Sangamo Therapeutics, Inc. 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, along with interim results of the CHAMPIONS Study evaluating SB-913 for MPS II, were presented today at the WORLDSymposium 2019 being held in Orlando, Florida. Sangamo believes data from these two studies provide complementary evidence supportive of a favorable safety profile and of the activity of the ZFN in vivo genome editing technology used in both SB-318 and SB-913.
“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.”
MPS I, also known as Hurler syndrome, is a rare genetic disorder caused by a deficiency of alpha-L-iduronidase (IDUA), a lysosomal enzyme which is required to break down or recycle the toxic buildup of glycosaminoglycans (GAGs). Without IDUA enzyme activity, GAGs accumulate in cells throughout the body, leading to widespread tissue and organ damage. The current standard-of-care treatment for MPS I is enzyme replacement therapy (ERT), given as weekly intravenous infusions. For severe MPS I patients, bone marrow transplant is also a common treatment. SB-318 is an investigational product candidate being evaluated to treat MPS I using ZFNs, which are designed to insert a normal copy of the IDUA gene into a precise location in the DNA of liver cells. The goal of SB-318 treatment is to enable a patient’s liver to produce a continuous supply of functional IDUA enzyme.
“It is a tremendous responsibility to undertake the first in vivo genome editing clinical trials, and we are learning quickly about our technology and about these rare diseases,” said Dr. Edward Conner, Chief Medical Officer of Sangamo. “While additional data will be critical in assessing the safety profile and potential therapeutic benefit of SB-318, these early data provide evidence of the progress that we are making toward a potential new treatment for MPS I using in vivo genome editing with ZFNs.”
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.
Sangamo has developed second-generation, potentially more potent ZFN constructs designed to increase editing efficiency. Preclinical data of these second-generation ZFNs were reviewed by U.S. regulators. The preclinical data showed three potential advantages for use in the clinic: (1) a 5- to 30-fold improvement in efficiency and potency due to structural changes; (2) the ability to function equally well in the patients who have a single nucleotide polymorphism (SNP) in the target locus in the albumin gene (approximately 20% of the population); (3) improved specificity. The second-generation ZFNs are already being manufactured and are expected to be ready for use in the clinic later this year. Additional data from Sangamo’s in vivo genome editing programs will be assessed before potential integration plans for the second-generation ZFNs are finalized.