemostasis (ISTH)

Company: uniQure (The Netherlands) Chiesi Farmaceutici (Italy)

Product: AAV5-hFIX - AMT-060

Action mechanism:

• gene therapy. AAV5-hFIX is an AAV5 vector carrying a therapeutic human Factor IX, or hFIX, gene cassette that uniQure has exclusively licensed from St. Jude Children’s Research Hospital in Memphis, Tennessee. It consists of a codon-optimized wild type FIX gene cassette, the LP1 liver promoter and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform.
• AMT-060 is being co-developed with Chiesi for Europe.

Disease: hemophilia B

Therapeutic area: Genetic diseases- Hematological diseases - Rare diseases

Country: Denmark, Germany, The Netherlands

Trial details:

• This phase I/II trial is an open-label, uncontrolled, single-dose, dose-ascending, multi-centre trial investigating an adeno-associated viral vector containing a codon-optimized human Factor IX gene (AAV5-hFIX) administered to adult patients with severe or moderately severe hemophilia B. The study includes 10 patients each receiving a one-time, 30-minute, intravenous administration of AMT-060, without the prophylactic use of corticosteroids. It study includes two dose cohorts of five patients each, with the first cohort receiving 5x10¹² gc/kg and the second cohort receiving 2x10¹³ gc/kg.
• Nine patients in the trial were classified as having severe (<1% FIX activity) hemophilia. One patient in the low-dose cohort had a moderate/severe (1.5% FIX activity) phenotype. Patients in the low-dose cohort were characterized by poorly controlled bleeding manifestations despite use of high-dose FIX replacement therapy during the year prior to study compared to the second-dose cohort.All but one patient in the study across both cohorts required chronic infusions of prophylactic FIX therapy at the time of enrollment. The remaining patient, who is in the second dose cohort, used FIX therapy on demand. (NCT02396342).

Latest news:

