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20-F – Annual and transition report of foreign private issuers [Sections 13 or 15(d)]

On December 18, 2017 Pharmaceuticals, Inc. (NASDAQ: REGN) and ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company, reported a clinical collaboration to advance ISA101, an immunotherapy targeting human papillomavirus type 16 (HPV16)-induced cancer, in combination with cemiplimab (REGN2810), a PD-1 (programmed cell death protein 1) antibody (Press release, Regeneron, DEC 18, 2017, View Source [SID1234522678]). Regeneron and ISA will jointly fund and conduct clinical trials of the combination treatment in cervical cancer and head-and-neck cancer.

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Expression of HPV oncoproteins contributes to the development of cervical and head-and-neck cancers, and approximately 55 percent of cervical cancers and over 60 percent of head-and-neck cancers are HPV16 positive.1

Regeneron and ISA will share clinical trial costs and exchange product supply. In addition, Regeneron will provide an upfront payment and an equity investment in exchange for an option to an exclusive, global license for ISA101. If Regeneron exercises its option to commercialize ISA101, there is potential for various milestone payments and tiered royalty payments to ISA contingent on regulatory approvals, sales and additional indications. Further financial details were not disclosed.

"Regeneron continues to expand and advance our immuno-oncology program by studying multiple combination therapies in order to fully explore the scientific possibilities in this relatively new field," said Israel Lowy, M.D., Ph.D., Vice President Clinical Sciences, Head of Translational Science and Oncology at Regeneron. "Early clinical results with ISA101 in HPV16-positive indications have been promising, and we’re eager to investigate the impact of adding cemiplimab with the goal of further enabling the body’s immune system to attack the cancer."

"This collaboration with Regeneron is a strong validation of our proprietary SLP (Synthetic Long Peptides) platform and know-how," added Ronald Loggers, Chief Executive Officer of ISA Pharmaceuticals. "We are proud to work with Regeneron, a science- and technology-driven biotechnology company, and aim to further strengthen our pioneering role in the development of innovative treatment options for oncology indications with a high unmet medical need."

Cemiplimab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement for immuno-oncology therapeutics, and was developed using Regeneron’s proprietary VelocImmune technology that yields optimized fully-human antibodies. Cemiplimab is currently being studied as a monotherapy in multiple cancers – including cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma (BCC), non-small cell lung cancer (NSCLC) and cervical cancer – and in various therapeutic combinations. Cemiplimab is currently under clinical development, and its safety and efficacy have not been fully evaluated by any regulatory authority.

ISA101 is an SLP immunotherapy based on the delivery of oncogenic antigens in the form of synthetic long peptides and targets HPV-induced diseases. This innovative concept was discovered by emeritus professor Cornelis J. M. Melief and his team at the Leiden University Medical Center and has been the subject of multiple studies and peer-reviewed publications. It is ISA´s most advanced clinical-stage immunotherapeutic and is in clinical development in advanced and recurrent cervical cancer and incurable HPV16-positive solid tumors (such as squamous cell carcinoma of the head and neck). The first proof-of-concept data on ISA101 as a monotherapy treatment were published in the New England Journal of Medicine2 and initial results from the recently completed ISA101 combination trials in advanced cervical cancer and head-and-neck cancer were presented at ASCO (Free ASCO Whitepaper)-SITC and ESMO (Free ESMO Whitepaper), respectively, in 2017.

WILEX AG: Subsidiary Heidelberg Pharma Signs Exclusive Multi-target Research Agreement with Takeda for the Development of Antibody Targeted Amanitin Conjugates

On June 19, 2017 WILEX AG (ISIN DE000A11QVV0 / WL6 / FSE) reported its subsidiary, Heidelberg Pharma GmbH, Ladenburg, Germany, has signed an exclusive multi-target research agreement with Takeda Pharmaceutical Company Limited (TSE: 4502) for the joint development of antibody drug conjugates (ADCs) that use Amanitin as the payload (Press release, Wilex, JUN 19, 2017, View Source [SID1234526974]).

