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Puma Biotechnology Updates Timeline for Filing New Drug Application

On March 28, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that based on its recent meetings with the U.S. Food and Drug Administration (FDA), the Company now plans to submit its New Drug Application (NDA) for the approval of neratinib for the treatment of extended adjuvant breast cancer that has previously been treated with a trastuzumab-containing regimen in mid-2016 (Press release, Puma Biotechnology, MAR 28, 2016, View Source [SID:1234510117]).

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Puma has recently conducted a series of meetings and communications with the FDA. The purpose of these communications was to provide the FDA with the data from neratinib’s non-clinical and clinical development programs that will form the basis of the Company’s NDA for neratinib for the treatment of extended adjuvant breast cancer that has previously been treated with a trastuzumab-containing regimen. The data discussed with the FDA included preclinical data (pharmacology, toxicology, reproductive toxicity, carcinogenicity) and clinical trial data, including the data from the Phase III trial of neratinib in the extended adjuvant treatment of HER2-positive early stage breast cancer (ExteNET trial) and the Phase II trial of neratinib monotherapy in the extended adjuvant treatment of HER2-positive early stage breast cancer where patients received loperamide prophylaxis in order to prevent the neratinib-related diarrhea. Following its review of this material, the FDA requested that Puma amend the current statistical analysis plan for the ExteNET trial to incorporate the FDA’s recommendations with regard to rules for censoring the data for recurrent disease events or death.

For the primary endpoint of the ExteNET trial (Invasive Disease Free Survival), the analysis was based on all recurrent disease events and deaths occurring within 2 years and 28 days post randomization. The FDA has requested that events (disease recurrence or deaths) observed after missing 2 or more scheduled disease assessments be censored at the last available disease assessment time prior to the event occurrence. The FDA’s requested approach was a sensitivity analysis used in the ExteNET trial’s original statistical analysis plan but will now be the primary analysis approach used in the trial’s updated statistical analysis plan. In order to accommodate this change, Puma expects to delay filing its NDA for neratinib for the treatment of extended adjuvant breast cancer that has previously been treated with a trastuzumab-containing regimen until mid-2016.

The primary analysis results of the trial do not appear to be altered materially by the updated analysis approach. Provided below are the results of the original and updated analyses of the primary endpoint of invasive disease-free survival (iDFS) for the intent to treat (ITT) population:

1. ITT population applying the original event and censoring rule:
– 179 iDFS events
– 33% reduction in risk of iDFS vs. placebo (hazard ratio=0.67 (0.50, 0.91), 1-sided P=0.005)
– iDFS rates 93.9% (neratinib arm) vs. 91.6% (placebo arm)

2. ITT population applying the revised event and censoring rule per FDA:
– 173 iDFS events
– 34% reduction in risk of iDFS vs. placebo (hazard ratio=0.66 (0.49, 0.90), 1-sided P=0.004)
– iDFS rates 94.2% (neratinib arm) vs. 91.9% (placebo arm)

Ligand Enters Into OmniAb® Platform License Agreement With ABBA Therapeutics

On March 28, 2016 Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) reported it has entered into a worldwide license agreement with ABBA Therapeutics AG, a Swiss biotechnology company developing innovative immuno-oncology therapies (Press release, Ligand, MAR 28, 2016, View Source [SID:1234510060]).

Under the license, ABBA will be able to use the OmniRat, OmniMouse and OmniFlic platforms to generate fully human mono- and bispecific antibodies. Ligand is to receive an initial access payment, and will be eligible to receive clinical milestone payments and royalties for each successful OmniAb antibody. ABBA will be responsible for all costs related to the program.

"OmniAb will provide ABBA with industry-leading technology for generation of novel antibody therapeutics to further their therapeutic strategy," said John Higgins, Chief Executive Officer of Ligand. "This is the third OmniAb license deal since the close of the OMT acquisition and the 19th overall OmniAb Ligand partner, and continues to show the licensing power that the OmniAb franchise brings to Ligand."

About OmniAb

OmniAb includes three transgenic animal platforms for producing mono- and bispecific human therapeutic antibodies. OmniRat is the industry’s first human monoclonal antibody technology based on rats. It has a complete immune system with a diverse antibody repertoire and generates antibodies with human idiotypes as effectively as wild-type animals make rat antibodies. OmniMouse is a transgenic mouse that complements OmniRat and expands epitope coverage. OmniFlic is an engineered rat with a fixed light chain for development of bispecific, fully human antibodies. The three platforms use patented technology, have broad freedom to operate and deliver fully human antibodies with high affinity, specificity, expression, solubility and stability.

Aduro Biotech and UC Berkeley Launch Industry-Leading Immunotherapeutics and Vaccine Research Initiative

On March 28, 2016 The University of California (UC) Berkeley, in collaboration with Aduro Biotech, Inc. (Nasdaq:ADRO), reported the launch of an innovative Immunotherapeutics and Vaccine Research Initiative (IVRI) (Press release, Aduro BioTech, MAR 28, 2016, View Source [SID:1234510057]).

