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Tempest Therapeutics Reports Proof of Mechanism Data for First-in-Class PPAR Alpha Antagonist

On November 13, 2018 Tempest Therapeutics Inc. reported a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting in Washington, D.C., describing lead compound TPST-1120’s two-pronged mechanism of directly targeting tumor cells dependent on fatty acid metabolism and driving a metabolic shift in the tumor microenvironment to glycolysis from fatty acid oxidation (Press release, Tempest Therapeutics, NOV 13, 2018, View Source [SID1234531259]). The resulting significant reductions in tumor growth and stimulation of durable anti-tumor immunity support Tempest’s rationale to advance the first-in-class oral small molecule inhibitor of PPAR alpha into clinical studies in patients with advanced solid tumors in early 2019.

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The poster titled "Antagonism of Peroxisome Proliferator Activated Receptor Alpha (PPARα) by TPST-1120 Suppresses Tumor Growth and Stimulates Anti-Tumor Immunity" describes studies that demonstrate significant anti-tumor efficacy of TPST-1120. As monotherapy, TPST-1120 prevented fatty acid oxidation and directly inhibited primary human tumor cells in culture and in human tumor xenografts in immune-deficient mice. In tumor-bearing immune-competent animals, TPST-1120 inhibited tumor growth as a single agent and in combination with chemotherapy or with anti-PD-1 antibodies.

For example, TPST-1120 plus gemcitabine significantly increased the long-term survival of mice with pancreatic tumors. TPST-1120 in combination with anti-PD-1 antibodies in mouse models of ovarian and colon cancer showed suppression of tumor growth and complete remissions in some animals. Importantly, cured mice were completely protected against autologous tumor re-challenge in the ovarian model, strongly suggesting immunological T cell memory against the primary tumor.

TPST-1120 elicits its potent anti-tumor effects through direct binding of the PPAR alpha transcription factor, inhibiting the expression of its regulated genes that are critical for fatty acid oxidation. Several malignancies such as hepatocellular carcinoma and renal cell cancer are reliant on fatty acid oxidation. In addition, suppressive immune cells in the tumor microenvironment such as a particular subset of macrophages, regulatory T cells and myeloid-derived suppressor cells all favor fatty acid oxidation. The utilization of fatty oxidation by tumor cells and suppressive immune cells underlines the tumor-intrinsic and tumor-extrinsic anti-tumor properties of TPST-1120.

"Immuno-metabolism is a rapidly evolving field, and it is increasingly recognized that regulating particular metabolic checkpoints that are essential to promote bio-energetic pathways necessary for sustaining tumor growth are important new targets in oncology. Our poster provides the rationale for advancing TPST-1120 into patients with advanced cancers and also provides insights into the clinical development of this first-in-human molecule," said Tom Dubensky, Ph.D., president and CEO of Tempest.

Syros Presents New Preclinical Combination Data on SY-1365 and First Preclinical Data from Oral CDK7 Inhibitor Program at EORTC-NCI-AACR Meeting

On November 13, 2018 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported preclinical data on SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, showing synergistic anti-tumor activity in combination with carboplatin, a standard-of-care therapy, in models of ovarian cancer and providing a mechanistic rationale for the ongoing investigation of the combination in the Phase 1 clinical trial of SY-1365 (Press release, Syros Pharmaceuticals, NOV 13, 2018, View Source [SID1234531258]). The Company also announced the first preclinical data on its class of highly selective oral CDK7 inhibitors, which showed significant anti-proliferative activity in preclinical models of breast and ovarian cancers. These data were presented at the 30th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Molecular Targets and Cancer Therapeutics Symposium in Dublin.

"Selective CDK7 inhibition represents a potentially transformative approach for treating a range of cancers that have eluded effective treatment," said Eric R. Olson, Ph.D., Syros’ Chief Scientific Officer. "Our presentations at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) meeting highlight our leadership in the field and support the ongoing clinical development of SY-1365 as well as the selection of SY-5609, a highly selective oral CDK7 inhibitor, as our next development candidate. Given the broad potential of CDK7 inhibitors as a new class of medicines, we believe physicians and patients will seek options across multiple modalities and believe an oral molecule could serve as an important complement to SY-1365. We are committed to maximizing the potential of CDK7 inhibition for patients, as we work to achieve our vision of developing new medicines that provide profound benefit for patients."

