CLDX: Celldex Therapeutics Analysis and Research Report
2018-03-10 - by Asif , Contributing Analyst - 89 views
Celldex Therapeutics, Inc., which is a biopharmaceutical company focused on the development and commercialization of several immunotherapy technologies and other cancer-targeting biologics. The company's drug candidates, including antibodies, antibody-drug conjugates and other protein-based therapeutics, are derived from a broad set of complementary technologies which have the ability to engage the human immune system and/or directly inhibit tumors to treat specific types of cancer or other diseases.
The company's latest stage drug candidate, glembatumumab vedotin (also referred to as CDX-011) is a targeted antibody-drug conjugate in a randomized, Phase 2b study for the treatment of triple negative breast cancer and a Phase 2 study for the treatment of metastatic melanoma. Varlilumab (also referred to as CDX-1127) is an immune modulating antibody that is designed to enhance a patient's immune response against cancer. The company established proof of principle in a Phase 1 study with varlilumab, which supported the initiation of combination studies in various indications. CDX-3379, a human monoclonal antibody designed to block the activity of ErbB3 (HER3), is in Phase 2 development in combination with cetuximab for the treatment of head and neck squamous cell carcinoma. The company also have a number of earlier stage drug candidates in clinical development, including CDX-014, an antibody-drug conjugate targeting renal and ovarian cancers; CDX-1140, a human monoclonal antibody targeted to CD40, a key activator of immune response; CDX-301, an immune cell mobilizing agent and dendritic cell growth factor; and CDX-1401, a targeted immunotherapeutic aimed at antigen presenting cells, or APCs, for cancer indications. The company's drug candidates address market opportunities for which the company believe current therapies are inadequate or non-existent.
Celldex Therapeutics is building a fully integrated, commercial-stage biopharmaceutical company that develops important therapies for patients with unmet medical needs. The company's program assets provide it with the strategic options to either retain full economic rights to its innovative therapies or seek favorable economic terms through advantageous commercial partnerships. This approach allows it to maximize the overall value of its technology and product portfolio while best ensuring the expeditious development of each individual product.
Clinical Development Programs
Glembatumumab vedotin is an antibody-drug conjugate, or ADC, that consists of a fully human monoclonal antibody, CR011, linked to a potent cell-killing drug, monomethyl auristatin E, or MMAE. The CR011 antibody specifically targets glycoprotein NMB, referred to as gpNMB, that is over-expressed in a variety of cancers including breast cancer, melanoma, non-small cell lung cancer, uveal melanoma and osteosarcoma, among others. The ADC technology, comprised of MMAE and a stable linker system for attaching it to CR011, was licensed from Seattle Genetics, Inc. and is the same as that used in the marketed product Adcetris®. The ADC is designed to be stable in the bloodstream. Following intravenous administration, glembatumumab vedotin targets and binds to gpNMB, and upon internalization into the targeted cell, glembatumumab vedotin is designed to release MMAE from CR011 to produce a cell-killing effect. Glembatumumab vedotin is being studied across multiple indications in company-sponsored trials and in collaborative studies with external parties. The U.S. Food and Drug Administration, or FDA, has granted fast track designation to glembatumumab vedotin for the treatment of advanced, refractory/resistant gpNMB-expressing breast cancer. A companion diagnostic is in development for certain indications, and the company expect that, if necessary, such a companion diagnostic must be approved by the FDA or certain other foreign regulatory agencies before glembatumumab vedotin may be commercialized in those indications.
Treatment of Metastatic Breast Cancer: Glembatumumab vedotin has been evaluated for the treatment of metastatic breast cancer (MBC) in multiple studies including a single-arm Phase 1/2 study (Journal of Clinical Oncology, September 2014); a randomized, controlled Phase 2b study compared to Investigator's Choice chemotherapy in patients with gpNMB-positive MBC called EMERGE (Journal of Clinical Oncology, April 2015); and the ongoing randomized, controlled Phase 2b study in patients with triple negative, gpNMB overexpressing breast cancer, called METRIC. The company expect to report topline primary endpoint data from the METRIC study during the second quarter of 2018.
The most recent data presented for glembatumumab vedotin in breast cancer are from the EMERGE study, the randomized, multi-center Phase 2b study in 124 patients with heavily pre-treated, advanced, gpNMB-positive breast cancer. Patients were randomized (2:1) to receive either glembatumumab vedotin or single-agent Investigator's Choice chemotherapy. Patients randomized to receive Investigator's Choice were allowed to cross over to receive glembatumumab vedotin following disease progression. Activity endpoints included response rate, progression-free survival (PFS) and overall survival (OS). The final study results, as shown below, suggested that glembatumumab vedotin induced significant response rates compared to currently available therapies in patient subsets with advanced, refractory breast cancers with high gpNMB expression (expression in at least 25% of tumor cells) and in patients with triple negative breast cancer. The OS and PFS of patients treated with glembatumumab vedotin were also observed to be greatest in patients with high gpNMB expression and, in particular, in patients with triple negative breast cancer who also had high gpNMB expression. Adverse events prominent with the glembatumumab vedotin arm included rash and peripheral neuropathy, while hematologic toxicity was more frequent and severe in the Investigator's Choice arm.
In December 2013, the company initiated METRIC, a randomized, controlled (2:1) Phase 2b study of glembatumumab vedotin versus Xeloda® in patients with triple negative breast cancer that over-expresses gpNMB. Clinical trial study sites were opened to enrollment across the U.S., Canada, Australia and the European Union. The METRIC protocol was amended in late 2014 based on feedback from clinical investigators conducting the study that the eligibility criteria for study entry were limiting their ability to enroll patients they felt were clinically appropriate. In addition, the company had spoken to country-specific members of the European Medicines Agency, or EMA, and believed an opportunity existed to expand the study into the EU. The amendment expanded patient entry criteria to position it for the possibility of full marketing approval with global regulators, including the EMA, and to support improved enrollment in the study. The primary endpoint of the study is PFS, defined as the time from randomization to the earlier of disease progression or death due to any cause. PFS is an established endpoint for full approval registration studies in this patient population in both the U.S. and the EU. The sample size (n=300) and the secondary endpoint of OS remained unchanged. Since implementation of these changes, both the FDA and central European regulatory authorities have reviewed the protocol design, and the company believe the METRIC study could potentially support marketing approval in both the U.S. and Europe dependent upon data results and review.