IVRI is UC Berkeley’s first-ever immunotherapy-focused initiative and, in partnership with Aduro, will combine UC Berkeley’s extensive research capabilities with the company’s expertise in immunotherapy discovery and development to identify and advance new treatment options and preventive modalities for cancer, infectious disease and autoimmune disease.

IVRI is designed to explore the unique synergy between cancer and infectious disease research and to accelerate breakthrough discoveries in both areas. IVRI researchers are working closely with collaborators and sponsors with the shared goal of discovering and advancing immunotherapeutics and vaccine strategies.

"In the last several years, we have learned so much about the role of the immune system in treating disease, and we look forward to harnessing that information across both research and industry to develop innovative new treatment options to improve patient care," said David Raulet, Faculty Director of the IVRI and a Professor of Immunology and Pathogenesis at University of California, Berkeley. "Through this initiative, we will leverage our powerful research networks to understand how we can better engage the immune system in treating cancer, infectious disease and autoimmune disease. By doing this, we hope to develop new methods for targeting and effectively controlling many different cancers, autoimmune and infectious diseases. Our goal is for these findings to pave the way for the development of innovative new treatment options."

Aduro Biotech, a leading immunotherapy company focused on the discovery, development and commercialization of therapies that transform the treatment of challenging diseases, is IVRI’s founding partner. Aduro will provide UC Berkeley with $7.5 million in research funding over the next three years, with an option for Aduro to increase and extend funding for up to an additional three years. As part of research projects, researchers at UC Berkeley will also have the opportunity to access the company’s novel technology platforms including LADD, STING Pathway Activators and B-select monoclonal antibodies, which are designed to harness the body’s natural immune system.

"Through this unique collaboration, there is tremendous opportunity to improve our understanding of the immune system’s potential to serve as an important weapon in treating cancer and infectious disease," said Stephen T. Isaacs, chairman, president and CEO of Aduro Biotech. "By combining UC Berkeley’s leading research and academic resources with innovative technology platforms, such as those developed by Aduro, we are confident that this initiative will lead to an improved understanding of, and potential treatments for, some of the most devastating diseases."

The IVRI officially launched with a reception on March 24, 2016 at the UC Berkeley campus, which featured remarks from James P. Allison, Chair of Immunology, MD Anderson Cancer Center, David Raulet, Faculty Director, IVRI, as well as Stephen Isaacs of Aduro. On March 25, 2016, a full day symposium on the topic "Harnessing the Immune System to Fight Cancer and Infectious Diseases" was hosted on the campus. The symposium featured a dynamic list of invited speakers from around the country, including Lasker Award winner James P. Allison, Director of the Emory University Vaccine Center, Rafi Ahmed, and Aduro’s Chief Scientific Officer, Thomas J. Dubensky, Jr. The symposium also featured a scientific poster session including presentations of basic and translational science in infectious diseases, immunology or immuno-oncology.

About Immunotherapeutics and Vaccine Research Initiative (IVRI)

The immune system is nature’s most powerful weapon against disease. Whether introduced to the host from the environment, arising endogenously or stemming from a dysfunction of the immune system itself, diseases are impacted by immune functions, and the immune response can be targeted for therapy. It is our vision that a fundamental understanding of immune recognition, cellular interactions and other elements of the immune system has high potential to lead to meaningful advancements in the treatment of many diseases.

The IVRI is envisioned as a center for research to develop mechanistic understanding and application of immunology, pathogenesis and vaccinology with the potential to profoundly impact the treatment of human disease. The initiative is founded on the principle that research that uncovers how the immune system controls infectious disease yields new approaches for treating cancer, and conversely, that studies of cancer immunology yield approaches for vaccines and therapies targeting infectious disease. UC Berkeley has an impressive record in this endeavor including advances that have led to cancer immunotherapeutics and novel vaccines. The IVRI will expand on and accelerate these advances by coordinating and directing the efforts of UC Berkeley researchers, their collaborators and sponsors towards ground-breaking discoveries, and the development of creative new applications in disease prophylaxis and treatment. The IVRI will facilitate communication and collaboration among researchers, streamline access to scientific and financial resources and promote not only the vision, ideas and accomplishments of its scientists, but also the translation of these ideas and findings for the development of new therapies for human diseases. By targeting synergies in the expertise and capabilities of its scientists and unifying their ingenuity with the objectives of its sponsors, the IVRI seeks to maximize the potential of its UC Berkeley researchers and accelerate the pace of discovery and translation.

FDA Does Not Grant Seven Year Orphan Drug Exclusivity for BENDEKA (bendamustine hydrochloride injection)

On March 28, 2016 Eagle Pharmaceuticals, Inc. (Nasdaq:EGRX) ("Eagle" or the "Company") reported that the U.S. Food and Drug Administration (FDA) has denied Eagle’s request for seven years of orphan drug exclusivity in the U.S., for BENDEKA (bendamustine hydrochloride injection, or bendamustine HCI), a liquid, low-volume (50 mL) and short-time 10-minute infusion formulation of bendamustine hydrochloride (Press release, Eagle Pharmaceuticals, MAR 28, 2016, View Source [SID:1234510046]).

