Expert Financial Analysis and Reporting

Overview

This report updates my investment thinking on Celldex and also provides a brief overview of its two late stage products. Rentega (rindopepimut) is a peptide cancer vaccine in late stage development in both recurrent glioblastoma (rGBM) and newly diagnosed glioblastoma multiforme ndGBM) brain tumors that express the EGFRvIII mutation; it could be approved in 2H, 2016 for rGBM and in 2017 for ndGBM. Glembatumumab is a combination of an antibody that binds with the cancer antigen gpNMB; it is fused with a toxin that is then delivered internally to the cancer cell and kills it. The first disease target is triple negative breast cancer, which is a severe form of breast cancer that has no effective therapies. It could be approved in 2017 if the current phase 2b METRIC trial is successful.

Celldex also has a highly prolific technology platform that has three other immuno-oncology products in phase 1/2 development and another in pre-clinical. There are likely to be other new products beyond these as the technology platform could give rise to one or two new products per year. These products are all very novel immuno-oncology products, but have not established proof of concept.

I have not tried to come up with sales or earnings estimates for Celldex in this report. Even with Rentega and glembatumumab, there is not enough data to define their clinical profile and begin to come up with sales estimates; this is even more the case with the four earlier stage compounds. Success with two or even one of these six products could potentially support the current valuation, but on the other hand it could be the case that most or all of these products fail to become commercial products.

There is a great deal of potential value in Celldex. Indeed I would not be surprised to see the Company acquired in the next three years or so by a larger biopharma company that needs to build a position in immuno-oncology. However, I am hard pressed to put a valuation on the Company. I think that the price behavior until 2016 and 2017, when we have a better perspective on the potential for Rentega and glembatumumab and perhaps a view into the promise of the earlier stage drugs. Until then stock price behavior is likely to be a function of the trend for biotechnology stocks as a group and clinical data for the six products in development.

Potential Catalysts for the Stock

I can see only one important catalyst in 2015; that is the final analysis of the Rentega data in rGBM. The year 2016 is then heavy with catalysts.

• mid-2015 The final results in the phase 2 trial of Rentega (rindopepimut) in rGBM will be reported in mid-2015. I expect them to be somewhat better than the interim results which led to the sharp upward price move in November 2014. This would lead investors to anticipate approval in rGBM.
• 2H, 2015 There could be interim efficacy analyses for the ACT IV trial of Rentega in ndGBM in mid-2015 and late 2015. Stopping the trial for efficacy is highly unlikely and I think that the Data Monitoring Board will simply recommend that the trial continue. These are not important events.
• mid-2016 I think that US approval for Rentega in rGBM could be received in mid-2016. In previous reports, I have estimated that the rGBM market in the US for patients with the EGFRvIII mutation is about 600 patients. With an estimated price of $100,000 this is a $60 million addressable market in the US.
• mid-2016 The top line results for the ACT IV trial could be announced in mid-2016. If successful, this could lead to approval in 1H, 2017. The success in the presumably more difficult to treat rGBM patients has led many investors (including me) to believe the trial will be successful. I have estimated that the ndGBM market in the US for patients with the EGFRvIII mutation is about 3,600 patients. With an estimated price of $100,000 this is a $360 million addressable market in the US.
• 2H, 2016 Enrollment for glembatumumab in the METRIC trial in triple negative breast cancer could complete in 2016 with topline data available later in 2016 or early 2017. I have no estimates on the size of the triple negative, gpNMB positive breast cancer population. However, the breast cancer market is huge and glembatumumab addresses a segment of the market that has no effective therapy.

There could also be data releases on interim results in the various trials for the earlier stage drugs varlilumab, CDX-1401 and CDX-301 that could have an impact on the stock. However, the timing and importance of such data is difficult to predict.

Investment Thesis

My History with Celldex

I began coverage of Celldex with a report entitled Celldex: Pipeline Promise Has Been Embraced by Wall Street (CLDX, $22.79) on October 21, 2013 at a price of $22.79. This was an extensive report that focused on the Company’s promising pipeline. I liked the fundamentals at the time, but the stock had just had a sharp run-up in price and I decided to wait for an opportunity that hopefully would allow me to get into the stock at a better price.