Enrollment (n=327) in METRIC was completed in August 2017. The study calls for 203 progression events for evaluation of the primary endpoint, which will be assessed based on an independent, central reading of patient scans. The sum of the data, including the secondary endpoints of response rate, OS, DOR and safety, will be important in assessing clinical benefit. Based on the current rate of progression events in the study, the Company projects that topline primary endpoint data should be available in the second quarter of 2018.
Efforts to ensure delivery of manufactured drug that is ready for commercialization and a companion diagnostic are underway. While Celldex Therapeutics has made and continue to make progress on these fronts, Celldex Therapeutics has made the decision to stage some of the more costly work in these areas to begin after Celldex Therapeutics has received results from the study. While this step will extend the timeline to complete its regulatory submissions, the company believe this is the most prudent use of its funds as the company seek to advance its pipeline overall. Assuming positive data, the company plan to work with the FDA on a regulatory strategy that would support submitting a Biologics License Application (BLA) in the second half of 2019.
Treatment of Metastatic Melanoma: Glembatumumab vedotin has been evaluated for the treatment of unresectable stage III or IV metastatic melanoma in two studies including a single-arm Phase 1/2 open-label study and an ongoing multi-cohort Phase 2 study. Results from the Phase 1/2 study were published in the Journal of Clinical Oncology in September 2014.
The most recent data for glembatumumab vedotin in metastatic melanoma are from the ongoing Phase 2 study. This study currently includes four single arm cohorts: (1) a single-agent cohort (enrollment completed; data presented at ASCO 2017), (2) a combination cohort with varlilumab (enrollment completed; data presented at SITC 2017), (3) a combination cohort with an approved checkpoint inhibitor (i.e., Opdivo® or Keytruda®) following progression on the checkpoint inhibitor alone (enrollment completed; follow-up continues), and (4) a combination cohort with CDX-301 (enrollment ongoing).
The primary endpoint for each cohort is ORR, except the fourth cohort which is assessing safety and tolerability in anticipation of additional combinations. Secondary endpoints include analyses of PFS, DOR, OS, retrospective investigation of whether the anticancer activity of glembatumumab vedotin is dependent upon the degree of gpNMB expression in tumor tissue and safety of both the monotherapy and combination regimens.
The company presented mature data from the single-agent cohort in an oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2017. The cohort enrolled 62 evaluable patients with unresectable stage IV melanoma. All patients had been heavily pre-treated (median prior therapies = 3; range 1-8) and had progressed during or after checkpoint inhibitor therapy, and almost all patients had received both ipilimumab (n=58; 94%) and anti-PD-1/anti-PD-L1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and fifteen had prior treatment with BRAF or BRAF/MEK targeted agents. Median OS for all patients was 9.0 months (95% CI: 6.1, 13.0). The primary endpoint of the cohort (threshold of 6 or more objective responses in 52 evaluable patients) was exceeded. 7 of 62 (11%) patients experienced a confirmed response. One patient experienced a complete response (CR), and six patients experienced partial responses (PR). An additional three patients also experienced single timepoint PRs. The median DOR was 6.0 months. A 52% disease control rate (patients without progression for greater than three months) was demonstrated, and median PFS for all patients was 4.4 months. Consistent with previous studies in melanoma and breast cancer, early development of rash was associated with greater clinical benefit, including more prolonged PFS and OS. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia and neuropathy experienced as the most significant adverse events. Pre-treatment tumor tissue was available for 59 patients. All samples were gpNMB positive, and 78% of patients had tumors with 100% of their epithelial cells expressing gpNMB. Given both the high level of expression and the intensity of expression across this patient population, identifying a potential population for gpNMB enrichment is not feasible; therefore, all patients with metastatic melanoma could be evaluated as potential candidates for treatment with glembatumumab vedotin in future studies.
Data from the second cohort, combining glembatumumab vedotin and varlilumab, were presented at the Society for Immunotherapy of Cancer's (SITC) 32nd Annual Meeting in November 2017. The cohort enrolled 34 patients with unresectable stage IV melanoma. All patients had been heavily pre-treated (median prior therapies = 3; range 1-8) and had progressed during or after checkpoint inhibitor (CPI) therapy (median prior CPI therapies = 2; range 1-4). Almost all patients had received ipilimumab (n=26; 76%) and/or anti-PD-1/anti-PD-L1 (n=34; 100%) therapy. Nine patients presented with BRAF mutation, and eleven had prior treatment with BRAF or BRAF/MEK targeted agents. Median PFS for all patients was 2.6 months (95% CI: 1.4, 2.8), and median OS for all patients was 6.4 months (95% CI: 3.2, 8.3). One of 31 patients eligible for response evaluation experienced a confirmed partial response (3%), and an additional two patients also experienced single timepoint partial responses. 52% of patients experienced stable disease (minimum of six or more weeks). A 19% disease control rate (patients without progression for greater than three months) was demonstrated. The safety profile was consistent with prior studies of glembatumumab vedotin, and there was no evidence of additive toxicity associated with the combination. Biological effects of varlilumab were consistent with prior observations and did not appear to be impacted by the addition of an ADC. Modest clinical benefit in the combination could be due to multiple factors, including potential lack of sensitivity to immunotherapy in patients with checkpoint refractory disease, many of whom progressed so rapidly that they experienced a very short duration of varlilumab treatment (median 2 doses); a possible dearth of antigen presenting cells in tumors; and the potential for immune checkpoint molecules to remain unblocked without checkpoint inhibitor therapy. Future cohorts are designed to address some of these potential factors. No significant correlation between rash and outcome was observed but will continue to be monitored in future cohorts.
Treatment of Other Indications: Celldex Therapeutics has entered into a collaborative relationship with PrECOG, LLC, which represents a research network established by the Eastern Cooperative Oncology Group (ECOG), under which PrECOG, LLC, is conducting an open-label Phase 1/2 study in patients with unresectable stage IIIB or IV, gpNMB-expressing, advanced or metastatic squamous cell carcinoma (SCC) of the lung, who have progressed on prior platinum-based chemotherapy. This study opened to enrollment in April 2016 and is ongoing. The study includes a dose-escalation phase followed by a two-stage Phase 2 portion (Simon two-stage design). The Phase 1, dose-escalation portion of the study is designed to assess the safety and tolerability of glembatumumab vedotin at varying dose levels. The first stage of the Phase 2 portion plans to enroll approximately 20 patients, and if at least two patients achieve a partial response or complete response, a second stage may enroll an additional 15 patients. The primary objective of the Phase 2 portion of the study is to assess the anti-tumor activity of glembatumumab vedotin in squamous cell lung cancer as measured by ORR. Secondary objectives of the study include analyses of safety and tolerability and further assessment of anti-tumor activity across a broad range of endpoints.
