On December 6, 2017 H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, reported that company scientists are presenting data from preclinical studies involving H3B-6545, an oral, selective small molecule covalent antagonist of wild-type and mutant Estrogen Receptor (ERα) at the 40th Annual San Antonio Breast Cancer Symposium (SABCS) in San Antonio, TX (Press release, H3 Biomedicine, DEC 6, 2017, View Source [SID1234522434]). The data will be shared in a poster presentation.

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The poster, presented by Manav Korpal, Ph.D., is titled "Development of a first-in-class oral selective ERα covalent antagonist (SERCA) for the treatment of ERαWT and ERαMUT breast cancer" and is taking place in the following session:

Session: Poster Session 1: Treatment: New Drugs and Treatment Strategies (5:00 PM – 7:00 PM)
Date/Time: Wednesday, December 6, 2017, 5:00 PM
Room: Hall 1

"We are encouraged by the initial results that H3B-6545 demonstrated over the current standard of care agents in preclinical models," said Markus Warmuth, M.D., President and CEO, H3 Biomedicines. "At H3, our research in breast cancer seeks to advance the understanding of this debilitating illness and work towards discovering novel treatments for those affected by the disease."

The poster presented at SABCS demonstrated that H3B-6545 has a unique mode of ERα antagonism and exhibits superior preclinical anti-tumor activity to fulvestrant in the MCF-7 xenograft model with once daily oral dosing, achieving maximal antitumor activity at doses >10x below the maximum tolerated dose in mice. In addition, H3B-6545 demonstrated superior preclinical anti-tumor activity to both tamoxifen and fulvestrant in patient derived xenograft models of breast cancer carrying estrogen receptor mutations. Based on these results, in September, 2017, H3B-6545 entered into a Phase 1 multi-center, open-label study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of the compound in women with ER-positive, Her2-negative metastatic breast cancer. Please refer to www.clinicaltrials.gov for additional clinical trial information.

"The results from the preclinical models indicate a new mode of inhibition, covalent antagonism of ERα, is potent in in vitro and in vivo models of breast cancer," said Pete Smith, Ph.D., Chief Scientific Officer, H3 Biomedicine. "The fact that current ER-directed therapies are only partially effective in the ERα mutant setting, and that a significant proportion of resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival, highlights the critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity."

About H3B-6545

H3B-6545 is an orally bioavailable, potent and selective small molecule modulator of wild-type and mutant Estrogen Receptor (ERα). Scientists at H3 Biomedicine have discovered a new class of ERα antagonists called Selective Estrogen Receptor Covalent Antagonists (SERCAs) that inactivate the estrogen receptor by targeting a cysteine that is not present in other nuclear hormone receptors. SERCAs have a unique biological and activity profile compared to Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs). Preclinical data indicates H3B-6545 inhibits the growth of cell line and patient-derived xenograft models of wild-type and mutant ERα with improved activity over standard-of-care therapies. Initial clinical development will target breast cancer patients with wild-type and mutant ERα and will assess the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of H3B-6545.

On December 6, 2017 Synaffix BV, a biotechnology company that has developed a proprietary site-specific conjugation platform technology to enable differentiated antibody-drug conjugates (ADCs), reported the launch of a new platform of highly potent cytotoxic ADC payloads that will­­ be integrated into its existing ADC platform (Press release, Synaffix, DEC 6, 2017, View Source [SID1234522419]). With this expansion, Synaffix becomes a one-stop provider for technologies required to rapidly translate antibodies into proprietary ADC products.

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The new toxSYN platform consists of four highly potent payloads, which offer multiple mechanisms of action and a viable path for commercialization when combined with the components of the company’s GlycoConnect and HydraSpace technologies:

Syneamicin functionalized calicheamicin (DNA damaging agent)
SYN-38 functionalized SN-38 (topoisomerase 2 inhibitor)
Synstatin E functionalized auristatin E (microtubule inhibitor)
Syntansine functionalized maytansine (microtubule inhibitor)
All the payloads have been clinically validated with well-known efficacy and safety profiles, and were selected to address the two types of biologies that exist across ADC targets which include rapidly-dividing cancer cells as well as quiescent cells, such as cancer stem cells.

