1stOncology™: Cancer Intelligence Service – Page 16448 – 1stOncology is recognized as a Top 10 Global Pharma Analytic Provider

Ionis’ 2015 Financial Results Outperform Projections

On February 25, 2016 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) reported it ended the year in a strong financial position, significantly outperforming its guidance for both pro forma net operating loss (NOL) and cash (Press release, Ionis Pharmaceuticals, FEB 25, 2016, View Source;p=RssLanding&cat=news&id=2143280 [SID:1234509206]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

Schedule Your 30 min Free Demo!

"We have a pipeline of drugs with the potential to change the lives of patients with many different diseases. In 2015, we completed target enrollment in three Phase 3 studies for our three most advanced drugs in development; nusinersen, IONIS-TTRRx and volanesorsen, bringing these important new medicines one step closer to potentially reaching the market. These drugs are being developed for six different patient populations. We believe the robust development plan for each of these three drugs supports their significant commercial potential. We and our partners are well along in preparing for regulatory filings and for commercialization of nusinersen and IONIS-TTRRx. Our wholly owned subsidiary, Akcea Therapeutics, has begun the key steps necessary to launch volanesorsen. Paula Soteropoulos and her team, working with experts in the field, have begun to implement a multi-step program to increase diagnosis and referral of patients with FCS to lipid-focused physicians. In addition, they are assembling the commercial infrastructure that will support the global launch of volanesorsen," said B. Lynne Parshall, chief operating officer of Ionis Pharmaceuticals.

"The majority of our drugs in Phase 3 and Phase 2 clinical development and our growing number of earlier stage programs provided us with numerous opportunities to highlight the breadth and depth of our pipeline in 2015. We reported positive clinical data from ten drugs in development. We designed these drugs to treat patients with a wide variety of diseases. In addition, in 2015 we advanced several earlier-stage programs into clinical development, including our drug to treat patients with Huntington’s disease. We believe these earlier-stage drugs represent the next wave of new medicines with the potential to fundamentally change the treatment of diseases that are currently untreatable," continued Ms. Parshall. "The innovations we have made in our technology have the potential to add significant value to our pipeline. The substantial increase in potency conferred by our LICA technology supports weekly, monthly, quarterly or even less frequent dosing. This is a major advance and broadens the reach of our technology to larger patient populations and new therapeutic areas. The additional potency we achieved with our Generation 2.5 technology also allows us to continue to expand the opportunities for our antisense drugs."

"In 2016, we plan to complete Phase 3 studies for nusinersen, IONIS-TTRRx and volanesorsen and report data from these studies in the first half of 2017. We plan to report additional data from the open-label studies of nusinersen and IONIS-TTRRx. Data from these open-label studies continue to support the potential of these important new drugs. We will continue to provide updates as Akcea builds its commercial infrastructure and prepares to launch volanesorsen. We also plan to report data from many clinical studies, including Phase 2 data from our novel antithrombotic drug, IONIS-FXIRx, and additional clinical data on the LICA drugs we are developing. All of these activities build upon the value we have created and provide us with an event-rich year ahead," concluded Ms. Parshall.

Ionis’ 2016 goals and the full list of corporate and drug development highlights can be found at the end of this press release prior to the financial tables.

Financial Results

"Over the past several years, we have ended each year in a better financial position than when we began. During this time, we advanced three important new drugs into Phase 3 development, initiated five Phase 3 studies on these drugs, advanced 12 Phase 2 drugs and multiple Phase 1 drugs, and translated our technological innovations into the next wave of drugs to enter clinical development. Over the last several years, we have consistently increased our revenues and cash balance while decreasing our pro forma NOL reflecting the successes in our partnerships. We continued this trend in 2015 by significantly outperforming both our pro forma NOL and cash guidance. We ended the year with a pro forma NOL of $16 million, which represents a more than 70 percent improvement over our original guidance. On a GAAP basis, our operating loss was $76 million. During 2015, we received more than $320 million from our partners and ended the year with more than $775 million of cash, which is $150 million more than our original guidance. As our drugs successfully advance, we generate cash and revenue from our partners. In addition to cash and revenue, our partners provide expertise and significant additional resources, which allow us to minimize our research and development spending. Importantly, we believe these contributions will maximize the commercial value of our partnered drugs. Furthermore, with three potentially transformational medicines close to commercialization, we are looking forward to adding product revenues and royalties to our revenue base over the next few years," said Elizabeth L. Hougen, chief financial officer of Ionis Pharmaceuticals.