Celldex Therapeutics has also entered into a Cooperative Research and Development Agreement, or CRADA, with the National Cancer Institute, or NCI, under which NCI is sponsoring a Phase 2 study of glembatumumab vedotin in uveal melanoma. The study is a single-arm, open-label study in patients with locally recurrent or metastatic uveal melanoma. The study has a two-stage design with a pre-specified activity threshold necessary in the first stage to progress enrollment to the second stage. The primary outcome measure is ORR. Secondary outcome measures include change in gpNMB expression on tumor tissue via immunohistochemistry, safety, OS and PFS. Data from this study were presented at the 9th World Congress of Melanoma in October 2017. Two (6%) objective responses were observed in 31 patients to date, and 35% of patients experienced stable disease greater than 100 days (median 5.5 months). The disease control rate (response rate + stable disease) for all patients on study was noteworthy at 61%. Median PFS was 3.2 months, and median OS was 11.8 months. For patients who experienced either a partial response or stable disease, median PFS was 5.5 months, and median OS had not yet been reached. The NCI is conducting exploratory immune correlates to provide insight into target saturation, antigen release and potential combination strategies.
Varlilumab is a fully human monoclonal agonist antibody that binds to and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. The company believe varlilumab works primarily by stimulating T cells, an important component of a person's immune system, to attack cancer cells. Restricted expression and regulation of CD27 enables varlilumab specifically to activate T cells, resulting in an enhanced immune response with the potential for a favorable safety profile. In preclinical studies, varlilumab has been shown to directly kill or inhibit the growth of CD27 expressing lymphomas and leukemias in in vitro and in vivo models. Celldex Therapeutics has entered into license agreements with the University of Southampton, UK for intellectual property to use anti-CD27 antibodies and with Medarex (acquired by Bristol-Myers Squibb Company, or BMS) for access to the UltiMab technology to develop and commercialize human antibodies to CD27. Varlilumab was initially studied as a single-agent to establish a safety profile and assess immunologic and clinical activity in patients with cancer, but the company believe the greatest opportunity for varlilumab is as an immune activator in combination with other agents. Currently, Celldex Therapeutics is focusing its efforts on a Phase 1/2 clinical trial being conducted in collaboration with BMS and their PD-1 immune checkpoint inhibitor, Opdivo. Varlilumab has also been explored in other combination studies, including with glembatumumab vedotin, and is being studied in ongoing and planned investigator-sponsored and collaborative studies.
Single-Agent Phase 1 Study: In an open-label Phase 1 study of varlilumab in patients with selected malignant solid tumors or hematologic cancers, varlilumab demonstrated an acceptable safety profile and induced immunologic activity in patients that is consistent with both its proposed mechanism of action and data in preclinical models. A total of 90 patients were dosed in the study at multiple clinical sites in the U.S. In both the solid tumor and hematologic dose escalations, the pre-specified maximum dose level (10 mg/kg) was reached without identification of a maximum tolerated dose (MTD). The majority of adverse events, or AEs, related to treatment have been mild to moderate (Grade 1/2) in severity, and no significant immune-mediated adverse events typically associated with checkpoint blockade have been observed. Durable, multi-year clinical benefit was demonstrated in select patients without additional anticancer therapy, including a complete response in a patient with Hodgkin lymphoma (ongoing at last follow-up at 2.8 years) and a partial response in a patient with renal cell carcinoma (ongoing at last follow-up at 3.7 years). In addition, a patient with renal cell carcinoma that experienced significant stable disease (4+ years) subsequently achieved a partial response maintained through last follow-up at 4.6+ years without additional anticancer therapy. Twelve patients experienced stable disease up to 14 months. Final results from the study in patients with solid tumors were published in the Journal of Clinical Oncology in April 2017.
Phase 1/2 Varlilumab/Opdivo® Combination Study: In 2014, the company entered into a clinical trial collaboration with Bristol-Myers Squibb to evaluate the safety, tolerability and preliminary efficacy of varlilumab and Opdivo, Bristol-Myers Squibb's PD-1 immune checkpoint inhibitor, in a Phase 1/2 study. Under the terms of this clinical trial collaboration, Bristol-Myers Squibb made a one-time payment to it of $5.0 million, and the companies amended the terms of its existing license agreement with Medarex (acquired by Bristol-Myers Squibb) related to its CD27 program whereby certain future milestone payments were waived and future royalty rates were reduced that may have been due from it to Medarex. In return, Bristol-Myers Squibb was granted a time-limited right of first negotiation if the company wish to out-license varlilumab. The companies also agreed to work exclusively with each other to explore anti-PD-1 antagonist antibody and anti-CD27 agonist antibody combination regimens. The clinical trial collaboration provides that the companies will share development costs and that the company will be responsible for conducting the Phase 1/2 study.
The Phase 1/2 study was initiated in January 2015 and is being conducted in adult patients with multiple solid tumors to assess the safety and tolerability of varlilumab at varying doses when administered with Opdivo, followed by a Phase 2 expansion to evaluate the activity of the combination in disease specific cohorts.
Data (n=36) from the Phase 1 dose-escalation portion of the study were presented in an oral presentation at the American Society of Clinical Oncology Annual Meeting in June 2017. The majority of patients had PD-L1 negative tumor at baseline and presented with stage IV, heavily pre-treated disease. 80% of patients enrolled presented with refractory or recurrent colorectal (n=21) or ovarian cancer (n=8), a population expected to have minimal response to checkpoint blockade. The primary objective of the Phase 1 portion of the study was to evaluate the safety and tolerability of the combination. The combination was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation. Marked changes in the tumor microenvironment including increased infiltrating CD8+ T cells and increased PD-L1 expression, which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies, were observed. Additional evidence of immune activity, such as increase in inflammatory chemokines and decrease in T regulatory cells, was also noted. Notable disease control was also observed (stable disease or better for at least 3 months), considering the stage IV patient population contained mostly (80%) colorectal and ovarian cases: 0.1 mg/kg varlilumab + 240 mg Opdivo: 1/5 (20%), 1 mg/kg varlilumab + 240 mg Opdivo: 5/15 (33%) and 10 mg/kg varlilumab + 240 mg Opdivo: 6/15 (40%).
