Celldex Therapeutics' CEO Presents at CDX-1127 Program Update Conference (Transcript)

| About: Celldex Therapeutics, (CLDX)

Celldex Therapeutics, Inc. (NASDAQ:CLDX)

CDX-1127 Program Update Conference Call

November 8, 2013 8:30AM ET

Executives

Anthony S. Marucci – President and Chief Executive Officer

Thomas Davis – Senior Vice President and Chief Medical Officer

Tibor Keler – Founder, Senior Vice President, and Chief Scientific Officer

Dr. Mario Sznol - Professor of Internal Medicine and Vice Chief of the Section of Medical Oncology, co-Director, Yale

Madhav V. Dhodapkar – Professor-Medicine and Chief-Hematology, Yale

Analysts

Howard Liang – Leerink Swann LLC

Biren Amin – Jefferies & Company

Bret Holley – Guggenheim Securities LLC

Joe Pantginis – ROTH Capital Partners LLC

Boris Peaker – Oppenheimer & Co., Inc.

Mara Goldstein – Cantor Fitzgerald Securities

Stephen Brozak – WBB Securities, LLC

Jonathan Aschoff – Brean Capital, LLC

Gregory Wade – Wedbush PacGrow

Operator

Good morning and welcome to the Celldex Therapeutics’ CDX-1127 program update call. My name is Stephanie, and I will be your operator on today's call. Before we begin our discussion, I have been asked to direct listeners to Slide 2 and caution you that today's speakers will be making forward-looking statements.

Such statements reflect on current views with respect to future events and are based on assumptions and subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such forward-looking statements.

Certain of these factors that might cause Celldex's actual results to differ materially from those in the forward-looking statements include those set forth under the headings Risk Factors and Management's Discussion and Analysis of Financial Condition and Results of operations in Celldex's Annual Report on Form 10-K, quarterly reports on Form 10-Q, and its current reports on Form 8-K, as well as those described in Celldex’s press releases and filings with the Securities and Exchange Commission. All forward-looking statements are expressly qualified in their entirety by this cautionary notice.

You should carefully review all of these factors and be aware that there may be other factors that could cause these differences. These forward-looking statements are based on information, plans, and estimates as of this call, and Celldex does not promise to update any forward-looking statements to reflect changes and underlying assumptions or factors, new information, future events, or other changes. Please be advised that the question-and-answer period will be held at the close of the call. Please also note that you can find a PDF of the slides for today’s presentation on Celldex’s website in the Investors & Media tab under Events.

I would now like to turn the call over to Mr. Anthony Marucci, President and CEO of Celldex Therapeutics. You may proceed.

Anthony S. Marucci

Good morning and thank you for joining us. I am Anthony Marucci, President and CEO of Celldex. Joining me on the call today are Dr. Tom Davis, Senior Vice President and Chief Medical Officer; Dr. Tibor Keler, Senior Vice President and Chief Scientific Officer; Chip Catlin, Senior Vice President and Chief Financial Officer; and two distinguished guests from the Yale Cancer Center, both experts in the field of cancer immunotherapy, Dr. Mario Sznol and Dr. Madhav Dhodapkar.

Dr. Sznol is the Professor of Internal Medicine and Vice Chief of the Section of Medical Oncology, co-Director of the Yale Spore in Skin Cancer and Translational Research Leader of the Melanoma Program. As a medical oncologist, he is focused on melanoma and immunotherapy therapy for many years.

He spent time at the NCI and The Cancer Therapy Evaluation Program where he oversaw development of biologics and immunotherapies. He also spent several years in biotech and has recently been deeply involved in the development of several checkpoint inhibitors including ipilimumab and BMS' Anti-PD-1 program, both alone and in combination, as well as anticancer vaccines.

Dr. Dhodapkar is the Professor of Medicine and Chief of the section of Hematology at Yale. His laboratory is studying how the immune system permits the transition of tumor cells and is investigating strategies for boosting a patient's immunity to tumors while using vaccines based on dendritic cells and immunomodulatory drugs. He has received a number of awards for his work including being named a New York Community Trust Scholar in Blood Diseases Research and receiving the Irma T. Hirschl Career Scientist Award and the Damon Runyon/Eli Lilly Translational Research Award.

In 2000, he received the NIH Mentored Physician Scientist Award, and in 1999 he received Cancer Research Institute Investigator Award. Dr. Sznol and Dr. Dhodapkar will offer a view comments later in the call and will be available during the Q&A for your questions.

Celldex was founded on the belief that harnessing the power of the immune system could break barriers in drug development for a host of devastating diseases. Growing interest in the therapeutic antibodies and the recent results being generated by CTLA-4 and PD-1 targeted therapies certainly seems to suggest that the field of cancer immunotherapy has finally come into its own and is here to stay. To this point, over the last few months, the CDX-1127 program has attracted a high amount of interest, especially given its early stage of development.

Over the next few days, we will present three different posters on the 27 program at the 2013 Society for Immunotherapy of Cancer Annual Meeting. While the data are being presented are from the Phase 1 and preclinical studies, given the level of interest in this program, we felt the best option for communicating the results in a practical and transparent way with the investment community was to hold a webcast to review the data. We have a lot to cover and want to leave considerable time to answer your questions.

So with that in mind, I will turn the call over to Dr. Tom Davis and direct you to slide three. Tom?

Thomas Davis

Thanks, Anthony. CDX-1127 is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. This is distinguished from those molecules that shut off T cells like CTLA-4 and PD-1. CD27 can be effectively activated by an agonist or a stimulatory antibody and will induce potent antitumor responses in vivo. Since CD27 expression is restricted to certain lymphocyte subsets and only activates in the co-stimulatory setting, its activation should lead to less innate or nonspecific toxicity.

On Slide 4, CDX-1127 is an agonist anti-CD27 monoclonal that has been shown to activate human T cells only in the context of specific T-cell receptor stimulation. T cells are typically stimulated to divide and mediate antitumor effects through a two-signal mechanism that involves receptor stimulation when engaged with an antigen presenting cell and a co-stimulatory signal, and CD27 can provide that potent co-stimulatory signal when engaged by its ligand, CD70, on antigen presenting cells.