"In 2016, we plan to continue to progress the drugs we have in development, including our Phase 3 drugs for which we are conducting multiple Phase 3 studies. We also plan to expand our pipeline and continue to invest in advancing our technology. Akcea plans to continue conducting the pre-commercialization activities and building the global medical, marketing and sales infrastructure to successfully commercialize volanesorsen. The efficiency of our technology and our business strategy allows us to do all of this while continuing to be fiscally prudent. We are also able to advance this large agenda while maintaining a strong cash balance because of the cash we generate as our partnered programs progress. As such, we are projecting a pro forma NOL in the low $60 million range and a year-end cash balance in excess of $600 million," concluded Ms. Hougen.

All pro forma amounts referred to in this press release exclude non-cash compensation expense related to equity awards. Please refer to the reconciliation of pro forma and GAAP measures, which is provided later in this release.

Revenue

Revenue for the three and twelve months ended December 31, 2015 was $51.6 million and $283.7 million, respectively, compared to $84.9 million and $214.2 million for the same periods in 2014. Ionis’ revenue in 2015 consisted of the following:

$91.2 million from Bayer in connection with its exclusive license agreement for IONIS-FXIRx;
$72.6 million from Biogen for advancing the Phase 3 program for nusinersen, advancing IONIS-DMPK-2.5Rx and IONIS-BIIB4Rx, and validating three new targets for neurological disorders, which have proceeded forward in drug development;
$22 million from Roche for initiating a Phase 1/2 study of IONIS-HTTRx;
$20 million from GSK for advancing the Phase 3 program of IONIS-TTRRx and initiating a Phase 1 study of IONIS-GSK4-LRx; and
$77.9 million primarily from the amortization of upfront fees and manufacturing services performed for its partners.
Already in the first quarter of 2016, Ionis has generated $7 million in milestone payments from Biogen for advancing the Phase 3 program for nusinersen, advancing IONIS-BIIB4Rx and from GSK when GSK initiated the Phase 1 study for IONIS-HBV-LRx.

Ionis’ revenue fluctuates based on the nature and timing of payments under agreements with its partners and consists primarily of revenue from the amortization of milestone payments, license fees and upfront fees.

Operating Expenses

In 2015, Ionis had higher operating expenses compared to 2014 primarily due to increased spending to support the Company’s ongoing Phase 3 studies for nusinersen, IONIS-TTRRx and volanesorsen, which are in the most expensive stage of development. In addition, Akcea continued to build its operations in preparation for the commercial launch of volanesorsen. As such, Ionis’ pro forma operating expenses of $97.1 million and $300.2 million for the three and twelve months ended December 31, 2015, respectively, were higher than the $66.3 million and $230.5 million for the same periods in 2014. On a GAAP basis, Ionis’ operating expenses for the three and twelve months ended December 31, 2015 were $114.5 million and $359.5 million, respectively, compared to $74.8 million and $261.9 million for the same periods in 2014. Ionis’ operating expenses on a GAAP basis included non-cash compensation expense related to equity awards, which increased due to the increase in the Company’s stock price in January 2015 compared to January 2014.

Gain on Investment in Regulus Therapeutics Inc.

In the third quarter of 2015, Ionis received nearly $26 million of cash and recorded a $20.2 million gain on its sale of a portion of its Regulus common stock. Regulus is a satellite company partner that Ionis co-founded to discover and develop antisense drugs targeting microRNAs. In total, Ionis has received nearly $50 million since 2014 from its sale of Regulus’ common stock. Ionis now owns approximately 2.8 million shares, or approximately 5%, of Regulus’ common stock.

Net Loss

Ionis reported a net loss of $71.4 million and $88.3 million for the three and twelve months ended December 31, 2015, respectively, compared to net income of $31.1 million and a net loss of $39.0 million for the same periods in 2014. Basic and diluted net loss per share for the three and twelve months ended December 31, 2015 was $0.59 and $0.74, respectively. Basic and diluted net income per share for the three months ended December 31, 2014 was $0.26 and $0.25, respectively, while both basic and diluted net loss per share was $0.33 per share for the year ended December 31, 2014. Ionis’ increased net loss for 2015 compared to 2014 was primarily due to the increased expenses related to advancing Ionis’ large pipeline partially offset by the Company’s increase in revenue in 2015.

