close

Clinical Trials

Date: 2017-07-10

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress

Company: Pfizer (USA - NY) Spark Therapeutics (USA - PA)

Product: SPK-9001

Action mechanism: gene therapy. SPK-9001  is an adeno-associated viral vector composed of a bioengineered AAV capsid and a codon-optimized expression cassette encoding a high-specific activity variant of human coagulation factor IX. Spark Therapeutics and Pfizer entered into a collaboration in 2014, under which Spark will be responsible for conducting all Phase 1/2 studies for any product candidates that may be developed under the SPK-FIX program, while Pfizer will assume responsibility for pivotal studies, any regulatory activities and potential global commercialization of any products that may result from the collaboration.

Disease: hemophilia B

Therapeutic area: Rare diseases - Genetic diseases - Hematological diseases

Country: USA

Trial details: This phase 1/2 trial is an open-label, dose-escalation study of SPK-9001 [adeno-associated viral vector with human factor IX gene] in subjects with hemophilia B. (NCT02484092)

Latest news:

  • • On July 10, 2017,  Spark Therapeutics announced that 10 participants in its ongoing Phase 1/2 clinical trial of SPK-9001 for hemophilia B, as of the June 5, 2017 data cut off, had their AIR reduced approximately 99 percent to a mean of 1.0 annual infusion as of the data cut-off date, compared with 67.5 annual infusions before SPK-9001 administration.
  • These interim data presented at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress indicate that nine of the 10 participants have not experienced a bleed since vector infusion; overall ABR was reduced by approximately 96 percent to a mean of 0.4 annual bleeds, compared with 11.1 bleeds before a single administration of 5 x 1011 vector genomes (vg)/kg body weight of SPK-9001. These data represent approximately 9.63 cumulative patient years of SPK-9001 exposure from the start of the trial, with one participant out approximately 18 months post-infusion and four additional participants out at least one year post-infusion. All 10 trial participants have shown consistent and sustained increases in factor IX activity level and a discontinuation of routine infusions of factor IX concentrates. Their mean steady-state factor IX activity level, or the average of each participant’s average activity level after 12 weeks, was 33 percent.
  • The first participant enrolled in the trial, who, as of June 22, 2017, had been followed for approximately 18 months post-infusion of SPK-9001, reduced to zero his number of intravenous factor IX infusions without having any bleeds. In the 12 months before SPK-9001 administration, he infused factor IX concentrates a total of 98 times and still experienced four breakthrough bleeds. His mean steady-state factor IX activity level after SPK-9001 administration was 33 percent of normal at the 18-month mark post-infusion.
  • As of the June 5, 2017 data cut-off date, nine of the 10 infused participants have not taken factor IX concentrates to prevent or control bleeding events since vector administration. As previously reported, one participant with severe joint disease has self-administered precautionary infusions for persistent knee pain. In the clinical trial to date, no serious adverse events (SAEs) have been reported, including no factor IX inhibitors and no thrombotic events.
  • As reported in December 2016, two of the 10 participants experienced an asymptomatic, transient elevation in liver enzymes, associated with a decline in factor IX activity in one of those participants, potentially indicative of an immune response to the Spark100 vector capsid. Elevations in alanine aminotransferase (ALT) occurred several weeks post infusion, and rapidly returned to baseline with a tapered course of oral corticosteroids. Both participants have continued to demonstrate stable factor IX activity levels, now 18 and 12 weeks’ post-cessation of steroids, respectively. Neither of these participants has experienced a bleed nor taken factor concentrates.
  • • On April 7, 2017, Spark Therapeutics announced updated preliminary data from 10 infused participants in the ongoing Phase 1/2 clinical trial of  SPK-9001 for hemophilia B. All participants have experienced consistent and sustained increases in factor IX activity following administration of the investigational therapy. These data have been  presented at the Hemostasis and Thrombosis Research Society (HTRS) 2017 Scientific Symposium by Adam Cuker, M.D., assistant professor of medicine at the Perelman School of Medicine of the University of Pennsylvania and a clinical investigator at Children’s Hospital of Philadelphia.
  • Data as of March 24, 2017 have been presented on 10 participants in the study, who were dosed with a single administration of 5 x 1011 vector genomes (vg)/kg body weight. All participants have discontinued routine infusions of factor IX concentrates. Based on individual patient history prior to the study, ABR was reduced by 96 percent to a mean of 0.39 annual bleeds, compared with 9.2 bleeds before SPK-9001 administration. AIR was reduced 99 percent to a mean of 0.98 annual infusions, compared with 68.5 infusions before SPK-9001 administration.
