UniQure Hemophilia B Gene Therapy Changes Ignite A Race To Market

UniQure is switching the gene therapy it plans to move into a pivotal trial in hemophilia B patients because the new version could have clinical benefits. Regulatory agencies in the US and Europe have given the change a green light, and uniQure plans to begin a pivotal trial in 2018.

UniQure NV is putting rivals Spark Therapeutics Inc./Pfizer Inc. to the test when it comes to the race to bring the first gene therapy for hemophilia B to market. The company has gotten a green light from the US FDA and European Medicines Agency to move forward with a pivotal trial testing a new version of the therapy.

In back-to-back announcements Oct. 19, the Netherlands-based gene therapy developer said it has made a big change to its lead program but that FDA and EMA are comfortable with the change. UniQure plans to advance a new gene therapy, AMT-061, which combines an AAV5 vector with the FIX-Padua mutant, into a pivotal study in 2018 for patients with severe and moderately severe hemophilia B, replacing the prior therapy AMT-060 that has already been tested in 10 patients in an ongoing Phase I/II clinical trial.

Hemophilia B is a rare inherited blood disorder characterized by mutations in the factor IX (FIX) gene, which can lead to deficient blood coagulation and an increased risk of bleeding. UniQure also announced it acquired a patent family that broadly covers the FIX-Padua mutation, or R338L mutation, a hyperactive variant of Factor IX, including claims issued in the US. UniQure acquired the patent family from the inventor, Paolo Simioni, a hemophilia expert at the University of Padua, Italy, who is recognized for identifying the mutant gene.

UniQure believes AMT-061 could offer improved efficacy and could apply to a broad set of patients with hemophilia B,

"We believe all or nearly all severely to moderately severe hemophilia B patients will be eligible for treatment," CEO Matthew Kapusta said during a same-day conference call announcing the updates.

The company's investors reacted positively to the update, with uniQure's stock jumping 60% on the Nasdaq to close at $15.16.

An Identical Structure With A Change

AMT-061 and AMT-060 are identical in structure except for two nucleotide substitutions in the coding sequence for FIX, the company said. The gene variant known as FIX-Padua expresses a protein with a single amino acid substitution that has been reported in preclinical and nonclinical studies to provide an eight- to nine-fold increase in FIX activity compared to the wild-type FIX protein. Other attributes are expected to be comparable, including the AAV5 capsid and the cell-based manufacturing platform.

AAV5-based gene therapies have been demonstrated to be generally safe and well-tolerated in multiple clinical trials, including three uniQure trials conducted in 22 patients, including hemophilia B and other indications, according to the company. Importantly, no patient treated in clinical trials with the company's AAV5 gene therapies have experienced any confirmed T-cell-mediated immune response, and AAV5 had the lowest prevalence of preexisting neutralizing antibodies (Nab) compared to other AAV vectors in an independent clinical trial. A Phase I/II study of AMT-060 further provided clinical evidence related to the presence of preexisting Nab to AAV5, suggesting that all or nearly all hemophilia patients may be able to be treated with AMT-061.

"The exclusion of patients from treatment due to pre-existing neutralizing antibodies to nay given vector is a significant detraction for the utility of the gene therapy and a major challenge for the field," said principle investigator Steven Pipe, professor of pediatrics and pathology and pediatric medical director of the hemophilia and coagulation disorders program at the University of Michigan.

"Having a vector like AAV5 we can administer to nearly all, if not all, hemophilia B patients is a tremendous advantage and one that is truly an advantage for patients," he said.

FDA agreed AMT-061 can be included under the existing breakthrough therapy designation and investigational new drug for AMT-060. EMA agreed that AMT-061 will be included under the current PRIME designation. UniQure announced AMT-060 had been accepted into PRIME, the European's priority review program, earlier this year. (Also see "Hemophilia B Gene Therapy Market PRIMEd In Europe" - Scrip, 4 May, 2017.)

Management outlined plans to initiate a Phase III clinical trial testing AMT-061 in the third quarter of 2018. The trial will be an open-label, single-dose, multi-center, multinational trial investigating the safety and efficacy of AMT-061 administered to adult patients with severe or moderately severe hemophilia B. The primary endpoint of the trial will be prevention of bleeding, with patients serving as their own control with a baseline established during a six-month operational lead-in phase prior to treatment. The company believes it could file the treatment with regulators based on data out to one year, though it plans to continue the trial for five years.

The company will not exclude patients in the trial on the basis of presence of pre-existing neutralizing antibodies in the hopes of demonstrating the broad applicability of AMT-061, management said.

"Should we successfully show that a screening test is not required with AMT-061, we may not be required to pursue a separate regulatory approval for a companion diagnostic test,” Chief Scientific Officer Sander van Deventer said.

The Race Is On

UniQure is racing with Spark and Pfizer to bring the first gene therapy to market for hemophilia B. Spark is riding momentum after FDA's Cellular, Tissue and Gene Therapies Advisory Committee unanimously recommended approval Oct. 12 of its investigational gene therapy, Luxturna (voretigene neparvovec), for the treatment of some patients with a rare inherited retinal disease that can cause blindness. (Also see "Spark's Gene Therapy Is On The Cusp Of Approval; Now It Gets Interesting" - Scrip, 12 Oct, 2017.)

Spark appears poised to bring the first gene therapy to the US, but uniQure already holds that title in Europe. The company's Glybera (alipogene tiparvovec) was the first gene therapy approved anywhere in the world. It was for an extremely rare indication, for familial lipoprotein lipase deficiency (LPLD), and the treatment never succeeded commercially; uniQure announced earlier this year that it was discontinuing the therapy to focus resources on other key areas, like hemophilia B. (Also see "White Flag Raised: UniQure Gives Up On Glybera, But Not Gene Therapies" - Scrip, 21 Apr, 2017.)

This is uniQure's second chance to show it can succeed clinically and commercially.

Spark/Pfizer's treatment, SPK-9001, is being tested in an ongoing Phase I/II trial, though Spark released positive interim data from the trial testing the therapy in 10 patients in July and showing a 99% reduction in annualized infusion rate and a 96% reduction in annualized bleeding rate. The company said it plans to present updated data at the American Society of Hematology meeting in December and transitionary efforts are underway.

Pfizer is charged with leading the late-stage clinical trial and paid Spark a $15m milestone payment for progress on the therapy in January. The two companies partnered on the gene therapy program in 2014, with Pfizer paying Spark $20m up front. [See Deal]