On March 21, 2017 Lin BioScience, a drug development company specializing in innovative therapies for oncology, ophthalmology, and cardiology, reported an exclusive licensing agreement with the University of Sydney for a microtubule-targeting agent to treat brain cancers (Press release, Lin Bioscience, MAR 21, 2017, View Source [SID1234520604]).

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The therapeutic candidate, LBS-002, is a small molecule that disrupts the division of cancer cells by preventing the formation of microtubules (the cell structures responsible for the segregation of chromosomes in cell division).

LBS-002’s ability to cross the blood-brain barrier shows promise for treating both primary and metastatic brain cancers

"To date, treating primary glioblastomas and metastatic brain cancers has been challenging because the blood-brain barrier prevents effective drugs from reaching their targets," stated Dr. Tom Lin, CEO of Lin Bioscience. "LBS-002’s ability to cross the blood-brain barrier enables it to overcome the permeability limitations experienced by traditional treatments, making it a promising therapeutic candidate. We’re excited to work with the expertise of Dr. Munoz, Dr. Kassiou and their teams at the University of Sydney to bring new cancer therapies to the clinic."

Under the terms of the agreement, Lin BioScience will gain exclusive global rights to the development and commercialization of intellectual property developed at University of Sydney by Drs. Lenka Munoz and Michael Kassiou. Further terms of the agreement are not disclosed.

"Our research has passed the discovery stage and now our goal is to progress into clinical testing," stated Drs. Munoz and Kassiou. "LBS-002 provides an exciting basis for a program that will lead to new treatments for brain tumors and we are very excited to be working with an innovative biotech like Lin BioScience in translating our fundamental research into clinical studies," said Drs. Munoz and Kassiou.

On 21 March 2017 4SC AG (4SC, FSE Prime Standard: VSC) reported that it will present two posters supporting the continued development of its product candidate 4SC-202, an epigenetic modulator with a unique mechanism of action that inhibits both the lysine-specific demethylase (LSD1) protein and class I histone deacetylase proteins (HDAC1, 2, 3), at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held on 1-5 April 2017 in Washington, D.C., USA (Press release, 4SC, MAR 21, 2017, View Source [SID1234518599]).

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Both posters will be published on 4SC’s website on 3 and 4 April 2017, respectively.
4SC-202 plus checkpoint inhibition – boosting the immune system to fight cancer

"In the first set of experiments, we investigated the anti-tumor activity and mode of action of 4SC-202, both as single agent and in combination with anti-PD1 and anti-PD-L1 antibodies, both checkpoint inhibitors, in immunocompetent and immunocompromised mice. 4SC-202 showed anti-tumor activity alone and synergized with checkpoint inhibition by stimulating the immune system and increasing the number of cancer-killing cytotoxic T cells in the tumor microenvironment. Most importantly, this was achieved without harming the viability of the anti-tumor T cells, which differentiates 4SC-202 from other HDAC inhibitors," summarized Frank Hermann, M.D., Chief Development Officer of 4SC.

"These promising preclinical results build a rationale for further clinical development of 4SC-202. As we see highly synergistic effects of 4SC-202 in combination with checkpoint inhibitors, we should investigate the addition of 4SC-202 in cancer patients who are not responding to treatment with checkpoint inhibitors alone. In these patients, 4SC-202 might help to reactivate the immune system to fight the cancer."

Abstract #2632 / Poster #21: 4SC-202 induces inflamed tumor microenvironment, strongly enhances tumor infiltration with cytotoxic T cells and primes tumors for anti-PD-1/PD-L1 therapy
Date: Monday, 3 April 2017
Time: 1 – 5 p.m. EDT
Location: Section 25
4SC-202 – a potentially interesting player in acute myeloid leukemia (AML)

"In the second set of experiments we investigated a different capability of 4SC-202: the ability to induce differentiation in acute myeloid leukemia (AML) cells, which is a therapeutic approach already in use to treat that disease. We evaluated the anti-tumor activity of 4SC-202 alone and in combination with various cytokines to identify a suitable combination," said Roland Baumgartner, Ph.D., Chief Scientific Officer of 4SC.

"Treatment with 4SC-202 alone induced differentiation in AML cells. In combination with the cytokine interferon-γ (IFN-γ), 4SC-202 induced an enhanced tumor-specific T-cell response that can act against residual malignant AML cells which additionally highlights the potential of 4SC-202 to boost anti-tumor immunity."