Balance Sheet

As of December 31, 2015, Ionis had cash, cash equivalents and short-term investments of $779.2 million compared to $728.8 million at December 31, 2014. Ionis’ cash balance increased in 2015 primarily due to the more than $320 million in cash Ionis received from its partners. Ionis’ working capital was $688.1 million at December 31, 2015 compared to $721.3 million at December 31, 2014.

Insmed Reports Fourth Quarter 2015 Financial Results

On February 25, 2016 Insmed Incorporated (Nasdaq:INSM), a global biopharmaceutical company focused on the unmet needs of patients with rare diseases, reported financial results for the fourth quarter and year ended December 31, 2015 (Press release, Insmed, FEB 25, 2016, View Source [SID:1234509205]).

Business Update

Global Phase 3 ARIKAYCE study advancing. Patient enrollment continues in the company’s global phase 3 study of ARIKAYCE (liposomal amikacin for inhalation or LAI) in nontuberculous mycobacteria (NTM) lung disease caused by Mycobacterium avium complex (MAC) (CONVERT or INS-212 study). The CONVERT study is taking place in 16 countries and more than 115 sites. The company continues to expect to achieve its enrollment objective in the second half of 2016.

EMA regulatory review of ARIKAYCE progressing. The company submitted its responses to the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) 120-day questions in December 2015 and expects to receive the CHMP’s 180-day list of outstanding issues (LOI) in the first quarter of 2016. Insmed anticipates responding to the LOI and participating in an oral hearing with the CHMP in the second quarter of 2016 to address the LOI on the company’s marketing authorization application (MAA) for ARIKAYCE. The company continues to expect the CHMP to render an opinion on its MAA around the middle of 2016.

Phase 1 clinical study of INS1009 underway. Insmed is conducting a phase 1 study of INS1009 in healthy subjects. INS1009 is the company’s nebulized treprostinil prodrug. The company believes INS1009 may offer a differentiated product profile with therapeutic potential in rare pulmonary disorders such as pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), sarcoidosis, and severe refractory asthma.

INS1009 patent issued. The U.S. patent and trademark office issued U.S. patent no. 9,255,064 (the ‘064 patent) on February 9, 2016. The ‘064 patent, entitled "Prostacyclin compounds, compositions and methods of use thereof" is the first patent to issue with claims reciting INS1009. Other treprostinil prodrugs are also claimed and described in the patent. Methods of using treprostinil prodrugs, including INS1009, are described in the patent. The ‘064 patent provides exclusivity for INS1009 until October 24, 2034.

"Last year, Insmed made important progress advancing our clinical and regulatory activities and establishing the foundation of our commercial infrastructure for ARIKAYCE in Europe," said Will Lewis, president and chief executive officer of Insmed. "We enhanced our global team and managed our resources, ending the year with $283 million in cash. In 2016, our priorities include completing patient enrollment in the phase 3 CONVERT study, advancing the European regulatory review of ARIKAYCE, and reporting new data from our internal research programs."

Fourth Quarter Financial Results

For the fourth quarter of 2015, Insmed posted a net loss of $31.2 million, or $0.51 per share, compared with a net loss of $17.6 million, or $0.36 per share, for the fourth quarter of 2014.

Research and development expenses were $19.6 million for the fourth quarter of 2015, compared with $14.8 million for the fourth quarter of 2014. The increase was primarily due to the company’s global phase 3 CONVERT study of ARIKAYCE in NTM lung disease.

General and administrative expenses for the fourth quarter of 2015 were $12.9 million, compared with $8.3 million for the fourth quarter of 2014. The increase was primarily related to pre-commercial activities in Europe and personnel-related expenses, including non-cash stock-based compensation expense.

Balance Sheet Highlights and Cash Guidance

As of December 31, 2015, Insmed had cash and cash equivalents of $283 million. The company is investing in the following activities in 2016: (i) clinical development of ARIKAYCE, (ii) regulatory and pre-commercial initiatives for ARIKAYCE, and (iii) preclinical and clinical activities for its earlier-stage pipeline. As a result, Insmed expects its cash-based operating expenses for the first half of 2016 will be in the range of $58 to $68 million

8-K – Current report

On February 25, 2016 Heat Biologics, Inc. ("Heat") (Nasdaq: HTBX), an immuno-oncology company developing novel therapies that activate a patient’s immune system against cancer, reported that the company will no longer enroll new patients in its Phase 2 monotherapy trial arm evaluating HS-410 alone for the treatment of non-muscle invasive bladder cancer (NMIBC) (Filing, 8-K, Heat Biologics, FEB 25, 2016, View Source [SID:1234509202]). Heat added the monotherapy trial arm in response to the intermittent global shortage of standard of care Bacillus Calmette-Guérin (BCG) in early 2015. The shortage has since then been resolved and as such, Heat will no longer enroll new patients in this trial arm based on discussions with the U.S. Food and Drug Administration (FDA). The decision does not relate to concerns regarding the safety profile of HS-410. The 16 patients currently enrolled, out of the anticipated 25 patients, can continue receiving HS-410 monotherapy per the study protocol. Heat anticipates reporting topline 6-month data from these 16 patients in the fourth quarter of 2016, contemporaneous with reporting data from the company’s BCG combination cohorts.

