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Flagship Ventures Launches Rubius To Develop Red-Cell Therapeutics

On December 9, 2015 Flagship Ventures, a leading innovation and venture firm focused on healthcare and sustainability, reported it has launched Rubius Therapeutics, to develop functionalized red blood cells for the treatment of autoimmune conditions, metabolic diseases, cancer, and other serious diseases (Press release, Rubius Therapeutics, DEC 9, 2015, View Source [SID1234520729]). Flagship has made an initial capital commitment of $25 million to enable Rubius to enter clinical testing of its novel therapeutic modality.

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Rubius is pioneering Red-Cell Therapeutics (RCTs). RCTs are a new treatment modality and possess pharmacodynamic and pharmacokinetic advantages over traditional therapeutics, in part due to their natural ability to engage and modulate the immune system and circulate for extended periods in the body.
"Working together with our collaborators, technology advances made at Flagship’s innovation foundry, VentureLabs, led to the creation of a completely new therapeutic modality," said Noubar Afeyan, Ph.D., senior managing partner and CEO of Flagship Ventures and a director of Rubius. "We believe Red-Cell Therapeutics will become a new standard of care in many areas of high unmet medical need."
One of the diseases Rubius intends to initially target is phenylketonuria (PKU), a disease of metabolism that affects as many as one in 13,000 births in the U.S. and is responsible for about 300 new cases each year. People born with PKU have a genetic defect that leaves them unable to break down a particular amino acid, one
of the building blocks of proteins. Left untreated, the amino acid, phenylalanine, builds up in the body and causes severe developmental problems and long-term health issues. Newborns are routinely tested for this genetic disease within days of birth.
Currently, the most effective treatment for PKU is a strict diet that lowers the amount of phenylalanine in the body. Rubius has developed and pre-clinically validated a Red-Cell Therapeutic capable of enzymatically reducing phenylalanine levels in human serum. By continually lowering phenylalanine levels in the bloodstream, RCT therapy promises to allow PKU patients to live normally without extremely restrictive diets.
"Red blood cells can now be produced in culture and engineered to possess enormous biotherapeutic properties," said Harvey Lodish, Ph.D., professor of biology and bioengineering at MIT and a member of the Whitehead Institute, who is a scientific founder of Rubius and has joined the firm’s board of directors. "They spend as much as four months in circulation, providing an opportunity for long and tunable therapeutic treatments. Red cells also have profound effects on the immune system and may ultimately transform the way we treat autoimmune diseases and allergies."
"Through its rapid prototyping capability, Rubius has generated and tested over 50 different RCTs for a wide array of indications including autoimmunity, oncology and infectious disease" said Avak Kahvejian, Ph.D., founding CEO of Rubius and Flagship VentureLabs partner. "The company is now poised to drive lead programs into the clinic, build a drug pipeline and further develop the Rubius Erythrocyte Design platform. We are expanding our R&D and management teams, and setting the stage for our next phase of growth."
Besides Dr. Afeyan and Dr. Lodish, the Rubius board of directors includes:

• Jim Gilbert, a healthcare investor and former partner and director at Bain & Co., who serves on several boards, including the board of Nestle Health Sciences. Jim serves as chairman of Rubius.

• Robert S. Langer, Ph.D., Institute Professor at MIT and the holder of more than 1,000 patents

• Dr. Roger Pomerantz, chairman and CEO of Seres Health and former worldwide head of licensing and acquisitions, senior vice president at Merck & Co. Inc.

• Dr. Michael Rosenblatt, executive vice president and chief medical officer of Merck & Co. Inc. , and former dean of the Tufts University School of Medicine.

• Peter Hutt, senior counsel at Covington & Burling and former chief counsel of the U.S. Food and Drug Administration.

Since emerging from Flagship VentureLabs 18 months ago, Rubius has been developing its RCT platform in stealth mode. The company has established a broad patent estate covering its platform and therapeutic products. Rubius is currently testing RCTs in animal models of disease, and plans to initiate human clinical trials in the very near future.