"We expect this important expansion of our ADC technology to further advance our internal research and facilitate collaborations with a much broader set of companies" said Peter van de Sande, CEO of Synaffix. "By providing these four distinct payloads through our new toxSYN platform, we can now enable any company with an existing antibody to rapidly establish a highly-competitive clinical-stage ADC program for its own development pipeline."

About Synaffix Site-Specific ADC Platform Technology

The growing experience of Synaffix and its collaboration partners continues to confirm the ability of our conjugation platform technology to consistently generate ADCs that are more effective and better tolerated when compared to all three major clinical-stage ADC conjugation technologies. The proprietary conjugation technology platform of Synaffix is comprised of GlycoConnect, the site-specific and stable antibody conjugation technology that involves proprietary enzymes and metal-free click conjugation components, and HydraSpace, the highly polar ADC-enhancing spacer technology.

GlycoConnect was shown to be capable of significantly enhancing the therapeutic index of an ADC on its own. The highly polar properties of HydraSpace improve the solubility and stability of the payload and the resulting ADC product, thus enhancing further the therapeutic index of the ADC.

Both technologies have demonstrated compatibility with all ADC payload classes and all IgG isotypes and can be applied directly to an existing antibody without any DNA and or protein engineering.

On December 6, 2017 Ayala Pharmaceuticals, a biopharmaceutical company dedicated to developing targeted cancer therapies, reported that they have entered into an exclusive worldwide license agreement with Bristol-Myers Squibb for two gamma secretase inhibitors in development for the treatment of cancers with altered Notch genes (Press release, Ayala Pharmaceuticals, DEC 6, 2017, View Source [SID1234522417]).

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Under the terms of the license agreement, Ayala will have exclusive worldwide development and commercialization rights for BMS-906024 and BMS-986115, two gamma secretase inhibitors previously developed by BMS as a Notch inhibitor for oncology indications. In connection with the license, BMS received an upfront payment, became a shareholder of Ayala, and is eligible to receive certain development, regulatory, and sales-based milestones, as well as tiered annual net sales royalties. Ayala is responsible for all future development and commercialization of BMS-906024 and BMS-986115.

Israel Biotech Fund identified the opportunity, led the due diligence and syndicated with aMoon and Harel Insurance in 2017 to form Ayala. The new company intends to develop BMS-906024 as a precision medicine for niche orphan patient populations harboring Notch activating mutations.

"We believe BMS-906024 is the best in class gamma secretase inhibitor," said Ayala’s Chairman of the Board of Directors, David Sidransky, MD. "Although most Notch targeted clinical trials have traditionally recruited non-selected populations, our approach is to target patients with specific Notch alterations whose tumors are expected to respond directly to this treatment." Dr. Sidransky is a Co-Founder and Managing Partner of Israel Biotech Fund. He was Vice Chairman of ImClone Systems until its acquisition by Eli Lilly and the chairman and board member of several NASDAQ listed biotech companies.

"This is an exciting opportunity in personalized therapy for Oncology, bringing new hope to cancer patients with no approved treatment options," said Roni Mamluk, PhD, CEO at Ayala. "We plan to initiate phase 2 clinical trials in 2018." Roni Mamluk, is the former CEO of Chiasma and a member of its board of directors.

"Partnering with Ayala allows for the continued development of BMS-906024 and BMS-986115 and demonstrates our commitment to seeking opportunities that enable the continued development of drug candidates that might benefit certain patients," said Tim Reilly, Vice President, Head of Early Oncology Development at BMS. "Dr. Sidransky and Ayala are strategically positioned to focus their resources on the targeted development of these candidates for the treatment of cancers with altered Notch genes."

