With AdComm meeting looming, FDA shares concerns about Spark’s lead gene therapy

Analysts at RBC and Evercore ISI expect a positive outcome from Thursday's meeting.

Spark Therapeutics’ inherited eye disorder treatment voretigene neparvovec faces an FDA advisory committee this week with a question mark over the efficacy endpoint used in trials.

It’s a pivotal moment for the gene therapy specialist, and the first time that one of its pipeline candidates has reached this stage of development. It also has the potential to be the first gene therapy to be approved in the U.S. if the FDA decides to give it a green light.

Voretigene neparvovec, which has been given the provisional name Luxturna, is under review at the regulator for a rare sight-robbing condition known as biallelic RPE65 mutation-associated retinal dystrophy that affects around 3,500 people in the U.S. and Europe and has no approved treatments. The therapy is delivered via injections beneath the retina in both eyes—spaced apart to reduce the risk of complications—and aims to correct the underlying genetic defect in the retina.

The FDA reviewer’s briefing document sets out a number of issues to be discussed at the meeting on Thursday, including whether multi-luminance mobility testing (MLMT)—which has never been used as an endpoint in any other clinical trial—is fit for purpose, particularly as Spark’s pivotal trial missed the secondary endpoint of improving visual acuity.

And of course, there’s also the thorny topic of safety. Serious side effects in early trials of gene therapies approach in the 1990s and early 2000s, linked to the adenoviral vectors used to deliver the gene sequences, have made regulators cautious, but Spark may draw comfort from the relatively easy time given to Novartis’ CAR-T therapy tisagenlecleucel-T in July.

The FDA reviewer cites a number of safety concerns with Spark’s therapy, including complication such as damage to the retina and macula of the eye, and it also wants to talk about the durability of the therapy and the risks that may be associated with re-treating the same eye.

Another key question the FDA wants to discuss with the panel is the best timing of the therapy, given that Spark’s trial involved children with significant sight loss, but the evidence points to less benefit from the therapy in more advanced disease.

Analysts at RBC Capital Markets said the tone of the FDA reviewer’s comments was “balanced” and took a “constructive stance”, and they see no reason to change their expectation of a positive outcome from the advisory committee for Spark and approval by the FDA’s PDUFA date of Jan. 12, 2018. They are predicting that sales of the gene therapy could reach around $550 million at peak.

The analysts also see the discussions and outcome of the meeting “as having read-through to the gene therapy space broadly, particularly FDA and panel members’ focus/comfort around safety and duration of response” as the U.S. waits for its first gene therapy approval.

Across the Atlantic in Europe, a couple of gene therapies have already been approved, namely uniQure and Chiesi's $1 million plus-per-course Glybera (alipogene tiparvovec) for lipoprotein lipase deficiency (LPLD) and GlaxoSmithKline’s Strimvelis for severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency. However, approval is clearly not necessarily followed by commercial success.

uniQure dropped plans to file in the U.S. in 2015 after FDA asked for two pivotal trials of the therapy, and Glybera was withdrawn from the EU market earlier this year due to a lack of demand. Meanwhile, GSK priced Strimvelis at a lower rate of around $650,00 a year, but hasn’t provided any updates on take-up and has said its rare disease operations could be up for sale.

Evercore ISI analysts also see the briefing doc as positive for Spark, noting that FDA is “raising no unexpected issues, and the AdComm appears designed to hone in on the appropriate patient population and timing of treatment as opposed to the approvability of the product itself, in our view.”