  • As of the data cutoff, nine of the 10 infused participants have not taken factor IX concentrates to prevent or control bleeding events since vector administration. As previously reported, one participant with severe joint disease has self-administered precautionary infusions for persistent knee pain. The mean steady-state factor IX activity level post 12 weeks treatment for the 10 participants was a sustained 33 percent (range as of the data cutoff: 14 to 81 percent). In the study to date, no serious adverse events have been reported, including no factor IX inhibitors and no thrombotic events. These data represent more than 2,400 cumulative patient days of exposure from the start of the trial.
  • Two of the 10 participants experienced an asymptomatic, transient elevation in liver enzymes, or decline in FIX activity, potentially indicative of an immune response to the Spark100 vector capsid, that occurred several weeks post infusion. Both participants received a tapering dose of oral corticosteroids, after which their alanine aminotransferase (ALT) levels returned to baseline. The activity level of one of these participants has stabilized at approximately 15 percent for more than nine weeks post corticosteroid use. The other participant had a factor IX activity level between 70 to 80 percent at completion of steroid use.
  • • On December 3, 2016, Spark Therapeutics and Pfizer announced updated preliminary data from the first nine infused participants in the ongoing Phase 1/2 clinical trial of investigational SPK-9001 for hemophilia B, who received a single administration of 5 x 1011 vector genomes (vg)/kg body weight. These data have been presented  at the Plenary Scientific Session of the 58th American Society of Hematology (ASH) Annual Meeting, in San Diego. The first participant to reach one year in the study, who has been followed for 52 weeks post-infusion of SPK-9001, has reduced to zero his number of intravenous factor IX infusions without having any bleeds. In the year before administration of SPK-9001, he infused factor IX concentrates prophylactically a total of 98 times and still experienced four traumatic bleeds. As of Nov. 30, 2016 , his steady-state factor IX activity level was 33 percent of normal.
  • As of Nov. 30, 2016 , the total clotting factor IX concentrates consumption in all nine infused participants over a cumulative 1,650 patient days following vector administration was reduced by 1.13 million international units based on their factor IX concentrates usage in the year before vector administration. Seven of the nine infused participants, who have progressed to at least 12 weeks post-vector administration as of Nov. 30, 2016 , experienced consistent and sustained factor IX activity levels, with a mean steady-state level greater than 28 percent. In the study to date, no participants developed factor IX inhibitors or experienced thrombotic events after the vector administration. No serious adverse events after SPK-9001 administration have been reported.
  • Two of the nine participants experienced asymptomatic, transient elevation in liver enzymes associated with an immune response to the Spark100 vector capsid during the first four to eight weeks following administration. In one participant, this response was accompanied by a decline in factor IX activity level from 32 to 12 percent, as of Nov. 30, 2016 . In the other participant, to whom steroids were administered more promptly, this response was accompanied by a decline from a peak factor IX activity level of 71 to 68 percent, as of Nov. 30, 2016 . Both participants were put on a tapering course of corticosteroids, and, to date, neither participant has experienced any bleeds nor has required infusion of replacement factor IX concentrates.
  • Eight of the infused participants have required no factor IX concentrates to prevent or control bleeding events since the day after vector administration. One participant with severe joint disease self-administrated a precautionary infusion two days after administration of SPK-9001 for a suspected ankle bleed and again at week 35, post the data cut-off date and despite a factor IX activity level of 36 percent, for a suspected knee bleed.
  • Additionally, to date, six of seven participants reported increased physical activity and improved quality of life based on the Haemophilia Quality of Life Questionnaire for Adults, a validated instrument that measures health-related quality of life in adults (? 17 years of age) with hemophilia. Two participants received the gene therapy product too recently to evaluate quality-of-life measures.
