Syndax Pharmaceuticals ASH 2020 KOL Conference Call. At this time, all participants lines are in a listen only mode. After the speakers' presentation, there will be a question and answer Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Melissa Forst with Argo Partners. Thank you.
Please go ahead, ma'am.
Thank you, operator. Welcome, and thank you to those of you joining us on the line and the webcast this afternoon. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors. This includes those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10 Q as well as other reports filed with the SEC.
Any forward looking statements represent the company's views as of today, December 6, 2020 only. And with that, I will turn the call over to Doctor. Bruce Morrison, Chief Executive
Officer of Syndax.
Thank you very much, Melissa. Good afternoon, and thank you to everyone for joining us on today's call and webcast. We're excited to be here today following today's oral presentation at the ASH Annual Meeting and Exposition, highlighting updated results from our Phase 1 trial of axotilumab, our potentially best in class monoclonal antibody therapy targeting the CSF1 receptor in patients with chronic graft versus host disease or c GvHD. On today's call, we will be revisiting some of that data as well as sharing additional insights into why we believe axitilumab represents a potentially significant advancement in the treatment of patients with chronic graft versus host disease. I'd like to begin with a brief overview of our company on Slide 3.
At Syndax, we are committed to helping realize a future in which people with cancer live longer and better than ever before. We are keenly focused on our 2 exciting and promising programs, while we also continue to look for additional oncology pipeline opportunities. I will briefly mention the Phase 1 program of SNDX-five thousand six hundred and thirteen, our small molecule inhibitor of the menin MLL interaction for the treatment of acute leukemia. Earlier this year, we shared initial clinical results from the ongoing AUGMENT-one hundred and one trial that validated this as a target to treat subset of acute leukemias. The trial continues to progress well, we anticipate presenting the completed Phase I portion of the trial at the end of the Q1 at a company sponsored event or at the AACR Medical Meeting in April of 2021.
We continue to anticipate initiating the Phase II portion of the AUGMENT-one hundred and one trial in early 2021. Based on existing regulatory precedence, assuming positive results, we believe the Phase II portion of AUGMENT-one hundred and one could potentially support a regulatory filing. Turning now to axitilumab, which is, of course, the focus of today's call. We're privileged to have with us here today 2 leading experts in the science and treatment of chronic graft versus host disease, Doctor. Mukta Arora of the University of Minnesota Medical School and lead author of the ASH presentation and Doctor.
Jeffrey Hill of the Fred Hutchinson Cancer Research Center. Moving to Slide 6. On today's call, Doctor. Arora will begin with a brief overview of the data presented at the ASH meeting earlier today. She will then review a selection of patient case studies, which we believe further support axotilumab's potential to play a meaningful role in the treatment of chronic graft versus host disease.
Doctor. Hill will then review the biology and treatment landscape of chronic graft versus host disease and review the significance of the CSF1 signaling pathway in the development of fibrosis. Finally, I will briefly review the axitilumab development path before opening the call up to questions. I'll now turn the call over to Doctor. Arora.
Hello. I will briefly review the results of the Phase III study evaluating axotilumab in chronic GvHD. Chronic GvHD commonly affects 30% to 50% of allogeneic transplant recipients. Cardiposteroids are the standard frontline treatment for these patients. Approximately 50% of the patients need second line treatment for disease progression or inadequate response.
So far, ibrutinib is the only approved second line treatment of chronic GVHD. Morbidity and mortality in patients needing second and further lines of therapy remains high. Amongst these patients, those with scleroderma migrations and lung disease are often difficult to treat and associated with poor outcomes. Development of novel agents to treat this disease remains an unmet medical need. The study is a Phase III clinical trial of agvetilumab in patients with chronic GVHD.
The eligibility criteria include those with active chronic GVHD who failed 2 at least 2 prior lines of treatment. All patients needed to have a KPS of more than equal to 60 and be older than 6 years of age. Eligible subjects were enrolled sequentially in escalating doses of axotilimab as shown in this figure. Axotilimab is given as an IV infusion every 2 weeks, except in cohort 5, where it's dosed every 4 weeks. The initial two cohorts at a dose of less than 1 milligram per kilogram were single subject cohorts, which could be expanded to 3 or 6 subjects depending on the DLTs.
The other cohorts followed the 3 plus 3 design. The number of patients enrolled in each cohort is given in the figure. There was 1 patient each enrolled in the 0.15 and 0.5 milligram per kilogram cohorts, 3 patients in the 1 milligram per kilogram cohort and 6 in the 3 milligram per kilogram cohorts. 4 patients have been enrolled in Cohort 5, which is dosed every 4 weeks. No DLTs have been noted in this final cohort.