CDX-1127 can substitute for CD70 and will cause activation of T cells that are in their appropriate setting, receiving T-cell receptor stimulation. This can result in a conversion of weak immune responses to strong immune responses that can last for a lifetime.

In addition to the immune-enhancing properties of CDX-1127, as outlined on the left hand side of this diagram, the CDX-1127 may also provide direct therapeutic effects against tumors with CD27 expression. Human B- and T-cell lymphomas often express CD27 at high levels, and CDX-1127 combines these tumor cells directly and activate immune cell killing through a mechanism known as antibody-dependent cellular cytotoxicity or ADCC. CDX-1127 binding to the tumor cells may also interfere with tumor cell growth by additional mechanisms.

Later in the call, Tibor will share some immune monitoring studies with you that further reinforced our understanding of the mechanism of CDX-1127. Before we get into the data, I’d like to provide you with an overview of the study. As you’ll see on Slide 6, the Phase 1 study employed a standard 3+3 dose-escalation design, escalating through 0.1, 0.3, 1, 3, or 10 milligrams per kilogram. Participants received a single dose followed by a 28-day monitoring period to evaluate safety and immune activity and then were dosed weekly to establish safety with maximum exposure.

Tumor responses were evaluated on day 85 and up to four retreatment cycles for a total of five total cycles were permitted. The Phase 1 design included expansion cohorts for investigation of safety and activity in select indications treated with a chosen dose of CDX-1127. As you can see, the expansion cohorts were designed very similarly, except that they eliminate the single-dose period.

Moving to Slide 7, study was designed with two arms to allow for independent dose-escalation in each arm. Solid tumors of various histologies which do not express CD27 and B lymphoid malignancies, which are frequently CD27 positive. The solid tumor dose-escalation arm is complete with 25 patients enrolled. The lymphoid malignancies dose-escalation arm is still ongoing. It has 17 patients enrolled to date, and the final cohort 10 milligrams per kilogram is currently accruing.

This is the Phase 1 study primarily intended to evaluate safety and as is common in this setting, we allowed a wide range of different cancers as you see outlined on this slide. In doing this, we assured a broad safety experience, but limited our ability to estimate anti-cancer effects in any specific disease setting. The most frequent tumor type in the solid tumor group was colon cancer, generally one of the tougher malignancies from the immunotherapy perspective. Beyond that, we see expected range of malignancies in both arms.

Patients on study had advanced disease, had progressed on previous therapies, and upon study entry had no remaining approved treatment options. In general, patients who were heavily pre-treated, the median number of prior therapies with solid tumors is 5 anti-cancer and 3 cytotoxic treatments. The lymphoid malignancies is 4 anti-cancer and 3 cytotoxic. As I just stated, our primary objective of this study was to determine the safety profile of CDX-1127.

On Slide 8, the safety data from the solid tumor arm is presented. CDX-1127 has been very well tolerated with minimal toxicities at all dose levels tested to date and several patients received multiple courses of treatment. The most common treatment-related adverse events are decreased appetite, fatigue, and chills; nothing surprising given the advanced stage of the patients enrolled in the study. We did see one Grade 3 drug-related toxicity, a patient with hyponatremia or low blood sodium levels that developed 14 days after single 1 milligram per kilogram dose of CDX-1127 in the solid tumor arm. This patient had low sodium levels prior to study entry, was asymptomatic throughout, and did not require significant intervention. Hyponatremia has not been attributed to CDX-1127 in any other patient, and we have no reason to believe CDX-1127 would induce low sodium levels.

The overall frequency of drug-related adverse events is very low, seen in only a handful of patients with most being mild in severity. No maximum tolerated dose was identified. We believe this safety profile differentiates CDX-1127 from other agents intended to specifically activate immune responses, many of which induce immune-mediated toxicities such as hepatic or bowel inflammation.

As we mentioned earlier, the lymphoid malignancies arm is now enrolling in the 10 milligram per kilogram cohort with no dose limiting toxicities noted to-date. Preliminary data suggests a consistent safety profile. Full safety data from this study will be reported at a later venue when it’s available.

Overall, from a safety perspective, we couldn’t be more pleased with the data. It’s important to note that many enrolled patients were quite mature ranging up to 92 years old, with a significant number of patients in their late 70s and 80s. The fact that CDX-1127 was well tolerated, even in an elderly patient population is important as many anti-cancer treatments are very toxic in those over at the age of 70.

Overall, the safety profile positions CDX-1127 very well, including combination use. Anyone who follows this space knows that future progress in immunotherapy lies in combination approaches, and the most promising candidates to date elicit impressive results in a distinct subset of patients.

Expanding this subset is the goal. To date, 1127 has demonstrated minimal toxicity with no worrisome overlap with toxicities seen with other immunotherapies. An agonist with this safety profile holds great potential in this context, particularly in combination with checkpoint inhibitors, where the presence of an antitumor immune response could significantly expand efficacy.

Of course, this safety profile must be associated with the necessary biologic activity. The results of the biologic and immune monitoring data collected during the study will be described by Tibor Keler. Tibor?

Tibor Keler

Thank you, Tom. The following slides will present data from patients in the solid tumor dose escalation arm. On slide 10, we show the pharmacokinetic profile for a patient treated at the 1 milligram per kilogram dose. And even at this modest dose level, good drug exposure was maintained throughout the three-month study period. As expected, during the multi-dosing, an accumulation of CDX-1127 occurs. So, these analyses suggest that CDX-1127 is performing as we would have expected for a fully human antibody.

Slide 11, looks at the numbers of the overall lymphocytes and two specific subsets. As seen in the top graph, we did not observe a major drop in lymphocyte counts, consistent with our preclinical studies that CDX-1127 is not a depleting antibody. However, we find that the FoxP3+ regulatory T-cell, which are increased in cancer patients and thought to limit immune responses were consistently lower after treatment.