Abstract #3088 / Poster #5: Combination of 4SC-202 and IFN-γ restores mature APC phenotype in AML cells
Date: Tuesday, 4 April 2017
Time: 8 a.m. – 12 p.m. EDT
Location: Section 3
Related articles

2 June 2016, 4SC at ASCO (Free ASCO Whitepaper): 4SC 202 and checkpoint inhibitors – strong partners in cancer treatment

21 March 2016, Epigenetic compound 4SC-202 strengthens endogenous immune response to cancer
Further information

About 4SC-202

4SC-202 is an orally administered small molecule for the treatment of cancer. 4SC-202 is an epigenetic modulator with a unique mechanism of action that inhibits both the lysine-specific demethylase (LSD1) protein and class I histone deacetylase proteins (HDAC1, 2, 3), which play significant roles in the regulation of signaling pathways in degenerated cancer cells.

4SC-202 has been investigated in a Phase I study with 24 intensively pretreated patients with several types of highly advanced hematologic cancers, and has proven to be tolerated. Positive signs of anti-tumor efficacy were observed with one complete remission for 28 months and one partial responder for 8 months.

Data from preclinical investigations showed that 4SC-202 strengthens the anti-tumor immune response. Treatment with 4SC-202 alters the tumor microenvironment and increases infiltration of immune cells into the tumor. In June 2016, further preclinical investigations showed that the combination of 4SC-202 with checkpoint inhibitors resulted in better anti-tumor activity than treatment with checkpoint inhibitors alone, suggesting a very promising clinical development path for 4SC-202 in both refractory and non-responding patients to treatment with checkpoint inhibitors.



About checkpoint inhibitors

The human immune system is capable of self-regulation via a wide variety of mechanisms to prevent excessive or misdirected defensive reactions. Tumors exploit these immune system "checkpoints" to switch off the immune response that specifically targets them. This is where checkpoint inhibitors are effective: they inhibit the signaling pathways to "release the brakes" on the immune cells and enable them to attack the cancerous tissue again.

Examples of checkpoint inhibitors that have returned promising data after investigation in clinical trials worldwide include drugs that block the PD-1 (Programmed Death-1) receptor on the surface of immune cells. The PD-1 receptor interacts with its ligands PD-L1 or PD-L2 on the surface of cancer cells to prevent the immune cells from attacking the tumor. With the PD-1 receptor or its ligand PD-L1 blocked, cancer cells can no longer escape the immune response.

On March 21, 2017 Pierre Fabre, the second largest privately held pharmaceutical company in France, and H-Immune SAS, an emerging biotechnology company focused on developing first in class immunotherapies for treatment of various cancers, reported that they have entered into a strategic research partnership which will utilize H-Immune’s unique technology platform to generate lead candidates of fully human antibodies to serve as the initial step in a program to develop immuno-oncology therapeutics (Press release, Pierre Fabre, MAR 21, 2017, View Source [SID1234518248]).

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As a newly established bioscience company in the immuno-oncology field and spin out from the French Atomic Energy Commission, H-Immune has developed a proprietary In Vitro Immunization (IVI) technology leveraging a breakthrough approach to generate a series of fully human monoclonal antibodies (mAbs) against any therapeutic target, taking advantage of the affinity maturation processes performed in situ by B lymphocytes.

Pierre Fabre is an ideal partner for H-Immune to help us begin to realize the full potential of our science and IVI technology which we plan to exploit through multiple industry partnerships, said Luc Boblet, PhD, Co-Founder and CEO of H-Immune. This collaboration is designed to catalyze and create tremendous ongoing scientific and product development synergy by leveraging each company’s strengths and assets.

Under the terms of the agreement, Pierre Fabre will have access to H-Immune’s IVI technology for three different discovery programs in the field of immuno-oncology.

This transaction strengthens Pierre Fabre’s position in the areas of immuno-oncology and novel cutting-edge biotherapeutics,said Laurent Audoly, Head of R&D of Pierre Fabre Pharmaceuticals. H-Immune is developing an antibody technology platform that we are looking forward to accessing as part of our ongoing efforts to identify and develop world-class novel cancer therapeutics. We believe this collaboration enhances the potential of both partners to deliver transformational therapies to patients in areas of significant unmet medical needs.

Pierre Fabre has a longstanding commitment to development of pharmaceuticals through its Pierre Fabre Immunology Centre of excellence (CIPF) based in Saint-Julien-en-Genevois, France, which is dedicated to the identification, development and manufacturing of biologics.

The financial terms of the agreement, which include expertise contribution, R&D funding, and milestone payments to H-Immune, were not disclosed.

On March 21, 2017 Onxeo S.A. (Euronext Paris, NASDAQ Copenhagen: ONXEO), a biotechnology company specializing in the development of innovative drugs for the treatment of orphan diseases, in particular in oncology, reported the presentation of data from three studies supporting the company’s primary drug candidates in oncology, AsiDNATM, Livatag and Beleodaq in poster sessions at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, one of the most prestigious meetings on preclinical cancer research, being held April 1-5, 2017 in Washington, D.C.