SY-1365 Preclinical Combination Data
The preclinical data presented at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) provide a strong mechanistic rationale for the ongoing clinical investigation of SY-1365 in combination with carboplatin in ovarian cancer patients. Homologous recombination deficiency (HRD), a cellular defect caused by the disruption of normal DNA damage repair processes, sensitizes cells to treatment with DNA repair inhibitors, including PARP inhibitors and DNA-damaging agents such as carboplatin. In preclinical models of ovarian cancer, SY-1365 was shown to inhibit DNA repair and decrease the expression of homologous recombination repair (HRR) genes, which are important for repairing harmful breaks in DNA. These data suggest that SY-1365 induces an HRD-like state, which may result in enhanced sensitivity to DNA-damaging agents and DNA repair inhibitors.

Consistent with the proposed mechanism-of-action, SY-1365 demonstrated synergy with carboplatin in ovarian cancer cell lines and demonstrated greater anti-tumor activity in combination with carboplatin in xenograft models of ovarian cancer than either agent alone.

Syros is currently conducting a Phase 1 clinical trial assessing the safety and efficacy of SY-1365 as a single agent and in combination with standard-of-care therapies in multiple ovarian and breast cancer patient populations. The ongoing trial includes a study cohort evaluating SY-1365 in combination with carboplatin in ovarian cancer patients who have relapsed after one or more prior therapies. Additional details about the trial can be found using the identifier NCT03134638 at www.clinicaltrials.gov.

Preclinical Data from Oral CDK7 Inhibitor Program
Syros created a suite of highly selective and potent orally available CDK7 inhibitors. The preclinical data at EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) detail for the first time the selectivity, potency and anti-tumor activity of these inhibitors. Using a representative member of Syros’ suite of oral CDK7 inhibitors, these data show:

200- to 1,200-fold greater selectivity for CDK7 over other members of the CDK family, including CDK2, CDK9 and CDK12.
Robust anti-proliferative activity in triple negative breast cancer and ovarian cancer cell lines, which was associated with the induction of apoptosis and cell cycle arrest.
Strong correlation between biochemical potency, CDK7 target engagement and tumor growth inhibition.
Substantial anti-tumor effects in multiple cell-line and patient-derived xenograft models of triple negative breast and ovarian cancers.
These data helped support the selection of SY-5609 as the Company’s next development candidate. Syros is currently advancing SY-5609 into Investigational New Drug (IND) application-enabling preclinical studies.

The poster presentations on the SY-1365 preclinical combination data and on the oral CDK7 inhibitor program are now available on the Publications and Abstracts section of the Syros website at www.syros.com.

Study Demonstrating Accuracy of DecisionDx-Melanoma Prognostic Test Across Melanoma Tissue Sources Presented at the American Society of Dermatopathology 55th Annual Meeting

On November 13, 2018 Castle Biosciences, Inc., the skin cancer diagnostics company providing molecular diagnostics to improve cancer management decisions, reported study results showing that the DecisionDx-Melanoma test accurately predicts risk for patients with cutaneous melanoma when using either biopsy or wide local excision (WLE) as the tissue source (Press release, Castle Biosciences, NOV 13, 2018, View Source [SID1234531257]). Highlights of the study were presented during an oral presentation at the American Society of Dermatopathology 55th Annual Meeting held November 8-11, 2018 in Chicago.

"This study demonstrates that the DecisionDx-Melanoma test provides an accurate, independent prediction of risk regardless of tissue source," said Sarah Estrada, M.D., FACP, Affiliated Dermatology, Scottsdale AZ, a study investigator. "Using biopsy or wide local excision tissue does not impact the ability of the DecisionDx-Melanoma test to accurately predict risk and inform patient management decisions."

Study Background

The DecisionDx-Melanoma test has been shown to provide an accurate, independent prediction of risk for patients with cutaneous melanoma.
The test has shown robust analytic reliability with 99% inter-assay concordance and 100% intra-assay concordance. Technical success exceeded 98% on samples with sufficient tumor content.
This study assessed whether test results or patient outcomes were associated with tissue source (biopsy or WLE) in an archival cohort of 537 patients with Stage I-III cutaneous melanoma for whom the tissue source was known.
Key Study Results

Among those who had biopsy tissue tested, a higher percentage had Stage I disease (68%) compared to those who had WLE tissue tested (19% Stage I; p<0.001).
Patients who had WLE tissue tested were significantly more likely to have Stage III melanoma (50%) compared to those who had biopsy tissue tested (17% Stage III; p<0.001).
Patients who had WLE tissue tested also were more likely to have higher risk pathologic features such as ulceration and increased Breslow thickness.
For both tissue sources, patients who had the lowest risk DecisionDx-Melanoma test result (Class 1A) had significantly improved distant metastasis-free survival and melanoma-specific survival rates compared to those who had the highest risk test result (Class 2B).
After adjusting for pathologic features among patients in the two tissue source groups, use of WLE tissue was not significantly associated with DecisionDx-Melanoma test class result.
In multivariate analysis, DecisionDx-Melanoma Class 2B (highest risk) was a significant independent predictor of recurrence, distant metastasis and melanoma-specific survival, while WLE tissue source was not found to be predictive of outcomes.
These results demonstrate that the DecisionDx-Melanoma test provides an accurate, independent prediction of risk regardless of tissue source.
About DecisionDx-Melanoma