The reduction of these Tregs was observed across all those levels and was not associated with signs of autoimmunity. Also, it is consistent with our observations of Treg depletion in our preclinical models. In these patients, we also observed an increase in Natural Killer cells, which as their name implies are lymphocytes that can have direct antitumor activity. This increase in NK cells was most pronounced in patients receiving 3 milligrams per kilogram, and this contributed to our rationale for choosing this dose for the expansion cohort.

Slide 12 shows evidence for T-Cell activation, but the CDX-1127 we didn't expect to activate the majority of T cells due to the specific regulation of CD27 signaling, but we did find a consistent increase in the number of T cells that upregulated the activation marker HLA-DR. This is a same marker that is associated with administration of ipilimumab.

Again, this observation was most prominent in the 3 milligrams per kilogram cohort. The bottom two graphs show the effect of CDX-1127 on T-cell function. Here, we analyze the T-cell response to viral antigens to which most people have been exposed or to an agent that nonspecifically activates T-cells. Importantly, there was no evidence that CDX-1127 inhibited this memory response to viral antigens, in fact improved responses were seen in many patients to both the recall antigens and to non-specific stimulation.

Perhaps the most important biomarker finding is shown on Slide 13. As shown in the top graph, we observed a significant increase in the serum levels of the interferon-gamma-inducible protein-10 or IP-10 shortly after CDX-1127 administration. The increase in the serum biomarker is consistent with the mechanism of action for CDX-1127, which drives interferon-gamma production when it engages and activates T cells. As shown in the bottom graph, we found the same pattern of IP-10 induction in our human CD27 transgenic mouse model treated with CDX-1127. This gives us great confidence in the length between our preclinical and clinical results.

Collectively, the immune monitoring data provides clear evidence of biological activity in patients and are remarkably consistent with our preclinical data. These data also reinforce the safety profile for CDX-1127 by demonstrating no loss of memory lymphocytes or their function nor was there over activation of lymphocytes that could leads to autoimmune toxicities.

I will now turn the call back over to Tom to discuss the clinical activity we have observed to date with CDX-1127. Looking broadly across both the solid tumors lymphoid malignancies arms on Slide 15, we’ve observed promising signs of clinical activity in an advanced, refractory patient population. It’s important to keep in mind that activity is not a primary end point in early Phase 1 study, and that this is a very heterogeneous refractory patient population treated at varying doses so that any results are essentially anecdotal.

I will go into some of the specifics in a moment, but at a high level, we have observed one ongoing complete response in an aggressively pretreated patient with Hodgkin disease, now with a progression free survival of nearly nine months, but essentially complete symptomatic improvement. We’ve also had two additional patients with significant tumor shrinkage, a 33% decrease, but it resists in the patient with Stage IV colorectal cancer, formerly a mixed response, and a 36% decrease by chosen criteria in a patient with Stage 3 marginal zone B-cell lymphoma.

Eight patients have had stable disease or better with the PFS range of 3 to over 14 months. Two patients received all five cycles of treatment and were on trial for greater than a year, one with follicular lymphoma and the other with renal cell carcinoma. In the dose-escalation lymphoid malignancies arm, 17 patients have been enrolled to-date. Enrollment was recently initiated in the 10 milligram per kilogram cohort and expanded development is being planned.

Currently, first response assessments are pending for four patients across the one and three milligram cohorts, and all patients in the 10 milligram per kilogram cohort in the lymphoid malignancies arm. We’ve provided specifics of these cases on Slide 16. The patient with a complete response is a 20 – 80 –a 28-year-old woman with Stage IV Hodgkin lymphoma with para-aortic nodal involvement. She has achieved a CR after three cycles of CDX-1127 at only 0.3 milligrams per kilogram and remains in remission at approximately nine months.

Interestingly, during treatment, the area of measurable lesions first increased by 9% and then regressed to a complete response at nine months. This pattern is consistent with the current perception of an immune-mediated response. The patient was heavily pretreated including high-dose chemotherapy with autologous marrow transplantation and that progressed after less than one month on Adcetris plus chemotherapy. The patient also experienced a complete resolution of our B symptoms; drenching sweats, pruritus or intense itching and weight loss. These are important markers of disease activity in Hodgkin lymphoma.

Another patient described on Slide 17 is a 69-year-old man with colorectal cancer that was metastatic to liver, lung, and peritoneum. He was treated with CDX-1127 at 1 milligram per kilogram and had a 33% unidimensional shrinkage of measurable disease. This shrinkage was associated with new lesions representing what is called a mixed response. Some of you may be familiar with immune related or IR response criteria. According to these criteria, the patient had an IR stable disease with 45% shrinkage in measurable lesions.

This patient had previously received three prior lines of therapy, including Avastin and Camptosar, 5-Fluoruracil, Leukovorin, and an investigative therapy, and had most recently progressed through Xeloda radiation within two weeks. The patient experienced a PFS of 5.7 months after treatment with CDX-1127.

The second patient with significant shrinkage is a 67-year-old man with Stage III marginal zone B-cell lymphoma. This patient received CDX-1127 at 0.3 mg/kg and experienced a 36% bi-dimensional shrinkage of measurable disease, including complete disappearance of disease in the inguinal and iliac regions. He was very heavily pretreated with 9 prior regimens of cytotoxic therapy, radiation, and Rituxan therapy, and went on to experience a PFS of 5.6 months after treatment with CDX-1127.

In addition to these patients, there are a handful of other interesting cases worth discussing on Slide 18. An 83-year-old man with Stage IV renal cell carcinoma metastatic to the liver and lung was treated on study. He completed 5 cycles of CDX-1127 at 3.0 milligrams per kilogram and remains progression-free without tumor growth at over 14 months after study entry. He had previously progressed at 3 months on Nexavar and Afinitor and at 9 months on Xeloda.

