information: Presentation of results at a congress
Announcement: presentation of results at the 61st Annual Meeting of the American Society of Hematology (ASH)
Company: Sangamo Therapeutics (USA - CA)
- gene therapy/genome editing product. Sangamo has developed an adeno-associated virus (AAV) carrying a clotting Factor VIII gene construct driven by Sangamo's proprietary synthetic liver specific promoter. The SB-525 vector encodes a liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing the potential for long-term hepatic production of FVIII in hemophilia A subjects.
- SB-525 is being developed as part of a global collaboration between Sangamo and Pfizer for the development and commercialization of gene therapy programs for Hemophilia A.
Disease: hemophilia A
area: Rare diseases - Genetic diseases - Hematological diseases
- The Alta trial is an open-label, adaptive, dose-ranging clinical study designed to assess the safety and tolerability of SB-525 investigational gene therapy in up to 20 adult subjects with severe hemophilia A. (NCT03061201)
- • On December 7, 2019, Sangamo Therapeutics announced updated follow-up results from the Phase 1/2 Alta study evaluating investigational SB-525 gene therapy in patients with severe hemophilia A. The data showed that SB-525 was generally well tolerated and demonstrated sustained increased Factor VIII levels following treatment with SB-525 through to 44 weeks, the extent of follow-up for the longest treated patient in the 3e13 vg/kg dose cohort. Data from 11 patients treated with SB-525 have been featured in a poster presentation today, December 7, 2019, at the 61st Annual Meeting of the American Society of Hematology (ASH) in Orlando.
Alta study data presented at ASH included 11 patients treated across four ascending dose cohorts: 9e11 vg/kg (2 patients), 2e12 vg/kg (2 patients), 1e13 vg/kg (2 patients) and 3e13 vg/kg (5 patients). The data cutoff date was October 17, 2019.An analysis of plasma FVIII antigen was assessed by ELISA and demonstrated antigen concentrations consistent with the FVIII activity measured by the chromogenic assay. Dose dependent increases in FVIII activity over baseline were observed across the dose cohorts. The lower-dose cohorts indicate durable FVIII activity with up to 52 weeks of follow-up.
In the 3e13 vg/kg dose cohort, patients achieved normal range FVIII activity within 5-7 weeks of treatment with SB-525. The first two patients treated in this cohort (Patients 7 and 8) have achieved stable FVIII levels, demonstrating durability in the normal range through 44 and 37 weeks, respectively, as measured by the chromogenic assay. The two patients most recently treated in this cohort (Patients 10 and 11), with 22 and 12 weeks of follow-up, respectively, demonstrated a similar pattern of FVIII expression. The FVIII expression pattern observed in Patient 9 differed from that of other patients in the cohort. Seven weeks following treatment, Patient 9 achieved normal range FVIII levels. Beginning at week 13, FVIII levels in that patient fluctuated in a range below normal, but still well above the level needed to prevent spontaneous bleeding. At week 18, FVIII levels in Patient 9 began to increase, and as of the latest measurement at week 24, continued to rise. No patient in the 3e13 vg/kg dose cohort has experienced bleeding events up to 44 weeks of follow-up, and no patient in this dose cohort required factor replacement following initial use of prophylactic factor.
SB-525 was generally well tolerated across all dose cohorts. The treatment-related adverse events include: alanine aminotransferase (ALT) elevation (36.4%, n=4), pyrexia (27.3%, n=3), increased aspartate aminotransferase (18.2%, n=2), tachycardia (18.2% n=2), fatigue (9.1%, n=1), hypotension (9.1%, n=1) and myalgia (9.1%, n=1). Treatment-related serious adverse events (SAEs) of hypotension (grade 3) and fever (grade two) occurred in one patient in the 3e13 vg/kg cohort six hours following dosing with SB-525 that fully resolved within 24 hours. No similar events were reported in the other patients dosed in that cohort. No patients treated with SB-525 experienced an ALT elevation associated with loss of Factor VIII expression. In the 3e13 vg/kg dose cohort, four patients experienced transient low grade ALT elevations (>1.5 x baseline) that were managed with a tapering course of oral steroids. The study does not use corticosteroids prophylactically, initiating them only in the event of an ALT elevation that is greater than 1.5x baseline.
Sangamo has completed the manufacturing technology transfer and initiated the transfer of the Investigational New Drug (IND) Application to Pfizer, which is expected to be completed in the first quarter 2020. Pfizer is enrolling patients in the Phase 3 lead-in study, the data from which is expected to provide a baseline for patients who are subsequently enrolled into the Phase 3 study (NCT03587116).
• On July 5, 2019, Sangamo Therapeutics announced updated results from the Phase 1/2 Alta study evaluating SB-525 gene therapy for severe hemophilia A. The data showed that SB-525 was generally well-tolerated and demonstrated a dose-dependent increase in Factor VIII activity levels. The first two patients treated at the 3e13 vg/kg dose rapidly achieved normal levels of FVIII activity as measured using a chromogenic assay, with no reported bleeding events, and the response continues to be durable for as long as 24 weeks, the extent of follow-up.
