On December 12, 2016 Novocure (NASDAQ: NVCR) presented data from its phase 2 pilot PANOVA clinical trial at its research and development day suggesting that Tumor Treating Fields (TTFields) plus first-line chemotherapies nab-paclitaxel and gemcitabine may be tolerable and safe in patients with advanced pancreatic cancer (Press release, NovoCure, DEC 12, 2016, View Source [SID1234517056]). The data also suggested an improved one-year survival rate among patients who received TTFields therapy with nab-paclitaxel and gemcitabine compared to a recent phase 3 trial of patients who received nab-paclitaxel and gemcitabine alone¹. Progression free survival and one-year survival rate of patients treated with TTFields plus nab-paclitaxel and gemcitabine were more than double those of nab-paclitaxel and gemcitabine-treated historical controls¹. Novocure will submit data for presentation at an upcoming medical conference.

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The second cohort of the prospective, single-arm study included 20 patients with advanced pancreatic cancer whose tumors could not be removed surgically and who had not received chemotherapy or radiation therapy prior to the clinical trial. The primary endpoint measured the incidence and severity of treatment-related adverse events. Patients reported no serious adverse events related to TTFields. Nine patients suffered from serious adverse events unrelated to TTFields therapy.

"We are extremely pleased with these results," said Dr. Eilon Kirson, Novocure’s Chief Science Officer and Head of Research and Development. "The results of the second cohort of our PANOVA trial support our preclinical work that has demonstrated increased cancer cell sensitivity when TTFields therapy is combined with taxane-based chemotherapies, such as nab-paclitaxel. We are finalizing plans and are eager to begin a phase 3 pivotal trial in advanced pancreatic cancer."

About Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer death in the U.S. The American Cancer Society estimated that about 53,000 people would be diagnosed with pancreatic cancer and about 42,000 people would die from the disease in 2016. Five-year survival among patients with metastatic pancreatic cancer is 2 percent. Tumor Treating Fields (TTFields) therapy is not approved for the treatment of pancreatic cancer by the U.S. Food and Drug Administration. The safety and effectiveness of TTFields therapy for pancreatic cancer has not been established.

On December 12, 2016 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, and Synthon Biopharmaceuticals B.V., an international biopharmaceutical company with highly focused development activities for new molecular entities in the therapeutic areas of oncology and autoimmune diseases, reported they have entered a license and collaboration agreement for the development of MGC018, an antibody-drug conjugate (ADC) directed against solid tumors expressing B7-H3 (Press release, MacroGenics, DEC 12, 2016, View Source [SID1234517232]). This molecule is based on a MacroGenics proprietary B7-H3 antibody and Synthon’s proprietary duocarmycin-based, linker-drug technology.

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Under the terms of the agreement, Synthon has licensed rights to its linker-drug technology to MacroGenics to enable future development and commercialization of MGC018. Synthon will also provide manufacturing support and supply ADC to MacroGenics and will be entitled to receive license fees, milestone payments and royalties based on successful development and commercialization of MGC018. Additional details of the transaction were not disclosed.

Based on favorable activity and safety profiles in the non-clinical setting, MacroGenics has selected MGC018 as its lead anti-B7-H3 ADC candidate. MacroGenics has recently initiated IND-enabling studies for this molecule.

"We are encouraged by the data generated with Synthon’s ADC platform and believe that MGC018 will nicely complement our broader portfolio of B7-H3-directed agents," said Scott Koenig, M.D., Ph.D., President and Chief Executive Officer of MacroGenics. "The team at Synthon brings tremendous expertise in linker-drug chemistry and product development that complements our existing capabilities. We look forward to continuing to collaborate with them on this important molecule."

Jacques Lemmens, founder and CEO of Synthon added: "We are very pleased with this commercial licensing agreement with MacroGenics, which enables us to deploy our unique linker-drug technology against a therapeutic target that is complementary to those in our own pipeline. We believe that such collaborations are an important means to accelerate the availability of important therapeutic treatment options to patients who need them."

MacroGenics’ B7-H3 Franchise

MGC018 represents the third molecule in MacroGenics’ franchise of B7-H3-directed molecules. In addition to MGC018, MacroGenics is pursuing two other therapeutic product candidates utilizing different and complementary immune-based mechanisms of action. The leading program, enoblituzumab, is an Fc-optimized monoclonal antibody directed against B7-H3 and is currently in clinical testing as both monotherapy and in combination with either pembrolizumab or ipilimumab. The second program, MGD009, also in clinical testing, is a bispecific DART molecule designed to target tumors expressing B7-H3 by recruiting and expanding T cells at the tumor site. MacroGenics retains worldwide development and commercialization rights to all three of these programs.