This decision does not impact the three additional randomized Phase 2 trial arms evaluating HS-410 in combination with BCG for the treatment of NMIBC. As previously announced, Heat completed enrollment of the 75 patients for these three combination trial arms in October 2015 and continues to expect to report one-year topline efficacy, immune-response and safety data in the fourth quarter of 2016.

About HS-410 (vesigenurtacel-L)

HS-410 is an investigational product candidate for NMIBC based on Heat’s proprietary ImPACT immunotherapy platform, designed to generate CD8+ "killer" T cells that attack cancer cells. HS-410 is currently being evaluated in a Phase 2, placebo-controlled NMIBC trial at multiple centers and has been granted U.S. FDA Fast Track Designation for the treatment of NMIBC.

Geron Corporation Reports Fourth Quarter and Annual 2015 Financial Results

On February 25, 2016 Geron Corporation (Nasdaq:GERN) reported financial results for the fourth quarter and year ended December 31, 2015 and recent events (Press release, Geron, FEB 25, 2016, View Source;p=RssLanding&cat=news&id=2143514 [SID:1234509201]).

Fourth Quarter and Year-End 2015 Results

For 2015, the company reported net income of $46,000, or $0.00 per share, compared to a net loss of $35.7 million, or $(0.23) per share, for 2014. For the fourth quarter of 2015, the company reported a net loss of $8.5 million, or $(0.05) per share, compared to a net loss of $8.9 million, or $(0.06) per share, for the comparable 2014 period. The company ended 2015 with $146.7 million in cash and investments.

Revenues for 2015 were $36.4 million compared to $1.2 million for 2014. Revenues for the fourth quarter of 2015 were $220,000 compared to $178,000 for the comparable 2014 period. Revenues for 2015 included the full recognition of the $35.0 million upfront payment from Janssen Biotech, Inc. (Janssen) as collaboration revenue upon the company’s transfer of the imetelstat license rights and completion of technology transfer-related activities outlined under the imetelstat collaboration agreement with Janssen in the third quarter of 2015. The upfront cash payment was received in December 2014 and recorded as deferred revenue at that time.

Total operating expenses for 2015 were $36.9 million compared to $37.5 million for 2014. Total operating expenses for the fourth quarter of 2015 were $8.9 million compared to $9.2 million for the comparable 2014 period. Operating expenses for 2015 included restructuring charges of $1.3 million in connection with the company’s organizational resizing announced in March 2015.

Research and development expenses for 2015 were $17.8 million compared to $20.7 million for 2014. Research and development expenses for the fourth quarter of 2015 were $4.0 million compared to $4.4 million for the comparable 2014 period. The decrease in research and development expenses in 2015 compared to 2014 primarily reflects the net result of lower personnel related costs due to the organizational resizing and reduced manufacturing costs for imetelstat drug product, partially offset by higher costs for the clinical development of imetelstat in collaboration with Janssen.

General and administrative expenses for 2015 were $17.8 million compared to $16.8 million for 2014. General and administrative expenses for the fourth quarter of 2015 were $4.9 million compared to $4.8 million for the comparable 2014 period. The increase in general and administrative expenses in 2015 compared to 2014 primarily reflects higher non-cash stock-based compensation expense.

Interest and other income for 2015 was $677,000 compared to $373,000 for 2014. Interest and other income for the fourth quarter of 2015 was $196,000 compared to $100,000 for the comparable 2014 period. The increase in interest and other income for 2015 compared to 2014 primarily reflects higher cash and investment balances with the receipt of the $35.0 million upfront payment from Janssen and higher yields on the company’s marketable securities portfolio.

