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UniQure, Pfizer updates hint at gene therapy potential in hemophilia B

ORLANDO — Gene therapies for the blood-clotting disorder hemophilia B are trailing about a year behind their hemophilia A counterparts, with pivotal study results from UniQure expected by the end of next year and Pfizer deep into its own Phase 3 trial.

Both companies provided updates at the American Society of Hematology’s annual meeting, while preclinical data were unveiled for a Takeda gene therapy as well as a second Pfizer project that works a different way.

UniQure’s gene therapy, is more central to the strategy of the biotech, which has no marketed products, than Pfizer’s is to the pharma. So UniQure took full advantage of the meeting to put out data supporting both the efficacy and the durability of its product in front of physicians who treat patients with hemophilia B.

The key results were a one-year update from three patients enrolled in a small Phase 2 trial. Treatment spurred blood levels of a key clotting protein called Factor IX higher, to an average of 41% of normal. That is down slightly from the six-month update, which showed levels at 47%. But the jump from less than 1% to 41% means the patients disease went from severe to mild.

None of the three patients experienced any bleeding events. One patient reported a single infusion of factor replacement therapy, the current treatment for the disease, but that was related to an episode of back pain rather than bleeding.

UniQure also reported long-term data from an earlier hemophilia B gene therapy called AMT-060, which uses a less-active gene cassette. Patients in that trial, now four years post enrollment, have not seen their Factor IX expression decline, standing at a mean of 7.5% over three and a half years.

This level also qualifies as mild disease. Patients in the trial no longer take factor replacement therapy, and their annualized bleeding rate has dropped to zero, compared to four per year before enrollment. And unlike patients enrolled in gene therapy trials for hemophilia A, those in the UniQure trial have not required immunosuppression via steroid treatment.

UniQure CEO Matt Kapusta said he believes that’s due to the use of adeno-associated virus 5 as the vector to deliver the gene cassette, called the Padua variant of the Factor IX gene.

“We think the immunogenicity profile of AAV5 has the potential to be superior to the other AAV serotypes that are used for systemic delivery,” he told BioPharma Dive in an interview.

Whether gene therapies can provide durable and sustainable cures is the key question surrounding the field. The four years of data from AMT-060 suggest that it could be, said Kapusta.

That’s in part tied to the fact that a whole Factor IX gene can be delivered virally, unlike Factor VIII in hemophilia A or dystrophin in the case of Duchenne muscular dystrophy, which are so large a shortened version must be used.

Moreover, many of these gene therapies are directed toward liver tissue. “Factor VIII is not actually produced in the liver, so you’re asking cells that typically don’t know how to produce something to produce very large quantities of a protein,” Kapusta said. “Factor IX is actually produced in the liver.”

Pfizer’s project, which uses the same Padua variant, started its Phase 3 trial 17 months ago, around the same time UniQure enrolled its first Phase 3 patient. But Stifel analyst Paul Matteis wrote in a Dec. 9 note to client that he thinks UniQure’s will reach patients first.

Kapusta said UniQure’s pivotal trial, which involved a six-month lead-in to measure patients’ use of factor replacement therapy and bleeding rates as a baseline, infused the first patient with its gene therapy in January.

Based on enrollment, Kapusta said the last of the 62 patients in HOPE-B will have had a final post-treatment follow-up in the fourth quarter of 2020, potentially allowing for a filing in 2021.

Data from Pfizer’s Phase 2 dosing trial of its gene therapy, which the pharma licensed from Spark Therapeutics, showed that one year after infusion 15 patients achieved an average Factor IX expression of 23%.

Twelve of 15 patients experienced no bleeding episodes, yielding an annual bleeding rate of 0.4. Five of the 15 patients reported a total of 20 factor replacement therapy infusions, while two patients were treated with corticosteroids in response to immune-related liver enzyme spikes.

The drug may not be the last word from Pfizer in hemophilia B gene therapy. The company also presented data from a study in mice of a gene therapy designed to aid blood coagulation by promoting production of thrombin via another antibody.

Similarly, Takeda had data from a study in mice and monkeys of TAK-748, an asset that came with its acquisition of Shire. This project, which is nearing first-in-human testing, uses a next-generation AAV vector that could avoid the immune-related response to AAV-based gene therapies, which can limit their effectiveness.