Genmab Achieves USD 5 Million Milestone in Daratumumab Collaboration with Janssen

On December 9, 2015 Genmab A/S (Nasdaq Copenhagen: GEN) reported it has reached a USD 5 million milestone in its daratumumab collaboration with Janssen Biotech, Inc. (Janssen) (Press release, Genmab, DEC 9, 2015, View Source [SID:1234508516]).

The milestone payment was triggered by progress in the ongoing Phase II study ("Carina" LYM2001) of daratumumab in NHL. The study evaluates daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). This milestone is related to progress in the arm of the study treating patients with DLBCL.

"Daratumumab is being investigated in numerous studies for multiple myeloma, covering all lines of therapy. We are very pleased to report progress in the first study of daratumumab in an indication beyond multiple myeloma," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Daratumumab has received Orphan Drug designation from the US FDA for DLBCL, MCL and FL.
Today’s news does not impact Genmab’s 2015 financial guidance.

About the LYM2001 study
This Phase II study (NCT02413489) is a three arm (DLBCL, FL, MCL), open-label multicenter study which will enroll up to 210 patients with relapsed or refractory non-Hodgkin’s lymphoma. Patients in the study will be treated with daratumumab monotherapy. The primary endpoint of the study is overall response rate. The safety profile of daratumumab in these diseases will also be assessed.

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.1 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,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 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.1

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.

Merck and Pfizer Initiate Two Phase III Studies of Investigational Immunotherapy Avelumab in Advanced Gastric and Gastro-esophageal Junction Cancers

On December 9, 2015 Merck and Pfizer reported the initiation of two Phase III studies of avelumab*, an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody, in treating advanced or metastatic gastric/gastro-esophageal junction (GEJ) cancers, which are aggressive cancers with poor survival rates (Press release, Merck KGaA, DEC 9, 2015, View Sourcepfizer.com/news/press-release/press-release-detail/merck_kgaa_darmstadt_germany_and_pfizer_initiate_two_phase_iii_studies_of_investigational_immunotherapy_avelumab_in_advanced_gastric_and_gastro_esophageal_junction_cancers" target="_blank" title="View Sourcepfizer.com/news/press-release/press-release-detail/merck_kgaa_darmstadt_germany_and_pfizer_initiate_two_phase_iii_studies_of_investigational_immunotherapy_avelumab_in_advanced_gastric_and_gastro_esophageal_junction_cancers" rel="nofollow">View Source [SID:1234508513]).

These pivotal trials are investigating avelumab in the first-line and third-line settings, with overall survival (OS) as the primary endpoint in both trials.

JAVELIN Gastric 100, a study comparing the switch from first-line chemotherapy to maintenance therapy with avelumab versus continuation of chemotherapy, is a multicenter, international, randomized, open-label Phase III trial designed to evaluate the potential superiority (based on OS) of maintenance therapy with avelumab in patients with unresectable, locally advanced or metastatic gastric/GEJ cancers whose disease has not progressed with first-line platinum-based chemotherapy. This is currently the only Phase III trial in gastric cancer that is designed to evaluate superiority of an immunotherapy compared with conventional platinum-based chemotherapy as a first-line maintenance treatment. The study will enroll 629 patients across more than 220 sites in Asia Pacific, Europe, North America and South America.

"The prognosis is generally poor for the majority of patients with advanced gastric cancers," said Dr. Luciano Rossetti, Head of Global Research & Development at Merck’s biopharma business. "By initiating these two Phase III trials in gastric and gastro-esophageal junction cancers, we are continuing the fight against cancer with an overarching goal of potentially improving survival for patients."

The third-line study, JAVELIN Gastric 300, is a multicenter, international, randomized, open-label Phase III trial designed to evaluate the potential superiority (based on OS) of avelumab in patients with unresectable, recurrent or metastatic gastric/GEJ cancers, compared with investigator’s choice of chemotherapy from a pre-specified list of therapeutic options. The study will enroll approximately 330 patients, spanning approximately 170 sites in Asia, Australia, Europe, North America and South America.