A 52-year-old man with Stage IV follicular lymphoma had a progression free survival of 14 months while receiving CDX-1127 at 0.3 milligram per kilogram for single dose and then 0.1 milligram per kilogram for 5 treatment cycles. And a 66-year-old male with Stage IV melanoma with visceral metastases had a PFS of 3.8 months. The last patient had previously progressed through IL-2 at 2 months, and Yervoy within 4 months in addition to two rounds of chemotherapy.

In summary, CDX-1127 has exceeded our expectations thus far in this ongoing Phase 1 Dose-Escalation Study. Our primary expectation was to establish a favorable safety profile and evidence of robust immunologic activity. We’ve met those goals. We’ve not reached the maximum tolerated dose, and to date CDX-1127 has demonstrated minimal toxicity and importantly no evidence of worrisome overlap with toxicity seen with other immunotherapies. We were also every pleased to see clear evidence of wide spread immunological activation including prominent increases in markers of lymphocyte activation, proliferation of NK cells, and a decrease in the suppressive Treg cells. In addition, the specific cases where we saw evidence of antitumor activity in refractory patients only add to our confidence that CDX-1127 is an active and important immunotherapy drug candidate.

As we mentioned earlier, we have initiated expansion cohorts of 3 milligrams per kilogram in both metastatic melanoma and renal cell carcinoma. Based upon data available at this time, the 3 milligram per kilogram dose provided no safety concerns, saturating pharmacokinetics, and good immune activation. From the early data, the 10 milligram per kilogram dose does not appear to improve upon those results and keep in mind that the weekly dosing leads to significant accumulation of drug compared to less frequent dosing. It’s too early to specify plans in lymphoid malignancy arms, but current results support additional disease specific work after we complete the 10 milligram dose.

Slide 19 revisits the treatment scheme of the expansion cohorts, while at this point in the study, we have a limited number of patients evaluable for anti-tumor activity from these expansion cohorts. We do want to provide an update as outlined on Slide 20.

I want to start by noting that again CDX-1127 has been well tolerated to-date in these expansion cohorts. The melanoma cohort has enrolled 14 patients at three milligrams per kilogram, 8 of these patients are still on treatment and 7 have not yet had a disease assessment. One patient with uveal melanoma, an aggressive form of the disease, experienced 12% shrinkage by RECIST and currently has stable disease ongoing at 5.7 months. The patient has completed two rounds of treatment and is now entering the third. This is a promising result based on the patient’s prior disease course.

The second cohort is in renal cell carcinoma; eight patients have currently enrolled, seven patients are ongoing, only one patient has reached today 85 to-date for follow-up, and that patient has experienced progressive disease. Based on the totality of the data, we’ve absorbed to-date and after completing the dose escalation study and its corresponding expansion cohorts, we intend to initiate additional studies of CDX-1127.

Particular area of focus will be combination studies. In preparation for this work, the company conducted a number of preclinical studies to explore possibilities for combination approaches, and I will close the call by asking Tibor to review the preclinical poster beginning on Slide 22.

Tibor Keler

As we have discussed, CDX-1127 is designed to activate immune responses against the patients with tumor. While we believe CDX-1127 can have utility as a single agent, we think combination approaches hold great promise. For CDX-1127, we think there’s an opportunity for combination regimens with both conventional therapies and particularly with immunotherapeutics agents like vaccines and checkpoint inhibitors. Combining with conventional therapies that cause tumor cell death without profound immune suppression would serve both to reduce tumor burden and to provide assorted tumor antigens. While combinations with agents at block checkpoints such as CTLA-4 and PD-1 would ensure that a developing immune response is not shut off and could potentially broaden that immune response.

Moving to Slide 23, we first looked at a combination study with a chemotherapy cyclophosphamide, where we have demonstrated a clear synergistic effect. Very limited activity was observed using monotherapy in these models with an advanced disease setting. However, the combination treatment of cyclophosphamide and CDX-1127 resulted in an 80% survival rate. Despite the potential for chemotherapy to limit immune response, we have heard the significant increase in the number of effector T cells and the effector T cell to regulatory T cell ratio in the and tumors of mice treated with a combination therapy.

Our results indicate that agents like cyclophosphamide that help control tumor growth without interfering with the immune response driven by CDX-1127 are valid combinations to test in patients. There’s been a particular motivation for testing CDX-1127 in combination with checkpoint inhibitor as shown on Slide 24. Essentially, the idea in stepping on the gas while taking the foot of the brakes.

As before, we used advanced disease models to limit monotherapy activity. Combining blockade of PD-1 signaling using a PDL-1 specific antibody together with CDX-1127 resulted in tumor regressions and increased survival in these challenging tumor models. Similarly, we also saw improved survival in combination with CTLA-4 blockade. And now, we are in the process of conducting additional studies and optimizing these treatment regimens to help inform the potential clinical trial designs.

With that, I’ll turn the call back to Anthony to close and we will open the call for your questions.

Anthony S. Marucci

Thank you, Tibor. And in closing on Slide 26, we believe we'll achieve proof-of-concept for 1127 in this study by establishing an excellent safety profile that we believe supports both single agent and combination regimens with minimal toxicity that importantly does not significantly overlap with other immunotherapies.

Immunological activity, that is consistent and its expected mechanism of action and anti-tumor activity in very advanced refractory patients including Hodgkin’s lymphoma, follicular lymphoma, renal cell carcinoma, colorectal cancer, and melanoma. Future data from these expansion cohorts will be important to understanding fixed single agent activity.

That said, based on the current data from the dose escalation studies, we are confident there will be -- we are well positioned to initiate combination studies of 1127 with both internal assets such as CDX-1401 and CDX-011 as well as external programs such as ipilimumab and other checkpoint inhibitors.

We are defining the specifics of these plans, and can describe them closer to the completion of this study and its corresponding expansion cohorts and look forward to updating you then.

Given the expertise in the fields of immunotherapy and solid tumors and lymphoid malignancies, we have asked Dr. Sznol and Dr. Dhodapkar from the Yale Cancer Center to join us for the question and answer portion for this call, and they have both provided insight to this study and we value their expertise and thought you would too.

