For some time, rindopepimut was the major reason why many have invested in Celldex Therapeutics (CLDX). However, late last year, Celldex generated a great deal of excitement after the final results from the company's Phase 2b metastatic breast cancer study of CDX-011 were released. The results were so good that the company plans to initiate a randomized trial suitable for accelerated approval in patients with triple negative breast cancer in the second half of 2013.
In addition to the CDX-011 accelerated approval study, Celldex plans to initiate new clinical studies and expansion studies for four other Celldex programs this year.
Celldex's primary focus is in oncology. There are four programs currently in clinical development for treatment of several cancers, and additional oncology programs are progressing toward clinical development. Celldex also expects data from three clinical studies by year end, including results from its Phase 2 study of rindopepimut with Avastin (bevacizumab) in refractory glioblastoma. The company also hopes to complete enrollment in the Phase 3 rindopepimut ACT IV registration trial in frontline glioblastoma.
Celldex's expertise is the design of new therapeutics and treatment regimens that maximize the beneficial aspects of the immune system, and counter its negative elements that are exploited by cancers and pathogens. These innovative programs include:
- APC Targeting Technology, a new class of vaccines based on Celldex's proprietary antibody-targeted vaccine technology that is used to generate an immune response against cancer and other diseases;
- Therapeutic Antibody Programs, a well validated approach to using antibodies that target cancer and other diseases directly or by interfering with the disease; and
- Immune System Modulators, drugs that activate or suppress specific parts of the immune system, including such molecules as Toll-like receptor (TLR) agonists that can activate patients' innate and adaptive immunity.
In June 2010, Celldex stock crashed after Pfizer (PFE) decided to end its collaboration with Celldex for CDX-110. Celldex vowed to continue research and development of rindopepimut, also known as CDX-110. CDX-110 is a immunotherapeutic that targets the tumor-specific molecule, epidermal growth factor receptor variant III, or EGFRvIII.
EGFRvIII is a mutated form of the epidermal growth factor receptor, or EGFR, that is only expressed in cancer cells and not in normal tissue, and can directly contribute to cancer cell growth. EGFRvIII is expressed in approximately 30% of glioblastoma tumors, also referred to as glioblastoma multiforme, the most common and aggressive form of brain cancer.
Glioblastoma multiforme tumor cells show a high resistance to radiation and chemotherapy. These tumors spread and infiltrate tissue so quickly that eradicative surgery is often impossible with recurrence occurring within months of the initial treatment.
According to the US National Cancer Registry, approximately 28,000 new cases of malignant gliomas are diagnosed in the United States and the European Union each year. The current standard of care involves surgery, followed by radiotherapy and chemotherapy. The relative survival rate for adults diagnosed with glioblastoma is less than 30% within one year of diagnosis. According to the Central Brain Tumor Registry of the United States, only 3% of patients live longer than five years after primary diagnosis. The median overall survival does not exceed 15 months despite surgical resection, radiotherapy, and chemotherapy even in selected clinical trial populations.
The research firm, GlobalData, estimated that the global glioblastoma multiforme therapeutics market was valued at $370 million in 2010. GlobalData forecasted that the market will grow at a compound annual growth rate of 2.4% to reach $449 million by 2018. This low growth rate is primarily attributed to the patent expiry of Merck & Co.'s (MRK) Temodal/Temodar (temozolomide) in Europe in 2009, and in the United States in 2014. GlobalData research found that the entry of low cost generics in Europe in 2010 led to a decrease in the market valuation.
According to the pharmaceutical industry research firm, Decision Resources, there is a significant opportunity for investigational glioblastoma drugs. Despite advances in treatment such as adjuvant radiotherapy in combination with Temodar/Temodal, prognosis remains poor as the majority of glioblastoma patients experience disease recurrence.
Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have granted orphan drug designation to rindopepimut for the treatment of EGFRvIII expressing GB. The FDA has also granted a Fast Track designation to the investigational drug.