The stock traded higher after my report, but then entered a long downtrend catalyzed by a correction in small biotechnology stocks, reaching $14 in November 2014. The price looked more attractive and this coincided with the emergence of a major catalyst when Celldex announced positive results of the phase 2 trial of Rentega (rindopepimut) in rGBM on November 14, 2014. In a report published on November 16, 2014, I upgraded Celldex to a buy.

The stock moved steadily higher to $20 or so and then on February 23, 2015 the Company announced that FDA had granted breakthrough status for Rentega. The stock quickly bounced to $24 and followed through to $29 where it now is. The difficult question investors are asking is what should be done with the stock now that it has doubled off the $14 level.

In this note, I look at key events that I believe will interact to determine the stock price over the next year. I am not buying the stock at these levels, but this should not be construed as a sell signal. This note gives an overview of those events and I urge you to read them before you decide what to do. Here are my thoughts on the stock.

Celldex Is a Leading Player in Immuno-oncology

Anyone who has read my reports knows that I am optimistic about immuno-oncology; this was the subject of my recent report Immuno-Oncology Promises to be the Next “Big Thing” In Biotechnology, Hence a quick view of Celldex’s positioning in immuno-oncology is the starting point for my discussion of the Company. This Company’s technology was largely spun out of Medarex. You may recall that the acquisition of Medarex propelled Bristol-Myers Squibb into a leadership position in the development of checkpoint modulators and with this a leadership position in immuno-oncology. Although a small company, Celldex has a strong technology pedigree and has used this to develop a broad pipeline that gives it the potential to be a leading player in immuno-oncology.

I am a layman with no expertise in molecular biology, but it has always struck me that harnessing the body’s immune system (immuno-oncology) to kill abnormal cells like cancer was a highly promising approach for developing new cancer therapies. The monoclonal antibody Rituxan, introduced in 1997, was the first blockbuster immuno-oncology drug. This has been followed by a number of other blockbuster monoclonal antibodies. Even now, nearly 30 years later, there are intense development efforts ongoing and more research dollars are spent by far on monoclonal antibody development than any other technology aimed at treating cancer. There is also a great deal of research using monoclonal antibodies to deliver a toxin, radioactive compound or other payloads that can kill cancer cells.

Prior to the introduction of the checkpoint inhibitor Yervoy by Bristol-Myers in 2011, most investors and large biopharm companies were skeptical on immuno-oncology other than monoclonal antibodies targeted at cancer antigens. In the case of checkpoint modulators, antibodies are used to block or activate specific checkpoints on T-cells. Promising clinical data has led to intense focus on checkpoint modulation. Immuno-oncology is also expanding (I could say exploding) with promising clinical data in checkpoint modulators, cancer vaccines, CAR-T cells, tumor infiltrating lymphocytes and there will be more to come.

Celldex Has Two Late Stage Immuno-oncology Drugs

Celldex is thoroughly enmeshed in the immuno-oncology gold rush. Its lead product is Rentega (rindopepimut), a peptide cancer vaccine. It is in advanced clinical trials in both recurrent glioblastoma (rGBM) and newly diagnosed glioblastoma (ndGBM). Very encouraging interim data from a phase 2 trial in rGBM looks like it will be sufficient for approval.

The topline results for in the phase 3 trial in ndGBM will be available in mid-2016 and the success in the much more difficult to treat rGBM patients would appear to augur well for its success. In the phase 3, Rentega targets GBM patients who have the EGFRvIII mutation that affects about 30% of the GBM population. (As a historical footnote, Pfizer originally licensed rindopepimut but returned it to Celldex in late 2010.)