Three partial responses (PR) were observed. A patient with PD-L1 negative, MMR proficient (MSI-low) colorectal cancer, typically unlikely to respond to checkpoint blockade monotherapy, achieved a confirmed PR (95% decrease in target lesions) and, following completion of combination treatment, continues to receive treatment with Opdivo monotherapy at 31+ months. A patient with low PD-L1 (5% expression) squamous cell head and neck cancer achieved a confirmed PR (59% shrinkage) and experienced PFS of 6.7 months. A patient with PD-L1 negative ovarian cancer experienced a single timepoint PR (49% shrinkage) but discontinued treatment to a dose-limiting toxicity (immune hepatitis, an event known to be associated with checkpoint inhibition therapy). A subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of PD-L1 and tumor-infiltrating lymphocytes in this patient population. In patients with paired baseline and on-treatment biopsies (n=13), only 15% were PD-L1 positive (³ 1% tumor cells) at baseline compared to 77% during treatment (p=0.015). Patients with increased tumor PD-L1 expression and tumor CD8 T cells correlated with better clinical outcome with treatment (stable disease or better).
The Phase 2 portion of the study opened to enrollment in April 2016 and completed enrollment in January 2018 with cohorts in colorectal cancer (n=21), ovarian cancer (n=58), head and neck squamous cell carcinoma (n=24), renal cell carcinoma (n=14) and glioblastoma (n=22). The primary objective of the Phase 2 cohorts is ORR, except glioblastoma, where the primary objective is the rate of 12-month OS. Secondary objectives include pharmacokinetic assessments, determining the immunogenicity of varlilumab when given in combination with Opdivo, evaluating alternate dosing schedules of varlilumab and further assessing the anti-tumor activity of combination treatment. The company plan to work with Bristol-Myers Squibb to present data from the study at future medical meetings in 2018.
Third-Party Sponsored Studies: Celldex Therapeutics has also entered into a CRADA with the NCI under which NCI is sponsoring a Phase 2 study of varlilumab in combination with nivolumab in relapsed or refractory aggressive B-cell lymphomas. Patients receive either nivolumab alone or the combination. The primary outcome measure is ORR. Secondary outcome measures include DOR, safety, PFS and OS. The study opened to enrollment in January 2018 and is expected to enroll 106 patients.
CDX-3379 is a human monoclonal antibody with half-life extension designed to block the activity of ErbB3 (HER3). The company believe ErbB3 may be an important receptor regulating cancer cell growth and survival as well as resistance to targeted therapies and is expressed in many cancers, including head and neck, thyroid, breast, lung and gastric cancers, as well as melanoma. The company believe the proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. The company believe CDX-3379 also has potential to enhance anti-tumor activity and/or overcome resistance in combination with other targeted and cytotoxic therapies to directly kill tumor cells. Tumor cell death and the ensuing release of new tumor antigens has the potential to serve as a focus for combination therapy with immuno-oncology approaches, even in refractory patients. CDX-3379 has been evaluated in three Phase 1 studies for the treatment of multiple solid tumors that express ErbB3 and is currently being evaluated is a Phase 2 study in combination with cetuximab in cetuximab-resistant, advanced head and neck squamous cell carcinoma.
The most recent data for CDX-3379 were reported from a Phase 1a/1b study conducted in solid tumors. The study included a single-agent, dose-escalation portion and combination expansion cohorts. The single-agent, dose-escalation portion of the study did not identify an MTD, and there were no dose limiting toxicities. The most common adverse events included rash and diarrhea and were predominantly grade 1 or 2. Four combination arms across multiple tumor types were added to evaluate CDX-3379 with several drugs that target EGFR, HER2 or BRAF. They include combinations with Erbitux® (n=16), Tarceva® (n=8), Zelboraf® (n=9) and Herceptin® (n=10). Patients had advanced disease and were generally heavily pretreated. Across the combination arms, the most frequent adverse events were diarrhea, nausea, rash and fatigue. Objective responses were observed in the Erbitux and Zelboraf combination arms. In the Erbitux arm, there was one durable complete response in a patient with head and neck cancer, who had been previously treated with Erbitux and was refractory. In the Zelboraf arm, there were two partial responses in patients who had lung cancer, one of whom had been previously treated with Tafinlar® and was considered refractory, as well as a single timepoint partial response in a patient with thyroid cancer. Initial data were presented at the American Society of Clinical Oncology Annual Meeting in June 2016.
Celldex Therapeutics has initiated an open-label Phase 2 study in combination with Erbitux in approximately 30 patients with human papillomavirus (HPV) negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma who have previously been treated with an anti-PD1 checkpoint inhibitor, a population with limited options and a particularly poor prognosis. The company opened the study to enrollment in November 2017. The primary objective of the study is objective response rate. Second objectives include assessments of clinical benefit response (CBR), DOR, PFS and OS, and safety and pharmacokinetics associated with the combination.
CDX-014 is a human monoclonal ADC that targets T cell immunoglobulin and mucin domain 1, or TIM-1. TIM-1 expression is upregulated in several cancers, most notably renal cell and ovarian carcinomas, and is associated with a more malignant phenotype of renal cell carcinoma (RCC) and tumor progression. TIM-1 has restricted expression in healthy tissues, making it potentially amenable to an ADC approach. The TIM-1 antibody is linked to MMAE using Seattle Genetics' proprietary technology. The ADC is designed to be stable in the bloodstream but to release MMAE upon internalization into TIM-1-expressing tumor cells, resulting in a targeted cell-killing effect. CDX-014 has shown anti-tumor activity in preclinical models of ovarian and renal cancers.
