Clinical Trials

Date: 2018-07-23

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the WORLD Symposium 2019

Company: Sangamo Therapeutics (USA - CA)

Product: SB-318 (adeno-associated virus serotype 2/6 (rAAV2/6) vectors encoding zinc finger nucleases (ZFNs) and the human alpha-L-iduronidase (hIDUA) gene)

Action mechanism:

• gene therapy/genome editing product. Using Sangamo's zinc finger nuclease (ZFN) genome editing technology, SB-318 is designed as a single treatment strategy intended to provide stable, continuous production of the alpha-L-iduronidase (IDUA) enzyme for the lifetime of the patient.
• SB-318 makes use of Sangamo's zinc finger nuclease (ZFN) genome editing technology that is designed to insert a corrective copy of the IDUA gene into a precise location in the DNA of liver cells with the goal of enabling a patient's liver to produce a lifelong and stable supply of enzyme. To restrict editing to liver cells, the ZFNs and the corrective gene are delivered in a single intravenous infusion using AAV vectors that target the liver. The ZFNs enter the cells as inactive DNA instructions in a format designed only for liver cells to unlock. Once "unlocked", the ZFNs then identify, bind to and cut the DNA in a specific location within the albumin gene. Using the cells' natural DNA repair processes, liver cells can then insert the corrective gene at that precise location.
• SB-318 has received Orphan Drug, Fast Track and Rare Pediatric Disease designations from the FDA, as well as Orphan Medical Product designation by the European Medicines Agency (EMA).

Disease: mucopolysaccharidosis I (Hurler syndrome)

Therapeutic area: Rare diseases - Genetic diseases

Country: USA

Trial details:

• The EMPOWERS Study is an open-label, ascending dose clinical trial designed to assess the safety, tolerability and preliminary efficacy of SB-318 in up to nine adult subjects with attenuated MPS I. The study is currently screening subjects at hospitals specializing in the care of patients with MPS I, including hospitals in Oakland, Gainesville, Atlanta, Minneapolis, New York and Cincinnati. (NCT02702115)

Latest news:

• • On February 7, 2019, Sangamo Therapeutics presented interim data from the Phase 1/2 EMPOWERS Study evaluating the SB-318 zinc finger nuclease (ZFN) in vivo (inside the body) genome editing product candidate in patients with Mucopolysaccharidosis Type I (MPS I). These data were presented  at the WORLDSymposium 2019 being held in Orlando, Florida. "The results so far suggest a dose-dependent increase in leukocyte IDUA enzyme activity," said Dr. Paul Harmatz, a professor at UCSF Benioff Children's Hospital Oakland and a lead investigator on the study. "Leukocytes are an easily accessible target tissue for IDUA and therefore provide an estimate of tissue enzyme activity for patients with MPS I. Whether these observed increases will translate into clinical benefit from SB-318 is yet to be determined."
• The primary objective of the EMPOWERS Study is to determine the safety and tolerability of SB-318, and secondary objectives include evaluation of change from baseline in IDUA activity and urine GAG levels. Biochemical measurements of urinary GAGs, as well as plasma and leukocyte IDUA activity, are assessed at screening and baseline visits, and every two to four weeks during the initial phase of the trial.
• Patients with mild MPS I receiving weekly ERT were enrolled in the study. One patient has been dosed with 1e13 vector genomes per kilogram body weight (vg/kg) of SB-318 and two patients have been dosed with 5e13 vg/kg of SB-318. None of the three patients enrolled in the study have received a bone marrow transplant.
• Safety data were collected and analyzed for the three patients. Administration of SB-318 was generally well tolerated. No treatment related serious adverse events (SAEs) have been reported. Of the six total adverse events (AEs) reported, all were mild or moderate and consistent with ongoing MPS I disease, and none were considered related to SB-318 treatment. The results suggest a dose-dependent increase in leukocyte IDUA activity, with activity levels rising above baseline and in the normal range (normal range is 6.0-71.4 nmol/hr/mg). Plasma IDUA activity was unchanged from baseline in all three patients. Baseline urine GAG measurements for the three patients in the EMPOWERS Study were in a range considered to be at or slightly above normal. In the limited duration data set available at the time of the WORLDSymposium presentation, urine GAG measurements show no meaningful change. The clinical relevance of the biochemical changes observed following administration of SB-318 will be assessed as clinical data and patient outcomes are analyzed following a trial of withdrawal from ERT. ERT withdrawal is expected for these patients later in 2019. Sangamo also expects to report analyses of liver biopsies later this year.
• • On July 23, 2018, Sangamo Therapeutics announced treatment of the first patient in the Phase 1/2 clinical trial evaluating SB-318, an investigational in vivo genome editing therapy for patients with mucopolysaccharidosis type I (MPS I, Hurler syndrome) (the "EMPOWERS Study").
• • On June 4, 2018, Sangamo Therapeutics announced that the Medicines and Healthcare Products Regulatory Agency (MHRA) of the United Kingdom has granted the Clinical Trial Authorisation (CTA) for enrollment of subjects into ongoing Phase 1/2 clinical trials evaluating SB-318, zinc finger nuclease (ZFN) in vivo genome editing treatment for Mucopolysaccharidosis Type I (MPS I).
• The SB-318 CTA application was based on the protocol of the ongoing Phase 1/2 clinical trial which includes only adult patients. Sangamo plans this year to request a protocol amendment for the SB-318 study to include younger patients.
• Sangamo expects to initiate clinical trial sites in the U.K. later this year for the SB-318  Phase 1/2 clinical trials.

Is general: Yes