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Françoise Bono, PhD, Chief Scientific Officer, commented, “The various data we will be presenting at the prominent AACR (Free AACR Whitepaper) oncology meeting demonstrates our commitment to further explore and advance our three core pipeline assets. These data support delayed tumor growth with the combination of our signal-interfering molecule AsiDNATM and PARP inhibitors, the ability of Livatag to reverse chemo-resistance compared to free doxorubicin and increased anti-tumor response through the combination of our marketed drug Beleodaq with immune checkpoint inhibitors. The results provide a strong rationale for the continued development of each product candidate, and this validation is directly in-line with our mission of identifying and developing innovative approaches to fight some of the most aggressive cancer indications. We look forward to presenting these findings at the conference.”

Details of the sessions on April 3 and 4 include:

Abstract 1110 / Poster 3 – AsiDNA induce tumor sensitivity to PARP inhibitors in homologous recombination proficient breast cancer
Session: PO.ET03.01 – DNA Repair
Date: Monday, April 3
Time: 8:00 a.m. – 12:00 p.m. ET
Location: Section 3

The study highlights the therapeutic interest of combining Onxeo’s lead signal-interfering DNA product candidate AsiDNA and PARP (PolyADP-Ribose Polymerase) inhibitors. This combination significantly decreases tumor growth independent of genetic mutations, in contrast to the antitumoral efficacy of PARP inhibitors alone, which are only effective against tumors bearing mutations on genes coding for proteins involved in homologous recombination (HR) pathway. In a preclinical murine tumor model, while the PARP inhibitor olaparib failed to prevent tumor growth and AsiDNA partially delayed this growth, the combination of olaparib and AsiDNA demonstrated synergistic antitumor efficacy.
Most interestingly, no resistant clones to AsiDNA appeared, suggesting sustained clinical efficacy, unlike most targeted therapies.

Abstract 3076 / Poster 14 – A novel nanoparticle formulation of doxorubicin is clearly differentiated from free doxorubicin in overcoming resistance mechanisms in chemo-resistant tumors
Session: PO.ET02.04 – Determinants of Drug Sensitivity and Resistance
Date: Tuesday, April 4
Time: 8:00 a.m. – 12:00 p.m. ET
Location: Section 2

The study demonstrates the therapeutic potential of Livatag, doxorubicin loaded nanoparticles, to reverse chemo-resistance compared to free doxorubicin in hepatocellular carcinoma (HCC, primary liver cancer), pancreatic cancer and sarcoma models. Livatag showed a dose-dependent inhibition of cell proliferation in all tested resistant cancer cell lines with superior activity compared to free doxorubicin and other tested drugs. Moreover, in contrast to free doxorubicin, Livatag showed consistent anti-proliferative activity in the absence or presence of inhibitors of efflux pumps and autophagy. In a range of in vivo models, Livatag was preferentially taken up by the tumor tissue and significantly reduced tumor growth when compared with free doxorubicin, with at least equivalent reduction in tumor growth compared to currently approved treatments. Furthermore, Livatag administered in combination with current treatments significantly increased the inhibitory effect of each drug without additional toxicity.
In this study, Livatag is clearly differentiated from free doxorubicin in its ability to overcome resistance mechanisms linked to efflux and autophagy, and its superior bio-distribution profile, both of which result in significantly enhanced activity on chemotherapy-resistant tumors.
These new results collectively support the strong rationale behind the ongoing Phase III ReLive clinical trial comparing Livatag to the best standard of care in patients with advanced HCC. Recruitment in this trial is complete, and preliminary results are expected mid-year.

Abstract 1059 / Poster 12 – Enhanced anti-tumor efficacy of a checkpoint inhibitor in combination with the HDAC inhibitor belinostat in a murine hepatocellular carcinoma preclinical model
Session: PO.ET02.02 – Combination Strategies: Novel Agents and Standard Therapies
Date: Monday, April 3
Time: 8:00 a.m. – 12:00 p.m. ET
Location: Section 1

Results demonstrated that Beleodaq (belinostat) improved anti-tumor therapeutic response induced by the checkpoint inhibitor, anti-CTLA4, showing significantly superior tumor growth inhibition compared to control groups. Importantly, treatment with the combination resulted in complete cessation of tumor growth in all mice during the belinostat treatment period. Mechanistic studies showed that Beleodaq (belinostat) induces an increase in the production of interleukins (proteins involved in the signaling and regulation of immune response) by activated T-lymphocytes, and a concomitant decrease in the regulatory T cells (immunosuppressive cells) in the spleens of treated animals. These results provide strong rationale for using belinostat, which is approved in the U.S. for the treatment of second-line peripheral T cell lymphoma (PTCL), in combination with checkpoint inhibitors to reinforce therapeutic response. Currently, only 20 to 40% of patients respond to checkpoint inhibitors alone. In parallel, a new oral formulation of belinostat will allow potential use in multiple clinical situations.
Further studies are ongoing in order to fully characterize this finding and to facilitate translation into patients.