ZGNX (ZGNX) 2017-12-04 Earnings Call Transcript

Good day everyone and welcome to the Zogenix KOL Call. Today’s conference is being recorded. And at this time, I would like to turn the conference over to Brian Ritchie, LifeSci Advisors. Please go ahead.

Thank you, operator, and thank you all for joining us this afternoon. With me on today’s call are Dr. Joseph Sullivan as well as representatives from Zogenix’s management team including Dr. Stephen Farr, Chief Executive Officer; and Dr. Brad Galer, Chief Medical Officer. In addition, Dr. Gail Farfel, Zogenix’s Chief Development Officer will also be available during the Q&A session. Please note that certain information discussed on the call today is covered under the Safe Harbor provision of the Private Securities Litigation Reform Act. We caution listeners that during this call, Zogenix management will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements, due to risks and uncertainties associated with the Company’s business. These forward-looking statements are qualified by the cautionary statements contained in Zogenix’s news releases and SEC filings, including in the annual report on Form 10-K and subsequent filings. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, December 4, 2017. Zogenix undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now, I’d like to turn the call over to Steve.

Thank you, Brian, and good afternoon to everyone who is joining us on today’s call. We are wrapping up, what has been an extremely productive and successful AES meeting for Zogenix. During Study 1 results, there were nine scientific poster presentations that provided further evidence supporting the continued investigations of ZX008 or low-dose fenfluramine in rare intractable forms of childhood-onset epilepsy. There were two poster presentations highlighting the significant burden Dravet syndrome and other forms epileptic encephalopathies plays on caregivers and family members. Most importantly, the updated study, when data presented at AES, further enhanced our confidence in the potential of the drug as a safe and effective treatment for Dravet syndrome. In addition, our Scientific Exhibit Room entitled, Low-dose Fenfluramine: An Update on Mechanisms, Efficacy and Safety in the Treatment of Epileptic Encephalopathies, which we hosted yesterday, was extremely well attended by various stakeholders throughout the day. This Scientific Exhibit Room highlighted all of the posters and publications focused on ZX008 generated to-date, particularly the positive secondary endpoints and safety data from Study 1, the continued safety and efficacy data from the Belgium open-label Dravet study, and new efficacy data in the open label Lennox-Gastaut syndrome study. I think, this event proved to be highly informative for everyone who attended. Also, yesterday evening, we were pleased to support a CME Symposium at the conference entitled, Dravet Syndrome: Emerging Insights, New Treatment Approaches. Attendance of the event was completely full. In order to put an appropriate close to AES 2017 for Zogenix, we are especially pleased to be joined for this call by Dr. Joseph Sullivan. Dr. Sullivan is Director of the Pediatric Epilepsy Center at University of California San Francisco and the Principal Investigator of Zogenix’s first Phase 3 trial Study 1 in North America for ZX008 in Dravet Syndrome. Yesterday, he presented updated Phase 3 clinical trial data during the symposium. Dr. Sullivan has been kind enough of to join us today to discuss these findings as well as the current treatment landscape in Dravet syndrome and the unmet medical need for treating patients with this debilitating condition. Following this, Brad will provide key highlights from other Zogenix sponsored posters presented over the last few days here at the AES Conference. At the conclusion of Brad’s presentation, we will open up the call for questions with Dr. Sullivan and the Zogenix team. It’s now my great pleasure to hand over the call to Dr. Sullivan. Joe?