Under the terms of the exclusive multi-target research agreement, Heidelberg Pharma will produce Antibody Targeted Amanitin Conjugates (ATACs) using antibodies from Takeda’s proprietary portfolio for up to three undisclosed targets. Takeda has an option for an exclusive license for global development and commercialization rights to each of the product candidates resulting from the research collaboration. If it exercises the option, Takeda would be responsible for further preclinical and clinical development, as well as potential commercialization, of any product candidate it licenses.

Professor Andreas Pahl, Chief Scientific Officer of WILEX AG and Heidelberg Pharma GmbH, commented: "We are delighted about the collaboration with Takeda, which has broad expertise in oncology and is a leading ADC company. We believe this partnership provides further validation of our technology. Working with Takeda will allow us to jointly test and expand the application of the ATAC technology to selected antibodies."

Heidelberg Pharma will receive an upfront technology access fee and payments for research services. In the event Takeda exercises its option for an exclusive license, Heidelberg Pharma would receive an option fee. Under the exclusive license agreement, Heidelberg Pharma would be eligible to receive clinical development, regulatory and sales-related milestone payments of up to USD 113 million for each product candidate, as well as royalties.

The expected financial impact of this partnership is already reflected in WILEX’s financial outlook for the current fiscal year provided in March 2017.

"We see significant potential for Heidelberg Pharma’s ATAC technology, combined with our deep oncology expertise, to develop ADC therapies for patients with unmet medical needs," said Christopher Arendt, PhD, Head, Oncology DDU & Immunology Unit, Takeda. "We are excited about this relationship with Heidelberg Pharma, as partnerships such as this one are integral for us to achieve our aspiration of curing cancer."

Takeda signed the agreement with Heidelberg Pharma through its wholly-owned subsidiary, Millennium Pharmaceuticals, Inc.

About Heidelberg Pharma’s proprietary ATAC technology
Antibody-drug conjugates (ADCs) combine the high affinity and specificity of antibodies with the potency of cytotoxic small molecules for the treatment of cancer and inflammatory diseases. Antibody Targeted Amanitin Conjugates (ATACs) are ADCs whose active ingredient is made up of amatoxin molecules. Amatoxins are small bicyclic peptides naturally occurring in the death cap mushroom. They inhibit mRNA transcription by binding to RNA polymerase II, a mechanism that is crucial for the survival of eukaryotic cells. In preclinical testing, ATACs have been shown to be highly efficacious, overcoming frequently encountered resistance mechanisms and combating even quiescent tumor cells.

VBL Therapeutics Provides Update on Long-Term Survival in Phase 2 Trials of Patients with Multiple Tumor Types

On June 19, 2017 VBL Therapeutics (Nasdaq:VBLT) reported an update on the long term status and survival of patients from three completed Phase 2 trials, which investigated the company’s lead candidate, VB-111, respectively in recurrent glioblastoma (rGBM), recurrent platinum-resistant ovarian cancer and radioiodine refractory differentiated thyroid cancer. All three trials had previously shown signals of an overall survival benefit for VB-111 (Press release, VBL Therapeutics, JUN 19, 2017, View Source [SID1234519623]). The company has continued to follow the survival of patients from these trials.

"We are pleased to report that in all three indications over 50% of patients have achieved long term survival following treatment with VB-111 as detailed below. Each of these Phase 2 trials enrolled difficult to treat patients for whom prior treatments had failed," said Prof. Dror Harats, CEO of VBL Therapeutics. "In addition, we continue to follow patients from our Phase 1 studies, who responded to VB-111 and have now survived for more than 5 years, although they were end-stage patients whose tumors had previously progressed in spite of several lines of therapy. We are now conducting pivotal trials with the goal of investigating these survival benefits and providing data to support regulatory approval and commercialization of VB-111. Our GLOBE pivotal trial in rGBM has completed enrollment and we expect top line data from the full dataset becoming available in early 2018. We expect patient enrollment in our planned Phase 3 OVAL study in ovarian cancer to begin in the second half of 2017. In addition, we plan to launch a combination study of VB-111 with a checkpoint inhibitor in lung cancer by year-end 2017."

Summary of Data

rGBM: In the Phase 2 study in rGBM patients, 12 months survival was 54% in patients who were treated with VB-111 through progression, including an rGBM patient who remains alive with complete response after 38 months, compared to 23% of patients who had limited exposure of a therapeutic dose of VB-111. According to a meta-analysis, the 12 months survival on Avastin (bevacizumab) is only 24%.

