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Aeterna Zentaris Files Additional Patent Application to Strengthen IP Protection of Zoptarelin Doxorubicin

On April 16, 2015 Aeterna Zentaris Inc. (NASDAQ: AEZS, TSX: AEZ) (the "Company") reported that it has filed an application for a patent (European Patent Office priority application: EP15000132) on a novel method of manufacturing zoptarelin doxorubicin, its hybrid cytotoxic molecule that is the subject of a pivotal ZoptEC (Zoptarelin doxorubicin in Endometrial Cancer) Phase 3 clinical study in women with advanced, recurrent or metastatic endometrial cancer who have progressed and who have received one chemotherapeutic regimen with platinum and taxane (either as adjuvant or first-line treatment) (Press release, AEterna Zentaris, APR 16, 2015, View Source;q=653 [SID:1234506590]). The claimed manufacturing process is expected to result in a significant reduction in the cost of goods sold, providing a stronger competitive position for the Company.

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Zoptarelin doxorubicin is a complex molecule that combines a synthetic peptide carrier with doxorubicin, a well-known chemotherapy agent. The synthetic peptide carrier is a Luteinizing Hormone Releasing Hormone ("LHRH") agonist, a modified natural hormone with affinity for the LHRH receptor. The design of the compound allows for the specific binding and selective uptake of the cytotoxic conjugate by LHRH receptor-positive tumors. Potential benefits of this targeted approach include a better efficacy and a more favorable safety profile with lower incidence and severity of side effects as compared to doxorubicin alone.

Because zoptarelin doxorubicin is a complex molecule, it is expensive to synthesize. The patent application, which is entitled "Enzymatic process for the regioselective manufacturing of N-Fmoc-doxorubicin-14-O-dicarboxylic acid mono esters", may, if granted, make it difficult for generic manufacturers to produce the compound on a financially feasible basis after the Company’s composition of-matter patent on zoptarelin doxorubicin expires.

David A. Dodd, Chairman and Chief Executive Officer of the Company explained the significance of the patent application for the new synthesis process: "We believe that zoptarelin doxorubicin has the potential to become the first approved therapy in the U.S. for treating women within the targeted Phase 3 indication, as well as additional cancers that we might evaluate in the future. Our commitment is to ensure that patients and their physicians have such therapies that can potentially improve and extend the quality of lives. With the 2015 expiration date of the U.S. composition-of-matter patent on the horizon, we sought a means to maintain our advantage for this compound beyond the five-year period of exclusivity granted to new chemical entities, which we expect to apply to zoptarelin doxorubicin. The compound could be a very important oncology tool if our ZoptEC Phase 3 study achieves its endpoints. By reducing the complexity of production and cost of the compound, we will have greater flexibility in potentially ensuring that patients on a worldwide basis have access and can benefit from this therapy. We believe this patent, if granted, could provide that advantage by giving us a significant production and cost advantage in support of further development in additional indications. Finally, we are most proud that this manufacturing process was invented by our colleagues within the Company’s Frankfurt-based research and development staff."

The Company owns all rights to the new process. The Company intends to file a PCT patent application in January 2016, claiming priority of the filed EP patent application.

About Zoptarelin Doxorubicin

Zoptarelin doxorubicin represents a new targeting concept in oncology using a hybrid molecule composed of a synthetic peptide carrier and a well-known chemotherapy agent, doxorubicin. Zoptarelin doxorubicin is the first intravenous drug in advanced clinical development that directs the chemotherapy agent specifically to LHRH-receptor expressing tumors, resulting in a more targeted treatment with less damage to healthy tissue. The Company is currently conducting a ZoptEC (Zoptarelin doxorubicin in Endometrial Cancer) Phase 3 trial in women with advanced, recurrent or metastatic endometrial cancer, while zoptarelin doxorubicin is also in an investigator-initiated Phase 2 trial in prostate cancer. Aeterna Zentaris owns the worldwide rights to this compound except in China. On December 1, 2014, the Company entered into a Master Collaboration Agreement, a Technology Transfer and Technical Assistance Agreement and a License Agreement with Sinopharm A-Think Pharmaceuticals Co., Ltd for the development, manufacture and commercialization of zoptarelin doxorubicin in all human uses in the Peoples Republic of China, including Hong Kong and Macau. Sinopharm A-Think is a subsidiary of Sinopharm, the largest medical and healthcare group in China and on Fortune’s Global 500 list.

About Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy in developed countries and develops when abnormal cells amass to form a tumor in the lining of the uterus. It largely affects women over the age of 50 with a higher prevalence in Caucasians and a higher mortality rate among African Americans. According to the American Cancer Society, there will be more than 54,000 new cases of endometrial cancer in the U.S. alone in 2015, with about 20% of recurring disease.

Lilly, Bristol-Myers Squibb Restructure Erbitux® (cetuximab) Collaboration in North America

On April 16, 2015 Eli Lilly and Company and Bristol-Myers Squibb reported that the companies have agreed to transfer rights to Erbitux (cetuximab) in North America, including the U.S., Canada, and Puerto Rico, from Bristol-Myers Squibb to Lilly (Press release, Bristol-Myers Squibb, APR 16, 2015, View Source [SID:1234503026]). Rights include, but are not limited to, full commercialization and manufacturing operational responsibilities. The companies’ decision comes after a 14-year successful collaboration, which includes Lilly’s wholly-owned subsidiary ImClone LLC. Bristol-Myers Squibb and Lilly will work closely to ensure a smooth transition on this important product for patients with certain advanced colorectal and head and neck cancers.

"Fully bringing Erbitux into the Lilly Oncology portfolio accelerates Lilly’s commitment and leadership in gastrointestinal cancers to include an effective treatment for advanced colorectal cancer as well as head and neck cancer," said Sue Mahony, Ph.D., senior vice president and president of Lilly Oncology. "Our good work on Erbitux began with its development at ImClone and has continued with Bristol-Myers Squibb. We look forward to carrying on these efforts for people battling select advanced colorectal and head and neck cancers."

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"Bristol-Myers Squibb is incredibly proud to have built Erbitux into a major brand and an important therapy for so many patients with certain colorectal and head and neck cancers," said Murdo Gordon, head of worldwide markets, Bristol-Myers Squibb. "This agreement further aligns our Oncology organization with our prioritized opportunities in immuno-oncology, across both solid tumors and hematologic malignancies."

The transition is expected to be completed in the fourth quarter of 2015. Bristol-Myers Squibb will receive tiered royalties based on net product sales in North America after the completion of the transition through September 2018.

OncoMed Presents Demcizumab Data From Phase 1b Clinical Trial in Non-Small Cell Lung Cancer Patients at the European Lung Cancer Conference

On April 16, 2015 OncoMed Pharmaceuticals reported new data from the Phase 1b clinical trial of demcizumab (anti-DLL4, OMP-21M18) in patients with first-line advanced non-small cell lung cancer (NSCLC) at the European Lung Cancer Conference (Press release, OncoMed, APR 16, 2015, View Source [SID:1234503024]). Demcizumab is a first-in-class monoclonal antibody targeting DLL4 with anti-cancer stem cell, dysangiogenesis and potential immune modulatory properties.

"Given the caveats that this is a relatively small, 46-patient, single-arm Phase 1b clinical trial of demcizumab plus standard of care chemotherapy, we are encouraged by the manageable safety profile as a result of our truncated dosing schedule, as well as improved response rates, and prolonged survival of certain patients," said Paul J. Hastings, Chairman and Chief Executive Officer of OncoMed. "We look forward to the further exploration of demcizumab’s activity in randomized clinical studies, such as our ongoing Phase 2 clinical trial."

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Phase 1b Results

The Phase 1b trial studied several doses of demcizumab (2.5, 5, and 7.5 mg/kg) in combination with carboplatin and pemetrexed (Alimta) every three weeks. Twenty-three subjects received continuous dosing of demcizumab with up to six cycles of pemetrexed and carboplatin followed by demcizumab maintenance. Twenty-three subjects received a truncated dosing schedule of demcizumab for four doses with pemetrexed and carboplatin, followed by pemetrexed maintenance.

Of 40 patients evaluable for efficacy, the overall RECIST response rate was 50 percent (1 complete response and 19 partial responses) and an additional 15 patients had a best response of stable disease, yielding a clinical benefit rate of 88 percent.