Synthon’s Unique Technology Based on Duocarmycin Analogs

Antibody-drug conjugates are designed to combine the specificity of antibodies directed against tumor-associated targets with potent cytotoxicity. Upon internalization of the ADC, the antibody-bound cytotoxins are released intracellularly, leading to programmed tumor cell death.

While the cytotoxins used in the majority of advanced programs in the field prevent tubulin polymerization during cell division, Synthon’s differentiating linker-drug technology − which applies valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA) − is based on synthetic duocarmycin analogs, which bind to the minor groove of DNA and subsequently cause irreversible alkylation of DNA. This disrupts the nucleic acid architecture, which eventually leads to tumor cell death.

Duocarmycins are able to exert their mode of action at any phase in the cellular cycle, whereas tubulin binders will only attack tumor cells when they are in a mitotic phase. Growing evidence suggests that DNA damaging agents, such as duocarmycins, are more efficacious in tumor cell killing than tubulin binders, particularly in solid tumors.

Although based on natural products, Synthon’s proprietary ADC linker-drug technology uses fully synthetic duocarmycin analogs. The unique design of the selectively cleavable linker connecting the antibody to a duocarmycin prodrug leads to high stability in circulation, and induces efficient release of the cytotoxin in the tumor.

On December 10, 2016 Corcept Therapeutics Incorporated (NASDAQ: CORT pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, psychiatric and oncologic disorders by modulating the effects of the stress hormone cortisol, reported efficacy data today from its Phase 1/2 trial of mifepristone to treat patients with metastatic (TNB). The data were presented at the 2016 San Antonio Breast Cancer Symposium (Press release, Corcept Therapeutics, DEC 10, 2016, http://www.corcept.com/news_events/view/pr_1481381366 [SID1234517022]).

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"The results of this trial support our hypothesis that cortisol modulation augments the benefits of chemotherapy in solid-tumor cancers that express the glucocorticoid receptor (GR)," said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. "As we have mentioned before, we are excited to report that investigators at the University of Chicago are leading a multi-center, placebo-controlled, Phase 2 trial of mifepristone in combination with nab-paclitaxel (Abraxane) to treat patients with advanced TNBC."

"Our oncology program continues to gain in depth and breadth," said Robert S. Fishman, MD, Corcept’s hief Medical Officer. "The Phase 1/2 trial of our proprietary cortisol modulator, CORT125134, continues to progress. Next year we plan to study this compound’s efficacy, in combination with Abraxane, as a treatment for patients with TNBC and ovarian cancer. Early next year, we will also advance to the clinic the selective cortisol modulator, CORT125281, which has shown great promise in animal models of castration-resistant prostate cancer (CRPC). Our study of selective cortisol modulators fits well with the important work with mifepristone being performed by University of Chicago investigators, who are leading a multi-center, double-blind, controlled Phase 2 trial of mifepristone plus enzalutamide (Xandie) in CRPC and are leading, as Dr. Belanoff said, a multi-center, placebo-controlled Phase 2 trial of mifepristone in combination with Abraxane to treat patients with TNBC."

Efficacy Results in Corcept’s Phase 1/2 Trial of Mifepristone to Treat TNBC

This open-label trial was designed to investigate whether the addition of mifepristone enhances the effect of denibulin (Halaven) in patients with TNBC whose tumors express GR, one of the receptors to which mifepristone binds.

The trial studied 21 patients with GR positive tumors, one with a GR negative tumor and one whose GR status is not known. As determined using the Response Evaluation Criteria in Solid Tumors (RECIST), efficacy results in this group were as follows: Four patients exhibited a partial response, defined as a 30 percent or greater reduction in tumor size, eight had stable disease and 11 had progressive disease. patient (who has exhibited a partial response) continues therapy (see Figure 1).

Figure 1

"These data are encouraging," said Dr. Fishman. "Six patients achieved progression-free survival (PFS) longer than the upper bound for PFS (15 weeks) in patients receiving Halaven monotherapy in a comparable population (Aegis et al., Annals of Oncology 23: 1441-1448, 2012). Median PFS in our trial was 11.1 weeks – compared to 7.2 weeks in the Halaven monotherapy study reported by Aegis. We continue to collect overall survival data. Eight study patients are known to be alive."

