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). Schedule your 30 min Free 1stOncology Demo! "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."
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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.
Year: 2016
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]).
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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]). Schedule your 30 min Free 1stOncology Demo! 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.
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"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.
Baxalta Announces Priority Review Status Granted by Health Canada for irinotecan liposome injection (nal-IRI) for New Drug Submission
On January 7, 2016 Baxalta Incorporated (NYSE: BXLT), a global biopharmaceutical leader dedicated to delivering transformative therapies to patients with orphan diseases and underserved conditions, reported that Health Canada has granted Priority Review status for its New Drug Submission (NDS) for irinotecan liposome injection, also known as "nal-IRI" (Press release, Baxalta, JAN 7, 2016, View Source [SID:1234508678]). Schedule your 30 min Free 1stOncology Demo! Baxalta is seeking marketing approval of nal-IRI from Health Canada for the treatment of patients with metastatic adenocarcinoma of the pancreas previously treated with gemcitabine-based therapy.
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Priority Review allows for expedited review of critical new drugs faster than the standard timeline. Review by Health Canada is expected to be conducted in the second half of 2016. Baxalta is responsible for the development and commercialization of nal-IRI outside of the U.S. and Taiwan under the exclusive licensing agreement with Merrimack Pharmaceuticals, Inc.
"We are encouraged by the decision Health Canada has made to review our NDS of nal-IRI on an expedited timeline," said Salim Yazji, M.D., vice president and global therapeutics head, Oncology, Baxalta. "Pancreatic cancer is one of the few cancers for which survival has not improved substantially over the last few decades, largely due to late diagnosis, aggressiveness of the disease and limited treatment options. This is an important milestone for our joint efforts to bring nal-IRI to more patients worldwide and fight this devastating cancer of the pancreas to help fill a significant unmet medical need."
The application is based upon the results of an international Phase 3 study (NAPOLI-1) conducted among patients with metastatic pancreatic cancer (mPaC) who previously received gemcitabine-based therapy. In combination with 5-fluorouracil (5-FU) and leucovorin (LV), nal-IRI achieved its primary and secondary endpoints by demonstrating a statistically significant improvement in overall survival, progression free survival and overall response rate compared to the control group of patients who received a combination of 5-FU and LV. The most common Grade 3 or higher adverse events in patients receiving nal-IRI and 5-FU/LV were neutropenia, fatigue and gastrointestinal effects. This was the first global Phase 3 study in a post-gemcitabine setting to demonstrate a survival benefit in the treatment of this aggressive disease.
Baxalta and Merrimack recently enrolled the first patient in an exploratory Phase 2 clinical study of nal-IRI in previously untreated, metastatic pancreatic adenocarcinoma to assess the safety and efficacy of the combination of nal-IRI, 5-FU and LV, with or without the addition of oxaliplatin, versus nab-paclitaxel and gemcitabine. Based on the current design of this study, data is expected in the first half of 2017. In addition to studying nal-IRI in patients with pancreatic cancer, there are ongoing Phase 1 studies of nal-IRI in patients with pediatric sarcoma, glioma, breast and gastric cancer.
A Marketing Authorization Application submitted by Baxalta is also under review in the European Union for the treatment of adult patients with metastatic adenocarcinoma of the pancreas who have previously been treated with gemcitabine-based therapy. The decision from Health Canada follows the recent U.S. Food and Drug Administration (FDA) approval of nal-IRI, Merrimack’s (Onivyde) New Drug Application for the same indication using the same clinical efficacy and safety data.
About Pancreatic Cancer
Pancreatic cancer is rare and deadly – accounting for less than three percent of all cancer cases worldwide, but the seventh leading cause of cancer death1. An estimated 340,000 new cases are diagnosed every year around the world1, about two-thirds of which are among people aged 65 or older2. It is estimated that there were 4,800 new cases of pancreatic cancer this past year in Canada specifically3.
Because the signs and symptoms of pancreatic cancer are non-specific and may not appear until the disease has spread to other sites, approximately 80 percent of patients are not candidates for surgery; these patients instead receive chemotherapy as the mainstay of their therapy4. This contributes to the five-year survival rate for all patients being less than six percent5. There is no consensus on the standard of care for patients with mPaC previously treated with a gemcitabine-based therapy.
About irinotecan liposome injection (nal-IRI)
nal-IRI is an investigational nanoliposome consisting of the chemotherapeutic, irinotecan, encapsulated in a liposomal sphere. Merrimack received FDA approval for nal-IRI under the brand name Onivyde for the treatment of patients with metastatic adenocarcinoma of the pancreas who have been previously treated with gemcitabine-based therapy. nal-IRI was granted Fast Track designation and Priority Review by the FDA for this indication. The FDA also granted nal-IRI orphan drug designation for patients with mPaC. Baxalta is responsible for the development and commercialization of nal-IRI outside of the United States and Taiwan under an exclusive licensing agreement with Merrimack. PharmaEngine holds the rights to commercialize Onivyde in Taiwan, following TFDA approval in October 2015.
