On December 8, 2018 Novartis reported data from subgroup analyses of the three pivotal Phase III MONALEESA trials showing that Kisqali (ribociclib) plus endocrine therapy extended progression-free survival (PFS) compared to endocrine therapy alone, regardless of the presence of visceral metastases in pre-, peri- and postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer[1] (Press release, Novartis, DEC 8, 2018, View Source [SID1234531964]). These data will be presented today at the San Antonio Breast Cancer Symposium (SABCS) (Abstract #P6-18-07).

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"Nearly 60% of patients enrolled in the MONALEESA clinical trials had visceral metastases, and all benefited from treatment with ribociclib in combination with endocrine therapy," said Denise Yardley, MD, Principal Investigator, Sarah Cannon Research Institute. "These results, coupled with the NCCN and ABC4 recommended treatment guidelines for HR+ advanced breast cancer patients with visceral metastases, support the use of ribociclib combination therapy as a standard of care in this patient population."

In patients with visceral metastases, Kisqali plus endocrine therapy extended median PFS by 11.5 months in MONALEESA-2 (24.9 months vs 13.4 months) and 13.4 months in MONALEESA-7 (23.8 months vs 10.4 months) compared to endocrine therapy alone. Median PFS for patients with visceral metastases in the MONALEESA-3 trial still has not been reached compared to 16.5 months median PFS in patients receiving endocrine therapy alone.

Kisqali plus endocrine therapy demonstrated consistent efficacy across the MONALEESA trials in patients with and without visceral metastases. In patients with visceral metastases and measurable disease, the overall response rate (ORR) in patients who received Kisqali plus endocrine therapy compared to endocrine therapy alone was 53% vs 40% (MONALEESA-2), 50% vs 38% (MONALEESA-7) and 48% vs 31% (MONALEESA-3). Patients without visceral disease showed an ORR of 59% vs 35%, 52% vs 32% and 49% vs 39% in the respective MONALEEA-2, MONALEESA-7 and MONALEESA-3 trials[3].

"Patients living with HR+/HER2- advanced breast cancer who have visceral metastases often have a poorer prognosis and are at higher risk for treatment resistance and disease progression than those without," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "These sub analyses reaffirm that it is critical to treat HR+ advanced breast cancer with a CDK4/6 combination therapy, such as Kisqali plus fulvestrant or an aromatase inhibitor, to give all patients, especially those with visceral metastases, the strongest option for delaying disease progression."

Adverse events for patients with visceral metastases were consistent with those observed in the overall study populations and generally manageable through dose interruptions or reductions.

About Kisqali (ribociclib)
Kisqali (ribociclib) is the CDK4/6 inhibitor with the largest body of first-line clinical trial evidence demonstrating consistent, superior and sustained efficacy compared to endocrine therapy alone[4].

Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably[4].

Kisqali was initially approved by the US Food and Drug Administration (FDA) in March 2017 and by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. In July 2018, Kisqali was approved by the FDA for the treatment of pre-, peri- or postmenopausal women in the US, and indicated for use in combination with fulvestrant as both first- or second-line therapy in postmenopausal women. In November 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending an expanded indication for Kisqali based on the MONALEESA-3 and MONALEESA-7 data. Regulatory filings are underway with other health authorities worldwide[4].

Kisqali is approved for use in more than 70 countries around the world, including the United States and European Union member states. Kisqali is not currently approved for use in combination with fulvestrant or in premenopausal women in Europe. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals[4].

Novartis is continuing to reimagine cancer by investigating Kisqali in early breast cancer (EBC). The NATALEE study is a Phase III clinical trial of Kisqali with endocrine therapy in the adjuvant treatment of HR+/HER2- EBC being conducted in collaboration with Translational Research In Oncology (TRIO)[4].

On December 8, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported IND-enabling data for ZW49, a novel biparatopic HER2-targeted ADC, at the San Antonio Breast Cancer Symposium in San Antonio, TX (Press release, Zymeworks, DEC 8, 2018, View Source [SID1234531961]).

