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Celsion Reports Translational Research Data from its Phase 1b Study of GEN-1 Immunotherapy in Recurrent Ovarian Cancer

On January 7, 2016 Celsion Corporation (NASDAQ: CLSN), reported new translational data from its Phase 1b study of GEN-1 in patients with platinum-resistant ovarian cancer (Press release, Celsion, JAN 7, 2016, View Source [SID:1234508682]). GEN-1 is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. The new data demonstrate that intraperitoneally-administered GEN-1 produces an immunologically distinct IL-12 protein that is localized at the tumor site and lasts for up to one week after a single treatment. Furthermore, concomitant increases in IFN-γ and TNF- α indicate that the IL-12 produced following treatment with GEN-1 treatment is immunologically active. Celsion Corporation is a fully integrated oncology company focused on the development of a portfolio of innovative cancer treatments, including directed chemotherapies, immunotherapies and RNA- or DNA-based therapies for the treatment of cancer and other difficult-to-treat diseases.

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"We now have clear clinical evidence that treatment of platinum-resistant ovarian cancer with GEN-1 produces a sustained, localized immune response, which then translates to the compelling activity and tolerability profile we have seen in early clinical studies," said Khursheed Anwer, Ph.D., executive vice president and chief scientific officer of Celsion. "These data also provide additional evidence of GEN-1’s ability to overcome the limitations associated with recombinant IL-12, which has a very short half-life and results in high systemic levels of IL-12, leading to potentially severe toxicities. We plan to build on these data and advance our understanding of GEN-1’s mechanism of action further with additional translational research as part of our ongoing OVATION Study."

The Phase 1B dose escalating study enrolled 16 patients with platinum-resistant ovarian cancer and evaluated the safety, tolerability and efficacy of GEN-1 in combination with pegylated doxorubicin as well as the effect of intraperitoneal injection of GEN-1 on IL-12 and tumor cytokine levels. Patients received pegylated liposomal doxorubicin on day 1 and GEN-1 on days 1, 8, 15 and 22. This treatment regimen was repeated every 28 days in the absence of disease progression or toxicity.

Celsion reported clinical findings from the Phase 1b study at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting in June 2015 demonstrating an overall clinical benefit of 57% for all treatment arms. The overall clinical benefit observed at the highest dose cohort in this difficult-to-treat patient population was 100% (PR=33% and SD=67%) in all six evaluable patients. A maximum tolerated dose was not reached and studies evaluating higher doses of GEN-1 are currently underway.

The new translational data reported today is highlighted below:

Intraperitoneal administration of GEN-1 in platinum-resistant ovarian cancer patients resulted in a significant increase in IL-12 levels in peritoneal fluid samples. IL-12 levels were quantifiable in 91% of evaluable fluid samples collected post GEN-1 treatment. None of the evaluable pre-treatment peritoneal fluid samples had any detectable IL-12 levels.

The IL-12 levels were detectable for at least seven days after GEN-1 treatment.

In comparison to peritoneal fluid, the IL-12 levels in plasma samples (systemic exposure) following GEN-1 treatment were not detectable or were very low in quantity.

Significant increases in levels of IFN-γ, a key downstream mediator of IL-12 action, were observed in peritoneal fluid but not in plasma samples. At least a 5-fold increase above pre-treatment level in IFN- γ was observed in most samples, with the highest increase observed at 120-fold. Similar results were observed with TNF-α levels, with the highest increase observed at 77-fold over pre-treatment control.

A publication of this data is being prepared for submission for major scientific review which will detail all cytokine levels observed in this study.

Celsion intends to collect additional translational data, including cellular responses in primary tumor tissue and peritoneal ascites, in its ongoing OVATION Study, a Phase I dose escalation study in newly diagnosed ovarian cancer patients in the neoadjuvant setting.

"With these remarkable findings we feel confident that the data we expect to collect from the OVATION Study will provide further evidence that GEN-1, our gene-mediated immunotherapy, has significant potential in oncology generally and in ovarian cancer specifically," noted Michael H. Tardugno, Celsion’s chairman, CEO and president. "Our clinical development program for ovarian cancer is now well positioned with compelling clinical and biological data, fully supporting our thesis for combining GEN-1 with Doxil and Avastin to treat platinum-resistant ovarian cancer patients in a study we expect to launch later this year."