On December 6, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from the positive, pivotal Phase III IMpower150 study of Tecentriq (atezolizumab) and Avastin (bevacizumab) plus chemotherapy (carboplatin and paclitaxel) in people with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, DEC 6, 2017, View Source [SID1234522415]). The study showed that people who received Tecentriq and Avastin plus chemotherapy had a 38 percent reduced risk of their disease worsening or death (progression-free survival, PFS) compared with those who received Avastin plus chemotherapy (hazard ratio [HR]=0.62; p<0.0001 95 % CI: 0.52-0.74; median PFS = 8.3 vs. 6.8 months). Importantly, a doubling of the 12-month landmark PFS rate was observed with the combination of Tecentriq and Avastin plus chemotherapy (37 percent) compared to Avastin plus chemotherapy (18 percent). The rate of tumour shrinkage (overall response rate, ORR), a secondary endpoint in the study, was higher in people treated with Tecentriq and Avastin plus chemotherapy compared with Avastin plus chemotherapy (64 percent vs. 48 percent). The safety profile of the Tecentriq and Avastin plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.

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The analysis of the co-primary PFS endpoint in IMpower150 was assessed in two populations: all randomised people without an ALK* or EGFR** genetic mutation (intention-to-treat wild-type, ITT-WT) and in a subgroup of people who had a specific biomarker (T-effector "Teff" gene signature expression Teff WT). IMpower150 met its PFS co-primary endpoint per study protocol for both populations assessed. In the Teff-WT population, the combination of Tecentriq and Avastin plus chemotherapy reduced the risk of disease worsening or death by 49 percent compared to Avastin plus chemotherapy (HR=0.51; p<0.0001 95% CI: 0.38-0.68; median PFS = 11.3 vs 6.8 months).
"This Tecentriq study is the first positive Phase III combination trial that showed a cancer immunotherapy reduced the risk of the disease getting worse when used as an initial treatment in a broad group of people with advanced non-squamous NSCLC," Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The IMpower150 study represents an important advance in lung cancer treatment, and we will submit these results to regulatory authorities around the world to potentially bring a new standard of care to people living with this disease as soon as possible."

The late-breaking IMpower150 data will be presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno Oncology Congress (Abstract #LBA1_PR) on Thursday, 7 December 6.15 pm. Central European Time (CET) and are also part of the official press programme. Early results from the co-primary endpoint of overall survival (OS) are encouraging. While they are not yet fully mature, these preliminary OS results will be presented at the ESMO (Free ESMO Whitepaper) IO congress. The next analysis of survival is expected in the first half of 2018.

About the IMpower150 study
IMpower150 is a multicentre, open-label, randomised, controlled Phase III study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and paclitaxel) with or without Avastin in people with stage IV or recurrent metastatic non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease. It enrolled 1,202 people of which those with ALK and EGFR mutations were excluded from the primary ITT analysis. People were randomised (1:1:1) to receive:

Tecentriq plus carboplatin and paclitaxel (Arm A), or
Tecentriq and Avastin plus carboplatin and paclitaxel (Arm B), or
Avastin plus carboplatin and paclitaxel (Arm C, control arm).
During the treatment-induction phase, people in Arm A received Tecentriq administered intravenously at 1200 mg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, people received maintenance treatment with Tecentriq (1200 mg every 3 weeks) until loss of clinical benefit or disease progression.

Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet. IMpower150 was designed to formally compare Tecentriq plus chemotherapy (Arm A) versus Avastin plus chemotherapy (Arm C), only if Tecentriq and Avastin plus chemotherapy (Arm B) is shown to improve OS in the ITT-WT population compared to Avastin plus chemotherapy (Arm C). These OS results are expected in the first half of 2018.

People in Arm B received induction treatment with Tecentriq (1200 mg) and Avastin administered intravenously at 15 mg/kg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. People then received maintenance treatment with the Tecentriq Avastin regimen until disease progression (Avastin) or loss of clinical benefit/disease progression (Tecentriq).

People in Arm C received induction treatment with Avastin administered intravenously at 15 mg/kg plus intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. This was followed by maintenance treatment with Avastin alone until disease progression.

The co-primary endpoints were PFS, as determined by the investigator using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1), and OS.

A summary of the IMpower150 Arm B vs Arm C PFS and ORR results are included below; additional data, including preliminary OS results and Arm A vs Arm C PFS will be presented as part of the Late-Breaking Abstract presentation.