The Phase 2 expansion is continuing to enroll at the milligram per kilogram dosing. The main endpoints for this trial were to evaluate the safety and tolerability of axotilumab in patients with chronic GVHD and to determine the maximum tolerated or recommended Phase 2 dose of the drug in subjects with chronic GVHD. This study also aims to assess the efficacy of axotelimab in terms of overall response rates in these patients. This slide shows the baseline demographics and characteristics of the 15 Phase 1 portion of the study. The median age of transplant was 60 years, 47% underwent a transplant using a biloablative conditioning and 60% underwent a related donor transplant.
93% received a paraglutide stem cells as the graft source. The median time from transplant to chronic GVHD was 6.8 months and was slightly shorter at 3.7 months in the milligram per kilogram cohort. The median time from chronic GVHD to the first cycle was 42 months. 8 patients had more than equal to 4 organs involved at baseline. Patients had failed a median of 4 prior lines of treatment, which included 11 patients having failed Ibrutinib, 9 ruxolitinib and 5 KDO-two-five.
All patients discontinued other medications besides a stable dose of steroids with or without calcimurin inhibitor prior to initiating axetinib. Slide here shows the duration of treatment and overall response in the patients. So this swimmer's plot includes data from the Phase 2 study as well. Overall, 14 patients are continuing treatment at 2 to 60 weeks from initiation. This includes 7 Phase 1 and 7 Phase 2 patients.
Response data is available for the Phase 1 patients. Responses have been observed in 5 of these 7 patients. Response is also seen in 1 patient who died of unrelated causes and one patient whom the medication was later discontinued. An initial response with later disease progression was seen in one patient. Responses were observed in all cohorts with an overall response rate of 57%.
Stable disease was seen in 36% and the median time to response was 1.9 months. The slide here shows the common organ involvement and the response seen in these organs. Complete responses were seen in 1 patient each with esophageal and lower GI involvement and in 5 of 9 and 2 of 12 patients with mouth and eye involvement. Partial responses were seen in 2 patients with eye involvement, 6 of 11 patients with joint and facial involvement, in 2 of 5 patients with lung involvement and 4 of 10 patients with skin involvement. Responses were seen after prior ibrutinib in 6 patients, ruxolitinib in 5 patients and KDO25 in 3 patients.
Patients reported improvement in Leigh symptom score and this was seen in most patients. This waterfall plot demonstrates a median reduction in overall score by 9.13. 67 percent of 12 patients achieved a 7 point reduction from baseline. One patient in the 3 milligram per kilogram Q4 week cohort experienced an increase in the Leigh symptom score and stopped treatment after 3 cycles. The slide here shows a summary of treatment emergent adverse events with axotilumab.
All patients experienced a related TEAE in all dosing cohorts. Related Grade 3 to 4 TEAEs were mostly biochemical changes, which are expected due to axotilumab's effects on Kupfer cells in the liver, which belong to the macrophage lineage, resulting in elevations in the liver enzymes, LDH and creatinine kinase. 2 episodes of pneumonia were seen, which were included in the related grade 3 to 4 TEAEs. Both patients in the less than 1 milligram per kilogram cohort have discontinued treatment, 1 due to disease progression and one due to physician decision. Another patient experienced disease progression in the 1 milligram per kilogram cohort.
Overall, one patient discontinued medications due to Grade 4 elevation and creatinine kinase, 3 due to physician decision, 1 died of a fall and 1 discontinued due to non compliance and 2 experienced disease progression. This slide shows the common TEAEs occurring in at least 5 patients regardless of rate. Most of these were biochemical changes based on the mechanism of action of axotilimab on the KUKPA cells and included elevation in AST, ALT, CPK, LDH, amylase and lipase. Besides these, fatigue was seen in 40%, nausea in 33%, pyrexia and increase in creatinine was seen in 33% each. This slide shows all infectious events of all grades experienced by the patients.
There were 3 episodes of pneumonia, 1 episode of conjunctivitis, 1 episode of norovirus gastroenteritis, 1 episode of influenza, 1 episode of a lower respiratory tract infection, 1 superficial Pseudomonas infection in a dermal ulcer and one episode of a URI. Of note, there was no episode of CMT viral reactivations. The URI influencer and one episode of pneumonia represent the same patient. This slide shows the efficacy of agvetilimab in sclerodermaic skin GVHD. Sclerodermaic skin GVHD is really hard to treat and especially patients who have these chronic leg ulcers with constant weeping wounds on their legs have a very poor quality of life.
This patient experienced chronic ulcers unresponsive to several prior therapies, which included Ibrutinib and ruxolitinib. And he had had these ulcers for several years prior to starting treatment. He was treated with 1 milligram per kilogram Q2 weeks of axotillinand. And these are his legs 3 months later. The ulcers are completely healed up and this resulted in a huge improvement in his functioning, pain and quality of life.