In July 2016, the company announced that enrollment had opened in a Phase 1/2 study of CDX-014 to patients with both clear cell and papillary RCC. In January 2018, the company amended the protocol, converting the study to Phase 1, expanding enrollment to include patients with ovarian clear cell carcinoma and enabling the evaluation of alternate dosing regimens. Enrollment is ongoing. The study includes a dose-escalation portion across three separate cohorts to determine the MTD followed by expansion cohorts of up to 15 patients each to assess the preliminary anti-tumor activity of CDX-014, as measured by objective response rate. Secondary objectives include safety and tolerability, pharmacokinetics, immunogenicity and additional measures of anti-tumor activity.
CDX-1140 is a fully human antibody targeted to CD40, a key activator of immune response which is found on dendritic cells, macrophages and B cells and is also expressed on many cancer cells. Potent CD40 agonist antibodies have shown encouraging results in early clinical studies; however, systemic toxicity associated with broad CD40 activation has limited their dosing. CDX-1140 has unique properties relative to other CD40 agonist antibodies: potent agonist activity is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40L binding is not blocked, leading to potential synergistic effects of agonist activity near activated T cells in lymph nodes and tumors; and the antibody does not promote cytokine production in whole blood assays. CDX-1140 has shown direct anti-tumor activity in preclinical models of lymphoma. Preclinical studies of CDX-1140 clearly demonstrate strong immune activation effects and low systemic toxicity and support the design of the Phase 1 study to rapidly identify the dose for characterizing single-agent and combination activity.
The company initiated a Phase 1 study of CDX-1140 in November 2017. This study, which is expected to enroll up to approximately 105 patients with recurrent, locally advanced or metastatic solid tumors, is designed to determine the MTD during a dose-escalation phase (0.01 to 3.0 mg/kg once every four weeks until confirmed progression or intolerance) and to recommend a dose level for further study in a subsequent expansion phase. The expansion is designed to further evaluate the tolerability and biologic effects of selected dose(s) of CDX-1140 in specific tumor types. Secondary objectives include assessments of safety and tolerability, pharmacodynamics, pharmacokinetics, immunogenicity and additional measures of anti-tumor activity, including clinical benefit rate. The company believe that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.
CDX-301, a recombinant FMS-like tyrosine kinase 3 ligand, or Flt3L, is a hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells in combination with other agents to potentiate the anti-tumor response. Depending on the setting, cells expanded by CDX-301 promote either enhanced or permissive immunity. CDX-301 is in clinical development for multiple cancers, in combination with vaccines, adjuvants and other treatments that release tumor antigens. The company licensed CDX-301 from Amgen Inc. in March 2009 and believe CDX-301 may hold significant opportunity for synergistic development in combination with other proprietary molecules in its portfolio.
A Phase 1 study of CDX-301 evaluated seven different dosing regimens of CDX-301 to determine the appropriate dose for further development based on safety, tolerability and biological activity. The data from the study were consistent with previous clinical experience and demonstrated that CDX-301 has an acceptable safety profile to date and can mobilize hematopoietic stem cell (HSC) populations in healthy volunteers.
CDX-301's potential activity is being explored in investigator sponsored and collaborative studies. A Phase 2 study of CDX-301 in combination with CDX-1401 is being conducted in malignant melanoma by the Cancer Immunotherapy Trials Network (CITN) under a CRADA with the Cancer Therapy Evaluation Program of the NCI. This study was designed to determine the activity of CDX-1401 with or without CDX-301 in melanoma. The primary outcome measure of the study is immune response to NY-ESO-1. Secondary outcome measures include analysis and characterization of peripheral blood mononuclear cells (dendritic cells, T cells, natural killer cells, etc.), additional immune monitoring, safety and clinical outcomes (survival and time to tumor recurrence). Enrollment is complete, and initial results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting. The data confirmed that CDX-1401 is capable of driving NY-ESO-1 immunity and further demonstrated the potential of CDX-301 as a combination agent for enhancing tumor specific immune responses. The NCI and CITN are planning to enroll additional cohorts to investigate alternative regimens of CDX-301.
CDX-301 is also being studied in a combination cohort with glembatumumab vedotin in a Phase 2 study in metastatic melanoma (opened to enrollment in January 2018) and is being studied in ongoing and planned investigator-sponsored and collaborative studies.
CDX-1401, developed from its APC Targeting Technology, is an NY-ESO-1-antibody fusion protein for immunotherapy in multiple solid tumors. CDX-1401, which is administered with an adjuvant, is composed of the cancer-specific antigen NY-ESO-1 fused to a fully human antibody that binds to DEC-205 for efficient delivery to dendritic cells. Delivery of tumor-specific proteins directly to dendritic cells in vivo elicits potent, broad, anti-tumor immune responses across populations with different genetic backgrounds. In humans, NY-ESO-1 has been detected in 20% to 30% of melanoma, lung, esophageal, liver, gastric, ovarian and bladder cancers, and up to 70% of synovial sarcomas, thus representing a broad opportunity. CDX-1401 is being developed for the treatment of malignant melanoma and a variety of solid tumors which express the cancer antigen NY-ESO-1. Preclinical studies have shown that CDX-1401 treatment results in activation of human T cell responses against NY-ESO-1.
The company completed a Phase 1 study of CDX-1401 which assessed the safety, immunogenicity and clinical activity of escalating doses of CDX-1401 with TLR agonists (resiquimod and/or poly-ICLC) in 45 patients with advanced malignancies refractory to all available therapies. Results were published in Science Translational Medicine in April 2014.
CDX-1401's potential activity is being explored in investigator sponsored and collaborative studies. A Phase 2 study of CDX-1401 in combination with CDX-301 is being conducted in malignant melanoma by the CITN under a CRADA with the Cancer Therapy Evaluation Program of the NCI. This study was designed to determine the activity of CDX-1401 with or without CDX-301 in melanoma. The primary outcome measure of the study is immune response to NY-ESO-1. Enrollment is complete, and initial results were presented at the 2016 ASCO Annual Meeting. The data confirmed that CDX-1401 is capable of driving NY-ESO-1 immunity and further demonstrated the potential of CDX-301 as a combination agent for enhancing tumor specific immune responses. The NCI and CITN are planning to enroll additional cohorts to investigate alternative regimens of CDX-301.
In September 2017, a randomized, open-label Phase 1/2 study of CDX-1401 in combination with atezolizumab and SGI-110 opened to enrollment in recurrent ovarian, fallopian tube, or primary peritoneal cancer. This study is being conducted under a CRADA with the NCI Division of Cancer Treatment and Diagnosis and is designed to determine the activity of atezolizumab alone, atezolizumab plus SGI-110 and atezolizumab plus SGI-110 plus CDX-1401. The primary outcome of the Phase 1 dose-escalation study is safety and only evaluates atezolizumab alone and in combination with SGI-110.