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Median progression-free survival (PFS) based on Kaplan-Meier estimates was 5.3 months and 5.8 months for the continuous and truncated cohorts, respectively. A worst-case analysis (to ensure that Kaplan-Meier estimates are not impacted by selective reporting) showed a median overall survival (OS) of 6.3 months for the continuous demcizumab cohort, and a median OS of 8.1 months for the truncated dose patients. Prolonged PFS and OS were observed for a subset of patients treated with continuous demcizumab. This was apparent by the plateau at the tail end of the Kaplan Meier curve. Specifically, of the 23 patients in the continuous dosing group, ten survived more than 300 days. In these 10 patients who survived more than 300 days, there was a cumulative 21.8 years of patient follow-up beyond those 300 days, and among these ten patients, only two patient deaths occurred as of the February 26, 2015 data cut off. Survival data from patients treated with the truncated demcizumab dose regimen is less mature, although the Kaplan-Meier curves, as of the February cut-off date, show a similar trajectory.

"Data from our Phase 1b study of demcizumab with standard-of-care pemetrexed and carboplatin in patients with advanced NSCLC demonstrates encouraging response rates, and intriguing signals of durability of disease control among a subset of patients. In this uncontrolled trial of a relatively small number of patients a group of patients receiving continuous demcizumab treatment had prolonged progression free and overall survival. These observations make demcizumab and chemotherapy worth exploring and understanding further in randomized clinical trials that are currently ongoing," said Jakob Dupont, M.D., Senior Vice President and Chief Medical Officer. "OncoMed is undertaking a series of biomarker and patient factor analyses to try to clarify the subset of patients with apparent improved outcome."

A randomized Phase 2 trial (DENALI) of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC has been initiated and is enrolling subjects in Europe, Australia, and the United States.

Safety and Tolerability and Biomarker Data

The regimen of demcizumab, pemetrexed and carboplatin was generally well-tolerated with fatigue, nausea and manageable hypertension being the most common demcizumab-related toxicities. Two cases of reversible Grade 3 pulmonary hypertension and heart failure occurred earlier in the trial in patients treated with continuous demcizumab for greater than 160 days. Subsequent patients were treated with a truncated risk mitigating demcizumab regimen (i.e., 63 days of treatment). The truncated demcizumab treatment and patient monitoring with BNP and ECHO appears to prevent the onset of late cardiopulmonary toxicity. There were no incidents of moderate-to-severe cardiopulmonary toxicity events observed using the truncated dosing regimen.

The Phase 2 dose of demcizumab at 5mg/kg every three weeks administered on a truncated dosing schedule was selected. Pharmacodynamic analyses of gene expression of patient samples demonstrated clear modulation of the Notch pathway that lasted up to 77 days after the last dose of study drug.

These data were presented at the European Lung Cancer Conference by Dr. Dupont on behalf of the demcizumab NSCLC study investigators in a poster titled "A Phase 1b study of anti-DLL4 (delta-like ligand 4) antibody demcizumab (DEM) with pemetrexed (PEM) and carboplatin (CARBO) in patients with 1st-line non-squamous NSCLC". A copy of the poster is available on the OncoMed website.

About Non-Small Cell Lung Cancer

According to the American Cancer Society, lung cancer (both small cell and non-small cell) is the second most common cancer in men and women and is by far the leading cause of cancer death. Non-small cell lung cancer is expected to make up the vast majority of the 224,210 newly diagnosed cancer cases and the 159,260 cancer deaths estimated to occur in the U.S. in 20141. Forty percent of patients with newly diagnosed non-small cell lung cancer have Stage IV disease. Treatment options for these patients include chemotherapy with or without targeted agents (such as bevacizumab or EGFR inhibitors). For first-line non-squamous NSCLC, one of the preferred chemotherapy regimens is pemetrexed (Alimta) with a platinum-based chemotherapy for four cycles, followed by pemetrexed maintenance.

About Demcizumab (anti-DLL4, OMP-21M18)

Demcizumab is a humanized monoclonal antibody that inhibits Delta-Like Ligand 4 (DLL4) in the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing CSC frequency, disrupting angiogenesis in the tumor and potentially augmenting anti-tumor immune response.

OncoMed has initiated and is enrolling a randomized Phase 2 trial (DENALI) of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC in Europe, Australia, and the United States. The DENALI trial is expected to enroll more than 200 patients. Patients will be randomized into one of three study arms to compare the efficacy and safety of demcizumab combined with carboplatin and pemetrexed versus carboplatin and pemetrexed alone. In all three arms, patients will receive carboplatin and pemetrexed for four cycles, followed by pemetrexed maintenance. In addition, patients in Arm 1 will receive the chemotherapy plus placebo, patients in Arm 2 will receive chemotherapy with one truncated course of demcizumab every three weeks for four doses and patients in Arm 3 will receive chemotherapy with two truncated courses of demcizumab with the second truncated course starting at Day 168.