Thank you, Steve for giving me the opportunity to present and overview here what I truly do feel is a changing landscape for those patients and their families living with Dravet syndrome in 2017. So, here is a brief outline of remarks I will make this afternoon. I first will have a few slides about the Dravet treatment landscape pre-2014. I will then highlight a case study of one of my patients, who ultimately enrolled in the ZX1501 and 1503 studies. I will then do a brief review of the emerging therapies, post-2014, and then go into a more detailed review of the data that was presented at this year’s AES. So, first, the data or lack thereof. This is something that as pediatric epileptologists we struggle with, because we are often not left with well-designed Phase 3 controlled clinical trials to help guide our treatment. And in fact, when a Cochrane review was done in 2013 to look for the efficacious treatment for Dravet syndrome, 14 studies were identified, 11 were excluded for the reasons you can see in the slide, and this was only left with two studies both of which evaluated stiripentol. And so, what did that data show? This actually showed that in a well done, randomized placebo controlled clinical trial involving 20 patients who received placebo and 21 who received stiripentol, when added to conventional treatments of valproate and clobazam that there was a 69% reduction in the treatment group compared to a 7% increase in placebo. And this really did highlight the value of going after a very specific epilepsy syndrome for the study of some of these effective treatments. So, despite stiripentol being the only drug that was shown to be efficacious in a Phase 3 trial, all of these other treatments are much more commonly used that you can see in this slide. And the reason why there is an asterisk next to stiripentol is because unfortunately it is not FDA approved in the U.S. and is difficult for many patients to treat. Perhaps if it was more easily to obtain, it would move -- be moved up here in the treatment paradigm, as I show on the slide. I’ll now go over a case study of a patient that I followed from early on. He presented to me at around nine months, was a previously healthy male who experienced two prolonged seizures in 2011. One of those seizures was a prolonged focal motor seizure of the right arm and the other one was a generalized convulsion. He had normal development prior to the seizure and still had normal development at the time that I saw him and had no other epilepsy risk factors. He did fairly well for the next nine months with no seizures but then experienced a generalized convulsion, two days after receiving his routine vaccines and interestingly had no fever at that time. He still was developing normally, and he’s still not treated at this time. About three months later, he then had a 45-minute generalized tonic-clonic seizure in the setting of fever and was at this time had a suspect of the diagnosis of Dravet syndrome and sent off confirmatory testing and he did reveal a non-sense mutation in his mutation in his SCN1A gene, he was 18 months at that time. He then went through many of the standard treatments that I showed you on the preceding slide including levetiracetam, valproic acid, clobazam, topiramate, stiripentol, and ultimately actually enrolled in the Epidiolex expanded access program. Stiripentol clearly shortened the overall duration of his seizures. So, he’s one of these children that I feel the background treatments never really had a significant overall impact on reducing the overall frequency of the seizures with his longest seizure-free period being between three and four weeks. So, what was left at that time is seizure frequency gradually escalated and recurring about three to four times a day and again these were convulsive seizures. His development stagnated. And it was around that time that we discussed enrollment in the ZX008-1501 program. Unfortunately, he was still on stiripentol because the observation was that that had reduced the duration of his seizures and the family was rightfully concerned about weaning off of that medication in order to go into the trial. But we weighted the risks and benefits and ultimately decided to do that. The seizure frequency did gradually increase but then we ultimately enrolled in the 1501 trial and he was randomized in July of 2016. He was -- he experienced no change in his seizure frequency during the double blind period but then did roll over into the open label extension and the dose was gradually increased to the 0.8 milligrams per kilogram as allowed per protocol. During that dose escalation and in the subsequent months that followed, his seizure frequency went down to about one per day or every other day which compared to his baseline represented a 75% reduction. But arguably and hopefully most clinicians would agree still having one seizure per day is a high seizure burden. So, we discussed retrial of valproate when that was allowed by the seizure protocol -- by the study protocol. And that allowed some additional seizure reduction where he’s now having about zero to one per week with again some two to four-week seizure-free periods. And I just want to read a quote from his family that maybe highlights the impact that this change has had on not only the child but the family as a whole. And I quote, “I hope you know how much you’ve done for and meant to our family. At our lowest points, you’ve been the thread holding us together and happily, you helped us climb to some new higher points recently. I believe you helped us find, ‘our son’. He’s blossomed in the last few months and we credit it to your efforts with the trial and his drug mix. You have our faith and support always.” So, with that backdrop, what is the changing landscape in 2017, and we’ll focus our attention here on the Epidiolex, a program as well as the ZX008. So, depicted on the slide here is the recent publication in the New England Journal of Medicine from this past May which revealed the primary outcome for the Epidiolex Dravet trial showing a 39% reduction compared to 13% reduction observed in the placebo arm. And you can see that the baseline numbers support that going down from 12 to 14 at baseline, down to 5.9 in the treatment group and this is statistically significant. Also of note is that in the treatment group, 5% of the patients were seizure-free compared to none in placebo. So, we were obviously very excited in the Dravet community to have now a second Phase 3 randomized controlled trial that showed efficacy in this devastating syndrome. Another way to look at some of this data is presented here, showing some of the responder rates. So, while we had that 39% reduction in seizures, you can see that there were some patients