On November 20, 2017 Samsung Bioepis Co., Ltd. reported the European Commission’s (EC) marketing authorization of ONTRUZANT, a biosimilar referencing Herceptin (trastuzumab), for the treatment of early breast cancer, metastatic breast cancer and metastatic gastric cancer (Press release, Samsung Bioepis, NOV 20, 2017, View Source [SID1234522145]). ONTRUZANT is the first trastuzumab biosimilar to receive regulatory approval in Europe.

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The EC approval of ONTRUZANT applies to all 28 European Union (EU) member states and the European Economic Area (EEA) member states of Norway, Iceland and Liechtenstein. ONTRUZANT will be commercialized by MSD, which is known as Merck in the United States and Canada.

"Breast cancer remains the most common form of cancer affecting women. We hope ONTRUZANT will play an important role expanding patient access to trastuzumab across the region," said Christopher Hansung Ko, President & CEO of Samsung Bioepis. "Through relentless process innovation and an uncompromising commitment to quality, we remain dedicated to advancing one of the industry’s strongest biosimilar pipelines, so that more cancer patients and healthcare systems across Europe will benefit from biosimilars."

ONTRUZANT is the fourth biosimilar developed by Samsung Bioepis to receive EC marketing authorization. Samsung Bioepis has also received marketing authorizations for Benepali (etanercept), Flixabi (infliximab) and Imraldi (adalimumab).

On November 20, 2017 Glactone Pharma reporrted that in strong competition and after external examination, it has been awarded a SEK 886,500 grant (approx. USD 106,000) from Vinnova (Sweden’s Innovation Agency) in the second phase of a program aimed at innovative startup companies (Press release, Glactone Pharma, NOV 20, 2017, View Source [SID1234522150]). The funded project will be used to characterize Glactone Pharma’s lead STAT3 inhibitor, a potential new drug for the treatment of cancers. A STAT3 inhibitor has great potential to address large unmet medical needs and help patients.

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Glactone Pharma’s objective for this project is to generate data on dosing and efficacy in relevant models and to obtain a correlation between pharmacokinetics and pharmacodynamics of the company’s lead compound. Having this data is important for predicting safe and efficacious doses both for non-clinical and clinical studies, thereby increasing the chances of success. STAT3 is a highly promising target in cancer with both preclinical and clinical data supporting the important roles that STAT3 plays in cancer occurrence and progression. Furthermore, STAT3 is involved in mechanisms that enable tumors and cancer cells to evade the immune system. The company’s lead compound has demonstrated the ability to modulate the immune system through STAT3 blockade in a disease model, and thereby acting as a cancer immunotherapy agent.

Immunotherapy is a treatment modality that activates and utilizes the body’s own immune system to recognize and attack tumors and is today the fastest growing and most promising area of cancer research.

Martin Johansson, CEO of Glactone Pharma, says: "The continued development of Glactone Pharma’s STAT3 inhibitor is greatly helped by this funding awarded by Vinnova and we can continue with our focus of bringing a novel drug to the clinic that potentially can help many patients. In addition, the grant is a recognition of the quality of the research that we are conducting at Glactone Pharma."

About STAT3
STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor/signaling protein that is frequently activated in many forms of cancer.

STAT3 plays crucial roles in both tumor cells and in the tumor microenvironment and is a highly promising target for cancer therapy. Direct STAT3 inhibitors have the potential to prevent metastasis, reverse drug resistance and induce apoptosis in cancer cells. Furthermore, STAT3 inhibitors can be combined with immunotherapies to increase response rates and efficacy and with targeted drugs and chemotherapy to reverse and overcome resistance and provide efficacious and safe cancer treatments.

STAT3 is an intractable drug target as it is an intracellular protein with no enzymatic activity and is activated by multiple upstream factors. Despite it not being a "classic drug target", Glactone Pharma has developed orally bioavailable small molecule inhibitors that can directly inhibit the function of STAT3.