The second product in advanced development is glembatumumab. This is an antibody that targets the glycoprotein gpNMB that is overly expressed on some cancer cells. This antibody is linked to a toxin which the antibody delivers internally to cancer cells and kills them. Phase 2 results from the EMERGE trial showed some exciting results in triple negative breast cancer which is an extremely aggressive form of breast cancer that has no approved or effective therapy. This is the disease target for the current phase 2b METRIC trial which could be the basis for regulatory approval if successful. Caution, EMERGE was a very small trial. Investors were excited with the EMERGE results in triple negative breast cancer. They also see the potential to expand usage to other forms of breast cancer and solid tumors that express gpNMB.

There is great hope that the Company can gain approval in triple negative breast cancer and then follow with entries into other forms of breast cancer and solid tumors. There is the hope that the phase 2b METRIC study now underway will be sufficient for approval. This trial ran into a stumbling block when the enrollment criteria proved to be so narrow as to slow enrollment. This was changed in November and the Company reports that the trial is now enrolling nicely and will likely report topline results in 2H-2016.

The Early Stage Pipeline is Very Promising

Late stage products generally drive a stock; these are drugs at phase 2b or later. Earlier stage products often don’t contribute much to stock value.  However, this may not be the case with Celldex, which has highlighted four products that are in human trials and one in pre-clinical. Like many other investors, I am extremely interested in these novel drugs:

• Varlilumab is both a checkpoint agonist (this is explained later) targeted at CD27 which appears on T-cells. However, CD-27 also is expressed on certain cancer cells. This provides a double barreled approach to treating some hematological and solid tumors.
• CDX-1401 is a fusion protein, one part of which is a fully human monoclonal antibody that targets the DCE-205 receptor on dendritic cells. This is linked to the NY-ESO-1 tumor antigen which has been detected in 20% - 30% of all melanoma, lung, esophageal, liver, gastric, prostate, ovarian and bladder cancers. CDX-1401 delivers the antigen to the dendritic cell with the purpose of creating a strong immune response against cancers that express NY-ESO-205.
• CDX-301 is a potent cytokine that stimulates the expansion of hematopoietic stem cells and dendritic cells. It was licensed from Amgen in March 2009. It has also demonstrated the ability to increase the number of circulating dendritic cells in both laboratory and clinical studies. It promises significant synergistic development opportunities in combination with drugs from Celldex and other companies.
• CDX-014 is new to the pipeline that is in pre-clinical studies. It is a fully human monoclonal drug conjugate that targets TIM-1. This is a molecule that is upregulated in clear cell cancers, including renal cell and ovarian carcinomas associated with kidney injury. TIM-1 has very restricted expression in healthy tissues, making it a promising target for antibody mediated therapy.

Looking At Biotechnology Stocks as a Group

Before I continue on the fundamental aspects as they pertain to Celldex, let me write a few words about the biotechnology group. An important issue to consider is that we are in a period of extreme enthusiasm for biotechnology stocks as they have been market leaders for the last several years. Some have said that we are in a biotechnology bubble. I am not smart enough to determine this and it is the case that the same people have been saying we are in a bubble for the last two years. However, I do recognize the risk of recommending stocks in a group that is hot. If something happens, to shift sentiment more in favor of other segments of the market we could see weakness in the group due to reallocation of investments away from biotechnology. All ships drop if the tide goes out.

Investment Conclusion on Celldex

The current market valuation of Celldex is $2.6 billion. Clearly, it is not an undiscovered stock. I am not sure that anyone can say exactly what the valuation should be of a company that is yet to have any sales; I know I can’t. Nevertheless, the valuation is richer than I would like.

Clearly, I am nervous about the biotechnology group as a whole. I dislike making price judgments on biotechnology stocks. I think this has caused a lot of investors to miss great price runs in some great companies which never seem to be cheaply priced at any time. Despite my trepidation at making price judgments, Celldex seems richly priced at the current market valuation.

What to Do with the Stock

So what should you do with the stock? That is up to you, but let me tell you what I would do. I think that Celldex is a strong participant in immuno-oncology which is a paradigm shifting technology. It is hard to tell who the big winners will be, but clearly Celldex is in the hunt and has the potential to be a big success on its own. More likely, in my opinion, it could be a takeover target within the next three years. There is potential for a big upside move even from these levels.

