Greetings, and welcome to the Insight gravitas 301 Results Conference Call. At this time, all participants are in a listen only mode. Question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. It's now my pleasure to introduce your host, Mike Booth, Head of Investor Relations for Incyte.
Please go ahead, sir.
Thank you, Kevin. Good afternoon, and welcome to Insight's conference call to discuss the results of the Phase III GRAVITAS-three zero one trial of Insight idacitinib for patients with steroid naive acute graft versus host disease. This conference call is being recorded and is also being broadcast as an audio only webcast. I'm joined on the call today by Herve Steven and Cristiana as well as by Peter Langmuir from our Clinical Development Group. Peter leads all of our GVHD clinical development efforts, including the reach and gravitas programs.
Hervein Peter will make some introductory remarks before we move to Q and Before we begin, we'd like to remind you that some of the statements made during the call today are forward looking statements, including statements we may make regarding our expectations for 2020 and beyond for commercialization of our product. Our development plans for the compounds in our pipeline as well as the development plans of our collaboration partners and potential future product launches. These forward looking statements are subject to a number of risks and uncertainties that may cause our actual results to differ materially, including those described in our 10 Q for the quarter ended September 30, 2019, and from time to time in our other SEC documents. I'll now pass the call to Herve.
Thank you, Mike and good afternoon everyone and thank you all for joining us to discuss the press release that we issued this afternoon. For the results of the valid test-three zero one trial, show that itacitinib in combination with corticosteroids did not result in a statistically significant improvement in overall response rate at day 28. Compared to steroid monotherapy in the overall population. In addition, the study showed no difference in the key secondary endpoint improvement in non relapse mortality at month 6. These results are disappointing.
In the next few minutes, we'll discuss with you what we currently know from an initial analysis of the trial result and place this in context of the overall GVHD program and our broader itacitinib clinical development plans. Peter will now provide more details on the trial results that we know today before I offer a few additional thoughts to place today's announcement in perspective. Peter?
Thank you, Herve. I'll start by running through the trial results as we know them today. The trial was initiated on the back of phase 2 data shown at ASH in 2016, which suggested that adding itacitinib to corticosteroids may increase efficacy in patients with acute GvHD. The results announced today suggests that inhibition of JAK1 with itacitinib in combination with steroids does not provide a clinically meaningful increase in efficacy over steroids alone, as initial therapy for rate at day 28 for itacitinib combined with steroids compared to steroids alone, this difference did not meet statistical significance. The response rates were 74% 66%, respectively, with a P value of 0.08 The response rates observed with itacitinib plus steroids are consistent 301 was that steroids alone would provide a 56% response rate.
However, the 301 study showed a higher than anticipated response rate for steroids alone. We have not identified any subgroup of patients that had a significantly greater or lesser benefit from the addition of itacitinib plus steroids. The complete response rate was 53% for itacitinib plus steroids, versus 41% for steroids alone. There was no significant difference in the longer term efficacy endpoints including in the key secondary endpoint of non relapsed mortality at month 6. No new safety signals were identified and the safety profile of itacitinib in combination with steroids was similar to that expected for the combination or for patients suffering from GVHD in the spine setting.
The most common adverse events were thrombocytopenia and anemia. Let me now move to what the result means for itacitinib and other GVHD settings and beyond, and I'll start with some background on GVHD. GVHD occurs when immune cells transplanted from a non identical donor, the graft, recognized the transplant recipient the host at foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. The pathogenesis of GVHD is a complex multi step process, but is primarily a T cell mediated process. Development of moderate grade 2 and more importantly, severe grade 3 or 4 acute GvHD after stem cell transplantation is associated with a significant decrease in survival.
In addition, once GVHD occurs it may not respond to treatment. As such, all patients undergoing allogeneic hematopoietic stem cell transplantation required GVHD prophylaxis. Now the biology and clinical manifestations of acute and chronic GVHD are different. Acute GVHD primarily manifested as immaculopecular rash, weight loss, diarrhea and or hepatitis, usually within 100 days of transplantation. Pathologically acute GvHD as a parent as an inflammatory T cell infiltrate with associated tissue destruction and apoptosis.