First, we would like to ask them to provide a brief statement on their perspectives on these results and then open the call to questions. Dr. Sznol?

Dr. Mario Sznol

Thank you. I reviewed the data very carefully, and I think people know my views about immunotherapy, and I think it is all about T cells, and I think it is very important to understand that CD-27 is really a very key module in T-cell activation, a critical module in T cell activation, and it is something – it is a target that we want to have in building the armamentarium to build an immunotherapy portfolio that would actually lead to cures of cancer. We’ve made a lot of progress with anti-PD-1 and anti-PD-24 on a combination study. We are still not showing everybody and we still haven’t addressed every diseases out there. I think that the clinical and preclinical data with CD27 is really very exciting, and the clinical data shows very low toxicity which means that you have an opportunity to combine it with other agents that the qualitative studies that were done showed that it had an important biological activity that correlated with what was seen in the animal models, and those really very heavily pre-treated patients, there was evidence of clinical activity, I mean I am not sure that any other agent in this heavily pretreated group of patients would have shown more activity, especially in diseases like colorectal cancer where you really haven’t seen much activity with PD-1 or CTLA-4 lone

And I’m actually very excited by the preclinical data, it is not just the preclinical data showing combinations of activity with checkpoint inhibitors. It is the actual biological activity of this agent and I think showing that you can reduce Tregs which is I think is very important component of future immunotherapy showing that you can cause infiltration of T cells in the tumor microenvironment is really very important and it addresses a whole group of patients, for which we really had no effective treatment and I’m not sure that PD-1 would address that group of patients and actually showing this change in the [T-effector to T-reg] ratio preclinically also something that we would like to achieve in the clinic and again the correlation so far between preclinical data and clinical data suggest that this would be achieved in clinic also. So, from my perspective, I think this is a key therapeutic agent. By itself, it will have some activity, but I think the real excitement here is using a rational in combination, and I think it has great promise in combination either with cytokines or with other checkpoints inhibitors.

Unidentified Company Representative

Thank you very much, Mario, Dr. Dhodapkar.

Madhav V. Dhodapkar

So I’m really glad to really join this call. As Mario mentioned, the space of checkpoint blockade is rapidly expanding, there is much excitement in the field. But I think it’s important to point out, at least as a basic immunologist, the interaction between CD27 and CD70, plays a non-redundant role in regulating immune tolerance and T-cell immunologic memory, so it’s really an important target that has yet not been exploited.

As a cancer immunologist, I have been very interested in seeing the first in human data and actually quite pleased to see that these therapies have been actually well tolerated even in elderly population with very few adverse events, which is going to be very important in terms of being able to take it to the next step in combination therapies.

Also as a hematologist we’ve known for sometime that CD27 expressed in lymphoid tumors and so – therefore it is actually quite exciting to see that there is some evidence, some early evidence of clinical activities in this setting, specifically the patient with refractory Hodgkin's disease that had failed several therapies including rituximab.

While I think at this stage of evaluation, you’re really not looking for clinical activity but rather safety profile, and evidence of immunologic activity and in this regard, I think I’m very encouraged by the data for acute induction of IP-10, and more importantly perhaps introduction in Tregs, which again points to this path – this agent is being very useful potentially down the line in the context of combination therapies.

So overall I think, I’m quite encouraged by the early clinical data for activity in B lymphoid tumors evidence for immunologic activity, as well as excellence tolerance profile, particularly in older individuals, which is really the place where we have real trouble being able to get chemotherapy.

So I think this is an exciting field, I think it’s likely to be I hope will be pursued further in any malignancies.

Anthony S. Marucci

Thanks very much. Operator we are ready to take our first question.

Question-and-Answer Session

Operator

(Operator Instructions) Our first question comes from the line of Howard Liang of Leerink Swann, you line is open.

Howard Liang – Leerink Swann LLC

Thanks very much for taking my question. I guess my first question is on the response in Hodgkin's patients. Can you talk about whether you looked at CD27 expression in that patient, and what do you think the mechanism of the response was, whether it's through T-cell activation or through ADCC just binding to the CD27?

Anthony S. Marucci

You are asking some critical question Howard, unfortunately this time I don’t have a good answer for you. We are actively collecting the tissue from this patient and other Hodgkin's patients on study in order to better understand what cells within the tumor express CD27 and that will of course give us some sense of the mechanism here. It is important to understand that Hodgkin's disease particularly nodular sclerosing Hodgkin's which this patient had is a broad mix of different cells and to even this date I think the actual malignant cell and what it expresses is not very well defined.

But we don’t have those answers by the time we present the final results from the study.

Howard Liang – Leerink Swann LLC

If I can just ask a follow-up question for Dr. Sznol, can you remind us the effect of PD-1 agents on Tregs and whether the activity here on Tregs other than that significant addition?

Unidentified Company Representative

I don’t think we have any data on the effects of anti-PD 1 blockade on Tregs, on a number of Tregs in peripheral blood or their function at least to my recollection. I haven’t seen any of those studies done and we haven’t done them. Maybe Dr. Dhodapkar would know because he has been involved in some of our (inaudible) studies, but I actually don’t know the answer to that question.

Unidentified Company Representative

We’re actively looking at those questions, but I think right now we don’t really have concrete information on that.

Howard Liang – Leerink Swann LLC

Thanks very much.

Unidentified Company Representative

Thank you, Howard.

Operator

Thank you. Our next question comes from the line of Biren Amin of Jefferies. Your line is now open.

Biren Amin – Jefferies & Company

Yes, thanks for taking my question. I just wanted to understand the rationale for the dose expansion cohort in RCC and melanoma and I guess why the Company didn't pursue colorectal, given the one patient observed a 33% tumor shrinkage? Thanks

Unidentified Company Representative

Thanks Biren. Biren, with a Phase I like this, it’s really impossible to estimate response rate overall. And I said as it had been seen with most of the immunotherapies in cancer, melanoma, renal cell carcinoma would appear to be the most responsive. So we have decided to start with melanoma and renal cell to explore the 3 milligram dose and see how well it works there, knowing that we then could expand. At this point based on the result, that the colorectal cancer patient we would like to expand into that indication, but that will happen after we complete melanoma and renal.