BIND Therapeutics Presents Complete Data on Clinical Activity of BIND-014 in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) at the 2016 Genitourinary Cancers Symposium

On January 7, 2016 BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine company developing targeted and programmable therapeutics called ACCURINS, reported the presentation of complete data from its phase 2 clinical trial of BIND-014, a PSMA-targeted ACCURIN containing docetaxel, in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) who either were or were not exposed to anti-androgens (abiraterone acetate and/or enzalutamide) (Press release, BIND Therapeutics, JAN 7, 2016, View Source [SID:1234508681]). BIND-014 was clinically active and well-tolerated and the study met its primary endpoint with 71 percent of patients achieving rPFS of at least 6 months. The complete data are being presented on January 7, 2016 during a poster session at the 2016 Genitourinary Cancers Symposium held in San Francisco.

"We are encouraged by the safety and activity profile of BIND-014 in this phase 2 trial, which support its potential to be a nanomedicine alternative superior to conventional docetaxel," said Hagop Youssoufian, M.D., M.Sc., chief medical officer, BIND Therapeutics. "Although these data are encouraging, recent advances with anti-androgen therapy limit our ability to compare BIND-014 data to historical benchmarks. At this time, we are not planning further development of BIND-014 in mCRPC given the evolving treatment landscape. We anticipate additional BIND-014 data from both the iNSITE 1 trial in squamous histology non-small cell lung cancer and the iNSITE 2 trial in multiple tumor types during the first quarter of 2016, which we expect to determine our next steps in the clinical development of BIND-014."

In addition to the primary endpoint, data presented from the trial included measurements of safety and tolerability, objective response rates (ORR), prostate-specific antigen (PSA) response, changes in circulating tumor cells (CTC) and overall survival (OS). Key results include:

BIND-014 administered at 60 mg/m² on day 1 of a 21-day cycle was clinically active and well-tolerated when administered to patients (n=42) with chemotherapy-naive mCRPC, including the 74% of patients with prior exposure to abiraterone acetate and/or enzalutamide.

Median rPFS of 9.9 months (95% CI, 7.1 – 12.6) was achieved (n=42 with 8 censored).
A confirmed ORR of 21% was observed in patients with measurable disease (n=19).
A 50% reduction in PSA was observed in 30% of PSA evaluable patients (n=40).
CTC conversion from ≥ 5 cells/7.5 mL blood at baseline to < 5 cells/7.5 mL blood was observed in 50% of patients.
Median OS was 13.4 months (95% CI, 9.9 – 18.6 months [n=42 with 10 censored]).

C4 Therapeutics Enters Strategic Drug Discovery Collaboration WITH ROCHE PHARMA in the Promising New Field of Targeted Protein Degradation

On January 7, 2015 C4 Therapeutics reported that they will enter into a strategic collaboration with Roche to develop novel treatments in the field of targeted protein degradation (TPD) using C4’s Degronimid technology (Press release, C4 Therapeutics, JAN 7, 2016, View Source;c4-therapeutics-enters-strategic-drug-discovery-collaboration.html [SID:1234508696]). C4’s Degronimids represent a new class of small molecules, TPD therapeutics, which target disease-causing proteins and facilitate their rapid destruction and clearance from the cell through the ubiquitin/proteasome system (UPS).

"Roche is a leader and early adopter of innovation in drug discovery and this significant collaboration comes at a critical time in our development," said Marc Cohen, co-founder and executive chairman of C4 Therapeutics. "This partnership strengthens our leadership position in the field of TPD therapeutic drug discovery. It is part of our strategy to enter into multiple target-specific partnerships that will allow us to pursue a broad set of indications in parallel, while supporting the continued development of our proprietary platform."

Under the terms of the agreement, C4 will initially develop TPD therapeutics that utilize Degronimid technology for a specific set of target proteins. After successful completion of a defined preclinical development phase, Roche has the option to pursue further pre-/clinical development and commercialization. C4 will receive an undisclosed upfront payment and additional development, regulatory and commercial milestone payments per target, as well as sales milestone payments and potential tiered royalties on sales of products resulting from the agreement. The potential value of the deal over time is greater than $750 million.