The slide here shows another patient with sclerodermaic skin disease with ulcerative who also had failed several prior therapies, including Ibrutinib. This patient was treated with 3 milligram per kilogram through 2 weeks of axotilumab. And 6 months later, his ulcers have shrunk and dried up and are healing nicely. He's also had a significant improvement in his scleroderma disease and was excited. This is my patient.
I know him well and he was really excited because he could bend down and tie his shoes for the first time after several months. This slide discusses another case study. This is a 30 year old with severe chronic GVHD involving many organs, including lungs, skin, eyes, GI, mouth, joints and fascia. Lung trolley GVHD is particularly debilitating because of its associated sharpness of breath, limited exercise capacity, poor quality of life and high mortality. This patient had a very poor quality of life with sharpness of breath due to lung chronic GvHD and also had significant weight loss.
So baseline weight was £91.3 For this patient, prior therapies included Ibrutinib, ECP, rituximab and imatinib. She was enrolled and started on axitilumab 1 milligram per kilogram Q2 weeks in August of last year. Response was noted starting reporting improvement in her sharpness of breath and has had some objective improvement in lung function tests as well, which is very encouraging. In addition, she struggled with weight loss and her weight has improved now to £101.9. This is another case study of a pediatric patient, a 16 year old with chronic GVHD involving multiple organs, skin, mouth, joints and fascia.
And he had scleroderma migrations with chronic ulcers. He had failed many prior regimens, including ibrutinib, ruxolitinib, ECP, rituximab, sirolimus, imatinib and steroids. He was mostly just staying at home and not doing much. He received axotilumab at a 1 milligram per kilogram Q2 weeks starting in March of this year. Response was noted in Cycle 2.
He is now on a Q4 week dosing and this kid has responded so well that he's joined Cross Country team and has held down a first part time job. To conclude, axotilumab demonstrates good tolerability with clinical activity demonstrated by a 57% response rate in a heavily pretreated patient population, including patients that have failed Ibrutinib, ruxolitinib or K DO2 fight. There was low rate of infection reported. Ongoing development of axitilumab will include a Phase 2 study, AKAVE-two zero one, planned for enrollment in 2021. This will be an open label, randomized, multicenter study to evaluate the efficacy, safety and tolerability of axotilumab at 3 different doses in patients with recurrent or refractory chronic GVHD who have received at least two lines of systemic therapy.
That's all that I have. Thank you very much. And now I'll turn the call over to Doctor. Hill.
Thank you, Doctor. Arora. I'm going to give you some insights into pathophysiology and treatment of chronic GVHD and hopefully give you some insights as to how axotilumab came to be being used in this manner for the treatment of chronic graft versus host disease. These are my conflicts of interest. So as Doctor.
Arora has mentioned, chronic GVHD typically occurs late post transplant. It often follows acute GVHD. The primary target organs are skin, lung, mouth, salivary and lacrimal glands. We're really worried about fibrosis, which is the cardinal feature, particularly sclerodermatous and bronchiolitis and budduransus as manifestations. It occurs in up to half of patients following allogeneic transplant.
It's associated with high morbidity. And as Doctor. Arora has mentioned, effective therapy has been historically limited to steroids now with Ibrutinib for refractory steroid refractory chronic GvHD also. So the pathways of chronic GvHD have really started to become more understood over the last 5 to 10 years. I've listed some of the pathways here that we know are aberrant from an immunological asset.
And I want to talk about the last two, excess IL-seventeen and alternatively activated macrophages. They're especially relevant to the topic of this talk. So when a T cell interacts with an antigen presenting cell in the context of TGF beta and IL-six and undergoes STAT3 phosphorylation. Raw gamma T is transcribed and IL-seventeen is produced. And this is the major cytokine of this Th17 lineage.
And this is particularly relevant to the macrophage mediated fibrosis. When we look at patients after an allograft, this is from a series in Australia, you can see that over time, we start to see increasing levels of IL-seventeen post transplant. And typically, in this period between day 60 and 180 when we start to see chronic GvHD manifested. The black bars are patients that receive placebo. The white are ones that receive tocilizumab.
That's not relevant for this, just that R17 is systemically dysregulated after transplant. And the other thing that we see, if we look in this case, oral lichenoid lesions in patients with chronic GvHD, we can see T cell infiltrate shown in the bottom marked by CD3 and IL-seventeen being secreted by these T cells, much more so than in the acute phase of the disease and that's shown in the numerically. So we clearly see systemic and local IL-seventeen dysregulation. So I'm showing you this because in these animal models back some 7 or 8 years ago now, we used a model of scleroderma where we transplanted GCSF mobilized grafts that were wild type and could secrete IL-seventeen or were genetically IL-seventeen deficient. And you can see that over time the skin in these animals becomes the dermis becomes thickened, they lose subcutaneous fat and the mass on staining shows collagen dense collagen and fibrosis.