On November 15, 2012, Celldex announced the presentation of three-year survival data from the Phase 2 rindopepimut clinical program in EGFRvIII-positive glioblastoma, a more aggressive form of glioblastoma typically associated with reduced long-term survival in comparison to the glioblastoma population as a whole. Across three Phase 2 studies of rindopepimut, survival data has remained consistent, suggesting that a substantial and continuing survival benefit exists in comparison to independent control datasets at the median and at three years.
In the multi-center Phase 2 ACT III study, the median overall survival was 24.6 months from diagnosis (21.8 months from study entry) and overall survival is 26% at three years. In the Phase 2 ACT II study, the median overall survival was 24.4 months from diagnosis (20.5 months from study entry) and overall survival is 23% at three years.
The long-term survival data across all three rindopepimut Phase 2 clinical trials was consistent and suggested that rindopepimut provided long-term survival beyond what is historically seen in this subset of EGFRvIII-expressing glioblastoma patients, a group that typically has more aggressive disease associated with a worse prognosis than the general glioblastoma patient population.
In addition to the presentation of updated survival data, Celldex also announced the presentation of data from a retrospective analysis of EGFRvIII expression status and associated clinical outcome in the Phase 3 Radiation Therapy Oncology Group's (RTOG) 0525 study. This analysis was conducted by the University of Texas MD Anderson Cancer Center in cooperation with RTOG to provide an assessment of the prognosis for patients with EGFRvIII-positive disease contemporary with the ACT III data.
"The results presented at SNO provide further validation for the rindopepimut clinical program," said Anthony Marucci, President and CEO of Celldex Therapeutics. "The median and long-term survival rates are impressive in comparison to both the MD Anderson and RTOG historical control datasets, with 23% to 33% of patients on rindopepimut surviving to the three-year mark versus 6% to 18% of patients in the historical control datasets. In addition, while the ACT II and ACT III data continue to mature, across all three Phase 2 rindopepimut studies, approximately 15% of patients are alive at five years compared to an expectation of 0%. These results support our belief that rindopepimut has the potential to dramatically alter the prognosis for patients with EGFRvIII-positive glioblastoma. To that end, we continue to actively enroll patients in the pivotal ACT IV study with more than 150 clinical sites around the world selected to participate and, to date, 118 of these sites actively screening patients."
In December 2011, Celldex initiated ACT IV, a pivotal, randomized, double-blind, controlled Phase 3 study of rindopepimut in patients with surgically resected, EGFRvIII-positive GB. The primary objective of the study is to determine whether rindopepimut plus adjuvant GM-CSF improves the overall survival of patients with newly diagnosed EGFRvIII-positive GB after Gross Total Resection, or GTR, when compared to treatment with TMZ and a control injection of KLH. KLH is a component of rindopepimut and was selected due to its ability to generate a similar injection site reaction to that observed with rindopepimut.
The ACT IV trial will enroll up to 440 patients at over 150 centers worldwide to recruit approximately 374 patients with GTR to be included in the primary analysis. Celldex expects to complete patient accrual by the end of 2013 and anticipate receiving data 18 to 24 months after completing accrual. The company anticipates ACT IV to cost over $60 million during its duration.
In December 2011, Celldex also initiated ReACT, a Phase 2 study of rindopepimut in combination with Avastin in patients with recurrent EGFRvIII-positive GB. ReACT will enroll approximately 95 patients in a first or second relapse of GB following standard therapy. The study will be conducted at approximately 20 sites across the United States. Approximately 70 patients who have yet to receive Avastin will be randomized to receive either rindopepimut and Avastin or a control injection of KLH and Avastin in a blinded fashion. Another 25 patients who are refractory to Avastin having received Avastin in either the frontline or recurrent setting with subsequent progression will receive rindopepimut plus Avastin in a single treatment arm. We expect data from this study to be available in the second half of 2013.
In addition, researchers at Stanford University are conducting an investigator sponsored, pilot trial of rindopepimut in pediatric patients with pontine glioma. Patient enrollment is ongoing for this trial.