About TNBC

TNBC is a form of breast cancer in which the three receptors that fuel most breast cancer growth – estrogen, progesterone and HER-2 – are not present. Because the tumor cells lack these receptors, treatments that target estrogen, progesterone and HER-2 are ineffective. Approximately 40,000 women are diagnosed with triple-negative breast cancer each year. It is estimated that more than 75 percent of these women’s tumor cells express GR. There is no FDA-approved treatment and neither a targeted treatment nor an app oved standard chemotherapy regimen for relapsed triple-negative breast cancer patients exists. Corcept has licensed patents from the University of Chicago covering the use of GR antagonists in combination with chemotherapy to treat TNBC and castration-resistant prostate cancer.

About CRPC

Castration-resistant prostate cancer (CRPC) is a form of the disease that progresses despite androgen receptor blockade. There are approximately 130,000 patients with metastatic CRPC in the United States. The prognosis for patients with metastatic disease is poor.

About Mifepristone

Mifepristone is the active ingredient in Corcept’s product, Korlym 300mg tablets, which the FDA has approved for the once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym (mifepristone) ameliorates the symptoms of Cushing’s syndrome by modulating the activity of cortisol at GR, one of the two receptors to which cortisol binds. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.

On December 10, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN), a global biotechnology company, reported data from an ongoing phase 1 clinical trial evaluating SGN-LIV1A for patients with metastatic breast cancer (MBC), with particular focus on triple-negative MBC (TN MBC), at the 39th San Antonio Breast Cancer Symposium (SABCS) taking place in San Antonio, Texas, December 6-10, 2016 (Press release, Seattle Genetics, DEC 10, 2016, View Source;p=RssLanding&cat=news&id=2228848 [SID1234517023]). SGN-LIV1A is an investigational antibody-drug conjugate (ADC) which consists of a LIV-1-targeted monoclonal antibody linked to the cell-killing agent monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1 is a protein expressed by most metastatic breast cancers. SGN-LIV1A is one of four clinical-stage empowered antibody therapies under development by Seattle Genetics for solid tumors.

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"Breast cancer is the most common cancer among women, with an estimated 1.67 million new cases per year worldwide. About 15 to 20 percent of breast cancers are triple negative, which means they lack expression of three breast cancer-associated proteins that serve as key therapeutic targets. Triple-negative breast cancers are more aggressive and generally have poor prognoses," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The data presented at SABCS on SGN-LIV1A demonstrate promising early antitumor activity with a 37 percent partial response rate in patients with triple negative metastatic breast cancer, for which there are no available targeted treatments. We are enrolling additional patients with triple negative metastatic breast cancer in our phase 1 study to optimize the dose and inform the next steps for development of SGN-LIV1A in this population with high unmet need."

Interim data from the ongoing phase 1 study of SGN-LIV1A in patients with MBC were previously presented at the 2015 SABCS. The following updated results from this trial describe safety data for all patients and antitumor activity data for patients with TN MBC.

Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-LIV1A in Patients with Metastatic Breast Cancer (Poster# P6-12-04, Poster Session 6 – Treatment: New Drugs and Treatment Strategies at 7:30 – 9:00 a.m. CT on Saturday, December 10, 2016)

Data were reported from 53 patients with LIV-1-expressing MBC who were treated with SGN-LIV1A monotherapy administered every three weeks. Of these patients, 35 had TN MBC. The median age of all patients was 56 years. Patients had received a median of four prior systemic therapies for metastatic disease. Key findings presented by Dr. Andres Forero-Torres, University of Alabama at Birmingham included:

Thirty of 47 efficacy-evaluable patients had TN MBC. Among these patients, 11 (37 percent) achieved a partial response (PR). The disease control rate (DCR) was 67 percent and the clinical benefit rate (CBR) was 47 percent. DCR is defined as patients achieving a complete response (CR), PR or stable disease (SD). CBR is defined as patients achieving CR or PR of any duration plus patients achieving SD lasting at least 24 weeks.
At the time of this interim data analysis, the estimated median progression-free survival for TN MBC patients was 12 weeks with seven patients remaining on treatment.
The maximum tolerated dose was not reached among doses ranging from 0.5 to 2.8 milligrams per kilogram (mg/kg). Dose escalation is complete and a disease-specific expansion cohort of TN MBC patients is currently enrolling.
For all patients in the study, the most common adverse events of any grade occurring in 20 percent or more of patients included fatigue (57 percent), nausea (53 percent), alopecia (42 percent), decreased appetite (34 percent) and constipation (32 percent).
The incidence of grade 3/4 neutropenia at the 2.5 mg/kg dose was 50 percent. Two patients (seven percent) experienced febrile neutropenia, and there was one treatment-related death due to sepsis. Based on these safety data, a separate expansion cohort at 2.0 mg/kg is currently being evaluated.
Peripheral neuropathy events occurred in 38 percent of patients and were generally low grade and manageable.
Enrollment continues for patients with TN MBC in the SGN-LIV1A monotherapy part of the study. In addition, enrollment is ongoing for patients with HER2+ breast cancer to evaluate SGN-LIV1A in combination with trastuzumab.
More information about the SGN-LIV1A phase 1 clinical trial, including enrolling centers, is available by visiting www.clinicaltrials.gov.