I am an investor and not a trader for the reason that I think that trading stocks is a losing game. There is a natural human tendency to be doing what the crowd is doing and the crowd is most bullish at the top and most bearish at the bottom. Put differently, I think that traders buy high and sell low. Moreover, they usually never get back into the stock at a lower level if they sell and almost always miss the spectacular long term appreciation that sometimes occurs with biotechnology.

I am focused on the long term and seldom try to catch trading moves. The result is that I sometimes go through painful downswings if I have the resolve that the long term potential is still there. Hence, I will not disturb my position even if, as is the case, I am a little nervous about the current stock price. Hence, I am holding on to my stock at these levels, but would not be buying.

Rentega (Rindopepimut) in Recurrent GBM

Design of the ReACT Trial

The phase 2 ReACT trial in recurrent glioblastoma was a randomized trial. There were two parts of the study, one in which enrolled patients had not received Avastin and one in which they had received Avastin. In both parts, Rentega plus Avastin was compared to Avastin alone. The results in the Avastin naive patients were strongly positive and will almost certainly be the basis for a potential regulatory filing. Results in Avastin experienced patients were equivocal and the Company will not follow-up with these types of patients.

Results for Avastin Naïve patients in ReACT. 

The Avastin naïve group within ReACT was not designed to be an approval study, but the results were surprisingly positive to the extent that regulatory approval based on the results is a strong possibility. Given the lack of treatment options, the FDA is likely to be responsive to the data. Avastin is the only drug approved in this indication and it was approved on the basis of objective response; there was no progression or survival benefit.

The primary endpoint was progression free survival at six months. In the interim analysis, the trial met this endpoint with a statistically significant p value of 0.048.  Very importantly, a clear benefit also was seen on the secondary endpoint of median overall survival. The median overall survival for Rentega was 12.0 months versus 8.8 months for the control arm for a difference in median overall survival on 3.2 months which had a p value of 0.02.

In a highly aggressive cancer like recurrent GBM, this is an impressive result. I would reiterate that the only other drug approved in this setting is Avastin and it has not shown a survival benefit. One of the most encouraging aspects that seem to occur with immunotherapies is that some patients experienced very long term survival; this is highly uncommon with chemotherapies and targeted therapies. Some percentage of Rentega responders appears to be experiencing a durable effect.

Results with ReACT are Not Final

There are still patients in both the Rentega and control arm who have not shown progression; importantly there are far more in the Rentega arm. In the Kaplan Meiers statistical analysis used in this trial, interim results are based on statistical handling of patients who have not progressed. There is a good possibity for change when all patients have progressed in both arms of the trial.

Kaplan Meiers uses a technique called censoring when final data on endpoints like progression free survival or overall survival has not been reached. In the event that some patients have not progressed or died, the time for this event is assumed to be at least as long as the time the patient has been in the study, Also, if the patient drops out of the study, the time at dropout is considered an event. The interim analysis used censored data so that as time goes on the actual time of occurrence of time to progression or death could be longer or perhaps shorter and this has the potential to change the results reported in the interim analysis. It is likely that trends in favor of Rentega will improve because more patients who have not actually had an event are in the Rentega group which appears so far to have better outcomes, but we can’t know for certain.

Celldex has arranged for a full expert interpretation for the primary endpoint of progression free survival at six months. They believe that they will have the final data set by mid-2015, including mature overall survival results. The data will be presented in peer-reviewed medical journals and meetings shortly thereafter.

Discussions with Regulators

Assuming the data remains consistent, Celldex then will have discussions with the FDA and EMA (the European equivalent of FDA). Management cautions that these discussions will take time and are not likely to be completed in a single meeting. The criteria for approval in Europe are somewhat different and it won't be until the completion of those discussions that the Company will really have an understanding of the likelihood for filing in Europe.

