Gene therapy, a groundbreaking concept whose inability to deliver on huge expectations was at least partly responsible for the 1999/2000 biotech boom and bust, is back on investors’ agenda.
Current hopes rest on several projects aiming to treat rare diseases – whose underlying basis in specific genetic mutations makes them a logical target for DNA therapeutics – and clinical trial readouts provide several important catalysts (see table below). What is more, in the past year cash has started flowing into the space again.
The poster child for this new wave of potential therapeutics is Uniqure’s Glybera, a treatment for lipoprotein lipase deficiency that last year became the first ever gene therapy to gain regulatory approval – albeit only in Europe.
Until then this was a field in which safety issues had scuppered initial hopes, in addition to delivery and immune response problems. The permanence of a treatment meant for instance that, in contrast to a drug, side effects could not be easily reversed.
While work using DNA to treat diseases has continued apace, cardiovascular and oncology indications are proving tough (Unequivocal failure sees Vical ditch gene therapy, August 13, 2013). Rather, in the latter it is through small-molecule and immune therapy approaches that most progress is being made.
Still, none of this detracts from the fact that in rare inherited disorders several gene therapy companies have secured large amounts of cash.
Uniqure itself completed a $92m float this month, though tellingly it chose Nasdaq and not an exchange in Europe, where it is based. Glybera has yet to be launched, and the cash will pay for a manufacturing plant as well as supporting its US development.
Another notable gene therapy business, Bluebird Bio, raised $116m in a Nasdaq IPO last June. Bluebird is working on the ex vivo insertion of functional gene copies into a patient's own hematopoietic stem cells, and its Lenti-D project, concerning the ABCD1 gene, is in a phase II/III study.
An ongoing earlier programme has shown the maintenance of safety and therapeutic benefits for more than five years. A related project, LentiGlobin, aims to treat beta-thalassemia and sickle cell disease by inserting a fully functional human beta-globin gene, and naturally all these studies involve very small numbers of patients.
|Clinical-stage gene therapy projects for rare, inherited disorders*|
|Status||Project||Company||Condition||Trial IDs||Patients (lead trial)||Primary completion (lead trial)|
|Approved||Glybera||UniQure||Familial lipoprotein lipase deficiency||NCT01109498||14||–|
|Phase III||AAV2-hRPE65v2||Spark Therapeutics||Leber's congenital amaurosis||NCT00999609
|Phase II/III||Lenti-D||Bluebird Bio||Childhood cerebral adrenoleukodystrophy||NCT01896102||15||Aug 2018|
|Phase II||AGTC-0106||Applied Genetic Technologies||AAT congenital deficiency||NCT01054339
|Phase I/II||LCA2||Applied Genetic Technologies||Leber's congenital amaurosis||NCT00749957||12||Sep 2014|
|StarGen||Sanofi/Oxford BioMedica||Stargardt disease||NCT01367444
|UshStat||Sanofi/Oxford BioMedica||Retinitis pigmentosa/Usher syndrome||NCT01505062
|AAV8-hFIX19||Spark Therapeutics||Haemophilia B||NCT01620801||15||Oct 2019|
|AskBio009||Asklepios BioPharmaceutical||Haemophilia B||NCT01687608||16||Nov 2019|
|LentiGlobin||Bluebird Bio||Thalassaemia||NCT01745120||15||Jul 2017|
|–||Généthon||Chronic granulomatous disease||NCT01855685||20||Sep 2015|
|Haematopoietic stem cell therapy||Généthon||Wiskott-Aldrich syndrome||NCT01347242
|SAF-301||Lysogene||Sanfilippo syndrome||NCT02053064||5||Jun 2014|
|Phase I||AAV2-sFLT01||Sanofi||Age-related macular degeneration||NCT01024998||34||Jul 2014|
|RetinoStat||Sanofi/Oxford BioMedica||Age-related macular degeneration||NCT01301443
|Neo-rhGAA||Sanofi||Pompe's disease||NCT01898364||21||Apr 2015|
|*comprises only projects with studies listed in clinicaltrials.gov|
Beyond Glybera the most advanced of these genetic disease assets is owned by the private company Spark Therapeutics, which is in phase III with an AAV vector delivering genetic material to correct mutations in the RPE65 gene.
Such mutations lie behind an inherited form of retinal degeneration called Leber's congenital amaurosis 2, and the trial should yield data next year. Spark, a spin-out of from The Children’s Hospital of Philadelphia, raised an impressive $50m in venture financing last October.
A gene therapy for another inherited form of blindness, choroideraemia, could enter phase III later this year. NightstaRx, an Oxford University spin-out, raised $20m in venture funding last month to run the trial (Syncona has the finishing line in sight with $20m gene therapy investment, January 31, 2014).
Interestingly enough, rare disease gene therapy seems to be an area without much big company involvement; the exception is Sanofi’s deal with the UK’s Oxford Biomedica.
This alliance’s earlier key focus had been the cancer vaccine Trovax, but this failed in a phase II study in renal cancer. Undeterred, Oxford has ploughed on with gene therapy, where it still boldly states that it wants to become the world leader.
The UK group can still count on Sanofi as a partner in three projects: StarGen, UshStat and RetinoStat. Indeed, the French group this month broadened its rights to all ocular indications for the first two.
All three Sanofi-partnered products use LentiVector technology to deliver healthy copies of the ABCR, MYO7A, and endostatin and angiostatin genes respectively. StarGen and RetinoStat studies could read out this year.
Of course, nothing is plain sailing in gene therapy. One company, Applied Genetic Technologies, has taken two projects into phase II, with one set to yield data in Leber's congenital amaurosis 2 this year.
But the group now describes these as mere proof-of-concept programmes for its AAV vector-based approach, and has switched its focus to three other preclinical-stage ophthalmology projects. The private group Asklepios Biopharmaceutical also has an AAV technology, but beyond signing a cross-licence with Genzyme last year it has had little to shout about.
Nevertheless, in the current market companies must make hay while the sun shines, and perhaps realising this Applied Genetic Technologies filed last month for an IPO to raise up to $70m. Others could yet follow before the current funding window shuts.