A phase III trial requiring patients with an inherited condition causing vision loss to be tested on their ability to negotiate an obstacle course in varying degrees of semi-darkness does not immediately sound like something that might lead to a landmark in the field of gene therapy.
But it has surely done so, and Spark Therapeutics’ lead candidate, SPK-RPE65, is now on course to become the first ophthalmic gene therapy – indeed the first gene therapy of any type – to reach the US market. After the two major setbacks this year – the failure of Celladon’s Mydicar in advanced heart failure and the disappointing results with Avalanche Biotechnologies’ AVA-101 in wet AMD – the news could hardly have been more welcome in the beleaguered gene therapy space.
But investor response has been surprisingly muted, with Spark seeing a rather paltry stock price gain of just 20% yesterday. Still its achievement should not go unrecognised: the pivotal trial of SPK-RPE65 was for treatment of types of inherited retinal dystrophy caused by mutations in the RPE65 gene has been an almost unqualified success.
The open-label study met its primary and two of three secondary endpoints, with no serious adverse events or deleterious immune responses. This was in spite of investor scepticism over Spark's amending of the trial’s statistical analysis plan, which looked like an attempt to give SPK-RPE65 a better chance.
It transpired that the relatively small study included two subjects who were not followed up, though neither received SPK-RPE65, and included a third whose vision was effectively too good to meet baseline entry criteria. Given just 31 patients were enrolled it seemed as if Spark might have to rely on modified intent-to-treat data or per-protocol analyses to show a positive result.
But in the event the endpoints were hit for the intent-to-treat population. And given that just 21 patients received SPK-RPE65, while 10 were controls, it is reasonable to assume the effect size must have been large.
Spark said a majority of the subjects given SPK-RPE65 derived the maximum possible benefit that could be measured by its function test, and this effect was confirmed by a parallel improvement in retinal sensitivity. It noted that some two thirds of the treated subjects were able to navigate the test course at the lowest light levels, while no control patients achieved this.
The study subjects were mostly children and young adults, with RPE-65 mutations that would be expected to lead to Leber congenital amaurosis. Detailed results from the study are expected to be presented at the Retina Society annual scientific meeting this weekend.
All the subjects were tested at baseline and at 12 months using a mobility test, effectively an obstacle course in which the subjects had to negotiate hazards, sometimes with both eyes clear or with one eye blindfolded and at varying intensities of light. Control arm subjects were later crossed over to treatment, and will be included in a subsequent analysis.
|Primary||Mobility test (MT) change score, bilateral||p=0.001|
|Secondary||Full-field light sensitivity threshold testing, averaged over both eyes||p<0.001|
|MT change score, first injected eye||p=0.001|
|Visual acuity, averaged over both eyes||p=0.17|
Spark plans to file regulatory applications for SPK-RPE65 next year, and given that it holds breakthrough therapy designation it should receive a rapid review. If approved, SPK-RPE65 would become the first gene therapy to reach the market in the US, and only the second in the western world after Uniqure’s Glybera got qualified EU approval for familial lipoprotein lipase deficiency.
The positive result propels Spark to the forefront of the ophthalmic gene therapy space. However, with this will come the burden of establishing a new pricing model for one-time gene therapies for rare diseases at a time of heightened public scrutiny of pharmaceutical costs.
If SPK-RPE65 is approved Spark will have to come up with a formula to earn perhaps $1m per patient or more, which may be in very reasonable in the context of restoring vision to patients – but which is less likely to be palatable to payors.