In June 2012, a survey of US oncologists surveyed conducted by the research and advisory firm, Decision Resources, found that they would prescribe CDX-110 to 36% of their newly diagnosed glioblastoma multiforme patients if the drug is approved.
Decision Resources predicted that CDX-110 would earn an 18% patient share in the US newly diagnosed glioblastoma multiforme market by 2020 because only about one-third of glioblastoma multiforme patients harbor the EGFRVIII variant targeted by the drug. The firm concluded that this limitation, combined with increased competition in the glioblastoma multiforme drug market, will limit the patient population eligible for the therapy.
CDX-011, also known as glembatumumab vedotin, is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (GPNMB). GPNMB is a protein overexpressed by multiple tumor types, including melanoma, breast cancer and glioma. The FDA has granted Fast Track designation to CDX-011 for the treatment of advanced, refractory/resistant GPNMB-expressing breast cancer.
GPNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize, and to correlate with reduced time to progression and survival in breast cancer. The GPNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics' (SGEN) technology.
In June 2008, Celldex initiated a Phase 1/2 study of CDX-011 administered intravenously once every three weeks to patients with locally advanced or metastatic breast cancer who had received prior therapy. For all patients treated at the maximum dose level, tumor shrinkage was seen in 62% (16 of 26 patients) and median progression free survival (PFS) was 9.1 weeks. A subset of 10 patients had "triple negative disease," a more aggressive breast cancer subtype that carries a high risk of relapse and reduced survival as well as limited therapeutic options due to lack of over-expression of HER2/neu, estrogen and progesterone receptors. In these patients, 78% (7 of 9 patients) had some tumor shrinkage, 12-week PFS rate was 70% (7 of 10 patients), and median PFS was 17.9 weeks.
In December 2012, Celldex presented positive final results from the Phase 2b EMERGE clinical trial of CDX-011 in patients with both triple negative breast cancer and high GPNMB expression. In December 2012, Celldex announced final results from the EMERGE study which suggested that CDX-011 induced significant response rates compared to currently available therapies in patient subsets with advanced, refractory breast cancers with GPNMB over-expression (expression in greater than 25% of tumor cells) and in patients with triple negative breast cancer. The overall survival, or OS, and progression free survival, or PFS, of patients treated with CDX-011 was also observed to be greatest in patients with triple negative breast cancer who also over-express GPNMB and all patients with GPNMB over-expression.
In December 2012, Celldex had its end of Phase 2b meeting with the FDA for the CDX-011 program. Based on this meeting, Celldex intends to initiate a randomized study of CDX-011 for accelerated approval in patients with triple negative breast cancer that also over-express GPNMB in the second half of 2013.
Since triple negative breast cancers do not express estrogen, progesterone, and HER2 receptors, these cancers are resistant to conventional targeted treatments, including hormonal and HER2-targeted therapies. According to the National Breast Cancer Foundation, triple negative breast cancer occurs in about 10% to 20% of diagnosed breast cancers.
Celldex plans to initiate a pivotal, randomized, accelerated approval study of CDX-011 in patients with triple negative breast cancers that over-express GPNMB in the second half of 2013. Last year, the FDA drafted new guidelines for clinical trials researching early stage triple negative breast cancer in an effort to expedite the development of drugs to treat these cancers.
CDX-1401, developed from Celldex's APC Targeting Technology, is a fusion protein consisting of a fully human monoclonal antibody with specificity for the dendritic cell receptor, DEC-205, linked to the NY-ESO-1 tumor antigen.
Researchers have detected NY-ESO-1 in 20% to 30% of all melanoma, lung, esophageal, liver, gastric, prostate, ovarian and bladder cancers. CDX-1401 is intended to selectively deliver the NY-ESO-1 antigen to dendritic cells to generate strong immune responses against cancer cells expressing NY-ESO-1.