C4’s Degronimid technology platform was pioneered in 2010 by researchers in the Bradner Laboratory at Dana-Farber Cancer Institute, and is exclusively licensed to C4 Therapeutics from Dana-Farber. Degronimids link drug-like small molecules to the cellular ubiquitin/proteasome system to naturally eliminate targeted proteins by tagging them with ubiquitin for destruction by the proteasome. Degronimids are capable of hitting many more targets than protein inhibitors or peptide-based approaches, and are active against previously undruggable targets, while also reducing potential for drug resistance. This paradigm shift in drug development is applicable to a broad range of diseases.
C4 Therapeutics recently announced that it was launched from Dana-Farber with the closing of a $73 million Series A financing to translate the breakthrough Degronimid technology into a new class of therapeutics that target proteins for degradation. The Company’s scientific cofounders include Ken Anderson, M.D., and Nathanael Gray, Ph.D., both from Dana-Farber Cancer Institute and James "Jay" E. Bradner, M.D., a former investigator at Dana-Farber.

About C4 Therapeutics
C4 Therapeutics is developing a new class of targeted protein degradation (TPD) therapeutics for the treatment of a broad range of diseases. Our Degronimid platform incorporates highly selective small molecule binders to target disease-causing proteins and facilitate their rapid destruction and clearance from the cell through the natural ubiquitin/proteasome system (UPS). Because of this distinctive mechanism, Degronimids are capable of hitting many more targets, including those previously thought to be undruggable, while reducing the potential for drug resistance. The broad applicability of Degronimids, and our chemical biology platform designed for accelerated validation, have the potential to make an unprecedented impact across many diseases through multiple industry collaborations as well as proprietary programs.

C4 Therapeutics Launches with $73M Series A Financing

On January 7, 2016 C4 Therapeutics reported that it has launched from Dana-Farber Cancer Institute with the closing of a $73 million Series A round of financing (Press release, C4 Therapeutics, JAN 7, 2016, View Source;series-a.html [SID:1234508695]).

The Company is developing novel treatments in the field of targeted protein degradation using proprietary Degronimid technology. The Degronimid platform technology was pioneered since 2010 by researchers in the Bradner Lab at Dana-Farber Cancer Institute and described in a seminal paper published in the Journal Science in June 2015. Degronimids represent a new class of small molecule targeted protein degradation (TPD) therapeutics that target disease-causing proteins and facilitate their rapid destruction and clearance from the cell. The Company has executed a license agreement with Dana-Farber that provides worldwide exclusivity for all applications of the Degronimid technology.

The groundbreaking Degronimid platform utilizes an innovative, all-chemical solution for potent, targeted and rapid protein degradation. Degronimids are novel chemical adapters that are conjugated with selective small molecules designed to recruit the cell’s ubiquitin/proteasome system (UPS) in order to "naturally" degrade targeted proteins. Degronimids offer a promising solution for the removal of previously undruggable proteins, including those that are known to develop resistance to inhibitors.

"We are building a word-class team of pioneers in the field of targeted protein degradation who are dedicated to our mission of developing a new class of therapeutics that will have a profound effect on many diseases," said Marc Cohen, Co-founder and Executive Chairman of C4 Therapeutics. "The use of Degronimids as a strategy for targeting traditionally undruggable proteins and overcoming resistance is extremely promising. By removing the need for ongoing target inhibition from the therapeutic equation, TPD therapeutics represent a new paradigm in drug development. C4 is a company that will develop many drugs over time in proprietary and partnered development programs."

C4 Therapeutics was co-founded by Ken Anderson, M.D., Kraft Family Professor of Medicine, Harvard Medical School, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber, and a world-renowned expert in protein degradation and multiple myeloma; Nathanael Gray, Ph.D., Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Principal Investigator at Dana-Farber and an expert in kinase inhibitors and drug discovery; software and biotech entrepreneur Marc Cohen; and James "Jay" E. Bradner, M.D., former Associate Professor of Medicine, Harvard Medical School and former Investigator at Dana-Farber. With Dr. Bradner’s new role at Novartis Institutes for BioMedical Research, he will no longer have involvement with the Company. C4 will be located at Mass Innovation Labs in Kendall Square, Cambridge. Cobro Ventures led the Series A round, with additional investments from Cormorant Asset Management, The Kraft Group, EG Capital Group, and angel investors. Other investors include Roche and Novartis.