Ovarian Cancer: In the Phase 2 study in recurrent platinum-resistant and refractory ovarian cancer, 53% of patients treated with a therapeutic dose of VB-111 in combination with paclitaxel were alive at 15 months, some of whom remain alive and are on active follow up. No patients in the sub-therapeutic dose were alive at the 15-month timepoint.

Thyroid Cancer: In the Phase 2 study in radioiodine refractory differentiated thyroid cancer, 53% of those who received multiple therapeutic doses of VB-111 were alive at 24 months, compared to 33% of those who received a single, sub-therapeutic dose of VB-111. 35% of patients on the therapeutic dose cohort remain alive at 39 to 46 months.
VBL’s presentation at BIO will take place tomorrow at 11.45am PDT in the San Diego Convention Center. A webcast of the live presentation can be viewed here: http://www.veracast.com/webcasts/bio/internationalconvention2017/17205139583.cfm.

About Ofranergene Obadenovec (VB-111)
Ofranergene obadenovec is a unique biologic agent that uses a dual mechanism to target solid tumors. Based on a non-integrating, non-replicating, Adeno 5 vector, ofranergene obadenovec utilizes VBL’s proprietary Vascular Targeting System (VTS) to target the tumor vasculature for cancer therapy. Unlike anti-VEGF or TKIs, ofranergene obadenovec does not aim to block a specific pro-angiogenic pathway; instead, it uses an angiogenesis-specific sensor (VBL’s PPE-1-3x proprietary promoter) to specifically induce cell death in angiogenic endothelial cells in the tumor milieu. This mechanism retains activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and shows activity even after failure of prior treatment with other anti-angiogenics. Moreover, ofranergene obadenovec induces specific anti-tumor immune response, which is accompanied by recruitment of CD8 T-cells and apoptosis of tumor cells. Clinical data indicate that continuous exposure to VB-111 can lead to attenuation of tumor growth and to tumor shrinkage, which can translate to survival benefit.

Ofranergene obadenovec completed a Phase 2 study in rGBM, which showed a statistically significant improvement in overall survival in patients treated with ofranergene obadenovec through progression, compared to either patients treated with ofranergene obadenovec followed by bevacizumab alone, or to historical bevacizumab data. In a Phase 2 trial for recurrent platinum-resistant ovarian cancer, ofranergene obadenovec demonstrated a statistically significant increase in overall survival and 60% durable response rate (as measured by reduction in CA-125), approximately twice the historical response with bevacizumab plus chemotherapy in ovarian cancer. In a Phase 2 study in recurrent, iodine-resistant differentiated thyroid cancer, ofranergene obadenovec met the primary endpoint demonstrating disease stabilization with a positive safety profile, along with a dose-response and evidence of an overall survival benefit. Ofranergene obadenovec has received Fast Track Designation for recurrent glioblastoma in the U.S. and orphan drug status for glioblastoma in both the U.S. and EU.

MetaStat Announces Completion of Second Milestone of its Pilot Research Project with Celgene Corporation

On June 19, 2017 MetaStat, Inc. (OTCQB: MTST), a personalized medicine company developing therapeutic and diagnostic treatment solutions for cancer patients, reported it has completed the second milestone under its pilot research project with Celgene Corporation (Press release, MetaStat, JUN 19, 2017, View Source [SID1234519622]). To date, MetaStat has received aggregate milestone payments of approximately $730,000 from Celgene pursuant to the terms of the pilot materials transfer agreement.

"We are very pleased to have successfully completed the second milestone and are now working on the next phase of the Celgene pilot research project," stated Douglas A. Hamilton, MetaStat’s President, CEO and Director.

Prestigious Nature Publication Highlights Novel PTEN Cancer Approach with Prescient’s PTX-100

On June 19, 2017) Clinical-stage oncology company Prescient Therapeutics Ltd (ASX: PTX; Prescient) reported that a pre-clinical study published in the scientific journal Nature this week indicates that Prescient’s geranylgeranyl transferase inhibitor GGTI-2418, known as PTX-100, plays a key role in mitigating a new cancer pathway discovered by Professor Michele Pagano at New York University’s Langone Medical Center, in New York (Press release, Prescient Therapeutics, JUN 19, 2017, View Source [SID1234519615]). Nature is regarded as one of the world’s most cited and prestigious scientific publications.

