UniQure went through some interesting de-risking two weeks back with the release of initial data (the first publicly) from Baxter International’s (BAX) Hemophilia B gene therapy program, BAX 335. Recall that uniQure also develops a hemophilia B gene therapeutic, AMT-060, in a phase I/II trial. In our deep dive on uniQure just two weeks ago we explained that Baxter’s program represented one of the primary risks to QURE in 2015 given that the street (and ourselves!) had no view on when or what Baxter’s data might look like.
Baxter’s data on Thursday the 12th were underwhelming, in our opinion, which we view as a de-risking event for uniQure’s Hemophilia B program. The market has not picked up on the significance of this, as QURE has essentially moved in tandem with sector sentiment in the weeks since. We see this as a product of QURE’s small following among U.S. investors and a lack of understanding (and hard data) regarding Baxter.
We expect this to change slowly as investors appreciate 1) that Baxter’s data weren’t particularly impressive and enrollment in the trial has been slow; 2) that QURE stands a good chance of impressing in relation to Baxter; and 3) that QURE’s gene therapy programs are meaningfully differentiated from the competition.
BAX-335 Data Summary
BAX 335 is an investigational factor IX (FIX) gene therapy for hemophilia B. Baxter presented the initial results during a symposium at the 8th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) on Thursday February 12th (Eastern time). We had a heckuva time tracking down details from the update, but were finally able to get some important information beyond what Baxter included in their short press release.
The trial is an open-label phase I/II dose escalation study to determine the optimal single dose of BAX 335 to be used in Hemophilia B. Baxter expects/ed to enroll 16 patients along the way. At the end of 2014, two years since the trial’s initiation, just six patients in 3 dosing cohorts have been treated with BAX-335, with evidence of a dose-related response (higher doses having better outcomes).
Low dose: 2E11 [vc/kg] (n = 2) BAX 335
Medium dose: 1E12 [vc/kg] (n=3) BAX 335
High dose: 3E12 [vc/kg] (n=1) BAX 335
No subjects in the study developed Factor IX inhibiting antibodies, the immune system essentially trying to stop the protein’s activity.
2 of 4 subjects receiving the 2 highest doses of BAX 335 had Factor IX activity at about 10% of normal. These patients also did not experience any bleeding events. Remember, bleeding events, and the inability to stop bleeding, are the hallmarks of hemophilia.
Of these 2 subjects, 1 subject receiving BAX 335 presented with elevated liver enzymes indicative of an immune response to the drug. Baxter is already seeing dose-limiting toxicities. The patient was treated with oral corticosteroids, per trial protocol.
Additional patients are being screened.
Enrollment has been VERY slow. The trial was initiated in late 2012. Six patients enrolled thus far suggests that Baxter is either not prioritizing this program OR it’s difficult to get hemophilia B patients on board with a gene therapy. We’ll know soon enough with uniQure set to begin enrollment in its own trial (under an aggressive enrollment plan, we would point out) in the very near term.
What does BAX-335 data mean for uniQure, as well as other gene therapy developers?
First, our primary concern was that BAX-335 would produce robust results, with FIX activity at >20% of normal. As we outlined in our recent uniQure report, there’s reason to believe that FIX activity >5% is all it may take to alter a patient’s quality of life, costs, and need for Factor IX rescue or prophylaxis.
BAX-335 uses a potentially superior manufacturing process compared to the process used by St. Jude’s (the early version of uniQure’s product). A recent publication by Asklepios states that Baxter’s new manufacturing process results in <10% empty capsids. BAX-335 also uses a potentially superior transgene – the FIX R338L variant (Padua mutation) – that could lead to greater coagulation activity for any FIX protein (compared to wild type FIX). Essentially, the R338L mutation could mean more efficient FIX protein, making up for less of it.
We were also concerned that BAX-335 would show a robust safety profile compared to results from St. Jude’s AAV2/8 product with new manufacturing processes and the use of a new transgene (incorporating the Padua mutation). BAX-335 appears to have a similar safety profile in the sense that therapeutic doses of BAX-335 resulted in 1 of 2 of the best responders (50%) demonstrating elevated liver enzymes, indicative of a capsid-specific immune response. Apparently, this has been mitigated with the use of corticosteroids.
As a reminder, it’s theorized that decreasing the amount of empty/contaminated capsids in the final gene therapy product should provide a superior safety profile and allow for lower doses to provide therapeutic expression of FIX.
Finally, it is unclear if/how Baxter is prioritizing this candidate. Baxter initiated enrollment in September of 2012. With a little over 2 years of open enrollment, only 6 subjects have been treated. This is slow considering the initial protocol called for 16 enrollees, 2 subjects per dose until both subjects in a single cohort demonstrate FIX activity at >10% of normal, or evidence of antibody immune response [1,2].
Why BAX-335 data provide a de-risking event. Positive read through to uniQure’s Hemophilia program.
First, we suspect that uniQure’s Hemophilia B gene therapy candidate – AMT-060 – could have a superior safety profile to BAX-335.
We come to this conclusion by comparing the safety profiles of uniQure’s AMT-021 (AAV5), St. Jude’s scAAV2/8-LP1-hFIXco, and Baxter’s BAX-335:
scAAV2/8-LP1-hFIXco (AAV8) did not show signs of elevated liver enzymes until a dose of 2E11 [gc/kg].
BAX-335 (AAV8) showing elevated liver enzymes in a single patient at 1E12 or 3E12 [gc/kg].
AMT-021 (AAV5) not showing elevated liver enzymes up to a dose of 2E13 [gc/kg]
By extrapolating the dose-response data from the St. Jude’s trial, BAX-335 should have the potential to produce therapeutic FIX activity (>5%) at a dose that should NOT cause elevated liver enzymes if it possesses a safety profile similar to AMT-021. With the highest dose of BAX 335 tested thus far (3E12 [vc/kg]) we’ve seen these ALT increases in tandem with 10% of normal FIX activity. Baxter hasn’t offered detailed data from which we can draw more conclusions.
Orginally published March 2, 2015 as PREMIUM content on Propthink. To read the rest of this article, you need to be a PropThink premium subscriber.
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