The transplantation conditioning regimen, innate immune system, and gastrointestinal microbiome all contribute to the pathophysiology of acute GvHD. Chronic GvHD on the other hand is manifested as fibrosis of skin, lungs, GI tract, and soft tissues that generally presents at least 100 days after transplantation. Pathologically, tissues affected by chronic UV gear relatively acellular and fibro proliferative and development of chronic GVHD is a complex multi phase process that involves various cell lineages and types of injury. Now we already know from the success of the REACH 1 and REACH 2 trials of ruxolitinib, the JAK inhibition results in a significant benefit over best available therapy in steroid refractory acute GvHD and the results of the REACH3 trial of ruxolitinib versus best available therapy and steroid refractory chronic GvHD are expected midyear. The results of the Gravitas-three zero one trial are obviously disappointing, but for the reasons I just highlighted, it is not clear that they have any through to other studies of itacitinib in chronic GVHD or GVHD prophylaxis.
We have an ongoing phase 3 study Ravataz-three zero nine, which is evaluating the combination of itacitimic corticosteroids compared to corticosteroids alone, in the frontline treatment of patients with chronic GvHD. This trial is designed to enroll 246 patients in the randomized part of the study with a primary endpoint of overall response rate at month 6. As is common in randomized pivotal trials, Gramitas-three zero nine trial includes suitable interim analyses to manage risk versus benefit. For prophylaxis, the phase 2 gravitas 119 study is ongoing, evaluating itacitinib in combination with commonly used prophylaxis regimen and we are exploring opportunities for studying itacitab in future trials in this setting. I will now pass the call back to Herve.
Thank you. So what does today's announcement mean for insights? We have worked diligently to significantly spend our development portfolio over the past several years, which now includes a diversified set of late stage assets, with the potential for multiple launches over the next year. In the past 12 months, we received approval for ruxolitinib in steroid refractory QGVHD followed by the success of the REACH 2 randomized Phase III study in this indication. We have also provided positive data from Pemigatinib leading to FDA submission in cholangiocarcinoma and Novartis provided positive updated data from CAPmatini last year, which will make it the first inside this covered molecule to be submitted to LDA.
We also announced a positive randomized phase 2 study with ruxolitinib Creme in Vitiligo, which led to the initiation of the phase 3 program and we made good progress with our PI3 kinase delta and PD-one programs. Coming up in the next few months, We are looking forward to the result of the REIT's free trial of ruxolitinib in steroid refractory chronic GvHD around midyear this year. So PDUFA date for pemigatinib in cholangiocarcinoma is in late May, and we are expecting initial Phase III results from ruxolitinib cream in atopic dermatitis in the coming weeks. We also have a rich mid and earlier stage portfolio and a very active and successful discovery. This development portfolio diversification strategy enables us to continue to build for long term growth.
Furthermore, Jakafi is performing very well in the U. S, and we remain very confident in our ability to reach our long term Jakafi revenue guidance start debt of $2,500,000,000 to $3,000,000,000. Royalty revenues from Jakavi, ex U S, and Aluminum Globally are also growing very strongly. The strength of insight in 2020 and beyond will come from the revenue growth from existing commercial products combined with a number of potential near term launches and significant data readout as well as optionality from the earlier stage portfolio. Even with reduced expectation for itacitinib, we are on a great trajectory as we continue to build a fast growing innovative and profitable biopharmaceutical company.
Operators, this concludes our prepared remarks. Please give your instruction and offer the call for Q And A. Thank you.
Our first question today is coming from Cory Kasimov from JP Morgan. Your line is now live.
Hi, this is Gavin on for Corey. Thanks for taking our questions. Just curious if you can provide context around both arms and baseline characteristics, anything worth highlighting that would between the two the two arms that you saw? Thanks.
Hi, this is Peter Langka here. So there were no major differences in baseline characteristics. It was quite a large study with 439 patients recruited. So actually the largest randomized study ever done in this patient population. And as you might expect from the size of the study, the baseline characteristics were well matched between the two the two arms.
So, and across the subgroups that we looked at, we didn't see any significant difference in the response outcomes between those subgroups.
Great. Thank you.
Thank you. Our next question is coming from Brian Abrahams from RBC. Your line is now live.
Hi, thanks so much for taking my question. I'm just wondering if coming out of these results, there might be any strategy you might look at to continue to pursue the drug in acute GvHD, for instance, uptight treating the dose, looking at certain combinations. Thanks.