Company Events

Publications and Presentations

The New England Journal of Medicine (NEJM) published two papers in which data from clinical studies of two hematologic myeloid malignancies, essential thrombocythemia (ET) and myelofibrosis (MF), suggest imetelstat may have disease-modifying activity by inhibiting the malignant progenitor cell clones responsible for the underlying diseases in a relatively select manner. The papers are available online in the September 3rd issue at www.NEJM.org.
Three presentations describing clinical and non-clinical data on imetelstat were made at the 57th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in December 2015:
Telomerase Inhibitor Imetelstat Therapy in Refractory Anemia with Ring Sideroblasts with or without Thrombocytosis (Abstract #55; oral presentation)

Data were presented for safety and efficacy as of the May 10, 2015 data cut. Nine patients with a form of the myelodysplastic syndromes (MDS) known as refractory anemia with ring sideroblasts (MDS-RARS) were enrolled in the study cohort, classified as having either intermediate-1 or intermediate-2 risk disease by the International Prognostic Scoring System (IPSS). Six of nine (66.7%) patients had prior treatment with erythropoiesis stimulating agents (ESAs).

Three of the eight (37.5%) patients who were dependent on red blood cell transfusions at study entry became transfusion independent, defined as not requiring transfusions for at least eight weeks. The median duration of transfusion independence was 28 weeks (range: nine weeks to 37 weeks).

Adverse events were similar in nature to the adverse events reported in the MF clinical study published in the NEJM.

Dynamics of Mutations in Patients with ET Treated with Imetelstat (Abstract #57; oral presentation)

Data from further mutational analyses of patient samples from the clinical study in ET showed that imetelstat treatment suppressed allele burdens of multiple gene mutations in addition to the JAK2 V617F, CALR and MPL mutations.

Activity of the Telomerase Inhibitor GRN163L (Imetelstat) on Acute Myeloblastic Leukemia Blasts Is Enhanced by DNA Methyltransferase Inhibitors Irrespective of TERT Promoter Methylation Status (Abstract #1267; poster presentation)

Data from an in vitro study showed that imetelstat has activity against samples derived from patients with high risk leukemias, and that activity was enhanced by the demethylating agent 5-azacytadine, which is currently used in the treatment of some patients with high risk MDS or acute myeloid leukemia.
Clinical Development by Janssen

IMbarkTM. In September 2015, the first patient was dosed in a Phase 2 clinical trial to evaluate imetelstat in patients with MF. The trial, referred to as IMbarkTM, will assess the efficacy, safety and tolerability of two dose levels of single-agent imetelstat and is designed to enroll approximately 200 patients (approximately 100 patients per dosing arm) with intermediate-2 or high risk MF, as defined by the Dynamic International Prognostic Scoring System, who have relapsed after or are refractory to Janus Kinase (JAK) inhibitor treatment. Patients will be assigned randomly, on a 1:1 ratio, to one of two dosing arms – 9.4 mg/kg or 4.7 mg/kg every three weeks. Patients will be blinded to the dosing arm assignment. Dose reductions for adverse events are allowed and will follow protocol-specified algorithms. An internal review of data from the trial is planned after approximately 20 patients per arm have been randomized and followed for at least 12 weeks in order to assess the adequacy of one or both of the initial dosing arms. As a result of this internal review, which is expected to occur in the second half of 2016, one or both dosing arms could continue as planned, be stopped or modified, or alternative doses could be selected.

The co-primary efficacy endpoints for IMbarkTM are spleen response rate and symptom response rate. Spleen response rate is defined as the percentage of patients who achieve ≥ 35% reduction in spleen volume from baseline at the Week 24 visit, as measured by imaging scans and assessed at a central imaging facility and by an Independent Review Committee. Symptom response rate is defined as the percentage of patients who have ≥ 50% reduction in Total Symptom Scores from baseline at the Week 24 visit, based on patient-reported outcomes on a modified Myelofibrosis Symptom Assessment Form version 2.0 electronic diary. The primary efficacy analysis of the co-primary endpoints will occur after all treated patients have been followed for at least 24 weeks, and the data cut for this analysis is expected to occur in the second half of 2017. Formal clinical data from this trial is expected to be presented at a medical conference to be determined in the future.

Further information about the trial, including participating medical centers around the world, can be found at View Source
IMergeTM. In January 2016, the first patient was dosed in a Phase 2/3 clinical trial to evaluate imetelstat in patients with MDS. The trial, referred to as IMergeTM, will evaluate imetelstat in transfusion dependent patients with IPSS Low or Intermediate-1 risk MDS who have relapsed after or are refractory to prior treatment with an ESA.