I would speculate that the Company is likely to file the NDA in 3Q, 2015. A normal review lasts 10 months, but I think that it could be given priority review and approved in six months. This suggests approval in mid-2016 for Rentega in rGBM.

Breakthrough Status

It was announced on February 23, 2015 that rindopepimut has been issued a breakthrough designation by the FDA for adult patients with EGFRvIII-positive, recurrent glioblastoma. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. In brief, this results in a more intensive FDA guidance, closer interactions with and directions from the agency including senior managers and eligibility for rolling review and priority review.

Preparing for Commercialization

Celldex is preparing a commercialization plan for Rentega in North America and Europe; they intend to market the drug with their own sales organization on both continents. They are bringing on new employees in product planning, marketing, sales, pricing and market access, business analytics, product distribution, companion diagnostics, information technology and senior executive leadership. This organization should number around 150 full time employees at the time of launch.

What is the Importance of Meeting the Primary Endpoint of Progression Free Survival at Six Months (PFS-6)?

There is some potential for the primary endpoint of progression free survival at six months to be worse than the p=0.048 seen at the interim look. As I mentioned earlier, I think that it is more likely that results will actually be better. However, biology and clinical trials can sometimes throw curveballs so some investors are asking what would happen if the p value moved higher than the p=0.05 that is the breakpoint below which the FDA considers the data as statistically significant.

From a clinical trial perspective, it is very important to meet the primary end point of a study. This is because the study is tied in with that data point. In designing ReACT, key opinion leaders recommended PFS-6 as the primary endpoint; probably because they thought that having positive results for overall survival benefit in rGBM would be difficult to achieve.

However, overall survival is the gold standard in virtually all cancer trials and it is a higher hurdle. It is close to impossible that this would slip to p ≥0.05. I think that in the event that PFS is not statistically significant but overall survival is that the drug would be approved. This is particularly true in rGBM where no drugs have been able to show a benefit in overall survival. Remember that Avastin was approved on the basis of higher objective response with no improvement in survival or progression.

Is Manufacturing Ready?

Celldex states that they have made a lot of progress with contractors for the commercial process in terms of having GMP issues resolved on the same timeline as filing the clinical data. They also think that they will be at commercial scale at the time of approval.

Rindopepimut in Newly Diagnosed GBM

ACT IV Study Design

The ACT IV study was designed to confirm the experience with Rentega in three prior Phase 2 studies in ndGBM. In those non-randomized studies, they saw a clinically significant survival benefit of up to six months in patients with minimal residual disease or small tumor burden after surgery. The ACT IV study is powered for a lesser three months improvement in survival.

The phase 3 ACT IV trial in ndGBM is much larger and comprehensive than the phase 2 ReACT trial in rGBM. Enrollment was completed in December 2014. They screened 4,800 patients for possible enrollment in 200 clinical sites in 22 countries. Management stated that about 30% of all patients screened had the EGFRvIII mutation which is 1,920 patients.

There were 745 patients enrolled in the trial. For the purpose of statistical analysis this was then reduced to 374 patients who also met the criteria for degree of resection/ minimal residual disease. The remaining 371 of the 745 enrolled will be evaluated but will not be part of the final analysis. These 371 will be evaluated for overall survival, progression free survival, safety and tolerability and quality of life. Celldex is trying to enroll the more fully resected and healthier patients for the study rather than taking all comers.

Timing of Interim and Final Analyses

The study is event driven with interim looks when 50% and 75% of events have occurred. The Data Monitoring Committee (DMC) will not provide interim data readouts on efficacy, but their timing may help to assess when final data can be expected. The hurdle is extremely high for early stoppage for efficacy and I don’t think investors should look for early stoppage of the trial for efficacy.

The first interim look is expected to occur in mid-2015, but because the trial is event driven this is only an estimate. A second interim analysis could be conducted roughly at the end of 2015 and the final analysis could come in mid-2016.

