UniQure, chasing Spark-level FIX activity, tweaks hemophilia B gene therapy ahead of 2018 pivotal tr

UniQure has modified its hemophilia B gene therapy to dial up factor IX (FIX) activity to the levels achieved by Spark Therapeutics’ rival product. The mid-development tweaks have the blessing of regulators, enabling uniQure to start a pivotal trial next year with its fast-track statuses intact. 

Amsterdam, the Netherlands-based uniQure has spent two years testing hemophilia B candidate AMT-060, a gene therapy that encodes wild-type FIX. The trial linked AMT-060 to improvements in clinical outcomes such as cessation of bleeding and use of replacement therapy. But it also showed Spark’s Pfizer-partnered SPK-9001 results in far higher levels of FIX activity than AMT-060.

Now, uniQure has unveiled AMT-061. 

To create AMT-061, uniQure has swapped out the wild-type FIX for gene variant FIX-Padua. SPK-9001 also uses FIX-Padua, a naturally occurring missense mutation associated with eight- to ninefold increases in FIX activity over the wild-type version. FIX-Padua features two nucleotide substitutions in the coding sequence and one amino acid substitution in the resulting protein.

Clinical data suggests these small changes have big effects. SPK-9001 has triggered improvements in FIX activity of more than 60%. AMT-060, even when given at the higher dose, has struggled to hit double figures.

Investors responded to the unflattering comparisons between AMT-060 and SPK-9001 that emerged at each interim data drop by beating down uniQure’s stock. UniQure and its champions tried to downplay the significance of the difference in FIX activity, arguing that the number was less important than the clinical outcomes achieved. 

The argument has its merits. FIX activity gains of 5% to 10% are thought to trigger clinical benefits. People given the high dose of AMT-060 fell into—and stayed in—that FIX window. The biotech’s champions even painted the wild-type gene as a strength, arguing that an identical gene found in humans may yield more durable responses than those achieved by Spark’s mutant gene. 

Ultimately, these pro-uniQure arguments—and those about its vector selection and manufacturing capabilities—were drowned out by the FIX activity data. In switching from AMT-060 to AMT-061, uniQure has conceded that investors and observers who fixated on FIX activity had a point. 

The question now is whether uniQure can seamlessly switch between the assets. Management has laid the groundwork for such a transition by acquiring FIX-Padua patients from Paolo Simioni, the author of landmark papers on the gene variant, and by putting its new asset through tests in nonhuman primates and getting the FDA and EMA to include AMT-061 under the regulatory designations they awarded to AMT-060.

That clears uniQure to move into a pivotal trial next year with its breakthrough and PRIME statuses intact. The open-label, single-dose trial will feature a six-month observational lead-in phase so patients can provide their own baseline control data. UniQure will run a three-patient dose-confirmation study in parallel to the lead-in phase. The dose-confirmation study is due to start in the third quarter of next year.