In contract, Spark’s approach utilizes a novel capsid, Spark-100, optimized for the liver, combined with a Padua variant trasgene, which provides a ~5-6 fold improvement in activity relative to expression. Initially discovered from a family in Italy who had abnormally high levels of Factor IX activity (~6 fold normal) with normal Factor IX levels with a mutation causing a single amino acid switch, gene therapy developers SHPG (via BXLT and Chatham) took this knowledge and cleverly installed this Padua variant into the gene therapy construct. Initial data was first presented at EHA which was followed by an additional update at WFH, and most recently at ASH. Nine patients have been treated at the same relatively low dose of 5 x 1011 vg/kg, and patients are demonstrating 15-70% Factor IX activity. Two out of the nine patients required on-demand treatment with steroids following LFT elevation, which coincided with a drop in expression. That said, in one of these two patients expression was “rescued” at 15% and appears durable, while the other continues to express at 68%. Overall, the majority of patients are between 20% and 50%. The company will likely provide continued updates in 2017 and Pfizer will be taking over development as the program enters the pivotal stage. We look for further updates on the potential regulatory and clinical strategy going forward. Dimension Therapeutics is using a “middle of the fairway approach” with the AAVrh10 vector (licensed from RGNX), and a codon optimized transgene along with a liver specific enhancerpromoter combination. The company utilizes a mammalian manufacturing process. In January, Dimension Therapeutics reported preliminary results from the hemophilia B gene therapy study of DTX101, showing robust Factor IX expression particularly at the middle dose level, but with waning effect coincident with LFT elevation. In the low-dose cohort (1.6 x 1012 vg/kg), FIX expression levels reached 10-11% normal and then stabilized at 3-4% of normal. In the high-dose cohort (5 x 1012 vg/kg), peak Factor IX expression reached 12-20% normal and seems to be stabilizing in the 5-8% range. LFT elevation was seen in most patients, and one experienced a Grade 4 elevation but in an unusual time course which might suggest a different type of pathology in that patient. According to recent commentary on the most recent earnings call, the company does not believe this is an immune response. LFT elevation has resolved (or is resolving) in all patients. Dimension Therapeutics continues to strategize over next steps in continuing its clinical trial, considering prophylactic steroids, a longer infusion period and a middle dose level. SGMO continues to advance its gene editing program, which is unique in that the company employs an integrating approach enabled by its zinc finger nuclease platform (see gene editing) combined with AAV6 for in vitro delivery of the FIX transgene to the liver in the albumin locus. Preliminary data is expected in early 2018. In a unique but promising approach, recent upstart LogicBio from Mark Kay’s lab at Stanford is working on a “promoterless” approach along with new AAV vectors, which would similarly utilize the albumin locus as a safe harbor for the FIX gene but a unique integration mechanism; early preclinical studies are encouraging. UCL recently created new AAV spin-out Freeline Therapeutics with hemophilia gene therapy pioneer Amit Nathwani as CSO; we look forward to additional details on the approach. Bioverativ (BIVV; transferred from parent Biogen) licensed an early in vivo lentivirus approach from TIGET, though data presented as ASGCT this year was a bit lower than we had anticipated, with very low levels of expression seen. It’s not clear if this is the approach being advanced or if other more optimized approaches are in development. SHPG (via Baxalta) previously reported data indicated that one out of three patients in the “middose” cohort had seen durable 20-25% Factor IX activity levels. However, at high doses, LFT elevation occurred and employing on-demand steroid treatment did not succeed in rescuing expression. SHPG indicated it will no longer be pursuing this clinical candidate but will evaluate preclinical candidates. We look forward to additional details and how the approach may differentiate in what is an increasingly crowded field.
Taken together, these approaches are pulling multiple levers (promoters, transgene, vector capsids, dose, immune suppression, etc.) and learning from each other's datasets to achieve high levels of durable activity. While it is early to declare winners and losers, Spark appears in the lead given the efficacy and lack of immunosuppression. Again, other parameters will be important (baseline immunogenicity, response rate, safety, Padua vs. wildtype, etc.). We note that the totality of experience dosing patients with gene therapy systemically is still small, and just one serious complication in one trial could reverberate across the broader field. We expect updates throughout 2017 from all these programs as well as clues from QURE and potentially Spark (and partner PFE now that development will be transitioned to them) on the scope of the registration-enabling trial, including number of patients treated and for how long.