Biren Amin – Jefferies & Company

Got it, thank you

Unidentified Company Representative

Thanks Biren.

Operator

Thank you. Our next question comes from the line from Bret Holley of Guggenheim. Your line is open

Bret Holley – Guggenheim Securities LLC

Thank you for taking the question. I'm just curious if the physicians could put into context – the long-term stable disease that you saw in renal cell cancer strikes me as pretty interesting, given the age of the patient. And I'm just wondering, I guess, how that would compare to the very earliest data, to [urivoid] and the PD-1 inhibitors?

Unidentified Company Representative

That question is directed to me. So [indiscernible] has a little bit of activity in renal cancer. It’s a little bit similar to melanoma, but only a small study was done by the NCI some years back. This is comparable to the kind of activity that was observed in that trial. For anti PD-1 or PDL-1 blockade seeing a response like this in the early days of PD-1 would have been very exciting. This is a prolonged stable disease as I recall. And we saw that in the trials of anti PD-1. With trails in anti-PD-1 we also saw some patients with substantial tumor aggression, but the overall rate of tumor aggression in the 25% or 30% range. I don’t think enough patients have been treated here to be able to say much more, other than their interesting activity.

Bret Holley – Guggenheim Securities LLC

And I guess my follow-up question would be on colorectal cancer and whether I guess CD27 might have unique properties in that setting. Is there any, I guess, first principles reason to think that it might be different than urivoid and the PD-1 inhibitors in the context of colorectal cancer?

Unidentified Company Representative

I think there is no question in colorectal cancers and immunotherapy-sensitive disease and there clearly, there is a correlation between T-cell infiltrating colorectal cancer and long-term outcome. But it may be that for different diseases, as you point out, you need a different set of signals and targets in order to get them to respond.

So interestingly enough with Anti-PD-1, there was a little bit of activity in colorectal cancer, there was a responder in the first Phase 1 trial. And there was a little hint of activity in the – even though we said there was no activity, there was, in fact a little hint of activity in the larger Phase 1 trial the Anti-PD-1 given every two weeks and Genentech has reported a response in colorectal cancer with their anti-PD-ligand 1. But so far the activity is very low. The fact that you have seen some activity with anti-CD27 is interesting. It could have activity on its own, but it also would be incredibly interesting to combine anti-CD27 with PDL-1 or PD-1 blockade in colon cancer. When people look at T-cell infiltrates in a lot of these tumors, a lot of those T cells actually express CD27. And that’s the other reason why I am excited about this is that there a target for those T cells within the tumor microenvironment.

Bret Holley – Guggenheim Securities LLC

Thanks very much I appreciate it.

Anthony S. Marucci

Thanks, Bret.

Operator

Thank you. Our next question comes from the line of Joe Pantginis of ROTH Capital Partners. Your line is open.

Joe Pantginis – ROTH Capital Partners LLC

Hey, guys thanks for taking the question. The first simple question is, you didn't identify the MTD. Do you intend to increase the dose at all to try to find it, or are you okay with the doses? And then the second question, a little more in depth, can you provide a little more color on the observations you made with regard to not seeing any lymphoid depletion, but do you see the positive impact of decreased regulatory T cells? And then linking that to the concept of do you see – this is something that constantly comes up maybe for the skeptics in the immunotherapy area with regard to the combination therapies and the underlying risk of potentially seeing too much immune activation? Thanks a lot.

Anthony S. Marucci

Sure, Joe. Thanks for the question. So we do know in solid tumors from the data that Tibor presented that we are getting good saturation of the CD27 system, and that is evidenced by circulating levels of antibody and saturation of cells expressing CD27. So with that said, we poised to go higher in dosing because we think we are getting maximum effects even at the 3 and 10 milligram doses. Now, this is a separate situation in hematologic malignancies where there could be a lot more CD27 expressed on the malignant cells themselves. We might find that there we need to go to higher doses to get full saturation. But obviously, it's still early in the study we don’t have the answer to that yet. Tibor?

Tibor Keler

Yes, Joe, so regarding your second question, about the lymphocyte depletion, as you know most T cells express CD27. And one of the concerns going into the study was to make sure that the antibody, in fact, didn't deplete T cells in a general fashion. This is an IGG-1 antibody that has the potential for the sector function. And so certainly from the safety perspective it is really nice to see that in fact, the lymphocyte population as a whole was not impacted. The specific effect that we see in terms of reducing the number of regulatory T cells, mechanistically is not fully understood.

Now, these cells certainly express CD27 and can express at a good level. So this maybe through effector function or it may be through a signaling event on regulatory T cells. And we are certainly exploring that, but I don’t have a specific answer of what distinguishes the impact on the regulatory T cells versus lymphocytes as a whole.

Joe Pantginis – ROTH Capital Partners LLC

And then just the whole concept of, since you reduce regulatory T cells, obviously there's potential synergy there for the types of combinations that you alluded to, especially with something like ipilimumab or PD-1. So I guess I just wanted to just flip the argument in saying, when you talk to people or investors or even physicians, sometimes there is sometimes some trepidation regarding combining these types of immune approaches. So any physician input here? They are talking about any of the potential underlying risks, even though there really hasn’t been any evidence to date.

Anthony S. Marucci

We will have Dr. Sznol comment on that.

Dr. Mario Sznol

I’ve said for a long time that when we start doing immune therapies, we are going to have to learn to manage autoimmune adverse events. As you know, in the combination of anti-PD-1 and anti-CD24, 50% of patients develop Grade 3 or 4 immune adverse events and we were able to manage those events relatively easily. It’s no different than managing febrile neutropenia, just managing a different set of event.