Celldex is developing CDX-1401 for the treatment of malignant melanoma and a variety of solid tumors which express the proprietary cancer antigen NY-ESO-1, which the company licensed from the Ludwig Institute for Cancer Research in 2006. Preclinical studies have shown that CDX-1401 is effective for activation of human T cell responses against NY-ESO-1.
On October 29, 2012, Celldex announced that The Phase 1 study of CDX-1401 was the first clinical study to demonstrate that an off-the-shelf vaccine targeting dendritic cells in vivo through DEC-205 could safely lead to robust immunity when combined with TLR agonists in cancer patients. Significant anti-NY-ESO-1 titers occurred in 79% of evaluable patients.
In 2013, Celldex plans to initiate a Phase 2 study of CDX-1401 in combination with CDX-301 sponsored by the Cancer Immunotherapy Trials Network of the National Cancer Institute.
CDX-1127 is a human monoclonal antibody that targets CD27, a potentially important target for immunotherapy of various cancers. Celldex entered into license agreements with the University of Southampton in the United Kingdom for intellectual property related to uses of anti-CD27 antibodies and with Medarex, a Bristol-Myers Squibb (BMY) subsidiary, for access to the UltiMab technology to develop and commercialize human antibodies to CD27.
CDX-1127 has been shown to activate immune cells that can target and eliminate cancerous cells in tumor-bearing mice and to directly kill or inhibit the growth of CD27 expressing lymphomas and leukemias. Both mechanisms have been seen even at low doses in appropriate preclinical models.
In November 2011, Celldex initiated an open label, dose-escalating Phase 1 study of CDX-1127 in patients with selected malignant solid tumors or hematologic cancers at multiple clinical sites in the United States. The Phase 1 study is designed to test five escalating doses of CDX-1127 to determine a Phase 2 dose for further development based on safety, tolerability, potential activity and immunogenicity.
On April 8, 2013, Celldex reported the results of an in vitro study analyzing the activation of human T cells with CDX-1127 at the American Association of Cancer Research (AACR) annual meeting.
"The results of this study confirm that CDX-1127 elicits potent activation of T cells by inducing their proliferation and release of important immune modulating cytokines," Tibor Keler, PhD, Celldex's Senior Vice President and Chief Scientific Officer stated. "Most importantly, we have shown that the activation is highly regulated, which limits any safety concerns related to non-specific stimulation of the immune system that similar candidates in this class have faced. This finding is supported by the good safety profile seen to date in our ongoing multi-dose Phase 1 human clinical trial. We believe CDX-1127 is an exciting entrant to the field of immunotherapy and look forward to presenting clinical data from planned solid tumor and hematologic expansion cohorts from our Phase 1 study by year-end."
The company anticipates reporting data from the CDX-1127 program in the second half of 2013.
CDX-301 is a FMS-like tyrosine kinase 3 ligand, or Flt3L, stem cell mobilizer and dendritic cell growth factor. CDX-301 has demonstrated a unique capacity to increase the number of circulating dendritic cells in both laboratory and clinical studies. In addition, CDX-301 has shown impressive results in models of cancer, infectious diseases and inflammatory/autoimmune diseases.
In February 2013, Celldex presented final results from a Phase 1 multi-dose study of CDX-301 in 30 healthy subjects. 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. The data from the study were consistent with previous clinical experience and demonstrated that CDX-301 was well-tolerated and could effectively mobilize hematopoietic stem cell populations in healthy volunteers. Based on the safety profile and the increases observed for CD34+ stem cells and dendritic cells, Celldex plans to initiate a pilot study in hematopoietic stem cell transplant by the end of 2013.
CDX-1307 utilizes monoclonal antibodies to deliver vaccine directly to the patient's immune system and focuses the immune system against hCG beta (hCG-β), a cancer-associated target believed to play a role in more aggressive forms of the disease. hCG-β is an established tumor-associated antigen that is over-expressed in a variety of common cancers including those of the colon, lung, pancreas, esophagus, breast, bladder, cervix, stomach, and prostate, but not expressed in most normal tissues.