The Phase 2 portion of the study is expected to add CDX-1401. The primary outcome of the Phase 2 portion of the study is a comparison of PFS between the three cohorts.
Other studies are ongoing and planned through investigator-sponsored and collaborative agreements.
Anti-KIT Program: CDX-0158 and CDX-0159
KIT activation is implicated in many disease processes including some cancers, neurofibromatosis, mast cell-related diseases and autoimmune diseases. The company conducted a Phase 1 dose-escalation study of CDX-0158, a humanized monoclonal antibody that is a potent inhibitor of wildtype KIT, in 28 patients with advanced refractory GIST and other KIT positive tumors with doses up to 15 mg/kg. No evidence of myelosuppression, an effect commonly associated with KIT inhibition, was observed in this study. Approximately two-thirds of the patients on study had infusion reactions that were manageable with pre-medication and longer infusion times. The biomarker data showed evidence of dose-related KIT engagement, and two patients experienced partial metabolic responses on fluorodeoxyglucose (FDG)-PET scan; however, these PET responses were not associated with tumor shrinkage.
Given the infusion reactions, modifications have been introduced into the Fc portion of the CDX-0158 antibody to prevent these interactions, which should eliminate the potential for Fc receptor mediated agonist activity. This second-generation version, called CDX-0159, also includes modifications to increase the half-life of the antibody, giving it an additional advantage over CDX-0158. CDX-0159 is being fully developed in-house with the intention of replacing CDX-0158 in clinical development. The company expect manufacturing and IND-enabling efforts for CDX-0159 will be completed in 2018.
The company believe there is untapped potential in immunotherapy that can be captured through the right combination and/or sequence of therapeutic agents. Immunotherapy approaches have encountered difficulties when following standard drug development. The mechanisms of action are complex; activity is generally not dependent on highest tolerated dose; and patient response is highly variable. The company's understanding of the immune system, cancer's effect on immune mediated mechanisms and the impact of conventional therapies on the immune system provide a new rationale for combining therapies that may lead to significant clinical benefit for patients with cancer or other diseases.
The company's intent is to leverage this knowledge and the availability of good, tested products that may not have optimal clinical activity as a monotherapy, but which the company believe may be very effective in combination approaches. The company's goal is to design and develop targeted products that maximize the efficacy of immunotherapy regimens through combinations of therapeutic agents in significant and growing markets. The company establish governmental and corporate alliances to fund development when appropriate and intend to commercialize its products either through its own direct selling efforts or, for products which the company cannot develop itself through to commercialization, through corporate partners. This approach allows it to maximize the overall value of its technology and product portfolios while best ensuring the expeditious development of each individual product.
Factors that may significantly harm its commercial success, and ultimately the market price of its common stock, include but are not limited to, announcements of technological innovations or new commercial products by its competitors, disclosure of unsuccessful results of clinical testing or regulatory proceedings and governmental approvals, adverse developments in patent or other proprietary rights, public concern about the safety of products developed by it and general economic and market conditions. See "Item 1A. Risk Factors."
The company may enter into co-development and commercialization partnerships for any of its programs where appropriate, including glembatumumab vedotin. In the past, Celldex Therapeutics has entered into collaborative partnership agreements with pharmaceutical and other companies and organizations that provided financial and other resources, including capabilities in research, development, manufacturing, and sales and marketing, to support its research and development programs and may enter into more of them in the future.
Partnership agreements may terminate without benefit to it if the underlying products are not fully developed. If the company fail to meet its obligations under these agreements, they could terminate, and the company might need to enter into relationships with other collaborators and to spend additional time, money and other valuable resources in the process. The company cannot predict whether its collaborators will continue their development efforts or, if they do, whether their efforts will achieve success. Many of its collaborators face the same kinds of risks and uncertainties in their businesses that the company face. A delay or setback to a partner will, at a minimum, delay the commercialization of any affected drug candidates, and may ultimately prevent it. Moreover, any partner could breach its agreement with it or otherwise not use best efforts to promote its products. A partner may choose to pursue alternative technologies or products that compete with its technologies or drug candidates. In either case, if a partner failed to successfully develop one of its drug candidates, the company would need to find another partner. The company's ability to do so would depend upon its legal right to do so at the time and whether the product remained commercially viable.
Research Collaboration and License Agreements
Celldex Therapeutics has entered into license agreements whereby Celldex Therapeutics has received licenses or options to license technology, specified patents and/or patent applications. These license and collaboration agreements generally provide for royalty payments equal to specified percentages of product sales, annual license maintenance fees, continuing patent prosecution costs and potential future milestone payments to third parties upon the achievement of certain development, regulatory and/or commercial milestones. Summarized below are its significant research collaboration and license agreements for its later-stage drug candidates.
Medarex, Inc. (Medarex), which was acquired by Bristol-Myers Squibb Company (BMS)
The company and Medarex have entered into an assignment and license agreement, as amended, that provides for the assignment of certain patent and other intellectual property rights and a license to certain Medarex technology related to the Company's APC Targeting Technology™ and an anti-mannose receptor product. Under the terms of the agreement, the company may be required to pay royalties in the low-single digits on any net product sale of a licensed royalty-bearing product or anti-mannose product to Medarex until the later of (i) the expiration of the last to expire applicable patent and (ii) the tenth anniversary of the first commercial sale of such licensed product.
Under a license agreement with Medarex, as amended, the company acquired access to the UltiMab technology to develop and commercialize human antibodies to CD27, including varlilumab. The company may be required to pay Medarex royalty payments in the low-to-mid single digits on any net product sales with respect to the development and commercialization of varlilumab until the later of (i) the expiration of the last to expire applicable patent and (ii) the tenth anniversary of the first commercial sale of such licensed product.
Rockefeller University (Rockefeller)
Under a license agreement with Rockefeller, the company acquired the exclusive worldwide rights to human DEC-205 receptor, with the right to sublicense the technology. The license grant is exclusive except that Rockefeller may use and permit other nonprofit organizations to use the human DEC-205 receptor patent rights for educational and research purposes. The company may be required to pay Rockefeller milestones of up to $3.8 million upon obtaining first approval for commercial sale in a first indication of a product targeting the licensed receptor and royalty payments in the low-to-mid single digits on any net product sales with respect to development and commercialization of the human DEC-205 receptor.