PVS-RIPO, more commonly referred to as the re-engineered poliovirus, is the Sabin type 1 polio vaccine, genetically modified so it cannot harm or kill normal cells (Company Web Page, Istari Oncology, NOV 19, 2017, View Source [SID1234522139]).
We believe there are several important advantages of PVS-RIPO as an immunotherapy for cancer treatment:
The poliovirus receptor CD155 is expressed in virtually all solid cancers, as well as dendritic cells, macrophages and other immune cells.
PVS-RIPO infects and kills tumor cells that express CD155.
PVS-RIPO infection of immune cells facilitates induction of an antitumor immune response.
PVS-RIPO is the only oncolytic virus that is not destroyed by the Type 1 interferon response caused by these viruses.
Other oncolytic viruses kill or limit dendritic cells. PVS-RIPO stimulates dendritic cell activity and immune function.
Cancer patients who are immune to polio and have been boosted with the Salk vaccine experience a recall immune response upon intratumoral PVS-RIPO infusion.
For targeting glioblastoma, the vaccine is delivered by direct intratumoral delivery via convection-enhanced delivery (CED), which by-passes the blood-brain barrier and reduces systemic toxicity. CED is commonly used, and we believe it is reproducible in multiple centers. Less than 5% of the tumor volume needs to be injected to achieve high drug concentrations throughout the tumor. BrainLAB and Therataxis software allow highly accurate and reproducible drug distribution and injection accuracy.
The FDA granted PVS-RIPO Breakthrough Therapy Designation on May 10, 2016. Breakthrough Therapy Designation conveys all fast track program features, more intensive FDA guidance on an efficient drug development program, an organizational commitment involving senior FDA managers, and eligibility for rolling review and priority review.
The FDA also granted PVS-RIPO Orphan Drug designation for glioblastoma on May 26, 2016. Benefits of this designation include tax credits of 50% of the clinical drug testing cost awarded upon approval, waiver of NDA/BLA application fee, and seven years of data exclusivity upon approval (that is, it bars the FDA from approving any other application for the same drug for the same orphan disease or condition for seven years).

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On November 20, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the Phase III IMpower150 study met its co-primary endpoint of progression-free survival (PFS) and demonstrated that the combination of TECENTRIQ (atezolizumab) and Avastin (bevacizumab) plus chemotherapy (paclitaxel and carboplatin) provided a statistically significant and clinically meaningful reduction in the risk of disease worsening or death (PFS) compared to Avastin plus chemotherapy in the first-line treatment of people with advanced non-squamous non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, NOV 20, 2017, View Source [SID1234522149]). Initial observations for the co-primary endpoint of overall survival (OS) are encouraging. These data are not fully mature and the next OS analysis is expected in the first half of 2018. Safety for the TECENTRIQ and Avastin plus chemotherapy combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.

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These data will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno Oncology Congress in Geneva, Switzerland in December 2017.

"We are extremely encouraged by these results and will submit these data to health authorities globally with the goal of bringing a potential new standard of care for the initial treatment of lung cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "In addition to first-line NSCLC, we are testing the ability of TECENTRIQ and Avastin to enhance the potential of the immune system to combat a broad range of other cancers."
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 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.

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. This analysis of the IMpower150 PFS endpoint was only statistically powered to demonstrate a comparison between Arm B versus Arm C.

The primary 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**) and in a subgroup of people who had a specific biomarker (T-effector "Teff" gene signature expression). IMpower150 met its PFS co-primary endpoint per study protocol for both populations assessed.

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 globally.1 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 Avastin (bevacizumab)
Avastin is a biologic cancer treatment approved in combination with chemotherapy for the first-line treatment of advanced NSCLC and, to-date, has helped over 500,000 patients lead longer lives. Avastin is considered a standard of care for the first-line treatment of advanced NSCLC and has been proven to significantly extend overall survival (OS). Avastin is currently approved in combination with any platinum-based chemotherapy in Europe, and with paclitaxel/carboplatin in the US, in first-line non-squamous NSCLC, based on results of the pivotal Phase III E4599 study. Avastin was the first medicine to help people with previously untreated advanced, non-squamous NSCLC live longer (OS) than one year when added to chemotherapy.
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 November 17, 2017 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported updated data from the dose expansion cohort of the Phase 1 study evaluating single agent ivosidenib in patients with progressive low grade isocitrate dehydrogenase-1 mutant (IDH1m) glioma (Press release, Agios Pharmaceuticals, NOV 17, 2017, View Source [SID1234522137]). The data were presented today in an oral presentation at the Society for Neuro-Oncology (SNO) Annual Meeting in San Francisco.