Yeah. At this point, it's probably, too early to say. I think in terms of uptight treating the dose, what the phase 2 study that we presented at ASH back in 2016 showed was that, when we looked at both 200 mg and 300 mg doses, we did see more cytopenias at the higher dose, which is what you would expect by going up on the dose. And particularly in the acute GVHD setting, where patients are still engrafting, you know, many of these patients come in with cytopenias. So we wanted to try to avoid any additional cytopenias from the drug in that setting.
So uptitration may not be an option, but at this point, I think we're still, looking at what else we may be able to do and and we're still looking at the data in general to see if there are any clues from there we might be able to take forward.
Yes, Vicky, just a comment in general. I mean, we have the top line results. That's what we are sharing with you. But obviously, there is an enormous amount of data that will be analyzed over the next weeks to, identify any potential next step that would be appropriate in that setting. I mean, so there is a lot of work in front of us on that front.
Thank you. Our next question is from Tyler Van Buren from Piper Jaffray. Your line is now live.
Hey guys, thanks and good evening. So it's clear that maybe a pure JAK1 inhibitor is not enough for the setting. But as we look to gravitas 309 in the chronic setting, is there anything mechanistically unique about JAK1 relative to JAK2 that would perhaps make it better suited for the chronic indication
I don't think we know that answer. I think the data that we've seen, pre clinically suggests that both Jacks may play a role and the Jack will maybe the more important of the 2 jacks, but in terms of relative, effects of the 2, I don't think we know the answer to that. You know, I I and I don't think it's actually clear and acute either because you remember that itacitinib was studied in a somewhat different setting from ruxolitinib where it is said that it was studied in the frontline treatment adding it on to steroids. So basically, adding it on to what is already a relatively effective treatment, whereas ruxolitinib was studied in the steroid refractory setting. So we haven't directly compared the 2, but you know, there there is clearly a role for JAK inhibition in chronic GVHD.
And so that's what we're looking to study in the 309
Okay. And for a quick follow-up, you mentioned the suitable interim analysis for 309. Can you provide any more color on those?
Yes, we don't have the full details on those, but basically there will be an interim analysis to look for utility based on the 6 month response endpoint. So we will have an opportunity to stop the study if it is not effective.
Great. Thanks so much.
Thank you. Our next question today is coming from Mark Frum from Cowen and Company. Your line is now live.
Hi, thanks for taking my questions. First, if you can just clarify, you mentioned that there was no difference in the non relapse mortality in this trial, but you gave the numbers on the other endpoints if it's possible. Would you be able to give the, the non re ops mortality rates by arm. If there was any trend either for or against the distillate
Yes. So there was not much of a trend there. I mean, for non relapse mortality, we saw 18% in the illicit environment 19% the in the corticosteroid only arm. So I remember lower number is better. So, but it was certainly not a statistically significant difference.
And consistent with what we saw in the response rate, the, non relapse mortality of 18% for the patients. And once again, it was the placebo steroid only arm that performed better than what we had anticipated.
Okay, great. And then, you know, recognizing your comments earlier that how you think maybe on some of the cell types that are involved and things like that make the chronic setting qualitatively different than the acute setting. Can you maybe highlight what of the cell types you think might be more potent or more amenable to JAK inhibition and therefore, give us more hope that 309 might be positive where 301 failed?
I'm not sure it's necessarily that the pathogenesis and chronic would be more susceptible. It's just it's different and the effects of JAK inhibition related to B cell regulation may play an additional role beyond what you see just in acute GvHD. So I think it's just a, it's a different pathological setting in which we know based on preclinical models that JAK inhibition can be effective.
Great. Great. Thank you.
Thank you. Our next question today is coming from Alethia Young from Cantor. Your line is now live.
Hey guys, thanks for taking my question. I guess, I was just curious and maybe it's too early to determine, but maybe are there any kind of effects from the placebo population that maybe are the amount of the different sites or anything that drove an effect here that you could modify in gravitasria and I are in the prophylactic study when it starts? Thanks.