University of Southampton, UK (Southampton)
Under a license agreement with Southampton, the company acquired the rights to develop human antibodies towards CD27, a potentially important target for immunotherapy of various cancers. The company may be required to pay Southampton milestones of up to approximately $1.0 million upon obtaining first approval for commercial sale in a first indication and royalty payments in the low-single digits on any net product sales with respect to development and commercialization of varlilumab.
Amgen Inc. (Amgen)
Under a license agreement with Amgen, the company acquired the exclusive rights to CDX-301 and CD40 ligand, or CD40L. CDX-301 and CD40L are immune modulating molecules that increase the numbers and activity of immune cells that control immune responses. The company may be required to pay Amgen milestones of up to $0.9 million upon obtaining first approval for commercial sale in a first indication and royalty payments in the low-single digits on any net product sales with respect to development and commercialization of the technology licensed from Amgen, including CDX-301.
Under a license agreement with Amgen Fremont, the company acquired rights to develop fully-human monoclonal antibody therapeutics. In May 2009, an amendment to the license agreement was entered into related to its exclusive rights to develop and commercialize glembatumumab vedotin, CDX-014 and antibodies to 10 other licensed antigens. Under the amendment, the company and Amgen Fremont agreed to modify the terms of its existing cross-license of antigens whereby its amended license is fully paid-up and royalty-free.
Seattle Genetics, Inc. (Seattle Genetics)
Under a license agreement with Seattle Genetics, the company acquired the rights to proprietary ADC technology, with the right to sublicense, for use with its proprietary antibodies for the potential treatment of cancer. Under the terms of the agreement, Celldex Therapeutics has the responsibility to use commercially reasonable efforts to develop, commercialize and market such treatment. In furtherance of these responsibilities, technical assistance from Seattle Genetics is available to it as necessary. The company may be required to pay Seattle Genetics milestones of up to $5.0 million and $8.5 million for glembatumumab vedotin and CDX-014, respectively, upon obtaining first approval for commercial sale in a first indication and royalty payments in the mid-single digits on any net product sales with respect to development and commercialization of these drug candidates. The term of the agreement varies country to country and may be until the later of the expiration of the last relevant patent or the tenth anniversary of the first commercial sale. The agreement allows it to terminate with prior written notice, with both parties being able to terminate the agreement for an uncured material breach or insolvency of the other party.
Yale University (Yale)
Under a license agreement with Yale, the company may be required to make a one-time payment to Yale of $3.0 million with respect to each therapeutic or prophylactic receptor tyrosine kinase (RTK) royalty-bearing product, including CDX-3379, that achieves a specified commercial milestone. In addition, the company may be required to pay a low single-digit royalty on annual worldwide net sales of each RTK royalty-bearing product, including CDX-3379. Unless earlier terminated by it or Yale, the Yale license agreement is due to expire no later than May 2038 but may expire earlier on a country-by-country basis under specified circumstances.
MedImmune, LLC (MedImmune)
Under an agreement with MedImmune, Celldex Therapeutics has an exclusive license, with the right to sublicense, to specified patent rights and know-how that are controlled by MedImmune and relate to the research, development, manufacture and commercialization of CDX-3379. The company may be required to pay Medimmune up to $45.0 million upon obtaining specified regulatory and development milestones in the first indication of CDX-3379. In addition, the company may be required to pay MedImmune one-time milestone payments of up to $125.0 million if specified annual net sale thresholds are met related to the first indication of CDX-3379. The company may also be required to pay MedImmune a tiered royalty on annual net sales of CDX-3379 at rates ranging from high single-digit to low teens percentages. These royalties may be reduced in specified circumstances and are payable on a product-by-product and country-by-country basis until the later to occur of ten years after the first commercial sale of the product in that country and the expiration of MedImmune's patent rights that cover the sale of the product in that country. The company may also be required to pay specified royalties on annual net sales of CDX-3379 at a rate in the low single digits to certain other third parties from whom MedImmune licensed certain intellectual property.
The biotechnology and pharmaceutical industry is intensely competitive and subject to rapid and significant technological change. Many of the products that Celldex Therapeutics is attempting to develop and commercialize will be competing with existing therapies. Other companies are pursuing the development of new therapies that target the same diseases and conditions that Celldex Therapeutics is targeting and may compete directly with its drug candidates. The company face competition from companies, major universities and research institutions in the United States and abroad, including a number of large pharmaceutical companies, as well as firms specialized in the development and production of vaccines, adjuvants and immunotherapeutic delivery systems. Some of its competitors possess substantially greater financial, technical and human resources than the company possess.
Competitors that Celldex Therapeutics is aware of that have initiated a pivotal study or have obtained marketing approval for a potential competitive drug/device for glembatumumab vedotin in the treatment of breast cancer include AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Immunomedics, Merck, Nektar Therapeutics, Novartis, Pfizer, Roche, and Tesaro.
The company's competitors may utilize discovery technologies and techniques or partner with collaborators in order to develop products more rapidly or successfully than it or its collaborators are able to. In addition, some competitors have significantly greater experience than Celldex Therapeutics has in conducting preclinical and nonclinical testing and human clinical trials of drug candidates, scaling up manufacturing operations and obtaining regulatory approvals of drugs and manufacturing facilities. Accordingly, its competitors may succeed in obtaining regulatory approval for drugs more rapidly than the company do. If the company obtain regulatory approval and commence commercial sales of its drug candidates, the company also will compete with respect to manufacturing efficiency and sales and marketing capabilities, areas in which the company currently have limited experience.
In addition, academic institutions, government agencies and other public and private organizations conducting research may seek patent protection with respect to potentially competitive products or technologies and may establish exclusive collaborative or licensing relationships with its competitors. Moreover, technology controlled by third parties that may be advantageous to its business may be acquired or licensed by its competitors, thereby preventing it from obtaining technology on commercially reasonable terms, if at all. The company will also compete for the services of third parties that may have already developed or acquired internal biotechnology capabilities or made commercial arrangements with other biopharmaceutical companies to target the diseases on which Celldex Therapeutics has focused both in the U.S. and outside of the U.S.
