Haemophilia gene therapy was a surprise hit at last year’s Ash meeting, with Spark and Biomarin vying to get an edge in haemophilia A. But a dearth of data from bigger players this year might leave the way clear for a little-known UK group, Freeline Therapeutics, to steal the show.
The privately held Freeline, whose technology originates from University College London, says it has developed an improved AAV viral capsid, which is used to deliver the therapy. Ash attendees will be looking for any signs of whether this leads to better efficacy.
Results with Freeline's haemophilia B project, FLT180a, look promising – with the caveat that data are so far only available for two patients treated as of June 26. These patients, given a low dose, 4.5x1011vg/kg, had respective peak factor IX (FIX) expression levels of 48% and 66% of normal at around 12 weeks after therapy.
This compares favourably with results seen with Pfizer/Spark Therapeutics’ fidanacogene elaparvovec (SPK-9001) and Uniqure’s AMT-061. The latter recently yielded initial efficacy data in three patients, whose mean FIX activity was 31% of normal at six weeks (Haemophilia B race heats up with Uniqure data, November 15, 2018). Earlier results with SPK-9001 found mean FIX expression levels of 36% of normal.
All three candidate use a Padua variant of the FIX gene, which is thought to lead to higher FIX activity than the wild-type gene – Uniqure claims to hold the patents on this variant, so legal wrangles look likely if the projects progress.
Freeline will need to replicate these results in more patients if it wants to shake up haemophilia B, but the hope is that a higher dose of FLT180a might perform even better.
The A team
Data from an investigator-led study of Freeline’s haemophilia A candidate, AAV8-HLP-hFVIII-V3, will also feature at Ash, but at present look less convincing.
Three patients have been treated so far, one at 6x1011vg/kg and two at 2x1012vg/kg. In all patients therapy led to factor VIII (FVIII) levels of 5IU/dl, above which spontaneous bleeding is rare; however, only one of the high-dose patients achieved normal FVIII levels, above 50IU/dl.
This puts Freeline’s project more in line with Spark’s SPK-8011, rather than Biomarin’s valoctocogene roxaparvovec (valrox), which excited attendees at last year’s Ash with its potential to normalise FVIII levels.
However, since then concerns have emerged about valrox’s durability (Snippet roundup: Biomarin gets a double dose of doubt, May 25, 2018). These worries will not be addressed until next year when Biomarin presents three-year data.
Spark, meanwhile, will be at Ash, but the group’s SPK-8011 presentation looks set to underwhelm – investors had been hoping for detailed FVIII data from the highest-dose cohort of its phase I/II trial, but instead the company will focus on long-term results with the lower two doses. An update on the highest-dose cohort should be available in mid-2019.
|Selected haemophilia-focused Ash abstracts|
|Saturday, 1 Dec|
|SPK-9001||Spark Therapeutics||FIX Padua haemophilia B gene therapy, ph1/2 trial||2198||6:15pm|
|Sunday, 2 Dec|
|SPK-8011||Spark Therapeutics||Haemophilia A gene therapy, ph1/2 trial||487||4:30pm|
|AAV8-HLP-hFVIII-V3||Freeline||Haemophilia A gene therapy, ph1/2 GO-8 trial||489||5:00pm|
|Monday, 3 Dec|
|FLT180a||Freeline||Haemophilia B gene therapy, ph1/2 trial||631||10:30am|
One issue with SPK-8011 has been immunogenicity, which the company has addressed with steroids. Spark is now expanding the phase I/II study to include a prophylactic steroid regimen, as well as a new manufacturing process.
A company that hopes to avoid the immunogenicity problem is Sangamo – but that group will also be noticeable by its absence at Ash. The company’s chief executive, Sandy Macrae, told investors in August that data with its Pfizer-partnered haemophilia A gene therapy, SB-525, would feature at the meeting, but later rowed back on this.
At last week’s Jefferies meeting in London Mr Macrae played this down, telling Vantage that getting into the Ash late breakers had always been a long shot. Sangamo will present data from the trial next year, including data from a new, high-dose cohort.
The chief exec added that he would rather report the results in full than dribble them out piecemeal. Investors appeared to disagree, sending Sangamo’s stock down 18% when the news emerged.
Either way, the low profile or absence of other haemophilia gene therapy players could give Freeline the chance to grab the headlines this year.
This story has been updated to reflect the fact that FLT180a uses the FIX Padua variant, and the trial of AAV8-HLP-hFVIII-V3 is investigator led.