The DecisionDx-Melanoma test uses tumor biology to predict individual risk of melanoma recurrence and sentinel lymph node positivity independent of traditional factors. Using tissue from the primary melanoma, the test measures the expression of 31 genes. The test has been validated in three multi-center studies that have included 690 patients and have demonstrated consistent results. Performance has also been confirmed in four prospective studies including 702 patients. The consistent high performance and accuracy demonstrated in these studies, which combined have included over 1,300 patients, provides confidence in disease management plans that incorporate DecisionDx-Melanoma test results.

Prediction of the likelihood of sentinel lymph node positivity has also been validated in two prospective multicenter studies that included over 1,400 patients. Impact on patient management plans for one of every two patients tested has been demonstrated in multi-center and single-center studies. More information about the test and disease can be found at www.SkinMelanoma.com.

NextCure Raises $93 Million in Series B Financing

On November 13, 2018 NextCure Inc., a privately-held biopharmaceutical company discovering and developing the next generation of immunomedicines for cancer and other diseases, reported the completion of a $93 million series B equity financing (Press release, NextCure, NOV 13, 2018, View Source [SID1234531256]). The financing was led by Hillhouse Capital Management and Quan Capital, and included Bay City Capital, Surveyor Capital (a Citadel company), Ping An Ventures, Taiho Ventures LLC, ArrowMark Partners and NS Investment. All existing investors also participated in this financing, including Canaan Partners, Lilly Asia Ventures, OrbiMed Advisors LLC, Pfizer Inc., Sofinnova Ventures and Alexandria Venture Investments. Additionally, Eli Lilly and Company invested $15 million in this financing in conjunction with the discovery and development partnership announced on November 5, 2018.

In connection with the financing, Michael Yi, M.B.A., (Hillhouse Capital Management) and Stella Xu, Ph.D., (Quan Capital) will join the board of directors.

The proceeds will be primarily used to support clinical development for the company’s two lead drug candidates, including NC318, preclinical development of additional novel immunomedicine drug candidates, and the Company’s activities under its previously announced collaboration with Eli Lilly and Company to discover and develop novel cancer targets with the Company’s proprietary FIND-IO platform.

"We are excited to welcome a distinguished group of new investors to NextCure and appreciate the strong support from our existing investors," said Michael Richman, NextCure’s President & CEO. "We have made tremendous progress in the past 2.5 years, and look forward to the continued clinical development of NC318 and advancement of our growing portfolio of first-in-class immunomedicines."

About NC318
NC318 is a first-in-class immunomedicine against a novel immunomodulatory target found on a restricted set of myeloid cells in the tumor microenvironment and on certain tumor types including lung, ovarian and head and neck cancers. Preclinical research shows that S15 promotes the survival and differentiation of suppressive myeloid cells and negatively regulates T cell function, allowing cancer growth. In preclinical studies, NC318 blocks the negative effects of S15. NC318 is a first-in-class immunomedicine that has the potential to treat multiple cancer types.

About FIND-IO
The FIND-IO platform is designed to identify novel cell surface molecular interactions that drive functional immune responses in the tumor microenvironment and other disease sites. NextCure has developed proprietary approaches to assess immune pathways in primary immune cells and established cell lines from immune lineages, including T cells, NK cells, macrophages, myeloid-derived suppressor cells, dendritic cells, as well as cancer cells. NextCure is utilizing FIND-IO technology to identify targets that impact immune function, addressing the major challenge of supplying next generation immunomedicines for patients that do not respond to current cancer therapies.

Y-mAbs Announces Third Quarter 2018 Financial Results and Recent Corporate Developments

On November 13, 2018 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (Nasdaq:YMAB) a late-stage clinical biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported financial results for the third quarter of 2018 (Press release, Y-mAbs Therapeutics, NOV 13, 2018, View Source [SID1234531251]).

"We are very pleased to report our first quarterly financials after Y-mAbs’ successful IPO in September, which have put us in a strong financial position to continue the important work on our two lead pediatric compounds, naxitamab and omburtamab. We plan to file BLAs for both of these compounds next year." stated Thomas Gad, Founder, President and Head of Business Development and Strategy.

Dr. Moller, Chief Executive Officer continued, "We have made solid progress with naxitamab and omburtamab in the clinic in recent months. Over the remainder of 2018, we have much to do and also numerous catalysts that have the potential to solidify us as a leader in pediatric oncology and a company focused on rapidly developing therapies to extend and enhance the lives of those living with rare pediatrics cancers."