And you can see that this is almost completely absent if the T cell cannot make IL-seventeen. Just showing us that this pathway is absolutely pivotal to fibrosis and the fibrogenic manifestations of chronic BVAT. There I showed you, this is a lung model of bronchiolitis obliterans that Bruce Blazer undertook. And here we used graphs that were either wild type or deficient in the transcription factor RORC and so could not differentiate down that T817 lineage. And what I want to show you is that the animals that received T cells that couldn't differentiate in the T817 lineage had normal lung volume compliance, normal elastance and normal resistance that was at the non GVHD controls.
Again, showing you the TH17 differentiation is critical not only in sclerosis in the skin but also bronchiolitis or bladder ants. So we really wanted to know what the mechanism and how R17 was inducing this. And this work was led in Australia by Kelly McDonald. And this comes down to this issue of alternatively activated macrophages. And it's important because if you look at the skin of animals that have developed fibrosis and you do immunohistochemistry from macrophages, if 480, you can see dense fibrosis when IL-seventeen is present, and it's completely absent in the animals that receive IL-seventeen grafts.
So this protection that you see in the absence of IL-seventeen is associated with the absence of the infiltration in the skin. And if you think about macrophages, they can be different they can differentiate along 2 different pathways, a classical GM CSF dependent pathway that is said to be inflammatory. INOS is one of the markers of this differentiation. CSF1 will differentiate macrophages into alternative M2 like phenotype. CD206 is a marker of this differentiation pathway.
And if we look at the skin of animals that are developing fibrosis, we can again see the dense macrophage infiltration in the skin. The macrophage is a donor in origin. This is a congenic donor marker. They express the M2 alternatively activated macrophage marker, but not the M1 marker. So donor M2 differentiated macrophage is associated with the process.
And if you we use a mac green donor here that had where GFPs expressed under the XF1 receptor promoter, you can see that macrophages in the skin are shown in red. And these red macrophages all express GFP for CFF1 receptor. And you can see on MERGE that they both emerge. So these macrophages that are infiltrating skin are CXF1 receptor positive donor macrophages. And if one blocks the CSF1 receptor in these animals with an antibody, this is M2079 as an Amgen antibody.
You can see that giving this antibody after transplant specifically depletes the subset of monocytes in the blood that are F480 positive, alloy6c low. And you do not get and it depletes macrophages out of the skin in these animals shown here relative to the Isofib control and shown numerically on the far right. And if you look at fibrosis in the skin of animals that actually have CSF1 receptor inhibition, you can see that you can prevent this dense fibrosis that you see in the immunoglobulin controls and that skin looks starts to look towards non GvHD controls that receive T cell or pleated grafts. And you can see in D that the total pathology in the cutaneous fibrosis comes back down to non GvHD controls. So blocking the CSF1 receptor will prevent fibrosis in these chronic GvHD systems.
What about the lung? Well, again, if you can see in the control immunoglobulin IgG treated animals, there is peribronchial fibrosis shown by the arrows here in the middle panel and that those are depleted by blocking and receptor on the far right panel. And when we do this, we again restore lung volume back to non GvHD controls. We restore compliance, elastance and resistance back to non GVHD controls. So we again can prevent bronchiolitis obliterans by interrupting this pathway.
Finally, Matt Collins in Newcastle published a lovely study earlier this year in patients post transplant. These patients were typically from memory between day 5140 that developed skin GvHD. And you can see in panel A that there are 11 C positive macrophages in the skin. And one can see that in the far right panel in B that in the chronic GvHD skin there is clearly infiltrative 11C positive cells. In panel C, in the 3rd column along, you can see that these cells are 11C positive, CD14 positive and reflect macrophages in the skin, again showing that the murine data is consistent with human clinical data in patients.
This is where we are with chronic GvHD pathophysiology. There are a number of immunological defects that are responsible for the disease. First of all, there is regulatory T cell defects and there is aberrant T cell differentiation characterized by T follicular helper T cells that secrete IL-twenty one expand germinal center B cells. These germinal center B cells go on to become plasma cells. They make auto and allo antibodies that can bind target antigens in the tissue.
They and they can bind Fc bind the macrophages, activate macrophages and induce fibrosis. There's also this aberrant TF17 differentiation that where these cells are very pro inflammatory release a number of cytokines including CSF1 and they drive this terminal macrophage differentiation process. So we can block these pathways early on with agents like ibrutinib that will block the general center B cell pathway. We can block this IL-twenty one and IL-seventeen pathway with KBO-twenty five or we can block cytokine signaling broadly with JAK1, two inhibitors. But you can see these are acting more proximal in the pathway.