I have no doubt when anti-CD27 is combined with other molecules we will see some form of adverse events related to induction of autoimmunity and inflammatory events. But I’m not concerned about it, because we already have a great deal of experience with ipilimumab that is already on the market, and it's being used by a lot of physicians and with the combinations that we’ve study that these events are equally manageable.

So the only risk that I could see is that, with an agent like anti-CD137, liver toxicity became limiting, but there was no evidence that liver toxicity here with anti-CD27 and that’s the other reason why I’m more excited about this molecule. There’s a lot of data showing combinations of [indiscernible] molecules co-inhibitory with inhibitors of these co-inhibitory pathways that are synergistic in animal models, but with some of the molecules, you may run into dose-limiting toxicity. This agent actually looks very clean.

Tibor Keler

Well, you should ask Dr. Dhodapkar to comment on hematologic malignancies where there might be a slightly different perspective.

Madhav V. Dhodapkar

I think they haven’t reached – yes, you’ve seen very little toxicity, but I think the bigger issue is going to be because there is a higher level of expression CD27 on these patients, actually requires dose levels would be different and the toxicity may differ at that stage, but at this point I think I’m very encouraged to see there’s almost nothing in terms of adverse event.

Anthony S. Marucci

Yes. So we would emphasize again, that we do need to get 10 milligram per kilogram dose level data and perhaps even higher doses to really understand key malignancies.

Joe Pantginis – ROTH Capital Partners LLC

Thanks guys.

Anthony S. Marucci

Thanks, Joe.

Operator

Thank you. Our next question comes from the line of Boris Peaker of Oppenheimer. Your line is open,

Boris Peaker – Oppenheimer & Co., Inc.

Good morning. Congratulations on the very encouraging data. I just wanted to probe further into the biomarker studies, particularly the T-cell and NK-cell biomarkers. I’m just curious if there was actual correlation between dose biomarkers and the responses that you reported today. And I guess as a follow-up question, when we just talk about side effects, a similar kind of question. Did we see a correlation between adverse events and side effects, or do those seem to be randomly scattered across the patient population?

Anthony S. Marucci

So with regards to the activation markers and other immune markers, as observed those both in patients that had better clinical outcomes and those that progressed rapidly. So with the small number of patients we have so far we don’t have a clear correlation. It’s something of course we are going to study very carefully as we move forward.

Boris Peaker – Oppenheimer & Co., Inc.

And on the side effect?

Anthony S. Marucci

Similarly there is no clear correlation here. I think what we do see is a fairly significant drop in the vast majority of patients. So it’s hard to make correlations with the small number of advanced and a small number of patients. But certainly in the next stage of development the expansion cohorts on Page 2 that’s an area that we will focus on.

Joe Pantginis – ROTH Capital Partners LLC

Okay. And lastly, on the Hodgkin’s disease patients that had a response, are there any unique biomarkers there that may help to further understand that response and maybe leverage that in future patient selection?

Anthony S. Marucci

So again a good question I think understanding the tumor tissue, which, as I described, we are currently pursuing will be very important to that and seeing how that matches up with the biomarkers. Unfortunately, we don’t have the answer yet. But that's a key question for us, and we would like the answer. Before we get into expansion cohorts.

Joe Pantginis – ROTH Capital Partners LLC

Great, thank you very much for taking my question.

Anthony S. Marucci

Thanks, Boris.

Operator

Thank you. Our next question comes from the line of Mara Goldstein of Cantor Fitzgerald. Your line is open.

Mara Goldstein – Cantor Fitzgerald Securities

Thanks very much. Just perhaps a follow-up, to some degree, on the prior question, and that is, on these parameters that you looked at in terms of [mean moderating] data, were there any differences across the different subtypes of solid tumors or are there different types of solid tumors that you observed?

Anthony S. Marucci

Mara, we haven't done very formal analysis because we have such few patients in which we have the ability to do this I think the ends will be too small to draw any significant correlations. And that’s, of course part of the rationale for doing expansion cohorts where we can really characterize the safety to clinical and certainly the immunological activity in a more defined patient population.

Mara Goldstein – Cantor Fitzgerald Securities

Okay. And just on the tumor infiltrates that you think that you are seeing, given the fact that some of the tumors are growing before they are shrinking, is there any uniformity around that that you can share with us?

Anthony S. Marucci

Well we see certainly in the preclinical models that we have – the significant sort of inflammatory response within the tumors. We are collecting tissue from patients where we have access to it and certainly believe that’s going to be a critical part in terms of defining what’s happening in patients and looking at the microenvironment within biopsy specimens from before and after treatment.

Mara Goldstein – Cantor Fitzgerald Securities

Okay, all right. Thank you.

Anthony S. Marucci

Thank you, Mara.

Operator

Thank you. (Operator Instructions) Our next question comes from the line of Steve Brozak of WBB Securities. Your line is open.

Stephen Brozak – WBB Securities, LLC

Yes, hi, good morning gentlemen. Looking at this, and obviously you’ve taken great pains to go out there and make sure that you remind us that the N is small. But are there any differentiators that you see in terms of blood work where there are things that are – obviously, again, the N is small, where there anomalies in terms of just overall health in terms – anything that you see that you would be looking for either in a good way or a bad way? And I have got one follow-up after that.

Anthony S. Marucci

Well, you emphasize that the N is small, and I can only say clearly what that means is not that we can rely statistically on the trends just the fact that these patients vary dramatically both in counts and in response to treatment. So when you have just a few patients with renal cell, a few patients with Hodgkin's disease, it ends up being impossible to make clear correlations. The simple answer is no, we are not seeing any clear trend yet. We simply need more mature data and more patients to know.

Stephen Brozak – WBB Securities, LLC

Okay. And following up on that, since you are basically triggering a global response, obviously, are there or have you looked at – and these patients have been very carefully monitored, but obviously they are very advanced oncology patients here, are there situations where you have detected other tumors that you haven’t seen before that in theory may have actually all of a sudden in a control population where you would have expected to see other tumor growth, where you didn’t see it something candidly that you were looking for but didn’t take place?

