The executive vice president of research and development at Jazz Pharmaceuticals discussed what the clinical community needs to know ahead of the regulatory decision on JZP-258 in the treatment of cataplexy and excessive daytime sleepiness in narcolepsy.
Robert Iannone, MD, MSCE
Last week, the FDA accepted a new drug application (NDA) for Jazz Pharmaceuticals’ oxybate agent, JZP-258, for the treatment of cataplexy and excessive daytime sleepiness in those aged 7 years and older with narcolepsy. The agency set the Prescription Drug User Fee Act (PDUFA) action date for July 21, 2020, when, if approved JZP-258 would join sodium oxybate (Xyrem) as the only approved agents for this indication.1
The NDA is supported by data from a phase 3 global, double-blind, placebo-controlled study, in which JZP-258 demonstrated highly significant differences compared to placebo in the weekly number of cataplexy attacks and the change in Epworth Sleepiness Scale (ESS) score. The treatment group showed clinically meaningful conservation of efficacy, while the placebo group experienced a significant worsening for both end points.2
To find out more about what the clinical community needs to know ahead of the regulatory decision as well as any potential future plans for JZP-258, NeurologyLive spoke with Robert Iannone, MD, MSCE, executive vice president, research and development, Jazz Pharmaceuticals, in an interview.
Robert Iannone, MD, MSCE: For starters, I think that they already know a lot about it. The primary data were presented at World Sleep in Vancouver in 2019. I would say that those data really clearly established JZP-258 as an oxybate that is as efficacious as Xyrem, and I think the design of that study really helped in that patients who were on Xyrem were transition to JZP-258 and they demonstrated maintenance of efficacy. In fact, when you look at things like cataplexy, there might even have been a slight trend downward as the dose was optimized. Obviously, there was not much room to show improvement as most patients on Xyrem already had a minimum number of cataplexy events each week, but clearly, JZP-258 was maintaining efficacy. Then, in the randomized withdraw portion, you could see that those patients who were withdrawn and allowed to go on to placebo, their narcolepsy symptoms returned— all the key symptoms—with the primary end point being cataplexy, the secondary end point being Epworth Sleepiness Scale.
I think the second key point there is that overall, the tolerability is just highly consistent with oxybate and Xyrem, in general. There may have been, in the phase 1 study, a hint toward even better tolerability around things like nausea and vomiting. That could be explained by the fact that JZP-258 has a slightly lower Cmax, and that may be having an impact on less nausea. So that’s the first piece—the efficacy and tolerability results that were already presented.
I think the other thing that the physician community at large, and certainly narcolepsy physicians, understand, is how important cardiovascular health is for narcolepsy patients. Narcolepsy patients are known to be at higher risk of cardiovascular morbidity than the general population, and we know from our experience with narcolepsy that a great majority of patients, especially those who are on the older side, are taking medications for cardiovascular issues such as hypertension. We also know that there's a proportion of narcolepsy patients—we think it's about 20%—who would have been offered Xyrem but were not because of the sodium content and their underlying cardiovascular risk.
The physician and the treating community is sort of well aware of the advantages of JZP-258, but certainly, we will be continuing to communicate that we feel given that the significant reduction in sodium with JZP-258, it will be a better and safer choice for all patients with narcolepsy, and will be more in line with what I would say is very broad accepted guidance around reducing sodium intake that comes from organizations such as the American Heart Association, or even the FDA. In those guidelines, the ideal total sodium intake for a day is set at 1500 mg, which could be exceeded just based on Xyrem alone. JZP-258 reduces, depending on the dose, the amount of sodium intake by between 1 g and 1.5 g daily.
Well, I think the fact that it is demonstrated now to be every bit as efficacious as Xyrem and has that 92% reduction in sodium—as a percentage, that's certainly high. But when you think about the amount of sodium that Xyrem patients are getting, which could be up to 1500 mg that’s a significant, significant reduction. Those are the really the 2 key things that we feel make this the safer product for all narcolepsy patients. These are patients who, remember, are going to be on this drug for a lifetime. Again, as you look at the underlying increased risk of cardiovascular morbidity and mortality from narcolepsy and the frequency of treatments related to that underlying cardiovascular risk, we think that for all patients JZP-258 is going to be a better choice. And there's really nothing in the marketplace that's comparable.
I would start with fact that we have an ongoing clinical trial in a related condition called idiopathic hypersomnia with JZP-258. That trial hit a key enrollment milestone last year with 50% enrolled, and we're expecting to complete enrollment this year. We're excited to see whether the benefits of JZP-258 could be extended to patients with idiopathic hypersomnia.
First and foremost, we certainly will be looking at other ways to capture, real-world evidence data or other information around the use of JZP-258 that really could support its adoption into clinical practice. We're certainly thinking through those kinds of studies as well at the moment. I would expect that, just as with any other product, we continue to collect information potentially even evaluated in additional clinical trials. But we do think that that with regard to efficacy and tolerability for narcolepsy, the trial that was done was certainly definitive and demonstrated.
The main condition that we've already made a decision about is ongoing as idiopathic hypersomnia. There certainly has been interest in using oxybate in other conditions, even beyond idiopathic hypersomnia is something that we continue to look at, but we don't have any additional plans at the moment.
We think that is a critically important fact. Xyrem right now is the only drug that is indicated both for both of those key symptoms of narcolepsy, cataplexy and excessive daytime sleepiness. Virtually all narcolepsy patients do have excessive daytime sleepiness, and a subset of those—typically the ones with type 1 narcolepsy—will also cataplexy. The cataplexy indication is unique to Xyrem, and we expect with JZP-258 we’ll have that same indication. Cataplexy is really potentially quite disruptive to patients. For some patients that have many, many episodes of cataplexy that could range from the milder side, of loss of body tone, to something more dramatic that can be quite disruptive. We think that treating those 2 hallmark symptoms, at a minimum, is really critical. And again, Xyrem is indicated for that and we expect that JZP-258 would be as well, based on the phase 3 data that we’ve read out.
The timeline is pretty aggressive for the FDA review given that it is being reviewed as an oxybate, rather than a novel chemical entity, and also has priority review. So, we're expecting the FDA decision, the PDUFA date, on July 21. It’s coming up on us, and we're quite excited about that. There will be some work after that to establish the scheduling, which we expect to be the same as Xyrem, given the regulation around that, and also some period of time to adapt to accommodate JZP-258, and hopefully that will allow for launch even this year.
Transcript edited for clarity.
1. Jazz Pharmaceuticals Announces FDA Acceptance of New Drug Application for JZP-258 for Cataplexy and Excessive Daytime Sleepiness Associated with Narcolepsy [press release]. Dublin, Ireland: Jazz Pharmaceuticals; Published March 25, 2020. Accessed March 25, 2020. investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-new-drug
2. Jazz Pharmaceuticals Announces Positive Top-line Results from Phase 3 Study of JZP-258 in Adult Narcolepsy Patients with Cataplexy and Excessive Daytime Sleepiness [press release]. Dublin, Ireland: Jazz Pharmaceuticals; Published March 26, 2019. Accessed March 25, 2020. prnmedia.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-positive-top-line-results-from-phase-3-study-of-jzp-258-in-adult-narcolepsy-patients-with-cataplexy-and-excessive-daytime-sleepiness-300819008.html.