"We are continuing to investigate avelumab in cancers with high unmet need and where there is a strong rationale for immunotherapeutic intervention," said Dr. Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs and Chief Medical Officer for Pfizer Oncology. "Advanced gastric cancer is a challenging diagnosis to face as a patient, and we are dedicating significant resources to evaluate avelumab as a potential new treatment option for patients in multiple settings of this disease."

The clinical development program for avelumab now includes more than 1,500 patients who have been treated across more than 15 tumor types, including breast cancer, gastric/GEJ cancers, head and neck cancer, Merkel cell carcinoma, melanoma, mesothelioma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and urothelial (e.g. bladder) cancer. Clinical trials for both of the gastric/GEJ Phase III trials in North America will be conducted on behalf of Merck by EMD Serono, the company’s US and Canadian biopharma business.

*Avelumab is the proposed International Non-proprietary Name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

References
1. Waddell T et al. Ann Oncol 2013;24 Suppl 6:vi57-63.
2. Wadhwa R et al. Nat Rev Clin Oncol 2013;10(11):643-55.
3. American Cancer Society. Survival rates for stomach cancer, by stage. Available from: View Sourcecancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-survival-rates." target="_blank" title="View Sourcecancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-survival-rates." rel="nofollow">View Source Last accessed December 2015.
4. National Cancer Institute Surveillance Epidemiology and End Results (SEER). SEER Stat Fact Sheets: Stomach Cancer. Available from: View Source stomach.html. Last accessed April 2015.
5. International Agency for Research on Cancer (IARC)/EUCAN. Gastric cancer: Estimated incidence, mortality & prevalence for both sexes, 2012. Available from: http:// eco.iarc.fr/EUCAN/Cancer.aspx?Cancer=8#block-table-a. Last accessed April 2015.
6. Mayo Clinic. Stomach cancer treatments and drugs. Available from: View Source mayoclinic.org/diseases-conditions/stomach-cancer/basics/treatment/con-20038197. Last accessed April 2015.
7. Buas MF & Vaughan TL. Semin Radiat Oncol. 2013; 23(1): 3-9.
8. Cunningham D et al. New Eng J Med 2006;355(1):11-22.
9. Macdonald JS et al. N Eng J Med 2001;345(10):725-30.
10. Cancer Research UK. What is advanced oesophageal junction cancer? View Source cancerresearchuk.org/about-cancer/type/oesophageal-cancer/treatment/advanced/what-is-advanced-oesophageal-cancer. Last accessed September 2015.

About Gastric and Gastro-esophageal Junction (GEJ) Cancers
Gastric cancer is uncommon in the US and Western Europe.1,2 Each year, there are approximately 22,000 new cases of gastric cancer diagnosed in the US and 80,626 cases diagnosed in the EU.3 Gastric cancer is much more commonly diagnosed in East Asia, Eastern Europe, and parts of South America.4 For patients with advanced gastric cancer, the prognosis is poor. The 5-year survival rate in the US is <20 percent for Stage III gastric cancer and <5 percent for Stage IV gastric cancer.5 Current treatment options for gastric cancer may include surgery, radiotherapy, chemotherapy, chemoradiotherapy and targeted therapies.2,6
Reliable data on the global incidence of GEJ tumors are not available, due to the historically complicated classification system and the likelihood of misclassification.7 Current treatment options for GEJ cancer may include surgery, chemotherapy, radiation therapy and targeted therapy.8,9 Despite advances in the field of GEJ, there is no cure for patients with cancer that has spread.10 There is a clear unmet medical need for new treatment options.

About Avelumab
Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

Ignyta Announces Initiation of STARTRK “Next Generation” Phase 1/1b Pediatric Clinical Trial of Entrectinib

On December 9, 2015 Ignyta, Inc. (Nasdaq: RXDX), a precision oncology biotechnology company, reported the initiation of STARTRK-NG, a new pediatric Phase 1/1b clinical trial of entrectinib, the company’s proprietary oral tyrosine kinase inhibitor targeting solid tumors that harbor activating alterations to NTRK1, NTRK2, NTRK3, ROS1 or ALK (Press release, Ignyta, DEC 9, 2015, View Source [SID:1234508511]).