that experienced a greater than 50% seizure reduction and even a greater than 75% seizure reduction. And while they did not reach statistical significance over placebo, as a clinician, if you have one of these patients and you fall into that group, it is certainly clinically significant for you. So, moving onto the ZX008 program. It is a very similar study design with a similar number of subjects that were randomized. However, in this study, there were two dosage arms; you can see here that they were equally randomized with 39 in the high dose, 40 in the low dose and 40 who received placebo. Baseline seizure frequency was higher, at about 40 per month. And all of these patients underwent a six-week baseline followed by a two-week titration and then a 12-week maintenance where all of the background antiepileptic drugs needed to remain unchanged. Within this trial, five subjects withdrew due to adverse events and all of those were in the high dose group. So, here is a slide that depicts our primary endpoint that shows a 63.9% reduction in the convulsive seizures compared to placebo in the high dose group, which was highly statistically significant, and as I mentioned before also translated into highly clinically significant. In this -- superiority was also shown in the low dose group but at a lower rate at 33.7%. Moving onto some other ways to look at the data. I now have shown you the median percent seizure reduction, where again the high dose is superior to low dose and to placebo at 72.4%, and that is statistically significant when compared to placebo. While there was a significant reduction in seizures in the lower dose group, that actual reduction did not reach statistical significance when compared to placebo. I keep alluding to these responder rates because we really want to know how many patients actually get that clinically meaningful reduction in seizures which some may define as 50%, others may define as 75%. And depicted on this slide, you can see that 70% of the patients receiving high dose achieved a greater than 50% reduction in seizures. And what I feel is the most dramatic finding is that 45%, almost half of these patients were starting out with a seizure baseline of around 40 seizures, experienced a greater than 75% reduction in seizures. So, this is how those responder rates are detected across the entire responder rate spectrum from zero percent, all the way up to seizure-free. And I’d also like to focus on the far right hand side of the graph where we look at those patients that may be “super responders" and have a greater than 90% or 95% reduction. And when we look at those patients, you can see here on this slide that in those patients receiving the higher dose, 7.5% were seizure-free throughout the entire treatment period, but an additional 17.5% actually only experienced a single seizure during that entire treatment period, which again for this patient population is a game-changing outcome. Even in the lower dose, we also saw 7.7% seizure free and still 5% that also have that near seizure freedom or one seizure during the treatment period. Another way to look at this and how does that translate into parental observations as to how meaningful are these changes, is to look at this global impression of change. And then so, one through seven liker scale that the family ranks, how much improved they feel their child is compared to the preceding month. As you can see, four in the middle represents no change and one all the way to the left represents very much improved and two is much improved. And as you can see, 55% in the higher dose and 41% in the lower dose had either very much improved or much improved descriptor. So, on to the adverse events. Here I have listed the most common adverse events that were seen in the trial and represented -- that occurred in more than 12.5% of the study subjects. 95% did occur in the treatment arm but a significant amount in the placebo arm also experienced this list of adverse events. And then, the specific adverse events of clinical interest. Everyone was very concerned about the cardiac safety profile. I am happy to report that there were no clinically significant abnormalities in the study. There were some observed trace mitral regurgitation as well as aortic regurgitation and those findings occurred in five patients in the placebo arm, seven patients in the low dose and nine patients in the higher dose. And interestingly, these findings also occurred in 21 patients that actually screen failed at the beginning of the study, really highlighting that this is a physiologic change that occurs in childhood. And one other point that I would like to share from my own personal experience in the study, I actually had two patients that developed trace mitral regurgitation who rolled over into 1503 and had a follow-up visit that trace mitral regurgitation had completely resolved and they had remained on the same dose of medication. So, in conclusion, I feel that ZX008 has resulted in a dramatic reduction in seizure frequency and we have demonstrated a dose response where a higher dose is clearly superior to lower dose. Equally important is we have a clinically significant number of patients which have achieved this outcome of near seizure freedom which we really haven’t seen with any of the preceding treatments available to us. It’s overall safe and well-tolerated, and there are no clinically relevant echocardiogram findings. Thank you. My final side here, my apologies. So in summary, a changing landscape. I truly think how does this translate and to how I approach my patients. So, I really feel that we can now start to talk about medications that may result in near seizure freedom. And while seizure freedom is still a very high bar, hopefully, I have shown you in that quote from the family that even if you are not seizure-free, but you get into that near seizure freedom category that that has a huge impact on the quality of life for these children. And now that we have additional medications in our tool box at our disposal, our hope is that once they are into real world clinical practice and we get to use them, we will actually be able to figure out whether one single drug or a combo of drugs is the approach to get a patient to that outcome. And then, as we get additional open label experience with these new agents and we are able to wean some of the background AEDs as allowed for protocol, this will allow for astute clinical observations regarding efficacy of various combination and maybe even monotherapy. And this is how we will truly move some of those agents from that first slide that I you showed you in terms of how they are introduced in treatment algorithm over time. So, I would now like to turn this over to Brad Galer. Brad?