The company also face competition in recruiting and retaining highly qualified scientific personnel and consultants and in the development and acquisition of technologies.
The company's competitive position will depend upon its ability to attract and retain qualified personnel, obtain patent protection or otherwise develop proprietary products or processes and secure sufficient capital resources for the often lengthy period between technological conception and commercial sales. The company will require substantial capital resources to complete development of some or all of its drug candidates, obtain the necessary regulatory approvals and successfully manufacture and market its drug candidates. In order to secure capital resources, the company anticipate having to sell additional capital stock, which would dilute existing stockholders. The company may also attempt to obtain funds through research grants and agreements with commercial collaborators. However, these types of funding are uncertain because they are at the discretion of the organizations and companies that control the funds. As a result, the company may not receive any funds from grants or collaborations. Alternatively, the company may borrow funds from commercial lenders, likely at high interest rates, which would increase the risk of any investment in it.
Celldex Therapeutics is a research and development company and have limited experience in commercial manufacturing. The company's ability to conduct late-stage clinical trials, as well as manufacture and commercialize its drug candidates, depends on the ability of Contract Manufacturing Organizations (CMOs) to manufacture its drug candidates on a large scale at a competitive cost and in accordance with current Good Manufacturing Practices (cGMP) and U.S. and foreign regulatory requirements, as applicable. The company also rely on CMOs for packaging, labeling, storage and shipping of drug product. In order for it to establish its own commercial manufacturing facility, the company would require substantial additional funds and would need to hire and retain significant additional personnel and comply with extensive cGMP regulations applicable to such a facility. The commercial manufacturing facility would also need to be licensed for the production of its drug candidates by the FDA. The company therefore work with CMOs under established manufacturing arrangements that comply with the FDA's requirements and other regulatory standards, although there is no assurance that the manufacturing will be successful.
To date, Celldex Therapeutics has utilized CMOs for the manufacture of clinical trial supplies of glembatumumab vedotin. In 2017, the company successfully transferred the monoclonal antibody (mAb) intermediate manufacturing process and manufactured a cGMP batch at Patheon Biologics in Brisbane, Australia. Piramal Healthcare UK Ltd. manufactures the antibody-drug conjugate with the vcMMAE linker-toxin. The drug substance is then filled and packaged at its drug product commercial manufacturer, BSP Pharma. The company rely on MilliporeSigma for supplying suitable quantities of vcMMAE. Any manufacturing failures or delays by its glembatumumab vedotin contract manufacturers or suppliers of materials could cause delays in its glembatumumab vedotin clinical studies, including the METRIC study and/or a biologics license application (BLA) filing and, if regulatory approval is obtained, commercial launch of glembatumumab vedotin.
The company operate its own cGMP manufacturing facility in Fall River, Massachusetts, to produce drug substance for its current and planned early-stage clinical trials. The company's Fall River manufacturing facility has 250L and 1000L bioreactor capacity and is able to manufacture in compliance with FDA regulations, allowing it to distribute drug candidates to clinical sites in the U.S. for early-stage clinical trials. The company currently manufacture CDX-1140, CDX-301 and CDX-1401 drug substance and CDX-014 mAb intermediate in its Fall River facility for its current and planned Phase 1 and Phase 2 clinical trials. CDX-014, an ADC, is then manufactured by Lonza (Visp). The company expect that its existing clinical supplies of CDX-3379 and varlilumab will be sufficient to carry out its current planned clinical development. Additional manufacturing options are under review and may involve utilization of the Fall River facility and/or a CMO. All products are then filled and packaged at contract manufacturers. Any manufacturing failures or compliance issues at contract manufacturers could cause delays in its Phase 1 and Phase 2 clinical studies for these drug candidates.
The manufacturing processes for its drug candidates and immunotherapeutic delivery systems utilize known technologies. The company believe that the drug candidates the company currently have under development can be scaled up to permit manufacture in commercial quantities. However, there can be no assurance that the company will not encounter difficulties in scaling up the manufacturing processes.
While the company believe that there is currently sufficient capacity worldwide for the production of its potential products through CMOs, establishing long-term relationships with contract manufacturers and securing multiple sources for the necessary quantities of clinical and commercial materials required can be a challenge due to increasing industry demand for CMO services. Qualifying the initial source of clinical and ultimately commercial material is a time consuming and expensive process due to the highly regulated nature of the pharmaceutical/biotech industry. These costs may be mitigated by the economies of scale realized in commercial manufacture and product sales. The key difficulty in qualifying more than one source for each product is the duplicated time and expense in doing so without the potential to mitigate these costs if the secondary source is never utilized.
The company currently rely on sole suppliers for key components of its drug candidates, including vcMMAE for glembatumumab vedotin and CDX-014 and Hiltonol® for CDX-1401. While the company work with the suppliers of these key components to ensure continuity of supply, no assurance can be given that these efforts will be successful. In addition, due to regulatory requirements relating to the qualification of suppliers, the company may not be able to establish additional or replacement sources on a timely basis or without excessive cost. If its suppliers were to terminate its arrangements or fail to meet its supply needs the company might be forced to delay its development programs or the company could face disruptions in the distribution and sale of any drugs for which the company obtain regulatory approval.
Use of third-party manufacturers limits its control over and ability to monitor the manufacturing process. As a result, the company may not be able to detect a variety of problems that may arise and may face additional costs in the process of interfacing with and monitoring the progress of its contract manufacturers. If third-party manufacturers fail to meet its manufacturing needs in an acceptable manner, the company would face delays and additional costs while the company develop internal manufacturing capabilities or find alternate third-party manufacturers. It may not be possible to have multiple third-party manufacturers ready to supply it with needed material at all or without incurring significant costs.
Celldex Therapeutics has a focused commercial team with broad experience in marketing, sales, distribution and product reimbursement. Celldex Therapeutics has also developed the capability to provide current and future market insights to its research and development organization regarding glembatumumab vedotin and its earlier-stage drug candidates. In the future, the company may choose to expand its commercial team and build a full-scale commercial organization which the company believe could provide it the opportunity to retain marketing rights to its drug candidates and commercialize such products itself where the company deem appropriate or pursue strategic partnerships to develop, sell, market and distribute its drug candidates where the company deem appropriate. The company may also choose to enter into strategic partnerships to develop, sell, market and distribute its other drug candidates, including glembatumumab vedotin.