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"These data highlight the potential efficacy of ZW49 versus leading HER2 ADCs and demonstrate the power of combining our therapeutic platforms to achieve greater efficacy and tolerability, thereby increasing the therapeutic window," said Ali Tehrani, Ph.D., President and CEO of Zymeworks. "With the recent submission of our IND for ZW49 we are pleased with the speed and trajectory of ZW49’s development and look forward to starting clinical trials in early 2019."

ZW49 is a HER2-targeted bispecific ADC that capitalizes on the unique geometry and antibody framework of Zymeworks’ lead clinical candidate, ZW25, and is armed with the Company’s proprietary ZymeLink-cytotoxic payload. This design results in enhanced internalization and delivery of the cytotoxin to cancer cells. In preclinical studies, ZW49 demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient derived xenografts and promising efficacy in a model of breast cancer brain metastases. These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development. Importantly, efficacy was observed at exposures that were well tolerated in preclinical studies suggesting a broad therapeutic window.

The poster is available through the conference website or through Zymeworks’ website at View Source

About the Azymetric Platform

The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving the antibodies the ability to simultaneously bind two different targets. This unique technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity, potentially significantly reducing drug development costs and timelines.

About the ZymeLink Platform

The ZymeLink platform is a modular suite of site-specific conjugation technologies, customizable linkers, and proprietary cytotoxic payloads designed for the targeted delivery of therapeutics with optimal tolerability and efficacy. The ZymeLink platform is compatible with traditional antibodies and with the Azymetric platform and is intended to facilitate the development of next-generation antibody-drug conjugates with broad therapeutic windows.

On December 8, 2018 Context Therapeutics, a clinical-stage biotechnology company, reported new preclinical data on Apristor (onapristone extended release), its first-in-class full progesterone receptor antagonist, showing that the investigational medicine inhibits tumor cell line growth in hormone receptor positive (HR+) breast cancer cell lines (Press release, Context Therapeutics, DEC 8, 2018, View Source [SID1234531939]). Additionally, it was shown that Apristor is synergistic with current standard of care therapies for HR+ metastatic breast cancer, including the Cdk4/6 inhibitor Ibrance (palbociclib) and the selective estrogen receptor degrader Faslodex (fulvestrant).

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"Progesterone receptor is the forgotten target", said Carol Lange, PhD, Professor of Medicine at the University of Minnesota and principal investigator of the research presentation. "HR+ breast cancer is driven by two hormones, estrogen and progesterone. While there are over half a dozen approved medicines to block estrogen and estrogen-related signaling, there are no FDA approved medicines in cancer to block progesterone. The data presented shows that blocking progesterone-related signaling via Apristor is not only active alone in tumor models but it also enhances the activity of medicines that either directly or indirectly target estrogen."

The data presented shows that:

Progesterone / progesterone peceptor (PR) is a unique target distinct from estrogen / estrogen receptor

PR is critical for in vitro growth of HR+ breast cancer cells

PR antagonism via Apristor reduces the expression of cancer promoting genes

PR antagonism is synergistic with Cdk4/6 inhibitors and a SERD

"We are encouraged by these new preclinical data, which speak to the important role PR plays in facilitating HR+ breast cancer disease progression," said Deepak Lala, PhD, Chief Technology Officer of Context. "This is the first study to show that PR antagonism is synergistic with new treatment modalities, including Cdk4/6 inhibition. "

About Apristor

Apristor (onapristone extended release) is Context’s wholly owned, first-in-class, orally active extended release formulation of onapristone, a full progesterone receptor antagonist. Progesterone receptor [PR] plays a critical role in facilitating breast cancer disease progression as well as therapeutic resistance to first line antiestrogen and/or Cdk4/6 inhibitor therapies. Apristor is the only full PR antagonist that is being developed to target breast cancer. Apristor has the potential to transform the treatment of breast cancer, through the potent inhibition of PR signaling thereby blocking breast cancer cell proliferation and overcoming resistance to first line antiestrogen and Cdk4/6 inhibitor therapy.