As designed, the trial consists of two parts, and a total of approximately 200 patients are expected to be enrolled. Part 1 of the trial is planned as a Phase 2, open-label, single-arm design to assess the efficacy and safety of imetelstat. Up to 30 patients are expected to be enrolled in Part 1, all of whom will receive imetelstat and be followed for safety, hematologic improvement and reduction in transfusion requirement. Before proceeding to Part 2, the data from Part 1 must support a positive assessment of the benefit/risk profile of imetelstat in these patients. The internal review of data from Part 1 to support advancing to Part 2 is expected to occur in the second half of 2016. Part 2 of the trial is planned as a Phase 3 double-blind, randomized, placebo-controlled design to compare the efficacy of imetelstat against placebo. Approximately 170 patients are expected to be enrolled in Part 2, who will be assigned randomly, in a 2:1 ratio, to receive either imetelstat or placebo.

The primary efficacy endpoint is designed to be the rate of red blood cell transfusion-independence lasting at least eight weeks, defined as the proportion of patients without any red blood cell transfusion during any consecutive eight weeks since entry to the trial. A primary efficacy analysis is planned to occur 12 months after the last patient is enrolled.

Further information about the trial, including participating medical centers around the world, can be found at View Source
Regulatory Designations

The United States Food and Drug Administration has granted orphan drug designation to imetelstat for the treatment of MF and for the treatment of MDS. In addition, the European Medicine Agency has granted orphan drug designation to imetelstat for the treatment of MF.

Celldex Reports Fourth Quarter and Year-End 2015 Results

On February 25, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported business and financial highlights for the fourth quarter and year ended December 31, 2015 (Press release, Celldex Therapeutics, FEB 25, 2016, View Source [SID:1234509195]).

"2015 was a year of considerable progress for Celldex and our growing pipeline," said Anthony Marucci, President and Chief Executive Officer of Celldex Therapeutics. "Most importantly, we completed the Phase 2 ReACT Study of RINTEGA in recurrent GBM, confirming a highly statistically significant long-term overall survival benefit. RINTEGA continues to tell a very consistent, impressive story across multiple, clinically relevant endpoints in both the recurrent and newly diagnosed setting, supporting our belief that RINTEGA will be an important treatment option for all patients with EGFRvIII-positive glioblastoma. With this in mind, we look forward to completing the Phase 3 ACT IV trial in the newly diagnosed setting and are confident we are preparing appropriately for potential commercialization."

"In addition to the strides made in the RINTEGA program, we continued to execute across the entire pipeline in 2015, initiating four new combination studies for the varlilumab program and continuing to enroll patients to ongoing studies of glembatumumab vedotin in both triple negative breast cancer and metastatic melanoma. We also have multiple studies advancing across our earlier-stage product candidates and recently received notice that our IND is now active for CDX-014, our ADC targeting TIM-1. We look forward to initiating the first Phase 1/2 study in renal cell carcinoma for this candidate this year. We are also finalizing preparations with Bristol-Myers Squibb to advance the varlilumab combination study with nivolumab into a broad Phase 2 program. With data reporting from multiple studies across our pipeline in 2016 and into early 2017, we believe the next twelve to eighteen months have the potential to be transformational for the Company," concluded Marucci.

Program Updates:

RINTEGA ("rindopepimut"; "rindo"; CDX-110), an EGFRvIII(v3)-specific therapeutic vaccine for glioblastoma (GBM)

The ACT IV study is a randomized, double-blind, placebo controlled study of RINTEGA plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled into ACT IV to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of overall survival as well as analyses of progression-free survival, safety and tolerability, and quality of life. The study design includes interim analyses conducted by an independent Data Safety and Monitoring Board (DSMB) for superiority and futility at 50% and 75% of events (deaths). The first interim analysis occurred in June 2015, and the DSMB recommended continuation of the study as planned. The required number of events to perform the second interim analysis were reached in late 2015, and the analysis will occur in March 2016. Final data from ACT IV are expected by the end of 2016, although our expectations regarding the timing for the final data read out may change based on event rates.

As previously reported, mature survival data from the Phase 2 ReACT study in patients with recurrent glioblastoma were presented in a podium presentation at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology (SNO) by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, and the lead investigator of the ReACT study. Patients on the RINTEGA arm experienced a statistically significant overall survival (OS) benefit [hazard ratio = 0.53 (0.32, 0.88); p=0.0137], and an impressive, long-term survival benefit was observed. At two years, the survival rate for RINTEGA patients was 25% versus 0% for control patients in the intent to treat (ITT) population, with five patients extending beyond two years. The primary endpoint of the study, progression-free survival at six months (PFS6), was met, and a clear advantage was demonstrated across multiple, clinically important endpoints including long-term progression-free survival, objective response rate (ORR) and need for steroids. 33% of patients on the RINTEGA arm who were receiving steroids at baseline were able to stop steroids for six months or longer compared to none on the control arm.