Thank you very much, Joe, for that great review and sharing your perspective on ZX008 in the clinical setting. Before I provide a summary of the AES meeting, I would like to add further commentary on the cardiovascular safety of ZX008 in our Phase 3 program, especially the occasional finding of trace regurgitation. I want to make it crystal clear that clinical guidelines categorized both absent in trace echocardiogram findings as normal and do not represent any evidence of cardiac valve disease. Trace regurgitation is considered a normal variance and is not a predecessor for the development of any valvulopathy. Most importantly, all eligible patients from our randomized trials entered study 1503, in open-label long-term safety study with continued cardiovascular monitoring as per protocol. 200 patients have now entered study 1503 with approximately half of those patients in the study for more than six months. In fact, we now have 44 children in the second year of ZX008 treatment, and there has not been any echocardiographic evidence, valvulopathy in any patient in any of our studies. That is not echo finding above trace regurgitation in any echocardiogram in any patient. In addition, to reiterate, the most recent DSMB review meeting that was held here in DC in November and after review an unblinded data of every patient’s echocardiogram, resulted in the recommendation to continue all of the trials without any modifications. I’m now going to provide a brief update on some of the key takeaways from posters presented here at AES over the past several days, which strongly support the continued investigation of ZX008 and refractory epilepsies. Findings from the ongoing prospective study of ZX008 in patients with Dravet syndrome in Belgium conducted by doctors Lagae and Ceulemans found that low-dose fenfluramine provided clinically meaningful reductions in major motor seizure frequency with sustained benefit noted for up to 6.5 years. These patients continue to have significant reductions in their major motor seizures with 91% having at least a 50% seizure reduction and 73% having at least 75% seizure reduction. The most common adverse events in this cohort were somnolence and anorexia. Furthermore, in this cohort, there continues to be no evidence of any cardiac valvulopathy or pulmonary hypertension in any patients. The next update is from the cohort of refractory Lennox-Gastaut syndrome patients enrolled in a core and long-term extension study, also conducted by the same investigators in Belgium doctors Lagae and Ceulemans. At week 20 of the core study, 8 of the total 13 enrolled patients or 62% had experienced at least 50% reduction in major motor seizures with fenfluramine. Of the 9 patients who then entered the extension study, 67% had at least 50% reduction in major motor seizures and 2 patients experienced 75% or greater seizure reduction. In this extension phase, there was a 58% median reduction in seizure frequency as compared to their baseline. In this cohort, again, ZX008 was generally well-tolerated and there were no clinical or echocardiographic signs of cardiac valvulopathy or pulmonary hypertension. With regard to dosing, the majority of these LGS patients have been titrated to optimal dosing, balancing efficacy with their adverse events. Of these responders, three patients were on 0.4 milligrams per kilogram per day, 1 was on 0.8 milligrams per kilogram per day and 2 were taking the maximum of 30 milligrams per day. In other posters presented here at AES, data presented focused on the mechanism of action, which demonstrated that fenfluramine acts as a positive modulator on the Sigma-1 receptor. And of note, a recent scientific publication found that positive modulators of the of the Sigma-1 receptor had antiepileptic activity in standard mouse seizure models. In addition, preclinical data presented here suggested that there maybe are a protective fenfluramine and a well accepted preclinical mouse model of Sudden Unexpected Death in Epilepsy or commonly referred to as SUDEP. Both Dravet syndrome and Lennox-Gastaut syndrome have been shown to have elevated incidence of SUDEP. The results of the study demonstrated that fenfluramine reduces the incidence and severity of both audiogenic seizures and seizure-induced respiratory arrest in this model of DBA/1 mice. We also presented data from a drug-drug interaction study assessing the pharmacokinetics and safety of ZX008 administered with and without a combination regimen of stiripentol, clobazam and valproic acid to European label to drug combination for stiripentol use. The result of this study importantly demonstrated that ZX008 did not have any significant effect or anything that can impact on the PK of any of these medications individually including clobazam or any of its metabolites. This drug combination did have a moderate effect on the PK fenfluramine and its metabolite norfenfluramine. And thus we learned that administering fenfluramine along with stiripentol, a well known potent CYP inhibitor can be easily managed by an appropriate, downward dose adjustments of fenfluramine, which we have done for study 1504. Lastly, our team has been very busy over the last several years, planning and performing important caregiver burden and pharmacoeconomic studies, both here in the United States and also in Europe. We had three such posters presented. These studies demonstrate that Dravet syndrome caregivers face substantial physical, emotional and time burdens including elevated levels of anxiety and depression and financial burden. In fact, one such study performed by Mark Jensen at the University of Washington reported that caregivers of children with epileptic encephalopathies including Dravet syndrome and Lennox-Gastaut syndrome reported significantly higher stress and caregivers of children with down syndrome and muscular dystrophy. In closing, I’d like to remind all of you that our AES posters can be found on our website, www.zogenix.com. I would now like to open up the call for Q&A. Operator?