In the study, Professor Pagano’s group in collaboration with Prescient’s Chief Scientific Officer Professor Said Sebti, demonstrated new details about the tumor suppressor gene, PTEN, which is defective in 30-60% of certain breast, brain and uterine cancers.

"When defective, PTEN cannot control a protein known as FBXL2, which is thought to be responsible for cancer growth in many patients." said Professor Pagano.

Professor Pagano’s study also showed in mouse models that when administered with Prescient’s drug candidate PTX-100, plus photodynamic therapy, FBXL2 is "switched-off" allowing abnormal cells to self-destruct. Therefore, patients whose tumors harbor defective PTEN may also be more likely to respond to a combination of PTEN and photodynamic therapy.

Professor Said Sebti said "These findings have important translational implications for Prescient as patients whose tumors harbor defective PTEN may be more likely to respond to a combination of PTX-100 and photodynamic therapy." "Furthermore, given that PTEN is known to also suppress the Akt tumor survival pathway, patients with PTEN defective tumors could respond to a combination of PTX-100 and an Akt inhibitor like PTX-200."

Prescient’s CEO and Managing Director, Steven Yatomi-Clarke said "This discovery of a new cancer-causing pathway targeted by PTX-100 is an exciting development for Prescient. Our precision medicine strategy uses targeted therapies to address specific cancer mutations. Therefore, this discovery opens up a new frontier of clinical possibilities for PTX-100."

PTEN has been the subject of cancer research for many years, but this new study is very exciting in showing a novel way in which defective PTEN adds to cancer risk, and more importantly, demonstrates that it can be inhibited with PTX-100."

PTX-100 was developed by Professor Sebti, Chair of the Department of Drug Discovery at H. Lee Moffitt Cancer Center, and Chief Scientific Officer at Prescient Therapeutics, and NYU President Andrew Hamilton while he was at Yale University. PTX-100 has already been tested as a single agent in patients with advanced solid tumors in a Phase 1 trial and will be the focus of studies in rare hematological malignancies.

The Nature publication can be previewed at www.nature.com.

FBLX2
FBXL2 is a cancer-causing protein in tumors where PTEN is defective prompting the researchers to look for ways to block FBXL2 in these cancers. To this end, they took advantage of the fact that FBXL2 requires a piece of lipid called geranylgeranyl to localize in the ER membrane near IP3R3, and disabled FBXL2 with GGTI-2418, a drug that blocks the attachment of geranylgeranyl to proteins.

GGTI-2418 was developed by Said Sebti, Chair of the Department of Drug Discovery at Moffitt Cancer Center, and Chief Scientific Officer at Prescient Therapeutics, and NYU President Andrew Hamilton while he was at Yale University. Currently being clinically developed by Prescient Therapeutics, GGTI-2418 (PTX-100) has already been tested as a single agent in patients in a Phase 1 trial, and will enter clinical trials in combination with other drugs.

Photodynamic Therapy
Photodynamic therapy (PDT) is a treatment that uses special drugs, called photosensitizing agents, along with light to kill cancer cells. The drugs only work after they have been activated or "turned on" by certain kinds of light.

Experiments showed that PDT significantly reduced tumor weight and cancer growth rate in mice where PTX-100 made sure that IP3R3 was there to trigger cell death. PDT had little effect on cancer cells with depleted supplies of PTEN or IP3R3. Pagano says his team in collaboration with Sebti’ s team is set to study next the effect of combining GGTI-2418 with PDT in patients with low PTEN, as well as the combination of GGTI-2418, PDT and P13K/AKT inhibitors.

Also of note, the research team found that blocking the ability of FBXL2 to target IP3R3 with GGTI-2418 made tumors in mice more vulnerable to photodynamic therapy or PDT. PDT, which is based on the ability of photosensitizer drugs to cause cytotoxicity after irradiation with visible light, has been applied in the clinic with encouraging results to treat non-small cell lung cancer, dermatological cancers, and premalignant lesions of the upper digestive tract, and is currently in clinical trials for treatment of a large variety of other malignancies, including prostate, brain, and breast cancers.