UniQure gene therapy delivers lasting efficacy in hemB, but Spark FIX comparisons continue to cast a shadow over data

UniQure has posted data linking AMT-060 to the near-cessation of spontaneous bleeding in hemophilia B

UniQure has posted fresh data from a phase 1/2 trial of its hemophilia B gene therapy. The 12-month low-dose data and six-month high-dose results link AMT-060 to the near-cessation of spontaneous bleeding and a sharp drop in Factor IX (FIX) replacement therapy, but the gene therapy continues to be dogged by comparisons to Spark Therapeutics’ rival program.

Comparisons between data generated by uniQure and Spark typically focus on FIX activity, an area in which the latter firm has a clear edge. Between seven and 51 weeks after administration of Spark’s gene therapy SPK-9001, FIX activity in a nine-patient study ranged from 12% to 65%. In contrast, mean FIX activity in the five-person, high-dose AMT-060 cohort clocked in at 3% to 12.7% in the 22 to 26 weeks following administration of the gene therapy.

Previous data drops showing the chasm in FIX activity have crushed uniQure’s stock price. And some analysts were quick to latch on to the latest data as further evidence Spark has the edge over its rival. Analysts at Chardan Capital Markets said the “high-dose cohort data may not return uniQure to a competitive position.”

Yet, FIX activity is just one yardstick by which to measure efficacy. And, perhaps unsurprisingly given SPK-9001’s advantage over AMT-060 in this regard, it isn’t the one uniQure looks to when assessing how its candidate held up to pre-trial expectations.

“Quite frankly, what we had in mind [going into the trial] is the clinical benefits, right, in terms of cessation of bleeding and reduction of replacement therapy usage. And I think we've probably exceeded our expectations there,” Matthew Kapusta, interim CEO of uniQure, said.

The annualized spontaneous bleed rate in the low-dose cohort fell from 8.3 to 3.4 following administration of AMT-060. No spontaneous bleeds were seen over the last 14 weeks of the analyzed period. The rate in the high-dose cohort fell from 3 to 0.7. Kapusta thinks these data, which hold up far better to Spark’s results than the FIX readouts, are what matter, and is content with the high-dose FIX data.

“In terms of FIX activity, we we're hoping in the 5-10% range because that's what we saw in our non-human primate animal studies. And that's what we've delivered,” Kapusta said.

The question of to what extent higher FIX activity benefits patients is yet to be answered definitively. Spark sees benefits in clearing 12%, the level at which it thinks patients become free from chronic bleeding in the joints. UniQure focuses more on passing the 5% mark that indicates a patient has a mild phenotype and is freed from the need to receive prophylactic FIX infusions. Three of the 10 patients in the uniQure study had mean FIX activity levels of below 5%.

Long-term considerations

Ultimately, durability of response may matter more than near-term FIX differences. In this regard, uniQure, which is deeper into development than Spark and has more than six years of data from an earlier academic study, can claim an edge.

Spark has also seen two patients experience autoimmune responses which caused FIX expression to fall. The responses were controlled with steroids and Spark thinks it can avoid a situation in which the responses raise the risk of bleeding. But uniQure sees safety as another area in which it may best Spark.

“The capsid, which is the viral vector we use to deliver [the gene therapy], has been tested in three clinical studies, in more than 20 patients and we've seen a very clean safety profile with no immune responses,” Kapusta said. “Hemophilia B patients are very conservative patients and it's safety first for these patients. We think we're really delivering that. We think it is a significant differentiator.”

Safety concerns for uniQure relate primarily to elevated liver enzymes. One patient in the low-dose cohort and two in the high-dose group experienced “mild, asymptomatic elevations in liver enzymes not associated with changes in FIX activity or a capsid-specific T-cell response.” These events were a cause of concern for analysts at Chardan.

The next step for uniQure is to discuss the safety and efficacy data with regulators and establish the authorities’ expectations for a planned pivotal trial. “That's something that we expect to have established over the course of the first half of next year,” uniQure CMO Christian Meyer said. Meyer declined to commit to an anticipated start date for the pivotal trial.

From uniQure’s perspective, a speedy start would be preferable. While the differences between uniQure and Spark’s data and the effect of differences in the trial population are a topic of debate, the lead held by the Dutch gene therapy specialist is inarguable. If uniQure can get to market first it will have a shot at racking up sales before competition intensifies. And, even if Spark ultimately has the more compelling gene therapy, AMT-060 could remain first choice for patients who have neutralizing antibodies to Spark’s vector.