The safety profile of Tecentriq and Avastin plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination. Serious adverse events related to treatment were observed in 25.4 percent of people who received Tecentriq and Avastin plus chemotherapy compared to 19.3 percent of those who received Avastin plus chemotherapy.

About NSCLC
Despite recent advances in the treatment of NSCLC, there is still a need for new treatment options. Lung cancer is the leading cause of cancer death globally1. Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.2 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.2
About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has eight Phase III lung cancer studies underway, evaluating Tecentriq alone or in combination with other medicines.

Tecentriq is already approved in the European Union, United States and more than 50 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the Tecentriq (atezolizumab) and Avastin (bevacizumab) combination

There is a strong scientific rationale to support the use of Tecentriq plus Avastin in combination. The Tecentriq and Avastin regimen may enhance the potential of the immune system to combat a broad range of cancers, including first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance Tecentriq’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.

About Roche in cancer immunotherapy

For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.

On December 6, 2017 Transgene (Paris:TNG) (Euronext Paris: TNG), a company that designs and develops viral-based immunotherapies, and BioInvent International AB (OMXS: BINV), focused on the discovery and development of novel and first-in-class immuno-regulatory antibodies to treat cancer and reported that they have entered a collaboration to co-develop next generation oncolytic virus (OV) candidates encoding an anti-CTLA-4 antibody sequence – potentially with additional transgenes – capable of treating multiple solid tumors (Press release, Transgene, DEC 6, 2017, View Source [SID1234522412]).

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Under the terms of the agreement Transgene will contribute both its OV design and engineering expertise as well as its proprietary engineered Vaccinia virus, derived from its Invir.IOTM platform. These oncolytic viruses are designed to directly and selectively destroy cancer cells by the intracellular replication of the virus in the cancer cell (oncolysis). Oncolysis is important as it induces an immune response against tumors (immunogenic lysis). In addition, the replication of the virus allows the expression of the genes carried by the oncolytic viral genome including therapeutic "weapons" that have been specifically designed to attack the tumor.

BioInvent will provide its cancer biology and antibody expertise to the collaboration as well as anti-CTLA-4 monoclonal antibody coding sequences, generated through its proprietary n-CoDeR/FIRST platforms, which will be encoded from in Transgene’s Invir.IOTM viral vectors. The local expression of such therapeutic payloads in the cancer cell is expected to augment the anti-cancer effects of viral oncolysis, by efficiently modulating the tumor micro-environment and increasing the immunocompetency of the tumor.

Encoding BioInvent’s anti-CTLA-4 antibody sequence in Transgene’s latest improved Vaccinia virus, promises to optimize the efficacy of this potent checkpoint inhibitor, while reducing the side effects seen when it is given systemically. There is also the potential for this novel OV product to be significantly more effective than the combination of these single agents. Transgene has generated preclinical proof-of-concept data showing that an oncolytic Vaccinia virus encoded with a checkpoint inhibitor demonstrated better overall survival than the corresponding combination as separate single agents.

The collaboration’s research and development costs, as well as the revenues and royalties from candidates generated by the collaboration, will be shared 50:50.

Philippe Archinard, PhD, Chairman and CEO of Transgene, said: "We look forward to starting this first, exciting collaboration with BioInvent. We believe that the next generation of multi-functional OVs derived from our Invir.IOTM platform, armed with highly targeted immune modulators such as those engineered by BioInvent, will provide patients with better clinical outcomes. Based on the compelling preclinical data we have generated, we expect the resulting OVs to deliver a significant improvement in overall survival, with an enhanced safety profile when compared to administering an OV and checkpoint inhibitor separately."

Commenting on the agreement, Michael Oredsson, CEO of BioInvent, said: "We are very pleased to announce this first collaboration with Transgene which will allow us to leverage our cancer antibody biology and immuno-oncology expertise. We are looking forward to working with Transgene to generate the next generation OVs capable of expressing immune modulatory antibodies in the tumor, thus enhancing their efficacy and improving their safety profile. We are confident that such next generation oncolytic viruses have the potential to significantly improve treatment of solid tumors."