"Nobody ever thought that you could make a modification to the transgene and not start over," Uniqure NV CEO Matt Kapusta told BioWorld, but that's what the company did with its gene therapy for hemophilia B, and Wall Street was delighted.

Share of Amsterdam-based Uniqure (NASDAQ:QURE) closed 60 percent higher, or $5.69, ending Thursday at $15.16 as investors took in the news that, after meeting with the FDA and EMA, the company plans next year to "expeditiously advance" into a pivotal study AMT-061 rather than AMT-060, previously regarded as the lead compound.

AMT-061, for which only preclinical data are available, combines an adeno-associated virus 5 (AAV5) vector with the FIX-Padua mutant to treat severe and moderately severe hemophilia B. It's identical to AMT-060, which has been tested in 10 patients in an ongoing phase I/II experiment, except for two nucleotide substitutions in the coding sequence for factor IX (FIX). The FIX-Padua gene variant expresses a protein with a single amino acid substitution that has been reported in preclinical research to provide an eightfold to ninefold increase in FIX activity compared to the wild-type FIX protein. AMT-061 deploys the same AAV5 capsid and proprietary, insect cell-based manufacturing platform as AMT-060, too.

U.S. regulators have agreed to include AMT-061 under the existing breakthrough therapy designation and investigational new drug (IND) status for AMT-060, and the EMA similarly said AMT-061 will be included under the current priority medicines, or PRIME, designation.

"The speed at which the gene therapy space is evolving is almost light speed," Kapusta said, pointing to "unprecedented success in gene therapy within hemophilia B," a competitive space. "As we started to get data on our product and other gene therapies started developing, and as we started interacting more with clinicians, it became clear that the market believed that higher levels of FIX activity may provide improved long-term outcomes for patients with hemophilia B – there are multiple reasons for that, but that was the perspective," he said. "The line in the sand had always been 5 to 10 percent, about five years ago, but I think that line started moving [as] more long-acting therapies were coming out and other gene therapies started producing clinical data.

"One thing, though, was pretty clear to us, as more data started coming in on our AAV5 vector," he said. "We [developed] a strong belief that AAV5 is a best-in-class vector for systemic intravenous administration to the liver. The reason for that is twofold. One is, we've now treated 22 patients with AAV5, our competitors have treated other patients with AAV5, and we're not aware of any T-cell immune response to the vector."

Such was not the case with other vectors. "In four other clinical studies that were done in hemophilia B with different vectors, all had patients that had immune response and or potentially lost significant amounts of FIX activity as a result of those complications," he said.

AAV5 can be given "to nearly all or all patients with hemophilia B," Kapusta said. "We've done a substantial amount of work that suggests we have the lowest prevalence of neutralizing antibodies, and even patients that have neutralizing antibodies can still derive a clinical benefit. So we said, 'What about the possibility of marrying a best-in-class vector with this hyperactive transgene?' We looked a number of variables. Could we manufacture it? Can we demonstrate that we can drive higher levels of FIX activity? We wanted to assess intellectual property [IP] and freedom to operate," and the regulatory route had to be considered, he said.

"In the last number of months, we've confirmed all those things," he said. "We've got our own manufacturing capabilities that have been doing this for 15 years," so Uniqure was able to prove to gatekeepers that AMT-061 is "highly comparable" to AMT-060. "That, in and of itself, is very unusual," he said. "I think our ability to navigate through the agencies and keep this on the same regulatory/clinical continuum, is what makes this extremely attractive and doable."

Endpoints to be negotiated

Regarding IP, Uniqure said Thursday that it acquired a patent family, with claims issued in the U.S. that broadly cover a hyperactive variant of FIX carrying an R338L mutation (another name for FIX-Padua) and its use in gene therapy for the treatment of coagulopathies, including hemophilia B. The patents were acquired from the inventor, Paolo Simioni, a hemophilia expert at the University of Padua, Italy, who is widely recognized as the first to identify that mutant. Simioni filed a Patent Cooperation Treaty (or PCT, i.e., international) application on Sept. 15, 2009, and applications are pending in the U.S., Europe and Canada.

The U.S. Patent and Trademark Office issued U.S. Patent No. 9,249,405 on Feb. 2, 2016, which includes claims directed to FIX protein with a leucine at the R338 position of the protein sequence, nucleic acid sequences coding for that protein, and therapeutic applications, including gene therapy. More fast-track, divisional patent applications have been filed in the U.S. and in Europe that would further strengthen Uniqure's IP, the company said.

"The IP was not a topic in our discussion with the agencies," Kapusta noted during a conference call with investors. "What was relevant for the agencies was the data, the clinical data that we have with AMT-060, the nonclinical data that we have with AMT-061, these initial, preliminary comparability data that we have, and the perspective that all critical quality attributes of AMT-061 outside of potency are going to be consistent with AMT-060. That was really a function of the agency's perspective of keeping this under" the regulatory statuses previously granted to AMT-060, he said.

The company plans to seek approval of AMT-061 with one year's worth of data in hand from the pivotal trial, and patients will be followed for five years. It's unclear yet what postmarketing work might be required. "We haven't gone that far yet," Chief Medical Officer Steven Zelenkofske told BioWorld. "That's a discussion we'll have when we have data and we sit down to talk about filing."

On the topic of endpoints, CEO Kapusta said there's "been a debate about whether or not annualized bleeding is the appropriate endpoint as opposed to FIX activity, which is a pretty well-characterized biomarker. A lot of the clinicians feel that FIX activity is established enough that it should be a viable surrogate for clinical benefit, which is typically deemed reduction or noninferiority in bleeding. In the end, I think it's really a negotiation with the agencies."

Steven Pipe, pediatric director of the hemophilia and coagulation disorders program at the University of Michigan, weighed in on the matter during Uniqure's conference call. "I remain firm that my opinion is FIX plasma level should be the primary outcome for all hemophilia B gene therapy trials and that all of the other elements – bleeding events, health-related quality of life, etc. – will be collected as part of the data," he said. "As I've mentioned previously, FIX levels since [forever] have been used to define hemophilia, and they've been the targets for all of our therapeutic interventions. That's the opinion that I would continue to put forward. Of course, the final design of clinical trial has to be negotiated with the regulators."

Leerink analyst Joseph Schwartz said that, "while the IP is a positive for Uniqure as AMT-061 enters phase III it may complicate future commercialization plans" for Philadelphia-based Spark Therapeutics Inc. and Pfizer Inc., of New York, developing SPK-9001. "We do not know whether Spark/Pfizer were also contemplating acquiring the said patent, and if so, why they lost the bid to Uniqure," he wrote in a report. "It is possible that the R338L mutation may not pertain to SPK-9001, but net-net, we believe the financial impact on Spark would be minimal due to the structure of the partnership and the relatively smaller market of hemophilia B vs. hemophilia A."

Spark has ongoing trials investigating gene therapies in hemophilia A and B. SPK-8011 is in a dose-escalation phase I/II study as a potential one-time therapy for hemophilia A. The company retains full global commercialization rights to the SPK-FVIII program. SPK-9001, which has received both breakthrough therapy and orphan product designations by the FDA, and access to the EMA's PRIME program, is in a phase I/II experiment against hemophilia B and is being developed in the Pfizer collaboration.