On December 7, 2018 GenFleet Therapeutics Co. Ltd. (Shanghai, China) reported that it raised RMB120 million ($17.4 million) in an untranched series A round to bring its first therapy into clinic next year (Press release, GenFleet Therapeutics, DEC 7, 2018, http://www.genfleet.com/en/pc/NewsDetials.aspx?Ttext=NTY= [SID1234574440]).

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Ally Bridge Group led the round, which saw participation from Sinopharm Capital and CSPC, and existing investors HighLight Capital, Qian Long Yu Han and TF Capital.

GenFleet’s most advanced compound, GFH018, is a small molecule inhibitor of transforming growth factor β receptor 1 (TGFβR1; ALK5). The therapy is being developed for hepatocellular carcinoma (HCC) and other "China-prevalent" cancers, co-founder and Chairman Qiang Lu told BioCentury. A first-in-human trial is expected to start in mid-2019.

GenFleet’s seven other undisclosed programs are in preclinical development for cancer or autoimmune disease.

While Lu said GenFleet’s eight programs will not yield "first-in-class therapies per se," they are higher risk and, according to Lu, no therapy against the targets have reached clinical proof of concept elsewhere. "We’re not pursuing another IDO and EGFR," Lu added.

GenFleet’s executive team brings with it a history of drug discovery in China. Lu and GenFleet co-founder and CEO Jiong Lan built the new drug discovery team at Yangtze River Pharmaceutical Group Co. Ltd. (Shanghai, China), Lu said, where he was CSO and VP and Lan was VP and general manager of the Yangtze River subsidiary Shanghai Haiyan Pharmaceutical Technology Co. Ltd. Lu was most recently SVP of operations at CStone Pharmaceuticals Co. Ltd. (Suzhou, China), and before that CSO and VP of Harbin Gloria Pharmaceuticals Co. Ltd. (Beijing, China).
GenFleet CSO Biao Zheng was a VP at Johnson & Johnson (NYSE:JNJ) and led immunology-focused collaborations out of the J&J Innovation Center in Shanghai. He also headed immunology discovery sciences in Shanghai for the GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) subsidiary GlaxoSmithKline Pharma GmbH.

According to BioCentury’s BCIQ database, there are two other TGFβR1 inhibitors in clinical development: galunisertib (LY2157299) from Eli Lilly and Co. (NYSE:LLY), which is in Phase II testing for multiple cancers; and vactosertib (TEW-7197, NOV1301, NOV130101) from MedPacto Inc. (Suwon, South Korea), which is in Phase I/II testing for myelodysplastic syndrome (MDS) and Phase I testing for metastatic gastric cancer and advanced solid tumors.

The target has recently generated partnership interest. In July, MedPacto teamed up with Merck & Co. Inc. (NYSE:MRK) and AstraZeneca plc (LSE:AZN; NYSE:AZN) to test vactosertib in Phase Ib/IIa trials in combination with PD-1 inhibitor Keytruda pembrolizumab in metastatic or locally advanced colorectal, gastric and gastroesophageal junction cancer or with PD-L1 inhibitor Imfinzi durvalumab for metastatic non-small cell lung cancer (NSCLC).

In 2015, Lilly announced a pair of partnerships to test galunisertib in combination studies with agents from Immunocore Ltd. (Abingdon, U.K.) and Bristol-Myers Squibb Co. (NYSE:BMY).

Lu said not including reserves, the series A will give GenFleet 18-24 months of runway. "Down the road we expect [to submit] two INDs per year," he added.

The early stage investment is a rarity for Ally Bridge. According to BCIQ, the firm has not invested in a round classified as a series A since 2015.