Our next question will come from Difei Yang with Mizuho Securities. Please go ahead.

Yes. So, historically, I’ve looked at patients who are having one seizure a month as don’t change anything because that’s good. And so, it’s in those patients that start having the three and four seizures a month that we start to introduce something. And so with a lot of these drugs that we’re seeing in these clinical trials, the efficacy you see varies soon, right. So, it doesn’t take long. It only takes one to two months for you to be confident of that newly added drug is responsible for the efficacy you’re seeing. So, you do that sequential therapy once these patients get into that active form of their disease fairly quickly. But you don’t want to do it too quickly because we know that there’s background variability, so.

Thanks, operator. First and foremost, I want to thank Dr. Sullivan for joining us this afternoon and also the audience for asking the questions to him as well. Obviously, we think this is a very exciting time for us at Zogenix. Great data presented at AES certainly reinforced the potential we believe of ZX008 to be an important new treatment for seizure control in children and young adults with Dravet syndrome. We’ve got a busy year ahead of us next year. And as you all know, we have our second trial reading out Study 1504 in the second quarter and then moving on to our regulatory submissions thereafter. So, thanks again for joining us today. Enjoy the rest of your day.

That will conclude today’s conference. Thank you all once again for your participation.

[Operator Instructions] We’ll hear first from Paul Matteis with Leerink. Please go ahead.

Great. Thanks so much for taking my questions, I appreciate it. I have a couple, first one for the Company, maybe Brad. Could you comment a little bit more on the time course of observing trace regurgitation on echocardiograms? And maybe in what proportion of patients does that kind of fluctuate in between trace and absent findings? Thanks a lot.

Thanks, Paul, for the question. Well, first, let me reiterate regarding what is trace mitral regurgitation. Again, I want to reiterate that it is a normal variant. As these machines become ultrasensitive, it gets easier and easier to pick up. With regards to the 2017 clinical guidelines from the American Society of Echocardiography, they deemed us as the same as absent. The FDA definition of valvulopathy does not include trace mitral regurg and also in clinical practice, in particular just talking to a cardiologist about the children’s practice but also throughout the country if not the world, many pediatric cardiologists who read echocardiograms, will view this as absence; it’s such a slight finding. With regards to what we’re seeing in the program, we do see the transiency of these. It’s not uncommon as we progress that it comes and goes. And again, that is something that we have seen and was reported in the Belgium study over 28 years when no one progressed above trace, if at all. The vast majority of the patients do not develop any signs of trace above the trace mitral regurgitation either.