In contrast, CXF1 receptor inhibition blocks this terminal pathway of fibrosis where we think that both the T and B cell pathways converge. And so offer a potentially a non redundant pathway of inhibition in chronic GvHD. Finally, I just wanted to show you that this pathway of CSF1 receptor is involved in fibrosis and other diseases and other tissues. This is another paper by Kelly's group looking at chemical induced liver fibrosis. And you can see the fibrosis staying red in panel A and the control and the periportally areas with bridging fibrosis.
And again, that is blocked by blocking the CSF1 receptor, you can see in the bottom panel, and blocking fibrosis in C together with the putative monocyte and macrophage populations in that organ. And so I want to conclude by showing you that CSF1 receptor dependent macrophages appear to represent a common terminal pathway of tissue fibrosis in chronic GvHD. Inhibition of CSF-one receptor offers theoretical advantages over agents acting more proximally, such as those acting on T or B cells. CSF1 receptor inhibition is active in both scleroderma and bronchiolitis obliterans in preclinical models. And moving CXCL1 receptor inhibition earlier into the treatment phase of chronic GvHD before dense fibrosis has been established would seem to be an attractive next step.
And finally, fibrosis and other diseases and target organs at least in preclinical systems also appears to the CSF1 receptor axis. So I'm going to stop there. I'd be happy to take any questions and I'm going to turn the call back over to Doctor. Morrison.
Thank you so much, Doctor. Varora and Doctor. Hill. On Slide 44, as discussed today, the CSF1 pathway appears to play a significant role in the development of fibrosis and the manifestations of chronic graft versus host disease. Due to the broad impact of chronic graft versus host disease across multiple organ systems, this disease also provides a platform for understanding the benefit of inhibiting monocyte derived macrophages within other fibrotic diseases where macrophages have been shown to play a significant role.
As you can see from our data, acitilumab has shown dramatic effects in preventing and even reversing fibrosis in multiple organ systems. I'd like to wrap up by mentioning the pivotal trial we are on track to initiate later this month. This trial is the axotilumab for graft versus host disease trial called AGAVE-two zero one, and it's outlined on Slide 45. The trial will enroll patients with chronic graft versus host disease, whose disease has progressed after 2 prior therapies. Patients must be at least 6 years of age and have met overall entry criteria.
This is a pivotal dose ranging trial in which patients will be randomized to 1 of 3 treatment groups, each investigating a distinct dose of axotilumab given either every 2 weeks or every 4 weeks. The primary endpoint is overall response rate using the 2014 NIH consensus criteria for chronic graft versus host disease. Secondary endpoints will include duration of response and validated quality of life assessments using the Lee's Symptom Scale. We anticipate beginning enrollment this year with top line data likely in 2023. We are actively evaluating options by which to build out the axotilumab franchise beyond chronic graft versus host disease and take advantage of what we believe are significant set of opportunities that could materially enhance Syndax shareholder value.
We anticipate there are multiple additional indications that would benefit from CSF1 pathway inhibition and reduction of the monocyte derived macrophage population, and we look forward to sharing those plans with you shortly. Before we open the call for questions, I'd like to note that joining us for the Q and A session will be both Doctor. Aurora and Doctor. Hill, as well as a few additional members of the Syndax management team, including Doctor. Peter Ordenlich, our Chief Scientific Officer Doctor.
Michael Myers, our Chief Medical Officer Michael Metzger, our Chief Operating Officer and Daphne Kiritis, Chief Financial Officer. Also joining will be Angelie Ganguly, VP of Corporate Development. Out of respect for Doctor. Rohrer's and Doctor. Hill's time, we would ask that you keep the initial focus of your questions to the axotilumab program, and we will leave time at the end to cover other Syndax focused topics.
With that, let's open the call for questions.
Our first question comes from the line of Phil Nadeau from Cowen. Your line is now open.
Good afternoon. Thanks for taking my questions. First, a question for the physicians, and that's on the durability of the response. Can you give us your perspectives on how long a response needs to be durable in order to be clinically meaningful? And how will that ultimately influence your choice of therapy?
Sasha, Laura, you want to take that question?
Yes, absolutely. That's a great question. We would want the response to be durable, absolutely. So complete durable response, as defined by taper of discontinue or discontinuation of immunosuppression has been there's no hard and fast definition, but approximately about 6 to 12 months continuing response is considered as durable in patients with chronic GVHD.
Great. And then just one follow-up question. It looks like axotilumab has activity across all organ systems. But when you look at the data, are there organ systems where the efficacy is particularly impressive to you in the data set that was presented at ASH?