As part of an ongoing initiative to expand RINTEGA’s potential product profile, Celldex intends to initiate additional studies of RINTEGA in 2016 including:

A study designed to evaluate RINTEGA when administered earlier in the treatment regimen in newly diagnosed glioblastoma. Patients will receive RINTEGA administered after surgery but prior to and concurrently with chemoradiation. In clinical trials conducted to date in the front-line setting, RINTEGA has been administered after surgery but upon completion of chemoradiation. This study is expected to initiate in the second half of 2016.

A study designed to evaluate the role alternative immune modifiers could play in combination with RINTEGA. Previous studies of RINTEGA have utilized GM-CSF. This new study will utilize imiquimod. Imiquimod is a topically administered immune response modifier that has broad commercial availability and could potentially serve as a second source of adjuvant if needed, especially outside the United States where GM-CSF is currently available through specialty distribution channels. The study is expected to initiate in March.

Glembatumumab vedotin ("glemba"; CDX-011), an antibody-drug conjugate targeting gpNMB in multiple cancers

Enrollment continues in the Company’s Phase 2b randomized study (METRIC) of glembatumumab vedotin in patients with metastatic triple negative breast cancers that overexpress gpNMB, a molecule associated with poor outcomes for triple negative breast cancer patients and the target of glembatumumab vedotin. Enrollment is open across the United States, Canada and Australia. The Company plans to open enrollment in up to 50 sites in the EU beginning in the first quarter of 2016, and enrollment is expected to be completed in the second half of 2016.

Patient enrollment continues in the Phase 2 study of glembatumumab vedotin in metastatic melanoma and is expected to be completed in the first half of 2016 with data presented at an appropriate medical meeting in the second half of 2016.

Celldex continues to advance plans to expand the study of glembatumumab vedotin in other cancers in which gpNMB is expressed.
A Phase 2 study in squamous cell lung cancer is expected to commence in Q2 2016.
Celldex and the National Cancer Institute (NCI) have entered into a Cooperative Research and Development Agreement (CRADA) under which the NCI is sponsoring two studies of glembatumumab vedotin—one in uveal melanoma and one in pediatric osteosarcoma. Both studies are currently open to enrollment.

Varlilumab ("varli"; CDX-1127), a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade

The Phase 1/2 study of varlilumab and nivolumab (Opdivo ) in adult patients with multiple solid tumors has completed enrollment to the dose escalation Phase 1 portion of the study. Celldex and Bristol-Myers Squibb have decided to advance this combination into Phase 2. While a maximum tolerated dose was not reached in Phase 1, a 3 mg/kg varlilumab dose has been identified for study in Phase 2. We anticipate the Phase 2 portion of the study will open to enrollment in the second quarter of 2016 and will include cohorts in advanced non-small cell lung cancer, colorectal cancer, ovarian cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma. This study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb. The companies are sharing development costs.

The Phase 1/2 study of varlilumab and atezolizumab (anti-PDL1) is currently enrolling patients with multiple solid tumors in the dose escalation Phase 1 portion of the study. The Phase 2 portion of the study will be conducted in renal cell carcinoma. This study is being conducted by Celldex under a clinical trial collaboration with Roche. Roche is providing study drug, and Celldex is responsible for conducting and funding the study.

Additional combination studies of varlilumab continue to enroll patients including:
A Phase 1/2 safety and tolerability study examining the combination of varlilumab and sunitinib (Sutent) in patients with metastatic clear cell renal cell carcinoma (CC-RCC).
A Phase 1/2 safety and tolerability study examining the combination of varlilumab and ipilimumab in patients with Stage III or IV metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive Celldex’s CDX-1401.

Celldex presented a preclinical poster on the contribution of varlilumab’s immune stimulating properties versus regulatory T cell (Treg) depletion in multiple tumor models in November at the 2015 Society for the Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting. Results suggested that cancers may respond to CD27 immune modulation by independent mechanisms, such as immune co-stimulation and regulatory T cell (Treg) depletion. Varlilumab has the unique ability to act through both of these mechanisms.