Yeah, it's probably a little early to give you a full answer to that, but at least on the initial look, we haven't seen anything, in the placebo population that was particularly unexpected. Now there were, somewhat more standard risk patients overall in the study than than we anticipated. Relative to high risk patients, but that didn't seem to affect the outcome of the study. So I'm not sure that there's there's anything we can learn from the performance of the placebo arm, I will say just in the prophylactic setting that that would be a different, combination with standard prophylactic regimens, not combination with steroids.
Thank you. Our next question today is coming from Mara Goldstein from Mizuho. Your line is now live.
Thank you very much for taking the question. So I'm just curious as to whether you can pause it. Any reason why you think, you might have seen the better response rate in the placebo on. And then secondarily, within the context of 309 in the interim analysis, is there the possibility to resize the trial based on what you're seeing out of 301?
Sorry, sorry, the second part was possibly resizing the trial?
Yes.
Okay. So to the first question as to why steroids perform better, it's not clear. And again, as we look into the data in more detail, we may be able to discern something. As I said, there were more, patients with standard risk GvHD than we had anticipated. So that clearly can increase the response rates of steroids alone.
But again, we didn't see standard versus high risk as being a differentiator in terms of the relative benefit of itacitinib, when added onto steroids. So, I think when we look into the data in more detail, we may be able tell a little bit more. And then in terms of the interim analysis for 309, in terms of the possibility of resizing, I think that's something that's often a consideration. However, it's probably worth saying that we've powered the study to look for what would be a clinically meaningful difference already at 2.46 patients. So, we could see a successful study if we increased it dramatically, but then the we detect may not be clinically meaningful.
So, most likely we would not increase the sample size, if it was futile at interim analysis.
Okay. Thank you.
Thank you. Our next question is coming from Andrew Berens from SVB Leerink. Your line is now live.
Thanks for taking the question. Can you guys give us an idea of what percentage of the patients in the trial had a rash versus GI symptoms versus hepatic symptoms in in the acute PhD setting. And then as a follow-up, I just and I know you kinda mentioned a bit, but did you see more of a delta in those patients that had symptoms other than just the rash?
So I don't have the the numbers, right here. What I can say, it was the distribution of the organ systems that were involved were not, unexpected or surprising in any way. And we didn't see any obvious difference in outcomes there. But again, that's not something we've had a chance to look at in great detail yet.
Thank you. Our next question is coming from Ren Benjamin from JMP Securities. Your line is now live.
Great. Thanks for taking the questions. Can you maybe provide your thought regarding the higher than anticipated placebo rate? I mean, is it just a better follow-up or just any thoughts and whether or not, you know, or and and there's a follow-up. The statistical assumptions that you have for both 309 and 119, that'd be great.
Yeah. Again, I mean, I think we we it's we need to dig into the data in a bit more detail to understand why the steroid placebo arm performed so well. Again, the, there were more standard risk patients that we anticipated, and so that's going to increase the bonds rate to steroids, but the steroid standard versus high risk distribution didn't seem to affect the additional benefit that you get from itacitinib. So, the in terms of the statistical assumptions, we had assumed a 6% response rate with steroids alone. And so with that, a 74% response with itacitinib plus steroids seen would have looked, much more meaningful.
So it was the head of combination outperformed exactly as we had expected. It was just the placebo arm, didn't, was better than we anticipated.
Yes, I'm sorry, I meant the statistical assumptions for 309 and 119?
Oh, so for 119, it's really just a descriptive study. We're looking at just a number of different endpoints related to incidents of acute GvHD, chronic GvHD need for treatment and so on. And so we'll look at the aggregate data, there to to decide where we might fast look at future studies. So we're in the process of exploring what additional studies in prophylaxis may look like.
Okay. And 309?
So, do I have to I don't have a statistics. I may need to come back
to you on
the statistical assumptions for that, but, yeah, it's basically looking for a difference in 6 months response rate, compared to steroids alone.
Got it. And is there any thoughts regarding rux in acute GvHD?
So we have to reach 1 and reach 2 results, which were in steroid refractory GVHD. So all of these patients continue on steroids as standard of care, but at that point, the steroids are no longer, providing any additional efficacy And so we know that ruxolitinib is effective in that setting. But, we haven't studied ruxolitinib in the upfront very naive setting where we studied innocent.
Got it. Thank you very much.
