Faculty Bibliography

Background: Mucopolysaccharidosis type II (MPS II, Hunter syndrome), is a rare, X-linked metabolic disease caused by mutations in the IDS gene, which leads to a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). MPS II is characterized by progressive respiratory and cardiac disease, skeletal abnormalities, and premature death with neurodegeneration in the severe form. SB-913 is a new type of gene therapy being developed for the treatment of MPS II. SB-913 uses zinc finger nuclease (ZFN)-mediated in vivo genome editing to insert a normal copy of the IDS transgene into liver cells, delivered via AAV2/6 vectors. The precision and specificity of the ZFNs allow for integration at a specified genomic location and result in high, continuous production of IDS, as demonstrated in an MPS II mouse model. SB-913 aims to provide lifelong production of IDS, with the goal of therapeutic benefit and eliminating the need for weekly enzyme replacement therapy. Methods: A Phase 1/2 clinical trial (CHAMPIONS) is ongoing in the U.S. to determine if SB-913 is safe and tolerable in patients with MPS II. The study is a multicenter, open-label, dose ranging trial with one-time peripheral intravenous infusion of SB-913, followed by three years of observation and testing. IDS activity and clinical endpoints will also be assessed. Key eligibility criteria include age >=18, diagnosis of attenuated MPS II, and lack of pre-existing antibodies to AAV6. Results: Four subjects have received a single infusion of SB-913, with two subjects in each of two dose cohorts (5e12 vg/kg and 1e13 vg/kg). The infusions were generally well-tolerated and no serious adverse events related to the study drug were reported, with maximum exposure of up to 5 months post-study drug administration. Additional analysis of the trial data will be presented as available. Discussion: Initial safety data from this clinical trial support further de-velopment of SB-913 for the treatment of MPS II

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. For insight into how GD management varies among countries, we analyzed treatment patterns in GOS. As of October 30, 2015, data on GD-specific treatment (enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy) received at any time were available for 647 patients. At analysis, velaglucerase alfa (316/573, 55.1%) and imiglucerase (184/573, 32.1%) were the treatments most widely used. Of the 647 treated patients, 446 (68.9%) had been treated for >5years and 368 (56.9%) had received only one GD-specific drug therapy. There were 377 patients who received velaglucerase alfa. Velaglucerase alfa was most widely used at 60U/kg every other week (134/492 dose entries, 27.2%), but there were differences in dosing between the three highest-enrolling countries (defined as >100 GOS patients enrolled in each), with most patients in Israel receiving <20U/kg, most patients in the United Kingdom receiving 20 to <40U/kg, and most in the United States receiving 60U/kg. This analysis provides a foundation upon which to examine real-life outcomes data from different treatment regimens globally.

Gaucher disease (GD) may worsen during pregnancy, leading to the discussion of continuing treatment during pregnancy. We examined fetal outcomes of pregnancies reported in the Gaucher Outcome Survey, an international GD-specific registry established in 2010. A total of 453 pregnancies were reported. Most pregnancies (336/453, 74.2%) were in women who did not receive GD-specific treatment during pregnancy, while enzyme replacement therapy (ERT) was received during 117/453 (25.8%) pregnancies. No pregnancies exposed to substrate reduction therapy were reported. The percentage of normal outcomes (live birth delivered at term with no congenital abnormalities) was similar in untreated and treated pregnancies (92.9% vs. 91.4%). The percentage of spontaneous abortions in untreated pregnancies was 3.6% (95% CI, 1.9%- 6.2%) compared with 6.9% (95% CI, 3.0%-13.1%) in treated pregnancies (p=0.1866). In women who received velaglucerase alfa <1month prior to conception and/or during pregnancy, 34/36 (94.4%) pregnancies had normal outcomes and 2 (5.6%) ended in spontaneous abortion. Normal outcomes were observed in the 20 pregnancies with velaglucerase alfa exposure starting <1month prior to conception and continuing through all trimesters. These observations, in addition to information in the literature, suggest that continuation of ERT during pregnancy may be appropriate for GD patients.

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n=847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received >/=1 GD-specific treatment at any time, most commonly imiglucerase (n=587), velaglucerase alfa (n=507), and alglucerase (n=102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. The aim of this analysis was to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.