About SGN-LIV1A

SGN-LIV1A is a novel investigational ADC targeted to LIV-1 protein utilizing Seattle Genetics’ proprietary ADC technology. LIV-1 is expressed by most metastatic breast cancers. It has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer. SGN-LIV1A consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker, using the same technology as ADCETRIS (brentuximab vedotin). It is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response.

About Breast Cancer

Breast cancer is a cancer which forms in breast tissue. Metastatic breast cancer occurs when the cancer has spread to other parts of the body. While most new diagnoses of breast cancer are made at an early stage, approximately one-third of these patients will eventually develop recurrent or metastatic disease. Breast cancers are commonly categorized by the expression (or lack thereof) of three key proteins, which serve are targets for therapeutics. These include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Triple-negative breast cancer (TNBC) lacks all three proteins and HR+/HER2- breast cancer expresses one or both hormone receptors (HR) but not HER2. According to the World Health Organization, breast cancer is the second most common cancer in the world and the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012. Furthermore, breast cancer ranks as the fifth cause of death from cancer overall. New treatment approaches are needed to improve outcomes for breast cancer patients, particularly for those with TNBC where there are currently no available targeted therapies.

On December 10, 2016 Syros Pharmaceuticals (NASDAQ: SYRS) reported the presentation of new data on SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, showing that SY-1425 inhibited tumor growth in multiple preclinical models of breast cancer driven by high levels of RARA gene expression (Press release, Syros Pharmaceuticals, DEC 10, 2016, View Source;p=irol-newsArticle&ID=2228847 [SID1234517024]). In these studies, SY-1425 showed significant anti-proliferative activity both as a single agent and in combination with standard-of-care breast cancer therapies in in vitro and in vivo models of breast cancer, including those resistant to existing treatments. These data were presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS).

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"Despite tremendous progress in treating certain types of breast cancer, two of the greatest remaining challenges are our ability to identify the right treatment for the right patient and cancer’s ability to become resistant to treatment," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "The new data on SY-1425 show that we have the potential to address both these challenges for subsets of breast cancer patients whose disease is driven by abnormally high expression of the RARA gene."

The data presented at SABCS show that subsets of breast cancer patients’ tumors have a highly specialized region of regulatory DNA, known as a super-enhancer, that is associated with the RARA gene and drives high levels of RARA gene expression. In preclinical models of breast cancer, high RARA gene expression was shown to be predictive of response to treatment with SY-1425. The data highlight that SY-1425:

Inhibited tumor growth in breast cancer cell lines as well as cell line-derived xenograft and patient-derived xenograft models of breast cancer with high RARA gene expression, including models of HER2-positive breast cancer resistant to treatment with trastuzumab and ER-positive breast cancer resistant to hormonal therapies. By contrast, SY-1425 did not inhibit tumor growth in models of breast cancer with low RARA gene expression.
Reduced the expression of genes responsible for tumor growth in HER2-positive and ER-positive breast cancer cells with high RARA expression.
Increased the anti-tumor effects of standard-of-care therapies, including tamoxifen and palbociclib in ER-positive breast cancer cells with high RARA expression and lapatinib in HER2-positive breast cancer cells with high RARA expression.
These data support the potential clinical development of SY-1425 in genomically defined subsets of breast cancer patients.

SY-1425 is currently in a Phase 2 clinical trial in genomically defined subsets of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Using its gene control platform, Syros discovered subsets of AML, MDS and breast cancer patients whose tumors have the super-enhancer associated with the RARA gene, which codes for the RARα transcription factor. The resulting over-expression of RARα locks the cells in an immature, undifferentiated and proliferative state. Treatment with SY-1425 in cancer cells with this super-enhancer promotes differentiation of these cells. Upon achieving clinical proof-of concept in AML and MDS, Syros plans to expand development of SY-1425 into genomically defined subsets of breast cancer patients.

SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by a fusion of the RARA gene with other genes. Syros in-licensed SY-1425 for development and commercialization in North America and Europe in cancer. Additional details about the ongoing Phase 2 trial in AML and MDS can be found using the identifier NCT02807558 at www.clinicaltrials.gov.