The two patients more recently treated at the 3e13 vg/kg dose level are demonstrating FVIII activity kinetics that appear consistent with the first two patients treated in this dose cohort at similar early time points. Data from 10 patients treated with SB-525 were presented during an oral presentation on July 6 at the XXVII Congress of the International Society on Thrombosis and Haemostasis (ISTH), in Melbourne, Australia.
Alta study data presented at ISTH included 10 patients treated across four ascending dose cohorts: 9e11 vg/kg (2 patients), 2e12 vg/kg (2 patients), 1e13 vg/kg (2 patients) and 3e13 vg/kg (4 patients). Factor VIII activity data presented at ISTH included results through June 18, 2019. All other data presented at ISTH were as of May 30, 2019.
Across the dose cohorts, patients demonstrated a dose-dependent increase in FVIII levels and a dose-dependent reduction in the use of FVIII replacement therapy. In the two patients treated with the 1e13 vg/kg dose, FVIII activity levels have been durable through weeks 52 and 32. For the four patients in the 3e13 vg/kg cohort, FVIII activity data were available through 24, 19, 6, and 4 weeks of follow-up, respectively. The first two patients treated in the 3e13 vg/kg cohort (Patients 7 and 8) remained in the normal range, as measured using a chromogenic assay, through 24 and 19 weeks of follow-up, respectively. The next two patients in the 3e13 vg/kg cohort (Patients 9 and 10), with 6 and 4 weeks of follow-up, respectively, demonstrated rapid FVIII activity kinetics that appear consistent with Patients 7 and 8 at similar early time points. Also noted in the presentation at ISTH, Patient 9 attained normal FVIII activity levels at week 7, subsequent to the data transfer for the conference. No patient in the 3e13 vg/kg dose cohort has experienced bleeding events as of the data cut-off date, nor have patients in this dose cohort required factor replacement following initial use of prophylactic factor.
- SB-525 was generally well tolerated. Patients in the Alta study were not treated with prophylactic steroids. One treatment-related serious adverse event (SAE) was reported. This patient experienced hypotension and fever six hours after completion of SB-525 infusion; this fully resolved with treatment and the patient was discharged as planned within 24 hours. No similar hypotension event was observed in the three subsequent patients dosed. Adverse events observed in 10% (n=1) or more patients included: increased alanine aminotransferase (30%) and aspartate aminotransferase (10%), pyrexia (30%), fatigue (10%), hypotension (10%), myalgia (10%), and tachycardia (10%). No patients treated with SB-525 have experienced an alanine aminotransferase (ALT) elevation associated with a loss of Factor VIII expression. In the 3e13 vg/kg cohort, two subjects experienced a transient grade 1 ALT elevation (>1.5 x baseline) managed with a tapering course of oral steroids.
- Based on the accumulating results from the Alta study, the FDA has granted regenerative medicine advanced therapy (RMAT) designation for SB-525 gene therapy to treat severe hemophilia A. RMAT designation is granted to regenerative medicine therapies intended to treat, modify, reverse, or cure a serious condition, for which preliminary clinical evidence indicates that the medicine has the potential to address an unmet medical need. The RMAT designation includes all the benefits of the fast track and breakthrough therapy designation programs, including early interactions with FDA.
The fifth patient in the 3e13 vg/kg cohort (Patient 11) is expected to be treated soon. Sangamo and Pfizer are working on plans to advance SB-525 to a registrational study. Pfizer will assume responsibility for SB-525 late-stage development and manufacturing. Transfer of the SB-525 manufacturing process from Sangamo to Pfizer has been initiated.
- • On August 8, 2018, Sangamo Therapeutics announced positive preliminary data from the Phase 1/2 clinical trial evaluating SB-525, a cDNA gene therapy candidate for Hemophilia A (the "Alta study"). To date, five patients have been treated at three dose levels. A sixth patient is scheduled for treatment later this month. During the initial dose escalation phase, this study enrolls two patients per dose cohort.
- Preliminary Observations: In the Alta study, SB-525 has been generally well tolerated to date with no treatment-related serious adverse events and no use of tapering courses of oral steroids. The fifth patient in the study, the first at the third dose level, was treated in June and has achieved therapeutic Factor VIII activity levels.
A dose dependent effect has been observed in the study, with patients in the second dose cohort reporting reduced use of factor replacement.
Sangamo and Pfizer expect to present detailed data from the Alta study at a hematology conference in the fourth quarter.
- • On August 25, 2017, Sangamo Therapeutics and Pfizer announced that the first patient received treatment in the Phase 1/2 clinical trial ("the Alta trial") evaluating SB-525, an investigational gene therapy for patients with hemophilia A.
- • On January 5, 2017, Sangamo BioSciences announced that the FDA has cleared its Investigational New Drug application (IND) for the SB-525 gene therapy program for the treatment of hemophilia A. The IND is now active and enables clinical development to assess the safety, tolerability and potential efficacy of SB-525 in adults with hemophilia A. SB-525 is one of four lead development programs for which Sangamo is planning to conduct clinical trials in 2017. Sangamo is evaluating SB-FIX, an in vivo genome editing therapy for hemophilia B, in a Phase 1/2 clinical trial, with sites currently screening patients for the study. This year Sangamo will also conduct two Phase 1/2 clinical trials evaluating in vivo genome editing therapies for lysosomal storage disorders MPS I (SB-318) and MPS II (SB-913).