And maybe to expand upon that, what’s the hurdle or what on a theoretical level for the protocol would be the impetus for the DSMB to actually recommend modification of this study, like would the manifestation of a few cases of mild regurgitation require a change in the echo frequency, would it be moderate, like how have you kind of codified this in the protocol and thought about the risk benefit and chatted about this with FDA?

Good question. Right from the very beginning when we were working with FDA on the monitoring program, there was never any stopping or changing. They always viewed it as a risked benefit that always needs to be in context if patients do develop valvulopathy, which again we have not had any case of valvulopathy that it’s in context of what the patient, the child is getting with regard to seizure reduction. And so, it’s a case by case basis, and that’s how it’s written in the protocol as agreed by the FDA. But again, reiterating, trace regurgitation is not valvulopathy, it’s normal variant.

Okay. Has any patient increased regurgitation discontinued because of the echo finding?

No.

Okay. And maybe just one question for Dr. Sullivan. I’m wondering, now you have seen the data for this, you’ve seen the data for CBD and let’s fast forward maybe a few years from now on a theoretical basis that both drugs are approved, which one do you see is a first line drug in Dravet and how would you think about this on a patient by patient.

Yes. I mean, I think it’s -- although, it’s not a head to head comparison of the two trials, I mean, I think the primary endpoints in terms of seizure reduction speak for themselves. And when I highlight the percentage of patients that achieve that 75% reduction in seizures, I mean, that is really the medication that we look forward, have been waiting for. And so in my practice, I would clearly be reaching for ZX008 first.

Okay. And how should we think about -- assuming that it follows the study, every three-month echoes, like how cumbersome is that? Do you see your patients that often already, how long does this take? Is this something that you and other epileptologists know how to do?

Sure. So, I typically -- I am seeing these patients every three to six months. The ones that I’m seeing every six months are the ones that are doing better. I don’t think that this is overly onerous, especially when the families realize that that’s the way that they need to be followed, if they’re going to remain on this drug. The echocardiograms that we’ve been doing, I’m not obviously doing echocardiograms myself, but it actually has been one of the easier study procedures that we’ve done in the study; it has not been difficult to get at all. Often these families in our opinion, in my, they should be -- these families should be taken care by someone who has experience in Dravet. And most of those patients are already in academic medical centers where echocardiogram is readily available. And so, it is very easy to coordinate those studies with their clinic visits. So, I don’t see it as being onerous for the child or the family.

Our next question will come from Annabel Samimy with Stifel. Please go ahead.

Maybe I can direct the first one to Dr. Sullivan. So, in the Phase 3, we had a good number of patients who obviously came down to zero to one seizures over the study period, and I guess that was around 25%. But, I mean I guess -- I am curious to think what the -- how clinically meaningful it is for patients who are at the two or three seizure breakthroughs. It seems like there is a lot of -- there’s quite a bit of variability in these -- in the patients, and they will see periodic breakthroughs. So, can you sort of characterize -- or qualify that for us and what kind of impact that has for these patients to get to let’s say, two or three and how many you believe are in that category, aside from the zero to one that you saw in the trial?

Sure. And I assume when you say two to three -- I mean, when we reported the zero to one, that’s in the 12-week treatment period, so you’re commenting on the same -- same time period of two to three of weeks?

Yes.

Yes. So, that...

Three or just like dramatically less, right?

Yes, even four. I mean, these patients that are enrolling in the study, these are the patients that have a very, very high seizure burden, as outlined by their baseline seizure frequency. So, if they actually even get down to four, in a three months period that’s averaging about one per month, that is still so dramatic in terms of what that translates into not only the child’s quality of life but just the caregiver burden, which are some of the other things that we’ve been looking on -- looking at. And arguably, I mean, there’s a point there, right, it’s all based on someone’s baseline. And so, this is not something what I’d be looking to start a drug -- if they already are having one seizure amongst, that’s not the patient population that we’re reaching for these novel therapies but it’s the other 80% that have this high baseline where that 75% reduction is still game changing. So, if you do that math that could even translate into eight seizures, in a 28-day period, if you’re starting up from 40.