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"Glioma is a difficult-to-treat disease with many patients diagnosed at a young age and exposed to surgery, radiation and chemotherapy and their associated side effects," said Ingo Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center, an investigator for the study. "The median treatment duration of 16 months and reduction in tumor growth rates compared to a pre-treatment interval is a signal of ivosidenib’s clinical activity in this population. I look forward to working with Agios and the neuro-oncology community to further refine imaging methodology and to assess the biological effects of IDH inhibitors in a perioperative study planned for the first half of 2018."

Ivosidenib is being evaluated in an ongoing Phase 1 dose escalation and expansion trial in advanced IDH1 mutant positive solid tumors, including glioma. Enrollment was completed in January 2016 and data from the glioma dose escalation and expansion cohorts were presented in November 2016. An update on patients with non-enhancing glioma is reported below.

As of the May 12, 2017 data cut off, 35 patients (11 from escalation, 24 from expansion) with non-enhancing disease have been treated with single agent ivosidenib. Eighteen patients (51%) remain on treatment.

Twenty-four patients had World Health Organization (WHO) classified Grade 2 tumors, eight had Grade 3 tumors, one had a Grade 4 tumor and two were unknown.
Patients received daily doses of ivosidenib ranging from 300 mg to 900 mg. Twenty-eight patients received a daily dose of 500 mg, which was selected as the expansion dose.
The median age of these patients is 38 (ranging from 21-71).
The median treatment duration was 16 months (ranging from 1.4 – 27.1 months).
The median number of prior therapies was 2 (ranging from one to five). The median duration of last systemic therapy was 9.6 months.
○ Sixty-three percent of patients had previously received temozolomide and 57% percent had previously received radiotherapy.
A safety analysis conducted for all 35 treated non-enhancing glioma patients as of the data cut-off demonstrated that ivosidenib was well-tolerated with a favorable safety profile in glioma patients.

No dose limiting toxicities were observed.
The majority of adverse events reported by investigators were mild to moderate, with the most common being headache, diarrhea, nausea and vomiting.
There were 5 patients with serious adverse events (SAE) and all were deemed unrelated to study treatment.
Efficacy data from all 35 non-enhancing glioma patients as of the data cut-off showed:

Two patients had a minor response by investigator assessment according to the Response Assessment in Neuro-Oncology for low grade glioma (RANO-LGG).
Twenty-nine (83%) patients had stable disease.
The median progression free survival (PFS) for all non-enhancing patients was 13 months, the median PFS for Grade 2 patients (n=24) has not been reached.
For patients in the expansion arm (n=24), the average six-month tumor growth was 24% prior to treatment and 11% following treatment with ivosidenib.
In addition, preclinical data for ivosidenib and AG-881, a brain-penetrant pan-IDH inhibitor, in an orthotopic mouse xenograft model of human mIDH1-R132H glioma are also being presented as posters.

Preliminary data suggest that both molecules suppress the oncometabolite D-2-hydroxyglutarate (2-HG) in an orthotopic brain tumor model.
○ At the doses explored, treatment with ivosidenib resulted in 85% maximal 2-HG inhibition and treatment with AG-881 resulted in >98% inhibition of 2-HG levels.
○ Neither molecule impeded the therapeutic effect of concomitant or sequenced radiation therapy.
"We are encouraged by both the ivosidenib clinical data demonstrating prolonged stable disease in patients with progressive, low grade glioma and the preclinical data with ivosidenib and AG-881 demonstrating reductions in the oncometabolite 2-HG," said Chris Bowden, M.D., chief medical officer of Agios. "We look forward to quantitatively assessing 2-HG and other biomarker effects with both molecules in our planned perioperative study."

Next Steps in Glioma

On November 1st, 2017, Agios announced plans to initiate a perioperative ‘window’ study in the first half of 2018 with ivosidenib and AG-881 in approximately 45 low grade glioma patients with progressive disease to further investigate their effects on brain tumor tissue. Patients will be randomized to either ivosidenib or AG-881 and treated for four weeks prior to previously scheduled surgery. An additional five patients will serve as a control arm. The study is designed with the following objectives:

To determine the amount of drug penetration in the brain
To confirm the magnitude of IDH target engagement as measured by 2HG levels in brain tumor tissue
To assess the impact of IDH inhibition on differentiation and epigenetic profiles in tumor tissue and
To assess the safety of both molecules.