Third Quarter 2018 and Recent Corporate Developments

After the close of the quarter, on November 1, 2018, Y-mAbs announced that that Dr. Jeong A Park from the Department of Pediatrics of Memorial Sloan-Kettering Cancer Center (MSK) will present preclinical data from the Company’s bispecific GD2 antibody in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on December 3, 2018, at 9:00 PM Eastern. Bispecific GD2 antibodies were tested in solid tumors in preclinical models with T-cells and were shown to exert anti-tumor effect against GD2(+) tumor xenografts or PDX tumors. Further, the bispecific GD2 antibodies induced rapid and quantitative T-cell homing to tumors, mediating antibody dependent T-cell mediated cytotoxicity (ADTC) against GD2, and were shown to infiltrate tumors with little to no immune response, also known as cold tumors.

After the close of the quarter, on October 23, 2018, Y-mAbs announced that the Committee for Orphan Medicinal Products of the European Medicines Agency recommended the granting of orphan medicinal product designation in the European Union for naxitamab for the treatment of relapsed or refractory high-risk neuroblastoma. Further, the positive opinion for orphan medicinal product designation had been sent to the European Commission, which may grant the orphan drug designation within 30 days thereof.

On September 25, 2018, Y-mAbs announced the closing of its initial public offering of 6,900,000 shares of its common stock, including the exercise in full of the underwriters’ option to purchase 900,000 additional shares of common stock, at a public offering price of $16.00 per share. The gross proceeds to Y-mAbs, before deducting underwriting discounts and commissions and estimated offering expenses payable by the Company, were approximately $110.4 million. All of the shares of common stock were offered by the Company, and Y-mAbs’ common stock is listed on The Nasdaq Global Select Market under the ticker symbol "YMAB."

On August 21, 2018, Y-mAbs announced that it had received Breakthrough Therapy designation for naxitamab, in combination with GM-CSF, for the treatment of high risk neuroblastoma refractory to initial therapy or with incomplete response to salvage therapy in patients older than 12 months of age with persistent, refractory disease limited to bone marrow with or without evidence of concurrent bone involvement.
Financial Results

Y-mAbs reported a net loss of $11.4 million or $0.42 per basic and diluted share for the third quarter of 2018 compared to a net loss of $3.8 million or $0.21 per basic and diluted share for the third quarter of 2017.

For the nine months ended September 30, 2018, Y-mAbs reported a net loss of $29.2 million, or $1.08 per basic and diluted share, compared to a net loss of $9.9 million reported for the same period of 2017, or $0.56 per basic and diluted share.

Cost and Operating Expenses

Research and development
Research and development expenses were $8.7 million for the third quarter of 2018, compared to $3.1 million for the same period of 2017, an increase of $5.6 million. The increase in research and development expenses primarily reflects the following:

$3.4 million increase in outsourced manufacturing for our lead product candidates, naxitamab and omburtamab
$1.3 million increase in outsourced research and supplies to support expanding development activities
$0.7 million increase in personnel costs
Research and development expenses were $23.2 million for the nine months ended September 30, 2018, compared to $7.7 million for the same period of 2017, an increase of $15.5 million. The increase in research and development expenses primarily reflects the following:

$6.4 million increase in outsourced manufacturing for our lead product candidates, naxitamab and omburtamab
$3.5 million increase in outsourced research and supplies to support expanding development activities
$2.1 million increase in clinical trial costs due to an increasing number of ongoing clinical trials
$2.4 million increase in personnel costs
$0.6 million increase in milestone payments
General and administration

General and administrative expenses were $2.7 million for the third quarter of 2018, compared to $0.8 million for the same period of 2017, an increase of $1.9 million. The increase in general and administrative expenses primarily reflects the following:

$1.1 million increase in personnel costs
$0.5 million increase in fees for auditors, legal advice and other consultancy services
General and administrative expenses were $5.9 million for the nine months ended September 30, 2018, compared to $2.3 million for the same period of 2017, an increase of $3.6 million. The increase in general and administrative expenses primarily reflects the following:

$1.4 million increase in personnel costs
$1.3 million increase in fees for auditors, legal advice and other consultancy services
Cash, Cash Equivalents, Investments and Restricted Investments

The Company had approximately $163.3 million in cash and cash equivalents as of September 30, 2018 compared to $90.5 million as of December 31, 2017. The increase is primarily driven by the $100.5 million net proceeds from the Company’s initial public offering, which is partly offset by the use of cash to fund the Company’s ongoing operations during the first three quarters of 2018.