And maybe we can -- I can direct this more to the Company with regards to durability. So, clearly, in the LGS study, you showed some pretty good durability. But, it looked like some patients were fluctuating quite a bit. Is this variability typical in this LGS population? Can you just share some general thoughts about the Phase 3 LGS expectations from this trial?

Annabel, this is Brad. I’ll start and maybe I’ll hand it over to Joe for his realized experienced. But I mean, with LGS, and also Dravet, but particularly LGS, there is a lot of variability with regards to seizure types and fluctuations, through the course of the disease. In addition, I mean, it is a much more heterogeneous population with regards to its etiology. And therefore, the variability of that probably is reflected in the variability seizure and the seizure types and fluctuations that you see during practice. So, what we saw or what Dr. Lagae and Ceulemans saw in their LGS study is not an expected from what you would see in practice. I mean, the reductions they do see, they are extremely pleased with. And again, these were their most refractory patients that have failed up to seven therapies, majority are on four concurrent therapies, these were the worse of the worse and the fact that the majority of such a dramatic effect, given with this variability I think speaks to itself. And I’ll let Joe answer.

Yes. I guess I would echo that and stress the heterogeneity of the Lennox-Gastaut population compared to Dravet. I know that given the space and the needs for these two patient populations, it’s often, they are lumped in but they are very, very different. So, I agree with Brad’s comments that there may be some subtypes that certainly even in our larger study, we may not be able to tease out which those types are in terms of etiology. But I think that that probably does get to why some patients may have a breakthrough seizure. But keep in mind that epilepsy is a moving target, right. So, just because someone has a breakthrough -- I often encourage my patients even with the conventional therapies that we are using to don’t look at a breakthrough as meaning that that trend is going to continue. You can have a breakthrough and then things can restabilize again. And so, I think that’s where sometimes it’s harder within a clinical trial to kind of hang in there as opposed to real world practice.

Okay. I guess, on the durability for the Dravet syndrome trial. That seems to be pretty consistent in terms of its effects throughout the course of the time that we’re reviewing them. Do you think that this is a good indicator, even the cohort is so small for what we could see in the 1503 trial, in the extension trial?

Annabel, it’s Gail. We are encouraged. We are particularly encouraged by the fact that there was improved control of the seizures in the LGS open label trial when they got to the open label portion where they could flexibly dose to optimal efficacy balancing tolerability. So, we consider that a good indication for the upcoming double-blind placebo-controlled trial.

Also just to reiterate with regards to the LGS trial, I mean, there are seven patients that are now being treated for six months and four that are for year and one actually 15 months. So, I mean, we are seeing similar things when they do respond, the effect continues.

Okay, great. And if I can just ask one more with regards to again sort of reiterating what Paul asked. I mean, we saw a lot of excitement around CBD, we saw a lot of excitement around fenfluramine. Clearly, these two products are going to be available to physicians. So, I guess, would it be something that you in clinical practice would start experimenting with your own cocktails, even before clinical full trials are available to you to identify the efficacy of the combination?

Absolutely, I would be surprised if any combination clinical trial would ever be done. I think that this is what we do. We know the handful of drugs that work in the seizure types. I think it’s -- any seizure, specific seizure syndromes, I think it’s important to get a better handle on some of the potential drug-drug interactions. But we can do that as help clinicians by following labs and following tolerability, just patient reported tolerability. And so, it is certainly not going to take long when we have two drugs that have superior efficacy to the other things available that they’re being used in combination and we get to see some signal as to how that goes and definitely do not need a trial.

And your next question will come from Jason Butler with JMP Securities. Please go ahead.

First one for the Company. Obviously you are early in the LGS study. But can you talk about what you learned from the conduct of Study 1 and how that’s conforming the conduct of the LGS study, anything you learned or anything about the -- how you targeted patients?

Hi, Jason, it’s Gail. Thank you for that question. We are very pleased with the conduct of Study 1 meeting to the data that we were able to report. And so, there are lessons that we will continue in terms of the selection of sites and the training of sites, the use of the e-diary and the way that the Company has worked with our CRO partners to bring in the data and clean the data, and of course our analysis plans. The populations from -- clinical operations perspective are probably more similar than they are different. And so, we are looking to being able to leverage our experience to an even better job, both, in terms of timing of recruitment as well as reporting of the LGS study.

