Explainer, Gene Therapy

Spark Therapeutics faces a grilling as FDA ponders a pioneering OK for gene therapy

With one of the most closely-watched FDA panel reviews of the year coming up for Spark Therapeutics’ $ONCE lead gene therapy, internal reviewers at the FDA have raised some serious questions for the experts to consider.

At the top of the heap of considerations the panel experts will field on Thursday are questions about the durability of this eye therapy, the possibility that patients will need multiple treatments in order to preserve vision gains, the right age to use it and the use of a completely novel endpoint for the primary goal when standard visual acuity achievements fell far short of the goal on statistical significance.

The reviewers readily agree that the gene therapy — angling to become the first such treatment approved in the US — met the main criteria for success. But the drug, voretigene neparvovec (or Luxturna), also was no once-and-done panacea.

Investors were upbeat but possibly a little ambivalent about the next step, with Spark’s stock up 1% in pre-market trading.

In the key study, investigators treated 21 patients with retinal dystrophy triggered by biallelic RPE65 mutations; 10 were recruited for the placebo group. Eleven of the 21 had a significant, two point or more improvement in light levels in both eyes, with 15 scoring a significant MLMT (multi-luminance mobility testing) gain in the first treated eye. That easily beat the response in the control arm.

Checking visual acuity, though, shows that the patients failed to demonstrate a significant improvement for the designated secondary, leaving Spark to seek a pioneering approval using an endpoint that’s never been used before in this way.

The FDA is asking the experts to consider the significance of the endpoint, the impact such improvements have on patients’ daily activities, as well as the consequences if patients need multiple treatments, given the fact that there’s no data on just how durable the treatment effect can be.

Notes the review:

(T)here is no available long term follow up data to address whether the effect decays over time. Therefore, the duration of AAV2- mediated transgene expression leading to sustained clinical benefits beyond one year is unclear.

The review also notes that Spark ignored a key piece of advice, avoiding a co-primary endpoint on evaluating how the first-treated eye was affected compared to both eyes, with reviewers concerned that a patient response could be judged a success even if vision in one eye deteriorated and only one eye improved.

This concern led FDA to recommend co-primary efficacy endpoints, i.e., MLMT score change using both eyes and MLMT score change using the first eye. However, Study 301 was designed with a single primary endpoint, an MLMT score change using both eyes.

None of that marks a kiss of death for this application. The reviewers are careful to avoid any harsh judgments or endorsements, staying neutral on the key questions regarding efficacy and safety. But it’s also not exactly the kind of discussion any gene therapy company wants to have just before a potential market launch like this.

While analysts have given Spark high marks for this therapy, with good odds of success, major questions remain on how these treatments will be covered by skeptical payers who may be asked to foot the bill on a million-dollar procedure. Will the payments be spread over time? And what happens if the gene therapy doesn’t work as billed, or fades over time?

RBC’s Matthew Eckler counted himself among the analysts who saw today’s review, with no big surprises, as a plus for Spark. He noted:

On first read, we see no major surprises in FDA briefing documents released this morning ahead of Thursday’s AdCom meeting for Luxturna. Focus of the FDA review is on efficacy (younger vs older patients, novel Phase III endpoint), safety (subretinal injection, immunogenicity), and duration of response; while the single voting question sets up a straight up/down vote. As outlined in our recent initiation (link), we anticipate a positive panel and approval by the 1/12/18 PDUFA. Separately, we see discussion and outcome Thursday as having read-through to the gene therapy space broadly, particularly FDA and panel members’ focus/comfort around safety and duration of response.

So far, two gene therapies have been approved in Europe, but the first one flat failed to gain traction and was dumped while the second is only rarely employed. With this first application in the US, Spark is initiating a discussion that will be closely followed throughout the industry.

The outcome is not assured.


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