The most dramatic is those photographs that we showed that in the sclerotomoid skin GVHD in patients who've had these chronic leg wounds for years, there's a dramatic improvement. And the second is lung GVHD, where we very rarely see good responses, and we've seen objective responses in some patients there. So those are the 2 that I would like to emphasize. But responses, as you correctly noted, have been seen in most targets.
Great. Thanks for taking my questions and congrats on the data.
Thanks, Phil.
Thank you. Our next question comes from the line of Bert Hazelt from BTIG. Your line is now open.
Thanks. Thank you for Doctor. O'Rourke and Doctor. Hill and your insights and perspectives. A question and then one related as well.
How does acotilumab compare in general to other therapies that are available or in development to treat GVHD? And then the ASH data was in heavily pretreated patients. Given its novel mechanism, that targets the monocyte macrophage lineage, where would you see axitilumab positioned in an overall treatment algorithm for chronic GVHD?
So maybe Doctor. Arora, if you can go first and then Doctor. Hill as well.
Sure. So what I'd like to say is you actually said it in your question that these are heavily pretreated patient populations. So this is not a trial of initial failure of therapy. So it's hard to compare. What we do know is that most of the patients, 7 of the patients that were enrolled in this Phase I study had failed Ibrutinib, which is the only approved second line treatment.
And in addition, 9 patients had failed ruxolitinib, 5 had failed KDO25, which are the promising agents, which would be other drugs that could be effective in treating chronic GVHD. And as Doctor. Hill's talk explained, this kind of is the final common pathway for treatment of chronic GVHD and may have advantages over drugs that work earlier in the pathway, if you will. Your other question as to where it would fit, I think what we really need to have is trials that focus on phenotypes and biomarkers and drive treatments towards those phenotypes. And then we'd be better able to answer the So far, what we know is that there's only one drug, Ibrutinib, which is approved as a second line treatment.
And there are promising agents and this appears very promising.
Doctor. Hill, anything you'd like to add?
So I would just say that none of our agents available to date are good at treating established fibrosis. Fibrosis. And so that so I think getting back to Doctor. Aurora's point about phenotype disease, phenotypes, I think when we have scleroderma BO, there's not a lot of data that there are other agents particularly good in that setting. So I think that this data is really intriguing that we can, at least in some patients, see reversal of scleroderma and improvement in bronchiolitis obliterans that's as physicians is very unusual.
So I would certainly see this agent as being perhaps useful in the phenotype of chronic GvHD where there is fibrosis. As to how it will fit in our treatment schema, we just need a lot more data. We need to know we need bigger patient series and we need to know more about the more recent studies with ibrutinib and ruxolitinib to have a good idea. So I think we I think from where does it fit in the scheme of things, we're just going to have to wait another year or so for a little more data to help sort of establish that. But I do think that the activity in established fibrosis is very intriguing and not something that we really have seen in the past.
Given its mechanism, just a quick follow-up. Given its mechanism, would you like to see it earlier on considered earlier on in the treatment algorithm?
Well, we think that as physicians, we think treating earlier is better. Sometimes that's not we don't have data to follow that as a hunch, and I think that this is the case here. We think that we intrinsically think if we can start a treatment that will before someone has developed dense fibrosis that we will have better chance of preventing sort of long term morbidity from that disease. But again so I think it makes some theoretical sense. But again, we would need to have well designed clinical study to test that.
Theoretically, I think it makes sense.
Terrific. I just have one more for the company, Briggs and your crew. Just could you remind the differentiated characteristics for axotilumab? There's a number of different anti CSF1R antibodies out there. And then secondly, is there a potential for a more significant regulatory consideration of this molecule such as breakthrough designation or others?
Is that something you're looking into?
So Peter, do you want to talk about the differentiation?
Yes. No, thank you. I mean, I think there's several major points. The one is the IgG4 peptide, which was designed specifically to avoid effector functions of the antibody other than ligand blocking. There's really only one other one that's similar to that and that would be the cabiralizumab.
And then, I think really the differentiation that we've taken is through this intermittent cyclical dosing strategy where we feel that the ability to deplete the circulating monocytes that are responsible for some of these fibrotic and inflammatory effects, we're regulating in a sort of intermittent dose fashion, which allows for some recovery in between doses. And I think that really translates into a very differentiated safety profile, yet to be seen if the efficacy is also dependent on that, but at least the therapeutic window is quite large using that approach. So I think it's really the ligand binding domain effect, the IgG4 subtype and our ability to establish a differentiated dosing schedule.
And Bert, I'll take your question about the regulatory strategy. We don't generally comment on other things other than the sort of filing strategy, which we've gone over for AASAR-two zero one. Obviously, we're aware of these other avenues that are available, and we would look into those as appropriate.