And then, just for Dr. Sullivan, thinking about the small number of patients that don’t achieve let’s say the 50% response threshold, how do you expect those patients to be managed? Would you keep some on drug, if they were no tolerability issues or would you look to add something else or would you look to discontinue them from a drug that wasn’t getting that kind of response?

Yes. I think it’s all about tolerability. So, if the drug is well tolerated, I mean, I feel like, I’m getting greedy now as a physician, right, where I want this 50%. I mean that certainly if things -- that’s an outcome that really does have real clinical significance. But, 35% is still clinically significant, if it is well tolerated. So I think that is really what is key. And obviously that balance between seizure control and tolerability starts to change as you get more patients that are seizure-free, families and clinicians alike are willing to tolerate a few more side effects. So, I wouldn’t look at my use of confirming any differently than I do with the current drugs that, if it’s a 25% reduction that ends up being hard to figure out. If I’m having to truly look at diaries and count and calculate, that probably has not been worthwhile clinical improvement and in that situation, I would, wean the patient off.

So, I’m going to change the subject a little to the non-cardiovascular related side effects. One thing stands out is the incidence of diarrhea. So, could you give us a little more color on what happened there? Is this significant indication of something or it’s well within expectations?

Hi, Difei, this is Brad. With regard to diarrhea, one, we’re not concerned about it. And if you actually look at the listing of adverse events, especially actually for the 0.2 dose, it looks as though many of these patients had a concurrent infection and also perhaps for antibiotics. We don’t believe that as something of concern or drug related. I don’t know if Gail you want...

Sure. Difei, it’s Gail. Brad is correct that most of the -- there was a high incidence of infections, antibiotic use, the typical things that you see in a pediatric study that’s running for a long period of time. So, most of this was not considered in any way related to the drug.

Okay. Thank you, Gail. And then, just a quick question on the LGS trial. I know it’s small patient numbers in the trial and it looks like the dropout rate is higher than Study 1. Is there any reason for that, and why do patients drop off?

It may appear higher but a lot of it, for instance one of those patients that was a protocol violation and actually was doing very well, and the parents decided to give the patient orthopedic surgery, which of course has stressed and worsened them and they lost their reduction and they had to ease. And it was a discontinuation...

Okay. That’s very helpful. Sorry, go ahead.

Sorry. Two, in the extension weren’t due to AEs but responded initially and lost -- one of which actually was doing very well and then again not unexpectedly from the LGS population develop the new type of epilepsy myoclonic type of seizure which is not uncommon with the natural history of this condition. So, we don’t think the AE profile that we see in LGS will be any different than we’re seeing in Dravet.

Thank you. [Operator Instructions] We’ll hear next from David Sherman with LifeSci Capital. Please go ahead.

I was just wondering if you could go back to potential use of the drugs -- was approved. Would the expectation for new patients coming in before there to be sequential use and to see who fails on the existing therapies before incorporating ZX008 or CBD or would those likely make it in two frontline therapies right when a patient came into practice?

Yes. So, because the trials are all for adjunctive therapy, it’s exceedingly rare that both practically but also clinically that we start using these therapies as first line treatment. As much as we don’t have data to drive the valproate and clobazam use, we’ve been doing it for 20 to 30 years and so we know the drugs well. So I still think that you are going to or I’m going to be using the valproate and clobazam as sort of first or second lines. And then that’s where I think the fenfluramine and Epidiolex would come into the picture. I do think though that then once we get more experience of those combinations and then we start to wean, because when we add a drug to an existing drug regimen, we are acknowledging that that existing drug regimen is sub-optimal. And so, when we add the new drug and see efficacies, let’s say, we get to that 75% reduction that I’m talking about, as far as we know there are not necessarily any synergistic reactions and so the goal is to wean those background meds. And then, just over time, we are going to be able to observe how that drug works in monotherapy. And then, I think that would potentially move up into that first line. But, that’s going to take some real world use in more patients outside of a clinical trial.

Got you. And then, what kind of timeframe would be required to consider a patient not being sufficient responder?

Thank you, everyone. That will conclude our question and answer session for today. I’d like to turn the conference back to Dr. Stephen Farr for any additional or closing remarks.