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.

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]).

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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.

TaiwanJ’s dual target pipelines focuses on new chemical entities that afford concurrent HMG-CoA reductase (HMGR) and histone deacteylase (HDAC) inhibition. Both are molecular targets for new anti-cancer and anti-inflammation drugs. HDAC suppresses the expression of anti-oncogenes and promotes tumorigenesis, as well as inflammatory and immune-activation genes. HMGR is the rate-limiting enzyme for cholesterol synthesis, which is up stream of Ras family oncoproteins activation through protein prenylation, and in turn suppresses the inflammatory cascade. Furthermore, HMGR inhibition has been shown to promote the function of HDAC inhibitors.

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The dual target inhibitors show improved preclinical safety and stability profiles over existing HDAC inhibitors (HDACi), and is expected to increase therapeutic index and widen therapeutic window clinically. The anti-cancer efficacy of HDAC-HMGR dual inhibition has been shown in colorectal cancer and liver metastasis in proof-of concept preclinical studies.

STX101 and STX105, our lead Syntides, are stabilized peptide therapeutics that inhibit an interaction essential in the Homologous Recombination (HR) DNA repair pathway.

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We are developing STX101 and STX105 as monotherapy candidates for specific types of cancers which are dependent on HR for chemo evasion. We are specificially pursing STX100 compounds for efficacy towards intrahepatic cholangiocarcinomas (ICC) and castration-resistant prostate cancer (mCRPC).

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These syntides are also being developed for combination therapy with current chemotherapy drugs, enabling a lower dosing, increased efficacy and reduced side effects.

Due to the targeting of HR, our compounds also hold particular promise for the treatment of children with Bloom’s syndrome.
STX100 series
C

STX201 pancreatic cancer
STX301 KRAS-driven cancers

TWJ101 is a novel small molecule that inhibits both histone deacetylase (HDAC) and HMG-CoA reductase (HMGR). Both are molecular targets for anti-cancer drugs. TWJ101 has shown significant anti-tumor effects in multiple preclinical models of colorectal cancer. The safety assessment studies for TWJ101 are scheduled to complete in 2017, and the IND application package is due to be submitted later in same year.

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TWJ101 presents a viable option for the treatment of mCRC and possibly other cancer types. The utility of TWJ101 in inflammation including IBD will also be explored.