BENDEKA was approved in December 2015 for the treatment of patients with chronic lymphocytic leukemia (CLL) and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Efficacy in CLL relative to first-line therapies other than chlorambucil has not been established.

Eagle believes that the FDA’s decision is incorrect, and that BENDEKA was automatically entitled to orphan drug exclusivity for CLL and indolent B-cell NHL upon the drug’s December 2015 approval. The FDA previously granted orphan drug designation for BENDEKA for both indications. Eagle is evaluating all options to challenge the FDA’s decision.

Orphan drug designation is granted by the FDA Office of Orphan Products Development to novel drugs or biologics that treat rare diseases or conditions affecting fewer than 200,000 patients in the U.S. The designation typically provides the drug developer with a seven-year period of U.S. marketing exclusivity upon approval, as well as certain financial incentives that can help support its development.

The FDA currently requires sponsors of certain orphan designated drugs to make a "clinical superiority" demonstration as a condition to obtaining the seven-year exclusivity period upon approval. The FDA applies this requirement whenever the FDA has previously approved another drug of the same active moiety for the same indication.

In September 2014, DepoMed, Inc. (DepoMed) prevailed in litigation in federal district court in the District of Columbia, challenging the FDA’s application of this clinical superiority demonstration requirement to its orphan-designated drug product, GRALISETM. DepoMed argued that the requirement violates the Orphan Drug Act, which automatically confers seven years of marketing exclusivity on orphan designated products upon approval. District Judge Ketanji Brown Jackson agreed with DepoMed’s position, and ordered the FDA to recognize orphan drug exclusivity for GRALISE without requiring proof of "clinical superiority." While the FDA granted orphan drug exclusivity for GRALISE without a clinical superiority demonstration, it has continued to require the clinical superiority demonstration for other orphan designated drugs, such as BENDEKA.

Eagle believes that the FDA’s rejection of orphan drug exclusivity for BENDEKA closely mirrors the decision that Judge Jackson overturned in the DepoMed litigation, and Eagle is evaluating all options to obtain a reversal of the FDA’s BENDEKA decision at this time.

"We are disappointed with the agency’s decision regarding orphan drug exclusivity for BENDEKA, which we believe to be incorrect," said Scott Tarriff, President and Chief Executive Officer. "With six Orange Book listed patents extending from 2026 through 2033, and additional pending patent applications, the market protection for BENDEKA is likely to be intact for many years. These patents will continue to be in effect beyond the seven years of exclusivity that would have been provided had the orphan drug exclusivity been granted. We believe the FDA’s decision will have little to no impact on our bendamustine HCI business in the near term," concluded Tariff.

The following table lists the patents for liquid bendamustine hydrochloride (HCl) formulations:

U.S. Patent No. Patent Expiration
8,609,707 8/11/2031
8,791,270*PED (Owned by Teva Pharmaceutical Industries, Ltd.) 7/12/2026
9,000,021 3/15/2033
9,034,908 3/15/2033
9,144,568 3/15/2033
9,265,831

1/28/2031
Under a February 2015 exclusive license agreement for BENDEKA, a subsidiary of Teva Pharmaceutical Industries, Ltd. is responsible for all U.S. commercial activities for the product including promotion and distribution. BENDEKA was launched by Teva in late January 2016. As previously announced, Eagle receives a 20% royalty on Teva’s sales of BENDEKA.

Indications

BENDEKA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

BENDEKA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

Important Safety Information

Contraindication: BENDEKA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol.

Myelosuppression: Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. Monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle.

Infections: Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred. Patients with myelosuppression following treatment with BENDEKA are more susceptible to infections. Patients treated with Bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate monitoring, prophylaxis, and treatment measures.

Anaphylaxis and Infusion Reactions: Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions.

Tumor Lysis Syndrome: Tumor lysis syndrome associated with bendamustine hydrochloride has occurred. The onset tends to be within the first treatment cycle with –bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly.

Skin Reactions: Skin reactions have been reported with bendamustine hydrochloride treatment including rash, toxic skin reactions, and bullous exanthema. In a study of bendamustine hydrochloride (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when bendamustine hydrochloride was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue BENDEKA.

Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with BENDEKA therapy has not been determined.

Extravasation Injury: Extravasations resulting in hospitalizations from erythema, marked swelling, and pain have been reported with bendamustine hydrochloride. Assure good venous access prior to starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of BENDEKA.

Embryo-fetal Toxicity: Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using BENDEKA.

Most Common Adverse Reactions:

• Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue.

• Most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting.

• Most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.

• Most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.

For BENDEKA Full Prescribing Information, please visit: View Source

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease.

T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed thatTigitexpression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.
Copyright © 2016 by The American Association of Immunologists, Inc.