  • • On July 25, 2016, Spark Therapeutics and Pfizer announced updated results of the first cohort from the ongoing Phase 1/2 clinical trial of SPK-9001 in development for the treatment of hemophilia B. Data presented at the 2016 International Congress of the World Federation of Hemophilia (WFH), current as of July 12, 2016, show that the low dose cohort of four subjects enrolled in the study experienced consistent and sustained factor IX activity levels following a single administration of SPK-9001 at the initial dose level (5 x 1011 vg/kg) studied in the trial. Across the four subjects, average steady-state factor IX activity levels are 31.8% ±6.9% (range 20% - 44%) of normal, determined by averaging levels beginning at 8 weeks post vector administration through follow up over 12-31 weeks. No sustained elevation in liver enzyme levels were seen. To date, SPK-9001 has been well-tolerated and no subjects have needed, or received, immunosuppression. None of the first four subjects, through a combined 76 weeks of observation, has received infusions of factor IX concentrates to prevent bleeding events. Only one precautionary infusion has taken place due to a suspected ankle bleed in one subject two days after administration of vector.
  • • On June 13, 2016, Spark Therapeutics announced updated results of the first cohort from the ongoing Phase 1/2 clinical trial of SPK-9001, which is being studied for the treatment of hemophilia B. These data were presented on June 11 at the 21st Congress European Hematology Association (EHA) by Dr. Spencer Sullivan, an Assistant Professor of Pediatrics and Medicine at the University of Mississippi Medical Center and a trial investigator, and were an extension of the data released on May 19th in the initial EHA abstract. Data presented show that the low dose cohort of four subjects enrolled in the study experienced consistent and sustained factor IX activity levels following a single administration of SPK-9001 at the initial dose level (5 x 1011 vg/kg) studied in the trial. Factor IX activity in the first two subjects, which had no history of liver disease, rose consistently and have stabilized at 28% of normal through the first approximately twenty-six weeks post-administration in the first subject, and at 41% of normal at fifteen weeks post-administration in the second. Factor IX activity level in the third subject, with a history of liver disease, also rose consistently and was at 26% of normal at approximately ten weeks post-administration. The fourth subject, also with a history of liver disease and not included in the previously disclosed data, saw a clinical response similar to the earlier subjects and was at 33% of normal through approximately seven weeks.
  • To date, over a combined 58 weeks of observation, none of the first four subjects received regular infusions of factor IX concentrates to prevent bleeding events. One precautionary infusion took place due to a suspected ankle bleed in subject number three two days after administration. Based on their pre-enrollment histories, it is estimated that the four subjects followed to date would have received more than 100 infusions of recombinant factor IX over the period of the study to prevent or treat bleeds as part of their normal care. Across the cohort, we saw no sustained elevation in liver enzyme levels and no drop in factor IX levels. To date, SPK-9001 has been well-tolerated and no subjects have needed, or received, immunosuppression.
  • •  On May 19, 2016, Spark Therapeutics and Pfizer announced that new data will be presented on June 11 at the European Hematology Association’s (EHA) 21st Congress. These data will show encouraging initial observations for the first subjects dosed in the Phase 1/2 clinical trial of SPK-9001, the lead investigational compound in the SPK-FIX program, which is being studied for the treatment of Hemophilia B. Data available demonstrate that the first three subjects enrolled in the study experienced AAV-mediated Factor IX activity levels following one administration of SPK-9001 at the initial dose level (5 x 1011 vg/kg) studied in the trial. Factor IX activity levels in the first two subjects, without prior history of liver disease, rose consistently through the first four weeks post-administration. At the time of abstract submission, the first subject stabilized at 28% of normal at eighteen weeks, and the second subject at 30% of normal at seven weeks post-administration. Factor IX activity level in the third subject, with a history of liver disease, also rose consistently and was at 16% of normal at three weeks post-administration. Data from a natural history of patients with hemophilia suggest that circulating factor activity levels sustained at a threshold of greater than or equal to 12% of normal generally are considered to be sufficient to reduce the risk of joint bleeds and the need for prophylactic clotting factor infusions. Over the combined 28 weeks of observation reported in the abstract, none of the three subjects received regular infusions of Factor IX concentrates to prevent bleeding events. Only one precautionary infusion has taken place due to a suspected ankle bleed in one subject two days after administration of vector. SPK-9001 has been well-tolerated and no subjects have needed, or received, immunosuppression.

Is general: Yes