CDX-1307 has been evaluated for the treatment of advanced colorectal, pancreatic, bladder, ovarian and breast cancers in two Phase 1 trials.
In October 2009, Celldex announced positive results from Phase 1 studies of CDX-1307 in patients with advanced epithelial cancers, including breast, colon, bladder and pancreatic cancer.
The studies enrolled more than 80 patients with heavily pretreated, advanced-stage breast, colon, bladder and pancreatic cancer, with an average of 4.6 prior therapies across the treatment population. All patient cohorts demonstrated a favorable safety profile with no dose limiting toxicity to date.
Researchers found that the combination of CDX-1307 with TLR agonists significantly enhanced immune responses against hCG-β, providing strong humoral responses in 88% of patients and cellular immune responses in 57% of patients analyzed to date. Immune responses occurred even in the presence of high circulating levels of hCG-β, suggesting that the CDX-1307 can overcome antigen tolerance in advanced and heavily pretreated cancers. Nine patients in the studies experienced disease stabilization from 2.3 months to 11.4 months following the initiation of CDX-1307 vaccination. Two of these patients have received multiple courses of CDX-1307 and continue treatment with stable disease at 6.4 and 11.4 months.
Celldex believe these data provide the basis for advancing CDX-1307 into a front-line patient population selected for hCG-β expressing cancers.
CDX-1135 is a molecule that inhibits a part of the human immune system called the complement system. The complement system is comprised of proteins that are initiators of the body's inflammatory response against disease, infection and injury. Excessive complement activation also plays a role in some persistent inflammatory conditions.
CDX-1135 is being assessed for certain rare renal diseases involving dysregulated complement and therapeutic intervention in Antibody-Mediated Rejection (AMR) and other inflammatory conditions where the complement system is thought to have a critical role in the disease pathogenesis.
Celldex is conducting a Phase 1 study of CDX-1135 as a therapy for dense deposit disease (DDD), a rare genetic condition affecting 2 to 3 people per million worldwide. DDD is a devastating disease that is caused by uncontrolled activation of the alternative pathway of complement and leads to progressive kidney damage in children. There is currently no treatment for patients with DDD and about one-half of those with DDD progress to end-stage renal disease within 10 years. Because DDD recurs in virtually all patients who receive a kidney transplant, transplantation is not a viable option for these patients. In animal models of DDD, CDX-1135 treatment showed evidence of reversal of kidney damage.
Celldex is planning to initiate a pilot study of CDX-1135 in a small number of DDD patients to determine the appropriate dose and regimen for further clinical development based on safety, tolerability and biological activity with data expected by the end of 2013.
Celldex is developing therapeutic human antibodies to a signaling molecule known as CD89 or Fcα receptor type I (FcαRI). CD89 is expressed by some white blood cells and leukemic cell lines, and has been shown to be important in controlling inflammation and tumor growth in animal models.
Celldex has proprietary, fully human antibodies to CD89 in preclinical development. Depending upon the specific antibody used, anti-CD89 antibodies can either be activating and thus stimulate immune responses, or down-regulating and anti-inflammatory.
Celldex also has a preclinical program, CDX-014, a fully-human monoclonal antibody-drug conjugate that targets TIM-1, a molecule that is highly expressed on renal and ovarian cancers with minimal expression in normal tissues. CDX-014 has shown potent activity in preclinical models of ovarian and renal cancer.
Celldex and Rockefeller University investigators are collaborating on an effort to develop a vaccine against the human immunodeficiency virus (HIV), the virus known to cause Acquired Immune Deficiency Syndrome (AIDS). The vaccine, called DCVax-001, is an APC-targeted vaccine consisting of a fusion protein of a human monoclonal antibody with specificity for the dendritic cell receptor, DEC-205 linked to an HIV antigen. This program has been funded through a grant from the Bill & Melinda Gates Foundation. The vaccine is currently being tested in a Phase 1 trial in healthy volunteers at Rockefeller University.
