DUBLIN – Gene therapy firm Freeline Therapeutics Ltd. secured the first $40 million tranche of an $80 million series C round from its founding investor and principal shareholder Syncona plc to generate further data from its two clinical-stage programs, in hemophilia B and Fabry disease, to fund expansion of its team and to continue the ongoing buildout of its manufacturing operations in Munich.

Chris Hollowood, executive chairman, Freeline and chief investment officer, Syncona

“It’s progressing nicely. It’s ramping nicely and needs the capital to execute on the business plan,” Chris Hollowood, who is both Freeline’s executive chairman and Syncona’s chief investment officer, told BioWorld.

In hemophilia B, Sevenage, U.K.-based Freeline is squaring up against two of the biggest names in gene therapy, both of which are already in phase III. “I don’t think there’s space for three, personally,” Hollowood said. “It will come down to the best product.” Freeline is playing to win, therefore, even if it is some distance behind its rivals.

Spark Therapeutics, whose $4.3 billion acquisition by Roche Holding AG finally closed this week, is developing fidanacogene elaparvovec (formerly SPK-9001 and PF-06838435), an adeno-associated virus (AAV) encoding a Factor IX variant that is eight to 12 times more active than the wild-type protein. Its expression is under the control of the high-efficiency Padua promoter.

The most recent data for the program, disclosed at this year’s American Society of Hematology (ASH) meeting, suggests that the durability of the therapy may be problematic. For 15 patients with at least one year of follow-up, mean steady-state factor IX (FIX) activity was 22.9%±9.9% of the normal range after a single 5 x 1011 vector genomes per kilogram of body weight (vg/kg) dose of the therapy. In May 2018, had Pfizer reported mean FIX activity of 14.3% to 76.8% for 10 patients with follow-up ranging from 12 to 52 weeks, and mean FIX activity of 38.1% to 54.5% for another three, who received vector made using an enhanced production process, after a minimum 12 weeks of follow-up.

Also at ASH, Uniqure NV, of Amsterdam, The Netherlands, reported 52-week data for an initial cohort of three patients on a phase IIb trial of fetranacogene dezaparvovec, an AAV5-based gene therapy in which the FIX gene is under the control of the Padua promoter. Mean FIX activity was 41% of normal for these three. The individual levels reached were 41%, 50% and 31% for the first second and third patients, respectively. The dose administered was 2x1013 vg/kg.

Freeline is still in the dose-escalation phase of a phase I/IIa study of its AAV-based gene therapy FLT180a, although it has not disclosed the doses it is employing. The first two patients on the lowest dose attained mean FIX levels of 40.5%±4.5% at 66 weeks and 74 weeks, respectively, after receiving treatment.

“Even at the lowest dose, we’re getting levels that are the same or better than the two other companies,” Hollowood said. It will disclose data from patients on higher doses before March 30 next year. “We believe that data will be suggestive of the target profile we’re looking for,” he said. The company aims to develop a curative therapy that would durably result in FIX levels of at least 50% of normal.

Freeline’s AAV capsid technology – details of which it has yet to disclose – and the quality of its manufacturing platform are the two key factors that will, it hopes, give it a competitive edge. The company’s scientific founder, Amit Nathwani, of University College London, who was first to demonstrate clinical proof of concept of gene therapy in hemophilia B, has developed AAV capsids with optimal transduction efficiency for human cells. Most AAV capsids were first optimized in mice, but were far less efficient in humans, Hollowood said. “He reversed the paradigm.”

Freeline acquired its mammalian-cell-based manufacturing platform from the Laupheim, Germany-based CDMO Rentschler Biopharma SE in 2016. The organization, which is now 50-strong, is headed by company chief technology officer and co-founder Markus Hörer, who transferred from Rentschler and built up the group. The platform is “hugely enabling,” Hollowood said, and yields high-quality vectors with “a very attractive” cost-of-goods profile. “It is consistent with taking a product to market and having a margin.”

Its Fabry gene therapy program, FLT190, is at an earlier stage of development and has yet to report data. It has two competitors here too. Brisbane, Calif.-based Sangamo Therapeutics Inc. is conducting a phase I/II trial of ST-920, an AAV2/6 vector encoding alpha-galactosidase A. Cambridge, Mass.-based Avrobio is in phase II with an ex vivo, lentiviral-based approach, which involves the isolation and transduction of patients’ CD34 hematopoietic stem cells.

Freeline has two preclinical programs, for Gaucher disease and hemophilia A, underway. It is also considering it long-term options in areas outside genetic disorders. “We have some ideas brewing that would take this company beyond monogenic disorders,” Hollowood said.

London-based Syncona remains Freeline’s main shareholder. Prior to the current round, the company raised £123.2 million (US$160 million), most of it from Syncona. “The wonderful thing about Syncona is we’ve got this great big balance sheet,” Hollowood said. It held £855.5 million in cash and equivalents on Sept. 30.

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