Glembatumumab Vedotin

Mechanism of Action

Glembatumumab is an antibody-drug conjugate that is comprised of a fully-human monoclonal antibody CR011 that is linked to a potent cell-killing drug, monomethyl-auristatin E, or MMAE. The CR011 antibody specifically targets glycoprotein NMB (gpNMB) that is over-expressed in a variety of cancers including breast cancer and melanoma. Following intravenous administration, the configuration is stable in the bloodstream. It then binds to gpNMB and internalizes into the cell where the MMAE is released and kills the cell.

Clinical Trial-METRIC Study

The FDA has granted Fast Track designation to glembatumumab vedotin for the treatment of advanced, refractory/resistant gpNMB-expressing breast cancer. The phase 2b METRIC study was originally designed to obtain accelerated approval. However, the enrollment criteria limited the ability of investigators to enroll patients. In addition, it was not clinically appropriate for European regulatory approval. Because of this, in the fourth quarter of 2014, Celldex amended the METRIC study and expanded patient entry criteria to position it for full marketing approval with global regulators, including the EMA, and to support improved enrollment in the study.

Celldex will target negative gpNMB positive patients in METRIC and this is intended to support registration if the results are positive. The planned enrollment size is 300. The primary endpoint of the study is PFS which they believe is appropriate as a primary endpoint in triple negative breast cancer. Overall survival is a secondary endpoint.

Both the FDA and central European regulatory authorities have reviewed the protocol design and Celldex believes the METRIC study could support marketing approval in both the US and. Based on current projections, Celldex believes enrollment will be completed in 2016. As a guess, I think that an NDA could be filed in 1H, 2017. Assuming priority review, approval could be received in late 2017 or early 2018. METRIC will be followed by a phase 3 study in all breast cancer patients expressing gpNMB.

Clinical Results

The phase 1/2 EMERGE study reported final results in December 2012. EMERGE was a randomized, multi-center study of glembatumumab in 122 patients with heavily pre-treated, advanced breast cancer; these patients had seen on average six previous treatment regimens. Patients selected for the study had to be gpNMB positive. Two thirds of patients were given glembatumumab and one third was given the investigator’s choice of therapy (IC). Patients given IC were allowed to cross over to glembatumumab if their disease progressed.

Upon final analysis, there were two groups in the study that were of particular significance. The first group was 33 patients who had overexpression of gpNMB. This was determined by their having 25% of their tumor cells express gpNMB. Of these 33 patients, 25 received glembatumumab and 8 received IC. The response rate in the glembatumumab group was 32% versus 13% in IC, median progression free survival was 2.7 months versus 1.5 months and median overall survival was 10.0 months versus 5.7 months.

In a second group, there were 16 patients in who had overexpression of gpNMB and were also triple negative and 12 of these received glembatumumab and 4 received IC. The response rate in the glembatumumab group was 33% versus 0% in IC, median progression free survival was 3.0 months versus 1.5 months, and median overall survival was 10.0 months versus 5.5 months. The data showed a substantially better response rate in patients with gpNMB over expression in 25% of tumor cells and in triple negative with positive gpNMB expressing breast cancer patients although the number of patients in each group was small.

As the expression rate increased there was a correlation of gpNMB expression with more shrinking of tumors and improving survival. However, they saw benefit in patients with a level of 10% gpNMB expression. The most frequent treatment-related adverse events were rash, fatigue, hair loss, pruritus, diarrhea and neuropathy. Of these neuropathy is the most troubling. In the study they saw that patients with pre-existing neuropathy experienced exacerbation. Hence, this is being screened for in the phase 3 trial and such patients will be excluded.

Key opinion leaders were impressed by the response rate in such a heavily treated group and approximate doubling in progression free survival and median overall survival. The principal criticism was the small number of patients in the study, but even with small numbers, a statistically significant benefit was seen in median overall survival in high gpNMB expression-triple negative group.

Varlilumab

Mechanism of Action

Varlilumab is a human monoclonal antibody that targets CD27; it is a checkpoint modulator that regulates the activity of T-cells. Investors are widely aware of checkpoint inhibitors like Yervoy (targets the checkpoint CTLA-4), Opdivo (targets PD-1) and Keytruda (targets PD-1). Some cancers have evolved the ability to produce proteins that activate PD-1 or CTLA-4 on T-cells. This turns down the activity of that T-cell against the tumor, which has the effect of putting the brakes on the immune system.