OncoMed has reported data from Phase 1b clinical studies of demcizumab plus standard-of-care in patients with first-line advanced pancreatic cancer and extensive stage non-squamous non-small cell lung cancer. Demcizumab was well tolerated in combination with standard-of-care therapies and use of a truncated dosing regimen appeared to successfully mitigate risks of moderate-to-severe cardiopulmonary toxicities without negatively impacting anti-tumor activity. In both Phase 1b studies, demcizumab demonstrated encouraging anti-tumor response rates. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing.

Demcizumab is part of OncoMed’s collaboration with Celgene Corporation.

Active Biotech and Ipsen announce their decision to discontinue the development of tasquinimod in prostate cancer

On April 16, 2015 Active Biotech and Ipsen reported top line results of the 10TASQ10 study (Press release, Ipsen, APR 16, 2015, View Source [SID:1234503022]). While the study showed that tasquinimod reduced the risk of radiographic cancer progression or death compared to placebo (rPFS, HR=0.69, CI 95%: 0.60 – 0.80) in patients with metastatic castration resistant prostate cancer (mCRPC) who have not received chemotherapy, tasquinimod did not extend overall survival (OS, HR=1.09, CI 95%: 0.94 – 1.28).

Efficacy results together with preliminary safety data do not support positive benefit risk balance in this population. Therefore the companies have decided to discontinue all studies in prostate cancer. Full results will be presented at an upcoming scientific conference.

Marc de Garidel, Chairman and Chief Executive Officer of Ipsen stated: "We are disappointed for prostate cancer patients. Ipsen remains strongly committed to oncology. We are grateful to the clinicians, caregivers, patients and their families who were involved in this study."

Professor Tomas Leanderson, President and Chief Executive Officer of Active Biotech stated:
"The outcome of the 10TASQ10 study is a major disappointment based on the promising phase II results. However, the data at hand is unambiguous and cannot motivate further development of tasquinimod in this patient population. I want to thank the clinicians, caregivers, patients and their families who were involved in this study."

Ipsen and Active Biotech are in communication with trial investigators, ethics committees and the relevant regulatory authorities, to provide them with updated and current information in compliance with local regulations. The companies are working with trial investigators and local regulatory authorities to ensure that patients who participated in the tasquinimod trials are transitioned to appropriate therapies so that trial participants receive appropriate care.

About tasquinimod
Tasquinimod is a novel oral immunotherapy that targets the tumor microenvironment by binding to S100A9 and modulating regulatory myeloid cell functions, exerting immunomodulatory, anti-angiogenic and anti-metastatic properties. Today the development of tasquinimod principally has been focused on the treatment of prostate cancer, but early clinical studies in other cancer indications are performed.

About the 10TASQ10 trial
The 10TASQ10 trial is a randomized, double-blind, placebo-controlled, global Phase III clinical trial evaluating tasquinimod in patients with metastatic castration resistant prostate cancer (mCRPC) who have not yet received chemotherapy. The aim of the 10TASQ10 study is to confirm tasquinimod’s efficacy, with radiological Progression Free Survival (rPFS) as primary endpoint and overall survival (OS) as key secondary endpoint. The Phase III 10TASQ10 trial met its enrollment target in December 2012 with more than 1,200 randomized patients as planned in the clinical protocol.

Medimmune and Immunocore announce new collaboration to conduct immuno-oncology combination trials in melanoma

On April 16, 2015 AstraZeneca reported that MedImmune has entered into a collaboration to conduct clinical trials in immuno-oncology with Immunocore (Press release, AstraZeneca, APR 16, 2015, View Source;medimmune-and-immunocore-announce-new-collaboration [SID:1234503020]).

Under the terms of the agreement, Immunocore will conduct a Phase Ib/II clinical trial combining MedImmune’s investigational checkpoint inhibitors MEDI4736 (anti-PD-L1) and/or tremelimumab (anti-CTLA-4) with IMCgp100, Immunocore’s lead T-cell receptor-based investigational therapeutic, for the potential treatment of patients with metastatic melanoma. MedImmune has an exclusive relationship with Immunocore for the development of IMCgp100 in combination with MEDI4736 and/or tremelimumab, and will have first right of negotiation for the future commercial development of these combinations for tumours expressing glycoprotein 100 (gp100), a tumour-associated antigen.