CDX-1401, an antibody-based NY-ESO-1-specific therapeutic vaccine for multiple solid tumors

As discussed above, a Phase 1/2 study examining the combination of varlilumab and ipilimumab continues to enroll patients with Stage III or IV metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, an off-the-shelf antibody-based dendritic cell targeted vaccine.

Celldex continues to support several external collaborations, including an NCI sponsored Phase 2 study of CDX-1401 and CDX-301 for patients with metastatic melanoma, which recently completed enrollment. Based on results to date, plans for additional studies are being considered by NCI. Additionally, Roswell Park Cancer Center is conducting an investigator sponsored study evaluating CDX-1401, poly-ICLC (Hiltonol) and the IDO1 inhibitor epacadostat (INCB24360) in patients in remission with ovarian, fallopian tube or primary peritoneal cancer. Patients’ tumors must have expressed NY-ESO-1 or the LAGE-1 antigen to be eligible for the study. Celldex is providing CDX-1401 and poly-ICLC in support of this study.

CDX-301 (recombinant human Flt3L), a potent hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells

A pilot study of CDX-301 alone and in combination with plerixafor (Mozobil) in hematopoietic stem cell transplantation (HSCT) is currently enrolling patients and sibling-matched donors. The Company presented early data from the non-plerixafor treated arm in this study in February at the annual meeting of the American Society for Blood and Marrow Transplantation. Three donor/patient pairs showed that CDX-301 given as a single agent was well tolerated and effective at mobilizing hematopoietic stem cells in healthy donors. The stem cell graft contained notable increases in naïve lymphocytes and plasmacytoid dendritic cells consistent with preclinical data suggesting a possible better outcome. Recipients experienced successful engraftment in an expected time frame. Additional subjects are being accrued to assess the potential synergy of combining CDX-301 with plerixafor in this setting.

CDX-301’s potential activity is also being explored in a Phase 1/2 study of CDX-301 and poly-ICLC in combination with low-dose radiotherapy in patients with low-grade B-cell lymphomas conducted by the Icahn School of Medicine at Mount Sinai.

Fourth Quarter and Twelve Months 2015 Financial Highlights and 2016 Guidance

Cash position: Cash, cash equivalents and marketable securities as of December 31, 2015 were $289.9 million compared to $304.6 million as of September 30, 2015. The decrease was primarily driven by our fourth quarter cash used in operating activities of approximately $22.9 million, partly offset by the receipt of $9.2 million from the sale of New Jersey tax benefits. As of December 31, 2015 Celldex had 98.7 million shares outstanding.

Revenues: Total revenue was $1.8 million in the fourth quarter of 2015 and $5.5 million for the twelve months ended December 31, 2015, compared to $1.5 million and $3.6 million for the comparable periods in 2014. The increase in revenue was primarily due to our clinical trial collaboration with Bristol-Myers Squibb and our research and development agreement with Rockefeller University.

R&D Expenses: Research and development (R&D) expenses were $23.9 million in the fourth quarter of 2015 and $100.2 million for the twelve months ended December 31, 2015, compared to $27.0 million and $104.4 million for the comparable periods in 2014. R&D expenses include stock-based compensation expense of $2.0 million and $6.2 million in the three- and twelve-month periods ended December 31, 2015 compared to $1.1 million and $3.5 million for the comparable periods in 2014.

G&A Expenses: General and administrative (G&A) expenses were $11.1 million in the fourth quarter of 2015 and $33.8 million for the twelve months ended December 31, 2015, compared to $6.2 million and $20.6 million for the comparable periods in 2014. The increase in G&A expenses was primarily attributable to higher personnel-related expenses as we prepare for potential commercialization and a $6.5 million increase in RINTEGA and glembatumumab vedotin commercial planning costs in 2015 as compared to 2014. G&A expenses include stock-based compensation expense of $2.1 million and $6.6 million in the three- and twelve-month periods ended December 31, 2015 compared to $1.0 million and $3.4 million for the comparable periods in 2014.

Net loss: Net loss was $32.7 million, or ($0.33) per share, for the fourth quarter of 2015 and $127.2 million, or ($1.31) per share, for the twelve months ended December 31, 2015, compared to a net loss of $31.8 million, or ($0.36) per share, and $118.1 million, or ($1.32) per share, for the comparable periods in 2014.

Financial guidance: Celldex expects that its cash, cash equivalents and marketable securities will be sufficient to fund our operating expenses and capital expenditure requirements through 2017; however, this could be impacted by our clinical data results from the RINTEGA program and their potential impact on our pace of commercial manufacturing and the rate of expansion of our commercial operations.