These three products are antibodies that bind to and block these receptors without activating them which essentially takes the brake off. Varlilumab binds with the CD27 receptor on a T-cell and activates a response of the T-cell to cancer. It has the effect of enhancing the T-cell response or as it is often described, puts the foot on the immune system accelerator. Both checkpoint inhibitors and agonists have the effect of enhancing the response of the immune system against cancer. It is logical to assume that varlilumab might be synergistic with Yervoy, Opdivo and Keytruda and certain other cancer therapies.

In addition to checkpoint modulation, varlilumab has an additional mechanism of action against cancer. CD27 is expressed on certain hematological and solid tumors. Virilumab acts in the same conventional, anti-cancer manner as other monoclonal agents against cancer cells expressing CD27.

Clinical Trial Results

Celldex is conducting an open label phase 1 study in patients with selected malignant solid tumors or hematologic cancers at multiple clinical sites in the United States. A total of 55 patients have been dosed in dose escalation cohorts in various solid and hematologic B-cell tumors. Another 31 have been dosed in expansion cohorts for melanoma and renal cell carcinoma. Side effects have been comparable to those seen with check-point blockade.

Data was presented in November 2014 that showed that it was well tolerated and produced effects as expected from its mechanism of action. Encouraging results seen thus far were:

• Two patients experienced objective responses including a complete response in Hodgkin’s lymphoma and a partial response occurred in renal cell carcinoma.
• Thirteen patients experienced stable disease with a range of 3-30.7+ months to-date.

Based on these results, an expansion cohort was added to enroll up to 15 patients with Hodgkin’s lymphoma and an abbreviated dose escalation in T cell hematologic malignancies is ongoing.

Collaborations

In May 2014, they entered into collaboration with Bristol-Myers to study varlilumab in combination with Opdivo. The Companies will share development expenses with Celldex being responsible for running a phase 1/2 study begun in January 2015 in adult patients with advanced non-small cell lung cancer, metastatic melanoma, colorectal cancer, ovarian cancer, and head and neck squamous cell carcinoma.

In May 2014, they also entered into clinical trial collaboration with Oncothyreon to evaluate the ONT-10 cancer vaccine of that company in combination with varlilumab. A phase 1 b study was started in November 2014 that will be conducted by Oncothyreon. This will be conducted in 42 patients with either advanced breast or ovarian cancer.

On March 17, 2015 Celldex announced today that it has entered into clinical trial collaboration with Roche to evaluate varlilumab in combination with Roche’s investigational antibody MPDL3280A; the latter is an antibody against the ligand for PD-1 (anti-PDL1). The Roche drug is in a Phase 1/2 study in renal cell carcinoma. Preclinical data suggest the combination of these two mechanisms is synergistic. In Celldex's Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory renal cell carcinoma were observed. Under the terms of this agreement, Roche will provide study drug and Celldex will be responsible for conducting and funding the study, which is expected to begin in 2015.

The Company is also finalizing designs of phase 2 studies that combine varlilumab with:

• Yervoy in metastatic melanoma,
• CDX-1401 in tumors that express NY-ESO positive,
• sunitinib in renal cell carcinoma,
• mek pathway agent (followed sequentially by a checkpoint inhibitor) for patients with B-raf mutated metastatic melanoma.
• investigator sponsored studies at various academic institutions.

CDX-1401

Mechanism of Action

CDX-1401 is a fusion protein, one part of which is a fully human monoclonal antibody that targets the DCE-205 receptor on dendritic cells. This is linked to the NY-ESO-1 tumor antigen which has been detected in 20% - 30% of all melanoma, lung, esophageal, liver, gastric, prostate, ovarian and bladder cancers. CDX-1401 delivers the antigen to the dendritic cell with the purpose of creating a strong immune response against cancers that express NY-ESO-205.