On March 7, 2013, Celldex announced financial results for the fourth quarter and the year ended December 31, 2012. The company reported a net loss of $16.8 million, or ($0.27) per share, for the fourth quarter of 2012 compared to net loss of $12.7 million, or ($0.29) per share, for the fourth quarter of 2011.
For the twelve months ended December 31, 2012, Celldex reported a net loss of $59.1 million, or ($1.02) per share, compared to a net loss of $44.8 million, or ($1.13) per share, for the twelve months ended December 31, 2011.
The company explained that the increase in net loss of $4.1 million between the fourth quarters of 2012 and 2011 was primarily due to higher research and development (R&D) expense as a result of higher clinical trials costs for the rindopepimut Phase 3 and Phase 2 programs. General and administrative (G&A) expense in the fourth quarter of 2012 increased by $0.3 million from $2.3 million in 2011 due primarily to higher personnel-related expenses in 2012. The increase in cash, cash equivalents and marketable securities of $6.3 million from September 30, 2012 primarily reflects the issuance of 3.5 million shares during the quarter through our Cantor ATM facility that raised net proceeds to Celldex of $20.9 million, partially offset by the company's fourth quarter operations-related cash burn of approximately $13.3 million and principal payments on its term loan of $1.3 million.
The net loss of $59.1 million for 2012 represents an increased loss of $14.3 million when compared to the net loss of $44.8 million for the same period in 2011 and was primarily due to increased R&D expense. R&D expense in 2012 increased by $15.0 million compared to 2011 and was primarily a result of increased later-stage clinical trials costs of $14.3 million in 2012 related to the rindopepimut program. G&A expenses increased by $0.8 million to $10.0 million in 2012 compared to $9.2 million in 2011, primarily due to increased personnel-related expenses and rindopepimut-related commercial planning costs in 2012.
At December 31, 2012, Celldex reported cash, cash equivalents and marketable securities of $84.0 million. Following recent financings, as of February 28, 2013, Celldex had cash, cash equivalents and marketable securities of approximately $189 million.
Firms analyzing Celldex hold the company in high regard. On March 8, 2013, Roth Capital reiterated Celldex as a "Focus Pick" due to its broad pipeline and the potential for accelerated approval for either ORR or PFS. Shares are "Buy" rated with a $16 price target. On March 8, Jeffries raised their price target for Celldex stock to $15 from $9. On March 8, Cantor Fitzgerald increased their Celldex price target to $16 from $13, predicting that Celldex will begin obtaining revenues from both CDX-011 and rindopepimut in 2016 versus its original forecast of 2017. The firm maintains a "Buy" rating on the stock. On March 6, Leerink Swann initiated coverage of Celldex with an "Outperform" and an $18 price target. On February 26, 2013, Oppenheimer reiterated their "Outperform" rating for Celldex and increased their price target to $13 from $10.
Celldex is well-financed. In the first quarter of 2013, Celldex raised net proceeds of $114.1 million. The company's current cash position allows it to support operations and clinical development through 2015.
Celldex ended 2012 reporting positive data from four clinical programs, including final results from their Phase 2b clinical trial of CDX-011 in metastatic breast cancer. The company now plans to initiate a randomized trial suitable for accelerated approval in patients with triple negative breast cancer that also over-express GPNMB in the second half of 2013.
In addition to the CDX-011 accelerated approval study, Celldex plans to initiate new clinical studies and expansion studies for four other Celldex programs in 2013. The company expects data from three clinical studies by year end - including from its Phase 2 study of CDX-110 (rindopepimut) with Avastin in refractory glioblastoma.
The 962M market cap company has six wholly-owned clinical-stage drug candidates that were derived from the company's antibody focused Precision Targeted Immunotherapy (PTI) platform, which consists of a complementary portfolio of monoclonal antibodies, antibody-targeted therapeutics and immunomodulators used in combinations to create novel disease-specific drug candidates.
There is a lot to like about Celldex Therapeutics.