Okay. Thank you. Congratulations on the data.
Thank you. Our next question comes from the line of Madhu Kumar from Baird. Your line is now open.
Hey, thanks for taking our questions. So I'll start out with kind of the consideration around the enzyme changes that were observed on axotelimab treatment. So you mentioned the idea that these are really kind of on target from modulation of cuprocell counts. And so how do you think about that practically in the clinic? How you manage these kinds of enzymatic changes that occur with the depletion of cuprosomes?
Patrick, Laura, you want to take that question?
Yes. So typically what we've seen is yes that there are enzyme elevations and we follow these patients along weekly and they tend to settle down before the next dose of the drug. We've had a couple of patients, I think, who were delayed because of the enzyme elevations initially, partly because physicians were resistant to give the drug in phase of enzyme elevations. But then as people grew more comfortable, we've been dosing the patients regularly despite the enzyme elevations, but they tend to settle down before the next dose.
Okay. And then kind of following from that, how important you mentioned maybe that there are kind of some promising agents that are having late stage clinical development. And I guess I'm going to focus on ruxolitinib. Given the Phase III data we now have ruxolitinib, do you envision practically that second line treatment of chronic GVHD goes to ruxolitinib and kind of the real question is beyond that and kind of what are drugs that work well in the post roxolutinib study? Like how do you think about what the landscape will look like a year or 2 from now?
So the way I envision it is that the choice of drugs, the more the better, that this is a patient population that needs these drugs, about half of them fail their initial treatments. And that the choice will depend on the clinical phenotype as well as the side effect profile of each of these medications. Okay.
Doctor. Hill, anything you want to add to that?
No. Only that I haven't seen a breakdown of the RACS Phase III data in relation to fibrosis, scleroderma, bronchiolitis, obliterans. So I guess I would be interested in that and as to whether responses are seen in those groups of patients as well. And again, that may help us think a little bit more about various treatments, but options. But I agree that it's going to come down to tolerability and disease phenotypes and response within those phenotypes that we as we get more data over time.
Okay. So I'll squeeze one last one in. Thinking about the adverse event profile you all have seen from axotelimab so far, how combinable do you think it is with both approved agents and kind of agents in late stage development? Like how would you consider kind of combining this with other drugs in the management of GVHD?
So I think, Doctor. Hill, you have an opinion on combinations.
Well, I think it depends a little bit on whether we think there are pathways that breaks that are sort of redundant or that are breaking through with one line of treatment. And again, some of this comes back to how we think about sort of pathophysiology at the current point in time. I mean, so again, we're going to need more data. And I think we're going to have to establish roles for individual agents before we can start combining them. I think raxolitinib is probably going to hit a number of more proximal cytokine signaling pathways upstream If they all converge through a macrophage mediated fibrogenic pathway, then there may or may not be a rationale to combine the agents.
I think combining agents is going to be difficult in a lot of these patients who have significant morbidity. So again, we need more data. But I'm not entirely convinced that combination therapies are something that are going to be particularly useful early on at least.
Okay. Thank you.
Thank you. Our next question comes from the line of Joel Beatty from Citi. Your line is now open.
Hi, thanks for taking the questions. The first one is on the duration of response that you've been seeing in the study for axitilomab. Could you characterize that a little bit more and kind of help put into context where it could turn out as the data matures?
Sure. The responses, there's been a lot of patients that are continuing on medications. So 14 patients so far are continuing on medications. And duration of the medications have ranged from a couple of weeks to over 60 weeks. So, responses in those patients are continuing to be noted.
And as far as the Phase 1 data is concerned, amongst the 7 patients who are continuing the medications, which is from 4 to 60 weeks, 5 of the responses are continuing and are durable. So that's the data we have so far and it appears very encouraging.
Okay, great. Yes, good to hear. And then maybe another question, Are there ways to help predict what patients will respond to therapy? Could you maybe elaborate on that a little bit more, such as characteristics that might be used for enrollment in clinical trials or if the drug ends up being approved?
Maybe, Doctor. Hill, any thoughts on that one?
That's a great question. That's a $64,000,000 question in the field, and the short answer is no, not at the moment. We don't have good biomarkers for disease phenotypes and responses. I think at the moment we're going to probably be focused more on clinical phenotypes and again the sclerosis features whilst we're the whole field I think is now focusing on being able to try and find either biomarker and or clinical correlates that sort of define responses to particular what are very expensive sort of therapies now. So I think great question.
And that's I think going to be the major focus for this field for the next one 3 years. Great. Thank you.
Thank you. Our next question comes from the line of David Lebowitz from Morgan Stanley. Your line is now open.
Thank you very much for taking my question. Looking across the data, I noticed that the number of prior treatments varied across the groups, being fewer treatments in the higher doses. Was there any different levels of responses in these patients that I guess responded better if they had fewer prior lines of therapy than those that had more?