"Drug discovery research around the ubiquitin/proteasome system is an exciting and growing field, and the discovery of Degronimids represents the first all-chemical solution to ligand-mediated protein degradation," said Dr. Nathanael Gray. "The Dana-Farber Cancer Institute has a strong track record of fostering the advancement of groundbreaking discoveries in numerous oncology applications. By licensing these technologies to companies such as C4, we are supporting the further development of highly promising therapeutic candidates for the betterment of human health."
In conjunction with the Series A financing, C4 announced the appointment of Jason Fisherman, M.D., as Chief Executive Officer of the Company and Member of the Board of Directors. Dr. Fisherman has an extensive track record of building companies as a venture investor at Synthesis Capital and Advent International, a global private equity firm, where his team led or managed over 35 investments in biotechnology, medical technology and healthcare information services. Prior to joining Advent International, Dr. Fisherman had over ten years of drug research and clinical development experience in biopharmaceutical companies, academia, and at the National Cancer Institute. Dr. Fisherman received a B.A. in Molecular Biophysics and Biochemistry from Yale, an M.D. from the University of Pennsylvania and an M.B.A. from the Wharton School of the University of Pennsylvania.

"We are pleased to have Dr. Fisherman join our growing team and believe that C4 will greatly benefit from his extensive financial, business and clinical development expertise," said Cohen. "Dr. Fisherman has 30 years of professional experience within the healthcare and life science industry and will help build our leading Degronimid pharmacology platform."

About C4 Therapeutics
C4 Therapeutics is developing a new class of targeted protein degradation (TPD) therapeutics for the treatment of a broad range of diseases. Our Degronimid platform incorporates highly selective small molecule binders to target disease-causing proteins and facilitate their rapid destruction and clearance from the cell through the natural ubiquitin/proteasome system (UPS). Because of this distinctive mechanism, Degronimids are capable of hitting many more targets, including those previously thought to be undruggable, while reducing the potential for drug resistance. The broad applicability of Degronimids, and our chemical biology platform designed for accelerated validation, have the potential to make an unprecedented impact across many diseases through multiple industry collaborations as well as proprietary programs.

Daratumumab Data Published in The Lancet Shows Encouraging Efficacy in Heavily Pretreated and Refractory Multiple Myeloma

On January 7, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported The Lancet has published data from the Phase II study (Sirius MMY2002) of daratumumab in patients with relapsed and refractory multiple myeloma (Press release, Genmab, JAN 7, 2016, View Source [SID:1234508679]).

Patients that received 16 mg/kg of daratumumab had a median of five prior lines of therapy and 95.3% were refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs, which are current standard of care treatments for multiple myeloma. The data showed a 29.2% overall response rate (31 of 106), including three stringent complete responses, ten very good partial responses, and 18 partial responses in patients treated with 16 mg/kg of daratumumab. The median time to response was one month among patients who responded to treatment. Median duration of response was 7.4 months, and median progression free survival was 3.7 months. The 12-month overall survival rate was 64.8% and at a subsequent cutoff, median overall survival was 17.5 months. Daratumumab was well tolerated, with fatigue (40%) and anemia (33%) of any grade as the most common adverse events (AEs). No drug-related AEs led to treatment discontinuation.

"Data from the daratumumab Sirius study illustrates the significant potential of daratumumab in patients with multiple myeloma who have undergone multiple rounds of prior treatment. Data from the study, now published in The Lancet, was the basis for the approval of daratumumab in heavily pre-treated or double refractory multiple myeloma by the U.S. FDA," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

In November 2015, the U.S. Food and Drug Administration (FDA) approved DARZALEX (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 A marketing application with data from the Sirius study and data from four other studies was submitted to the European Medicines Agency (EMA) by Janssen in September 2015 and was subsequently granted accelerated assessment.

About the Study (Sirius MMY2002)
This two-part study enrolled 124 patients who have received at least three prior lines of therapy, including both a proteasome inhibitor and an immunomodulatory agent, or who are double refractory to a proteasome inhibitor and an immunomodulatory agent. Examples of proteasome inhibitors are bortezomib or carfilzomib and examples of immunomodulatory agents are pomalidomide or lenalidomide. Part 1 defined an optimal daratumumab regimen going forward, while part 2 was an expansion, based on the optimal regimen determined in Part 1. The primary objective of the study was to define the optimal dose and dosing schedule, to determine the efficacy of two treatment regimens of daratumumab as measured by overall response rate (ORR), and to further characterize the safety of daratumumab as a single agent.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.3 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including PIs or immunomodulatory agents, have poor prognoses and few treatment options.6

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.10 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,7,10 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,7,10 antibody-dependent cellular phagocytosis8,11 and antibody-dependent cellular cytotoxicity.7,10 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (Tregs) both of which express CD38. These reductions in MDSCs and Tregs were paralleled by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.10

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.