Wednesday morning, Baxalta Incorporated (BXLT), a soon to be publically traded spin-off of Baxter International Inc. (BAX), presented updated data from an ongoing phase I/II open-label clinical trial assessing BAX335 at the 2015 International Society on Thrombosis and Haemostasis (ISTH) Congress. As a reminder, BAX335 is an investigational gene therapy being developed for hemophilia B and consisting of an AAV2/8 vector carrying the FIX-Padua transgene.
I previously wrote about BAX335 after Baxter reported initial data from this trial in February 2015, suggesting then that this first data set was a derisking event for uniQure’s (QURE) hemophilia B program: BAX335 was unable to facilitate >20% FIX activity without immune complications. With today’s updated data from a larger patient population, I wanted to publish my thoughts as they relate to the hemophilia B gene therapy space as a whole. In addition, since I am currently bullish on uniQure, I wanted to explain what these data mean in relation to uniQure's AMT-060.
Updated BAX335 Data
As of the time of data collection, a total of seven patients have been treated with BAX335:
BAX335 Dose Cohorts:
Low dose: 2E11 [vc/kg] (n=2)
Medium dose: 1E12 [vc/kg] (n=3)
High dose: 3E12 [vc/kg] (n=2)
No patients have developed FIX inhibitors (immune response against FIX protein) to date.
“Some FIX expression was observed in the lowest dose cohort.”
“In the [medium] dose cohort, two patients have experienced no bleeds without regular infusions of FIX, and one of these patients has had sustained FIX [activity] levels of 20-25% for 12 months.”
“In the highest dose cohort, expression levels have peaked above 50%, though the two patients in this cohort experienced an immune response which has led to decreased FIX expression, with one patient resuming regular FIX infusions.” These two patients were observed to have T-cell mediated immune responses.
As shown below, one patient in the middle cohort had sustained 20-25% FIX activity at 52-weeks post treatment, with no bleeding episodes or exogenous FIX infusions required:
This one patient reaching a 5% FIX activity threshold without signs of elevated liver enzymes or a T cell immune response is encouraging for BAX335 as a potential therapeutic.
Nevertheless, it’s unclear – with current data – if this can be translated to a larger patient population (2 out of 3 patients in the middle cohort experienced no bleeding episodes post-treatment). In addition, it’s unclear – despite high FIX expression – if the high dose of BAX335 will be viable given the T-cell mediated immune responses (resulting in treatment with corticosteroids) observed in both patients in the high dose cohort.
Results from one of these patients is below and demonstrates one of the potential negative consequences of T-cell mediated immune responses in AAV gene therapy – loss of transgene expression/activity (this is the same issue Spark Therapeutics (ONCE) apparently had with their previous AAV8 hemophilia B gene therapy discussed in their S-1):
Study investigators believe the dramatic decrease in FIX activity is due to the delayed start of corticosteroids; however, a larger sample size will be needed to determine if this is true.
What This Means for the Hemophilia B Gene Therapy Landscape
These data are promising, but not a home run. So far the investigators have been unable to dose BAX335 as high as hoped without evidence of a T-cell mediated immune response or decreased FIX expression, despite improvements in manufacturing compared to the AAV8 hemophilia B candidate investigated at St. Jude’s. This leaves the door open for improvements from other companies pursuing gene therapies for hemophilia B since this apparent T-cell mediated immune response could be due to manufacturing or capsid characteristics specific to BAX335 (and other AAV8 gene therapies).
For example, uniQure just began assessing AMT-060 (AAV2/5 with hFIXco transgene) in a phase I/II trial. As a reminder, uniQure uses an improved baculovirus manufacturing process compared to the triple transfection method used by St Jude’s (recall BAX335 uses improved purification during triple transfection manufacturing to significantly decrease the amount of empty capsids in the final product). UniQure has previously demonstrated the ability to dose an AAV2/5 gene therapy (AMT-021) at doses up to 2E13 [vg/kg] without evidence of elevated liver enzymes or T-cell immune response. In other words, if manufacturing is the limiting aspect, AMT-060 could have an upper hand.
In the future, if AMT-060 or other hemophilia B gene therapies do not show superiority to BAX335, there is still room in the hemophilia B treatment landscape for more than one winner. Preexisting neutralizing antibodies to wild-type AAV vectors used in gene therapy are key exclusion criteria for administration of these gene therapies to date. According to Boutin et al, the seroprevalence for healthy individuals is about 40% for both AAV5 and AAV8. Approximately 40% of patients diagnosed with hemophilia B may be ineligible for gene therapy with either an AAV5 or AAV8 vector! Patients who have preexisting neutralizing antibodies against AAV8 simply cannot receive BAX335, and the same for AMT-060 and AAV5. And, patients receiving AAV8 gene therapy that need retreatment cannot subsequently receive an AAV8 gene therapy due to the now-present neutralizing antibodies – retreatment would require a non-AAV8 gene therapy.
I’m intrigued by the BAX335 data, which are certainly promising and support continued clinical advancement, but, there’s room for improvement - and room in the treatment landscape for other winners.
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