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Immunocore and MedImmune will collaborate to establish a dosing regimen for IMCgp100 combined with MEDI4736 and/or tremelimumab within the Phase Ib study. The Phase II study will assess the safety and efficacy of the different combinations.

The companies have a pre-existing research collaboration and licensing agreement, announced in January 2014, to develop novel cancer therapies using Immunocore’s Immune Mobilising Monoclonal T-Cell Receptor Against Cancer (ImmTAC) technology.

"We are pleased to expand our partnership with Immunocore, a leader in the discovery and development of novel T-cell receptor-based drugs, to include this combination clinical trial in melanoma," said Dr. Ed Bradley, Senior Vice President and Head of the Oncology Innovative Medicines unit at MedImmune. "Immuno-oncology is a priority area for us and by employing combinations with biological synergies, we believe we have the potential to enhance treatment effectiveness and ultimately to see improved overall survival rates. Our partnership with Immunocore is further evidence of our belief that combination therapies have the potential to be one of the most effective ways of treating cancer."

"We are excited to deepen our relationship with MedImmune through this combination study agreement. We look forward to a successful partnership in the development of novel combination treatments in metastatic melanoma, which we believe have the potential to be best-in-class treatments," said Eliot Forster, Chief Executive Officer of Immunocore.

MEDI4736, tremelimumab and IMCgp100 are members of a new class of cancer treatments known as immunotherapies, which are designed to enhance the body’s own immune system in fighting cancer.

AstraZeneca and MedImmune have a broad programme of immuno-oncology combination trials underway and planned to address multiple immune pathways, harnessing the company’s own extensive pipeline and working in partnership to explore the significant potential of immunotherapies in transforming the way cancer patients are treated.

NOTES TO EDITORS

About IMCgp100 and ImmTACs

Immunocore’s proprietary technology is focused on small protein molecules called ImmTACs (Immune Mobilising mTCR Against Cancer) that enable the immune system to recognise and kill cancerous cells.

ImmTACs have ultra-high affinity for intracellular cancer targets, are synthetic, soluble T cell receptors (TCRs) that recognise diseased cells containing disease specific targets. The ImmTACs enable circulating T-cells to selectively identify and kill diseased cells. The ImmTAC platform is unique and has very high specificity and potency as well as broad applicability to a wide range of intracellular targets. ImmTACs can access up to nine-fold more targets than typical antibody-based therapies, including monoclonal antibodies.

The most advanced ImmTAC, IMCgp100, is currently in Phase IIa clinical trials for the treatment of late stage melanoma. Following completion of a Phase I study at the end of 2013, which showed promising results with an encouraging safety profile and early signs of efficacy, Immunocore initiated a Phase IIa study to optimize the dosing regimen of IMCgp100. Immunocore has a growing internal pipeline of ImmTACs addressing many different cancer types and has developed a broad database of intracellular cancer targets.

About MEDI4736

MEDI4736 is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics.

MEDI4736 was accelerated into Phase III clinical development in non-small cell lung cancer and head and neck cancer. The OCEANS clinical development programme will evaluate MEDI4736 as monotherapy and in combination with a CTLA-4 (tremelimumab) in lung cancer, across the spectrum of the disease. In head and neck cancer, MEDI4736 is being investigated both as monotherapy and in combination with tremelimumab, looking at patients with different PD-L1 expression status who have failed on chemotherapy.

About tremelimumab

Tremelimumab is a fully human monoclonal IgG2 antibody, which stimulates the immune system to destroy cancer cells through binding to the protein CTLA-4, expressed on the surface of activated T-lymphocytes.

Tremelimumab has been granted Orphan Drug Designation by the US FDA for the treatment of patients with malignant mesothelioma. It is also currently being studied in combination with AstraZeneca’s anti -PD-L1 investigational immunotherapy, MEDI4736, in tumour types including non-small cell lung cancer and head and neck cancer. It is also being studied in combination with Iressa (gefitinib) in EGFR mutated non-small cell lung cancer and with MEDI6469 (a murine OX40 agonist) in solid tumours.