Doctor. Araya?
Yes. So I'd say that responses were seen in all groups. And the numbers are too small for us to really look at individual features to know. Overall, yes, we had a great response rate of 57% in a heavily pretreated cohort. And responses were noted in every cohort.
Thank you for that. And I guess looking forward at the characteristics of this drug and other drugs, I know that the people tend to look at these types of therapies in various lines as what's going to be first line, second line, third line. Do you think that there are certain characteristics across each drug that people will tend to look at the drugs and which ones to choose as more as a patient based and characteristic based? And then how would the niches ultimately, I guess, break down?
So again, I'd like to again emphasize Doctor. Hill's point about sclerotic manifestations being really difficult to treat. And this is one drug where we see patients we've seen a signal that patients with sclerotic GVHD and bronchiolitis obliterant lung GVHD, who are typically patients who do not respond to most treatments appear to respond to this drug. So that's where I think the promise lies.
Thanks for taking my question.
Our next question comes from the line of Peter Lawson from Barclays. Your line is now open.
Hi. Thanks for taking the questions and congratulations on the data. Are there any kind of SIP interactions we should be thinking about or lack of? It sounded like from the presentations today at ASH, I guess there's some kind of worries around some of the other molecules that have CYP450 kind of interactions. Anything we should be thinking about for this drug and how it could open up to potential combinations?
Maybe I'll have Michael Myers take that question please.
Yes. So thank you for that question, Peter. So based on the fact that this is a large molecule
Can you hear me?
Based on the fact that this is a large molecule, we don't expect that there will be CYP interactions. So it is not metabolized by CYP450 as far as we can tell. There should not be drug drug interactions. That is one of the differentiating factors between this molecule and the small molecules that are used to treat chronic graft versus host disease or other where the even the other small molecule CSF1R inhibitors.
Got you. Thank you. And then just maybe a question for Doctor. Hill and Doctor. Ora.
Just the fact that it is a large molecular antibody, does that change in any way how you could potentially use it, whether it would be 1st, 2nd or third line?
I don't think it does. It will be based on the clinical data as it becomes available.
Doctor. Hill, anything you want to add to that?
Yes. I would agree with that. I mean there are pros and cons of being able to give a drug once every 2 or 4 weeks obviously, but having to give it systemically. So I think it will be based more on clinical need initially, but I don't think that an agent that's required to be given systemically every 2 or perhaps 4 weeks is going to be problematic in this population, maybe beneficial in some settings perhaps.
Yes. Peter, the other thing that I would add in terms of combinability is we do not see cytopenias. So that is another differentiating factor nor do we really see any biochemical effects. So I think that means that this drug could be combined if in fact it is necessary to combine drugs. And I definitely agree with Doctor.
Hill that combinations may not be an optimal treatment paradigm for chronic graft versus host disease.
Got you. Thank you. And then just maybe a quick follow-up with Doctor. Hill and Doctor. Ora.
Just on we've had a fantastic set of data, like the Roxad data, REACH3, axetilumab data. Do you think that kind of changes the way some of your colleagues also be thinking about how you will be using these drugs with it, whether it will be more driven by the number of organs that are affected or the fibrosis or clinical phenotypes of the patients. It just seems we're in a kind of an interesting transition point for chronic GvHD.
Well, sorry,
you guide Doctor. Ora.
I would agree that it's an exciting time for chronic GVHD that there's these new drugs available. And as more drugs get approved for treatment of this disease and as more data becomes available, as we know more about the responses with different clinical phenotypes that may drive physician decision into picking which drug, but it will also be based on the adverse event profile of each drug.
Yes.
I would agree with that. It's going to as we talked about, it's going to be clinical phenotypes initially that are probably going to guide therapy. I would point out that ruxolitinib, ibrutinib, axolitinib now, they're all based on good preclinical animal systems that have all seemed to be translated very well. So I think I'm plugging it, but I think it goes back to sort of agents that are being used and designed logically and rather than being sort of just trialed without a good logic. So I think we're in a new space where we do have systems that actually do allow us to identify agents that have translate seem to be translating well into the clinic.
So it's a I think we're in a good place.
Great. Thanks so much for taking the questions.
Thanks, Peter. So Melissa, I think that's the end of our questions. Any other did you want to allow people to come back on again? I think Doctor. Roar and Doctor.
Hill can drop off.
All right. Thank you.
Thank you very much. Bye.
Thank you. Thank you very much.
I think we're at the end of our time anyhow. So I want to thank everybody for joining on this conversation and we look forward to updating you on the program and chatting with others of you concerning broader Syndax questions. Thanks so much for joining the conference.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.