Caladrius Tightens Strategic Focus and Provides 2016 Revenue Guidance
On January 6, 2016 Caladrius Biosciences, Inc. ("Caladrius" or the "Company") (NASDAQ: CLBS), a cell therapy company combining an industry-leading development and manufacturing services provider with a therapeutic development pipeline, announces an increased focus of its strategic priorities and provides 2016 revenue guidance based on growth at its PCT subsidiary.
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Following a comprehensive review of the Company’s existing operations and development pipeline, as well as an updated assessment of current market dynamics, current and expected future competitive therapies, and the Company’s financial resources, Caladrius has decided to shift greater focus and resources to its growing cell therapy process development, optimization and manufacturing services business at its PCT subsidiary. The rapidly developing cell therapy industry, with several cell-based therapies approaching market approvals which are expected to generate additional demand for commercial manufacturing infrastructure, along with PCT’s continued trend of strong revenue growth, supports the Company’s commitment to focus on growth opportunities for PCT. The Company has also reconfirmed its commitment to pursue further development of its immune modulation platform, with a Phase 2 proof-of-concept clinical trial for a T regulatory cell therapy as the primary focus, while choosing to discontinue the current Phase 3 study of CLBS20 as monotherapy for metastatic melanoma.
"Moving forward, we strongly believe PCT represents a compelling opportunity for near- and long-term shareholder value creation and we intend to continue to invest resources in expanding that business, where we are already experiencing noteworthy year-over-year revenue growth," stated David J. Mazzo, Ph.D., Chief Executive Officer of Caladrius.
"For nearly 17 years, PCT has been an integral partner to the regenerative medicine industry by leveraging its cell therapy-focused, bicoastal development and manufacturing infrastructure to support biotechnology and cell therapy companies," said Robert A. Preti, Ph.D., Chief Technology Officer of Caladrius and President of PCT. "We continue to focus on the design and implementation of sustainable, scalable, reliable and well-controlled manufacturing processes with optimized cost-of-goods as these are all critical success parameters in bringing new cell therapy and immunotherapy treatments to market. We are looking forward to further acceleration of these activities."
Dr. Mazzo continued, "The treatment paradigm in metastatic melanoma was transformed during the course of 2015 by the accelerating adoption of multiple immune checkpoint inhibitors used as monotherapy and in combination treatments. These new drugs have significantly improved outcomes in metastatic melanoma and therefore have altered the opportunity for a monotherapy such as CLBS20 in a landscape that is quickly converting to combination therapies. Therefore, we have concluded that, as designed, our current program in metastatic melanoma will not optimally leverage this asset and we will therefore discontinue the ongoing Phase 3 clinical study with CLBS20 as a monotherapy for the treatment of recurrent Stage III or Stage IV metastatic melanoma. As a result, we will reduce associated staff by approximately 40 employees at our Irvine, California facility. That said, we continue to believe in the potential of CLBS20 as a life-prolonging immunotherapeutic and will pursue licensing or partnership opportunities for its continued development as part of a combination therapy and in different oncology indications. The emphasis will be on collaborating with a company that will allow us to exploit the novel antigen presentation and T cell activation approach of CLBS20."
On the development front, Caladrius will focus its efforts on its T regulatory (Treg) cell therapy product candidate, CLBS03. CLBS03 is based on the Company’s novel immune modulation approach that seeks to restore immune balance by enhancing Treg cell number and function. The Company is planning to commence enrollment in a Phase 2 study for adolescents with recent-onset type 1 diabetes in the first quarter of 2016, in collaboration with Sanford Research, a non-profit research organization that supports an emerging translational research center focused on finding a cure for type 1 diabetes.
"The opportunity provided by polyclonal T cells in the treatment of autoimmune diseases is compelling and we are excited to be at the forefront of this technology’s development and to be working with recognized leaders in the field, such as Drs. Jeffrey Bluestone and Stephen Gitelman of the University of California, San Francisco and Dr. Kevan Herold of Yale University. We believe CLBS03 has the potential to be paradigm-changing in the treatment of recent-onset diabetes and, potentially, other autoimmune diseases. We look forward to initiating our Phase 2 clinical program in conjunction with Sanford Research in the first quarter of 2016," concluded Dr. Mazzo.
Financial Guidance
For 2015, Caladrius expects total revenue to be approximately $23 million, representing an increase of approximately 28% compared with 2014. For 2016, Caladrius expects total revenue to exceed $30 million, representing an increase of greater than 30% compared with the expected results for 2015. In order to accommodate this projected growth, Caladrius has budgeted to spend $6 million in capital improvements to increase PCT’s Allendale, NJ clean room capacity by 60%, and expects to complete the build-out in 2016. Caladrius also estimates that it will incur restructuring charges of approximately $1.0 million in connection with one-time employee termination costs, including severance and other benefits, in the first quarter of 2016. The Company estimates that the staff reduction will result in over $4 million in annualized compensation-related savings, and anticipates significant cost savings associated with terminating the CLBS20 study, which had been estimated to cost $35 million through its completion. In addition, with a narrowed focus on research and development initiatives, as well as a re-sizing of the Company’s general and administrative infrastructure, Caladrius expects to lower R&D, G&A and overall cash burn in 2016 compared to 2015. The Company also expects to incur significant non-cash intangible asset and goodwill impairment charges associated with the termination of the CLBS20 study and will assess the impact as of December 31, 2015 during its annual intangible asset impairment review process.