Thank you. Our next question is coming from George Farmer from BMO Capital Markets. Your line is now live. Hi, thanks for taking my questions. I want to know on the adverse event, rate profile.
You said it was balanced between the two arms. But what about grades of thrombocytopenia and anemia? Were they equivalent in both arms?
Yeah, it was approximately equivalent. We didn't see very much significant increase in cytopenias overall or at the higher grades of cytopenias between the two arms.
Okay. And then is have you been saying thinking about any other possible indications for itacitinib beyond GvHD?
Right. So we have a couple of other studies that are ongoing or just getting started. So one is, a, a study in patients, who develop bronchiolitis obliterans after lung transplants. It's one of the major complications causes some mortality after a lung transplant and the pathophysiology is very similar to chronic GvHD. And so we have a study that's just opening in that setting.
We have a study that's open looking at cytokine release syndrome after CAR T therapy. So it's really getting at the potential effect of itacitinib on blocking inflammatory cytokines, that cause basically the leading cause of morbidity and mortality after CAR T cell treatment. And then we're also exploring, itacitinib in different settings in myelofibrosis as well, given its Jack inhibition.
Thank you. Our next question is coming from Evan Seagerman from Credit Suisse. Your line is now live.
Hi, all. Thank you for taking the questions this today. One on duration, I don't know if you had mentioned this earlier in the call, but did you see anything that might be concerning duration of response with adacitinib. Just trying to get any potential read throughs to some of the other trials. And any comments on the Cmax or TMAC?
I know that those were also secondary outcome measures. Anything that you learned there? Is it still too early to tell?
It's too early to say anything really about the pharmacokinetics. At this point, I mean, other than it looks like the patients did get atacitinib. But we haven't had a chance to explore the PK data in any detail. Sorry, the first part of the question was around. No significant difference in duration of response.
Next question is coming from Jay Olson from Oppenheimer. Your line is now live.
Hi, thanks for taking the question. Since itacitinib did achieve a numerical benefit on the primary day 28 ORR endpoint, although it was not set Sig. I was wondering if you saw a similar numerical improvement on the key secondary mortality endpoint
No. I think we so we saw a numerical improvement in in in overall response rate. We saw numerical improvement in complete response rate But when we look at the longer term outcomes, particularly non relapse mortality, we didn't really see any difference. So it was 18% versus 19% on non relapse mortality. And that could have been affected by differences in in subsequent therapy.
So we know that many of these patients after they came off, the randomized treatment went off to other therapies. And so that's something we're looking at in some more detail to try to understand if that impacted the longer term outcomes like 6 month long relapse mortality.
Okay, great. Thank you. And maybe as a follow-up, could you comment on the important of the mortality endpoint in the gravitas 309 study?
It's a little bit of a different setting there. I mean, in in the 309 study, the 6 month response rate is the primary endpoint. And so responses take longer to achieve and also we hope will be more durable. So that 6 month response rate is the primary endpoint. We're looking at a number of other, secondary endpoints, including overall survival, relapse rate, safety, obviously, and GVHD symptoms as well.
But the nonrelapsed mortality is not something that is as closely followed in chronic GVHD as it is in acute.
Okay, great. Thanks for taking the questions.
Our next question is coming from Michael Schmidt from Guggenheim. Your line is now live.
Hey guys, thanks for taking my question. I just had a follow-up to a prior question. Regarding, gravitas, 309 I guess, how well do steroids work in the acute sorry, in the chronic setting? And I guess, what is the bar here for, it's a fitment to improve over.
The response rates to steroids are roughly similar to what you see in acute GvHD for the upfront. So I think, so again, it's it's steroid naive chronic GvHD. So it's roughly about a 50% response rate expected with steroids alone.
Very helpful. Thank you.
Thank you. We've reached the end of our question and answer session. I'd like to turn the floor back over to Herve for any further or closing comments.
Okay. Thank you for your time today and thank you Peter for the clarification we could give at this point. As we said, I mean, there is still a lot of work ahead of us to analyze the data in more details and be able to answer questions that we can in the future. And we'd look forward speaking to many of you in the coming days at the JP Morgan Conference in San Francisco. And on our Q4 call in mid February.
But for now, we thank you again for your participation in the call today. Thank you, and goodbye.
Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time and have a wonderful day. We thank you for your participation