On December 7, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported new preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, showing that it inhibits tumor cell growth in hormone receptor-positive (HR-positive) breast cancer cell lines that are resistant to treatment with CDK4/6 inhibitors and that it has synergistic activity in combination with fulvestrant in these treatment-resistant cells (Press release, Syros Pharmaceuticals, DEC 7, 2018, View Source [SID1234531956]). These data are being presented by Syros’ collaborators from Dana-Farber Cancer Institute at the San Antonio Breast Cancer Symposium (SABCS).

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"While CDK4/6 inhibitors have emerged as an important class of treatments for HR-positive metastatic breast cancer, patients eventually develop resistance," said Rinath M. Jeselsohn, M.D., Instructor in Medicine at Dana-Farber and principal investigator of the research presentation. "These data shed light on potential mechanisms behind resistance to CDK4/6 inhibitors, pointing to CDK7 as one of the genes critical to the growth of treatment-resistant HR-positive breast cancer cells and selective CDK7 inhibition as a promising new approach for the treatment of HR-positive breast cancer. I look forward to the continuing to evaluate SY-1365 in the ongoing Phase 1 trial focused on breast and ovarian cancers."

Researchers from Dana-Farber characterized an HR-positive breast cancer cell line that is resistant to treatment with CDK4/6 inhibitors, and they demonstrated that these cells have alterations in the RB-pathway, including loss of the retinoblastoma (Rb) protein, higher levels of p107, CDK2 and cyclin E2, and lower levels of the estrogen receptor.

The aim of this study was to identify genes critical for the growth and survival of these cells by evaluating both resistant and sensitive cell lines. The researchers also tested SY-1365 in these resistant cell lines as a single agent and in combination with fulvestrant, an estrogen receptor degrader. The data, highlighted in a Spotlight poster discussion session, show that:

CDK7 and ESR1 are critical for in vitro cell growth in both CDK4/6 inhibitor-sensitive and CDK4/6 inhibitor-resistant cells.
SY-1365 significantly arrests cell cycle progression and reduces the expression of cancer-promoting genes in both CDK4/6 inhibitor-sensitive and -resistant cell lines.
SY-1365 in combination with fulvestrant demonstrates synergistic activity in CDK4/6 inhibitor resistant cells.
"We are encouraged by these new preclinical data, which speak both to the importance of CDK7 inhibition in HR-positive breast cancer and to the specific potential of this approach in patients who develop resistance to CDK 4/6 inhibitors.," said David Roth, M.D., Chief Medical Officer of Syros. "We are particularly pleased by the data for SY-1365 in combination with fulvestrant, which demonstrate synergistic activity in CDK4/6 inhibitor-resistant HR-positive breast cancer cells. These data support the ongoing clinical evaluation of SY-1365 in combination with fulvestrant in HR-positive breast cancer patients who progress after treatment with a CDK 4/6 inhibitor. We are actively enrolling patients in the Phase 1 trial and are committed to exploring the full potential of CDK7 inhibition with SY-1365 for people with difficult-to-treat cancers."

The ongoing Phase 1 trial of SY-1365 is a multi-center, open-label trial designed to evaluate the safety, tolerability and anti-tumor activity of SY-1365 in patients with advanced solid tumors. Following completion of the dose escalation portion of the trial, Syros opened expansion cohorts to further assess the potential of SY-1365 in multiple ovarian and breast cancer patient populations. The expansion cohorts are evaluating SY-1365: as a single agent in primary platinum-refractory ovarian cancer patients; as a single agent in ovarian cancer patients who have relapsed after three or more therapies; in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies; and in combination with fulvestrant in patients with HR+ metastatic breast cancer who have progressed after treatment with a CDK4/6 inhibitor. An additional cohort is enrolling patients with any solid tumor accessible for biopsy to further evaluate the mechanism of action of SY-1365. Additional details about the trial can be found using the identified NCT03134638 at www.clinicaltrials.gov.