Thomas Davis

To date no but again with this early interim look we really haven’t had a chance to dwell on these data and expect to do it when we have a final data. Our plan certainly is to have a much more comprehensive presentation likely in June of next year with perhaps a complete presentation on the hematologic malignancies at a meeting at the end of next year.

Stephen Brozak – WBB Securities, LLC

Okay. So at that point, then, you would expect to be able to give that, per a real Wall Street granularity on what you would start to look for and then we could start to build our expectations as to what you would see being the better response for some patients than others. Is that pretty much an accurate statement?

Thomas Davis

That’s accurate yes, the expansion cohorts are critical to that we are at a point of mid study where we need to start making plans to solid tumors and are actively doing that . We need a little more data on hematologic malignancies, but then we are backing things out in the next year and by the end of next year I think we’ll have a very clear plan of both what we know and what we are planning to do.

Stephen Brozak – WBB Securities, LLC

I actually do have one item here because it is, I mean this is a different kind of treatment protocol than people are expecting. Have you started to see queries concerning, well, we would be interested in this from other thought leaders and other people in terms of clinicians? Because obviously this is something that a lot of people will be interested in.

Thomas Davis

I think we had great interest from potential pharmaceuticals partners as well as clinicians to work with this molecule, quite frankly though, this is the first time that we’ve really released the data and it will be I think a point of particular interest at the Society for Immunotherapy, where the posters are going to be hung. So we can’t tell you there is interest and we look forward to sort out all the great ideas that are coming through.

Stephen Brozak – WBB Securities, LLC

Again, congratulations. This is terribly exciting, and I look forward to seeing what happens next.

Thomas Davis

Thanks, I appreciate it.

Operator

Thank you. Our next question comes from the line of Jonathan Aschoff of Brean Capital, LLC. Your line is open.

Jonathan Aschoff – Brean Capital, LLC

Hi thanks. Yes, question for Tom. Could you help us better understand just how, I guess for lack of a better term, far gone these patients were, the melanoma and the renal cell expansion cohorts, just so at least we can better interpret seven of eight analyzed progressing?

Thomas Davis

So we didn’t formerly change to entry criteria for the expansion cohorts. So it’s still an advanced patient population who have received or refused all approved therapies. So they are growing aggressively some of them are growing quite quickly. And I guess, I would suggest you keep in mind that it does take a little bit of time for immune therapies to work in those patients who blast right through initial treatments are unlikely to ever be able to benefit.

Jonathan Aschoff – Brean Capital, LLC

Can you help us understand how many folks may have lasted several rounds outside of the one uveal?

Thomas Davis

Well, at this point those are ones that we can evaluate that’s the only that has made it out after the first evaluation. So, yes there certainly are patients who are progressing rapidly.

Jonathan Aschoff – Brean Capital, LLC

Okay. And when may we see those full data sets?

Thomas Davis

So again I expect it by June of next year, we’ll have the full data on melanoma and hopefully on renal cell as well. And can use those results to better estimate what the response rate will be in refractory patients. The thrilling part of our plan is then move into much earlier patients. We’ve talked about combinations, but we also want to work in patients who have a more intact immune system.

Jonathan Aschoff – Brean Capital, LLC

Okay thank you.

Unidentified Company Representative

Thanks Jon.

Operator

Thank you. Our next question comes from the line of [indiscernible] your line is open.

Gregory Wade – Wedbush PacGrow

Good morning. It’s actually Greg Wade here this morning. Two questions, could you help us understand the combination work you’ve done with colorectal cancer tumors preclinically and then Tom what you need to see in the colorectal cancer setting to either prove that adjuvant might be an opportunity there or disprove that? Thanks.

Anthony S. Marucci

Sure, so the model we run which is a CT 26 model which we previously published, we see very good single agent activity when we treat relatively early after challenging the animals with the tumor. We were interested if as team with other immune modulatory antibodies if you delay treatment until tumors are actually actively growing to significant size. We typically don’t see single agent activity in those models and so that’s a setting which we use to look at different combination, it’s really our initial study and looking at check point blockade or even combination with chemotherapy.

So we haven’t had a chance to optimize the regimen. But essentially provided these agent in sort of an overlapping fashion and we are very pleased to see that even in these aggressive tumor models we could drive tumor regression in at least some of the animals. The goal now would be to see whether or not there is a different outcome whether we change the regimen as you can imagine there is the rationale for looking at different types of regimens in terms of when to start one type of therapy versus the other.

And your second question, I still don’t understand what you’re asking here, what we will need to see in colorectal cancer to think it is worth pursuing. Clearly any shrinkage in refractory patients is promising and hence we certainly would like to consider treating more colorectal cancer patients, trying to move earlier in disease course in patients with measurable disease where we can evaluate the response rate will be important. Ultimately, however it may have the potential to work very well in the adjuvant setting, patients who have little to no residual disease where we could potentially clear all disease or at least reduce to a level where they have a much longer progression [free] survival.

I think just one response that we’ve seen on this trial is quite notable and the investigators certainly very interested in it as well. And it deserves great attention single agent. Ultimately, however we are still most excited about the potential combinations.

Gregory Wade – Wedbush PacGrow

Thank you.

Operator

Thank you. I am not showing any further questions at this time. I want to turn the call back over to Mr. Anthony Marucci for closing remarks.

Anthony S. Marucci

Thank you operator. First of all I would like to thank Dr. Sznol and Dr. Dhodapkar this morning for joining us and taking time out obviously out of their another busy clinical schedule. So, thank you both for joining us this morning. We are gratified that the immunotherapy space has moved to the forefront of cancer drug development. As we truly believe immunotherapy, especially targeted immunotherapy holds the key for long-term clinical benefits for patients.

We are excited to be participating in this space and look forward to keeping you updated as we advanced 1127 and other immunotherapeutic product candidates in our pipeline. We also encourage you to visit the scientific publication section of our website tomorrow morning. The posters will be hung up early tomorrow morning at the Cincy meeting. At which we will post a PDF on our website for your review.

At this time I’d like to thank you for your time and have a great day.

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