STARTRK-NG (which stands for "Studies of Tumor Alterations Responsive to Targeting Receptor Kinases – Next Generation") is a multicenter, open label, dose-escalation and expansion study designed to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), tolerability, pharmacokinetics and preliminary clinical activity of entrectinib in children and adolescents with recurrent or refractory extracranial solid tumors or primary central nervous system (CNS) tumors, including indications such as neuroblastoma.

"We are excited to expand the clinical development program for entrectinib with this first clinical study in pediatric patients," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "There is abundant scientific evidence suggesting that inhibition of oncodrivers such as Trk and ALK could be effective in many cancers in children and adolescents. Because entrectinib is the most potent Trk inhibitor in the clinic, without undesirable off-target activity, as well as a potent inhibitor of ALK, and given entrectinib’s clinically demonstrated activity in the central nervous system, we look forward to conducting this study of entrectinib for the benefit of these patients."

The clinical sites participating in the STARTRK-NG trial are the four Alex’s Lemonade Stand Foundation for Childhood Cancer Centers of Excellence:

The Children’s Hospital of Philadelphia,
Dana-Farber/Boston Children’s Cancer Hospital,
Texas Children’s Cancer Center, and
University of California, San Francisco.

About Entrectinib

Entrectinib is a novel, orally available, selective tyrosine kinase inhibitor targeting tumors that harbor activating alterations to NTRK1/2/3 (encoding TrkA/ TrkB/TrkC), ROS1 or ALK. Entrectinib is the most potent Trk inhibitor in the clinic, without undesirable off-target activity, and the only Trk inhibitor with clinically demonstrated activity against CNS metastases. In addition to the STARTRK-NG trial, this product candidate is in a Phase 2 clinical trial called STARTRK-2. The trial is a global, multicenter, open label, potentially registration-enabling Phase 2 clinical trial of entrectinib that utilizes a basket design with screening of patient tumor samples for the relevant targets. Such a basket design takes full advantage of entrectinib’s demonstrated preliminary clinical activity across a range of different tumor types and molecular targets.

Pieris Pharmaceuticals Announces First Cancer Immunotherapy Collaboration

On December 8, 2015 Pieris Pharmaceuticals, Inc. (NASDAQ: PIRS), a biotechnology company advancing novel bio therapeutics through its proprietary Anticalin technology platform, reported a research collaboration and license agreement with Roche in cancer immunotherapy (CIT) (Press release, Pieris Pharmaceuticals, DEC 8, 2015, View Source [SID:1234515041]). Under the terms of the agreement, Pieris will discover, characterize and optimize Anticalin-based drug candidates against an undisclosed target. Roche and Pieris will evaluate different drug formats against this target and advance them through preclinical development, with Roche being responsible for IND-enabling activities, clinical development and worldwide marketing of any resulting products. Pieris will receive an upfront payment of CHF 6.5 million (~$6.4 million USD) and committed research funding, and may receive development and regulatory-based milestone payments, sales-based milestone payments as well as mid single-digit to low double-digit royalties on any future product sales. If all milestones and other conditions are met, the total payments to Pieris could surpass CHF 415 million (~$409.3 million USD), excluding royalties.

"Our partnership with Roche is a significant step forward for Pieris," commented Stephen Yoder, President and CEO of Pieris. "The decision by the leader in the development and commercialization of cancer biologics to collaborate with Pieris underscores the unique potential of Anticalin-based proteins as a differentiated class of immuno-oncology drugs. As we initiate this collaboration, we will continue to vigorously advance our fully proprietary programs, including our lead CD137-HER2 bispecific."

With its immuno-oncology PRS-300 Series, which remains proprietary to the Company, Pieris is developing bispecific Anticalin-based protein therapeutics against a variety of tumor and immunomodulatory targets. These compounds, including its lead program PRS-343 (CD137/HER2 bispecific), aim to activate the immune system in the tumor microenvironment, with the goal of increasing efficacy as well as improving safety compared to existing approaches. This collaboration represents Pieris’ first partnered immuno-oncology program and leverages Pieris’ capability to address a target in multiple ways through Anticalin-based drug candidates in different formats.