• • On July 11, 2017, uniQure presented new clinical data demonstrating that the presence of pre-existing anti-AAV5 neutralizing antibodies (NABs) does not predict the potential efficacy of AAV5-mediated gene transfer in patients with hemophilia B. Clinically meaningful factor IX (FIX) activity levels from the ongoing Phase I-II trial of AMT-060 were observed at NAB titers up to 1:341, determined as corresponding up to the 90th percentile of a healthy control population. NABs were quantified in the blood sera of these patients using a highly sensitive assay. These clinical data were presented in a poster presentation at the 26th Biennial Congress of the International Society on Thrombosis and Hemostasis (ISTH).
• The presence of pre-existing NABs to adeno-associated virus (AAV) vectors has long posed a critical challenge for the clinical application of gene therapies, as patients who currently screen positive for NABs are generally excluded from treatment. Researchers from uniQure recently presented data in non-human primates suggesting that AAV5 could successfully mediate gene transfer in the presence of NABs at levels as high as 1:1031. In a poster presentation at the ISTH meeting, a re-analysis was described of pre-gene transfer screening samples from the 10 patients who have been treated in the ongoing Phase I/II trial of AMT-060 for hemophilia B. The patients had tested negative for pre?existing anti-AAV5 NAbs using a green fluorescent protein?based (GFP) assay before receiving treatment. These samples were later re-assessed using a highly sensitive luciferase-based (LUC) NAB assay. Anti-AAV5 NABs were detected retrospectively in three patients who had been treated with the low dose (5x1012 gc/kg) of AMT-060. However, all three patients presented increases in FIX expression and, especially, the patient with the highest NAB level (titer 1:341) had the highest FIX-activity (steady-state FIX 6.8% of normal; latest FIX measurement 10.7% of normal) among all five patients treated in the low-dose cohort. None of the three patients who tested positive for NAB titers, experienced over time elevations in liver enzymes post gene transfer, FIX activity loss, or clinically relevant T-cell responses to the capsid. "These clinical data show that hemophilia B patients presenting with neutralizing antibodies may be considered eligible for AAV5-mediated gene transfer," stated Matthew Kapusta, chief executive officer at uniQure.
• • On July 10, 2017, uniQure has announced updated results from its ongoing, dose-ranging Phase I/II trial of AMT-060 in an oral presentation at the 26th Biennial Congress of the International Society on Thrombosis and Haemostasis (ISTH). The data includes up to 18 months of follow-up from the low-dose cohort and up to one year of follow-up from the second dose cohort. The AAV5-based AMT-060 remains safe and well-tolerated with up to a year and a half of follow-up, with no serious adverse events and no development of inhibitors. All patients are now past one year of follow up with no loss of Factor IX (FIX) activity and no capsid-specific T-cell activation.
• One-year follow-up data from the second-dose cohort continue to show a dose response with substantial improvement in disease state in all five patients, including the discontinuation of routine prophylactic FIX infusions in all patients that previously required chronic replacement therapy. The annualized spontaneous bleeding rate for the second dose cohort declined 84% to a mean of 0.5 annual bleeds after gene transfer. During more than 1,700 cumulative patient days of observation, only one patient in the second cohort reported two unconfirmed spontaneous bleeds, and no such bleeds were reported by any patient during the last six months of observation.
• Data as of May 12, 2017: All 10 patients in the study have demonstrated improvements in their disease state as measured by reduced FIX replacement therapy and bleeding frequency. In the second-dose cohort, no spontaneous bleeds were reported in the last six months of follow-up, with a reduction in the annualized spontaneous bleed rate of 84% compared to the one-year period prior to administration of AMT-060. Total bleeds were reduced by 64%.
• As previously announced, eight of the nine patients that required chronic FIX infusions prior to administration of AMT-060 have discontinued prophylaxis after treatment. All eight patients remained prophylaxis-free at the last follow up. Across both dose cohorts, cumulative annualized FIX consumption decreased by 79%, from 2.64 million to 544,741 IU. Through up to 12 months of follow-up among the five patients in the second-dose cohort, the mean steady-state FIX activity persisted at approximately 7% of normal. The mean FIX activity at the last follow-up (52 weeks) was 8.82%, ranging from 5.2% to 10.7%. AMT-060 continues to be well-tolerated, and there have been no severe adverse events. In both dose cohorts, FIX activity remained consistent and stable through up to 18 months of follow-up with no emergence of late immune response or loss of FIX activity in any of the patients.
• As previously announced, three patients experienced mild, asymptomatic elevations of alanine aminotransferase (ALT) soon after administration. For these patients, ALT levels returned to their baseline readings, no recurrence of ALT elevation has occurred, and no loss of FIX activity was observed.  No patients across either cohort have developed inhibitory antibodies against FIX, or demonstrated sustained AAV5 capsid-specific T-cell activation.
• • On December 4, 2016, uniQure announced new and updated results from its ongoing, dose-ranging Phase I/II trial of AMT-060 in patients with severe hemophilia B. The data includes up to 52 weeks of follow-up from the low-dose cohort and up to 31 weeks of follow-up from the second dose cohort. New data presented from the second-dose cohort show a dose response with substantial improvement in disease state in all five patients, including the discontinuation of precautionary Factor IX (FIX) infusions in all four patients that previously required chronic replacement therapy. To date, only one spontaneous bleed was reported after discontinuation of prophylactic FIX replacement therapy.
• All five patients in the low-dose cohort, who bleedings were previously uncontrolled despite being managed with prophylactic therapy, continue to maintain robust, constant and clinically meaningful levels of FIX activity for up to 52 weeks post treatment, with a complete cessation of spontaneous bleedings in the last 14 weeks of observation.
• These clinical data from both patient cohorts were presented at the 58th American Society of Hematology (ASH) Annual Meeting taking place in San Diego, California.
• Key Data Update from Phase I/II Clinical Trial of AMT-060 in Hemophilia B Patients - Data as of October 15, 2016:  All 10 patients in the study have demonstrated improvements in their disease state as measured by reduced FIX replacement therapy and bleeding frequency. In the second-dose cohort, only one spontaneous bleeding episode was reported over a period of 96 weeks of combined patient observation, representing a reduction in the annualized spontaneous bleed rate of 76% compared to the one-year period prior to administration of AMT-060.
• Bleeding data was also evaluated from the low-dose cohort. The frequency of spontaneous bleeds declined significantly over time, with no spontaneous bleeds reported by any patient in their last 14 weeks of observation. With up to 52 weeks of follow-up, the annualized spontaneous bleed rate for the four patients that discontinued prophylactic FIX infusions was reduced by 59% compared to the one year period prior to administration of AMT-060. The one patient in the low-dose cohort that remained on prophylaxis also experienced a 45% reduction in spontaneous bleeds.
• Eight of nine patients in the study that required chronic FIX infusions prior to administration of AMT-060, including all such patients in the second dose cohort, discontinued prophylaxis and remained prophylaxis-free at the last follow up (22-52 weeks).
• Among the four patients in the low-dose cohort that discontinued prophylaxis, annualized consumption of FIX concentrate following AMT-060 administration was reduced substantially by more than a cumulative total of 1,329,000 international units (85%), compared to their pre-trial usage levels. The one patient who remained on prophylactic FIX therapy in the low-dose cohort has reduced frequency of bleeding episodes and also requires materially less FIX concentrate after treatment with AMT-060.
• Through up to 6 months of follow-up among the five patients in the second-dose cohort, the mean steady-state FIX activity was approximately 7% of normal, with expression up to a FIX activity of 13% of normal.
• In both dose cohorts, FIX activity remained consistent and stable through up to one year of follow up with no emergence of late immune response or loss of FIX activity in any of the patients.
• AMT-060 continues to be well-tolerated, and there have been no severe adverse events. Three out of the total of 10 patients (two in the second-dose cohort and one previously reported from the low-dose cohort) experienced mild, asymptomatic elevations of alanine aminotransferase (ALT) and received a tapering course of corticosteroids per protocol. Importantly, the temporary elevations in ALT were not associated with any loss of endogenous FIX activity or T-cell response. No patients across either cohort have developed inhibitory antibodies against FIX, or demonstrated sustained AAV5 capsid-specific T-cell activation.
• AMT-060 continues to demonstrate a very low screening failure rate, with all patients screened in the study testing negative for pre-existing anti-AAV5 NABs. To date, 25 patients have been screened for pre-existing anti-AAV5 NABs with a fully validated assay across several clinical studies with only one patient excluded due to a borderline positive result. This collective data set suggests that a large proportion of the hemophilia patient population may be eligible for treatment with AMT-060.
• • On November 30, 2015, uniQure announced that the first cohort of five hemophilia B patients has been dosed in the Phase 1/2 study of AMT-060.
• • On April 6, 2015, uniQure provided an update on multiple gene therapy programs. As of the end of the first quarter 2015, the company has initiated the first clinical trial site in Germany for its clinical trial in hemophilia B patients and anticipates providing top-line data and initial results on this trial in the second half of 2015.

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