Clinical Trials

Celldex has completed a phase 1 trial aimed at assessing safety, immunogenicity and clinical activity of escalating doses of CDX-1401 with TLR agonists (resiquimod and/or Poly ICLC). The phase 1 trial was enrolled 45 patients with advanced cancers that were refractory to all available therapies. Of these patients, 60% had confirmed NY-ESO expression so that there was some potential to see an efficacy signal.

Based on signals from the phase 1 trial, CDX-1401 is being targeted for the treatment of malignant melanoma and a variety of solid tumors which express the proprietary cancer antigen NY-ESO-1. The following trials are planned or beginning to enroll.

• An NCI-sponsored Phase 2 study of CDX-1401 and CDX-301 in patients with metastatic melanoma.
• A phase 1/2 study of CDX-1401 and an IDO inhibitor in patients with NY-ESO-1 positive ovarian cancer.
• Additional studies are slated in 2015, including Celldex-sponsored studies in combination with virilumab and Yervoy. The inclusion of CDX-1401 in this study is based on published data showing an increased response to checkpoint inhibitors if patients had a preexisting immune response to NY-ESO.
• In addition to Celldex sponsored studies, there will CDX-1401 trials in investigator sponsored studies at academic centers.

Clinical Trial Results

In the phase 1 trial, 13 patients maintained stable disease for up to 13.4 months with a median of 6.7 months. Treatment was well-tolerated and there were no dose limiting toxicities. Encouraging B-cell and T-cell responses were seen. Follow-up over a period of time suggested that exposure to CDX-1401 could result in better outcomes in metastatic melanoma when patients later received the checkpoint inhibitor ipilimumab. The strong immune response generated CDX-1401 may predispose patients to better response to checkpoint blockade. This resulted in the phase 2 trial just mentioned.

CDX-301

Mechanism of Action

CDX-301 is a potent cytokine that stimulates the expansion of hematopoietic stem cells and dendritic cells. It was licensed from Amgen in March 2009. It has also demonstrated the ability to increase the number of circulating dendritic cells in both laboratory and clinical studies. It promises significant synergistic development opportunities in combination with drugs from Celldex and other companies.

Clinical Trials

There are a number of interesting ongoing trials:

• The previously mentioned NCI-sponsored Phase 2 study of CDX-1401 and CDX-301 in patients with metastatic melanoma,
• a pilot clinical study of CDX-301 for the mobilization and transplantation of allogeneic hematopoietic stem cells in patients with hematological malignancies undergoing hematopoietic stem cell transplantation. The study will explore the study CDX-301 alone and in combination with Mozobil.
• an investigator-sponsored Phase 1/2 study that involves intratumoral injection of CDX-301 in combination with low-dose radiotherapy for patients with low-grade B-cell lymphomas.
• Celldex anticipates a number of investigator sponsored studies at various academic institutions.

Clinical Trials Results

In February 2013, Celldex announced final results from a dose-escalating Phase 1 study of CDX-301 in 30 healthy subjects in collaboration with Rockefeller University. The Phase 1 study evaluated seven different dosing regimens of CDX-301 to determine the appropriate dose for further development based on safety, tolerability, and biological activity. CDX-301 was shown to be well-tolerated and to effectively mobilize hematopoietic stem cell populations in healthy volunteers.

CDX-014

Mechanism of Action

This is new to the pipeline that is in pre-clinical studies. It is a fully human monoclonal drug conjugate that targets TIM-1. This is a molecule that is upregulated in clear cell cancers, including renal cell and ovarian carcinomas associated with kidney injury. TIM-1 has very restricted expression in healthy tissues, making it a promising target for antibody mediated therapy.

Clinical Trials

They are completing manufacturing in IND enabling studies to support the initiation of Phase 1 clinical studies in renal cell carcinoma and potentially other TIM-1 expressing tumors in 2016.

 

Tagged as Celldex Therapeutics, CLDX, glembatumumab, Rindopepimut, varlilumab + Categorized as Company Reports