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.

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"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.

On November 13 2018 FUJIFILM Corporation (President: Kenji Sukeno) reported that it has succeeded in stably encapsulating the anti-cancer agent topotecan*, approved for the treatment of several solid cancers, in newly invented liposome (Press release, Fujifilm, NOV 13, 2018, View Source [SID1234538525]). When preclinical studies in mice were conducted using a drug where topotecan was encapsulated in liposomes (development number: FF-10850), in addition to confirming high tumor shrinking effects, improved pharmacological efficacy was demonstrated when administered in combination with an immune checkpoint inhibitor**, with prolonged survival compared to monotherapy. Going forward, based on the results of these nonclinical studies, the company will prepare for the early initiation of clinical studies of the drug candidate.

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Fujifilm conducts research and development on the potential use of encapsulating drugs in liposomes, artificially constructed vesicles made from organic phospholipids that make up cellular membranes, by harnessing its advanced nano-dispersion technology, analysis technology, and process technology cultivated through its wide range of product development. In another study the liposome drug candidate FF-10832, which encapsulates the anti-cancer agent gemcitabine*** , has been observed to protect gemcitabine from elimination and demonstrate an enhanced permeability and retention (EPR) effect*4 by which the FF-10850 accumulates within tumor and releases gemcitabine. A Phase I clinical trial of FF-10832 is underway in the U.S.
Topotecan has an extremely short half-life*5 in the blood, and also has the issue of causing serious bone marrow suppression*6 as a side effect in more than 80% of patients. A liposome drug where topotecan is encapsulated can be considered as a way to resolve these issues; however, topotecan has a tendency to pass through the liposome membrane, resulting in a problem where topotecan would leak into the blood before reaching the tumor. By enhancing the strength of the liposome membrane with the addition of new materials to the liposome ingredients, Fujifilm has succeeded in stably encupsulating topotecan. Fujifilm is conducting research on the drug as a candidate anti-cancer agent (development number: FF-10850), and has obtained the following results in studies in mice.

[Research Result 1] High tumor shrinking effects confirmed with monotherapy

1) Experiment:
Mice with transplanted human-derived ovarian cancer cells (ES-2) were administered with topotecan and FF-10850, respectively, and the efficacy and tolerability were confirmed for each dosage. The period of administration was five consecutive days for topotecan and two cycles of one administration per week for FF-10850.
2) Results:
With topotecan, efficacy was observed with 30 mg/m2 (6 mg/m2 x five times), while with FF-10850, efficacy was confirmed with 3 mg/m2 (1.5 mg/m2 x twice). When the two drugs were compared, FF-10850 demonstrated efficacy that was greater than or equal to topotecan with 1/10 of the total dose of topotecan.
With FF-10850, tumor shrinking effects were seen with 8 mg/m2 (4 mg/m2 x twice). Furthermore, the relative body weight change which is an indicator of tolerability, was less than that of topotecan.
[Chart] Tumor volume and relative body weight change upon administration of FF-10850 and topotecan
Based on the above, FF-10850 is expected to have high pharmacological efficacy that exceeds that of topotecan while maintaining tolerability even when dosage is increased.

[Research Result 2] Improved pharmacological efficacy observed when administered in combination with an immune checkpoint inhibitor

1) Experiment:
Monotherapies and combination therapy with an immune checkpoint inhibitor** and FF-10850 was conducted on mice transplanted with mouse-derived colorectal cancer cells (CT26), and efficacy and tolerability were confirmed. The period of administration was three cycles of two administrations per week for the immune checkpoint inhibitor (30 mg/m2) and three cycles of one administration per week for FF-10850 (6 mg/m2).
2) Results:
When administered as a monotherapy, the median value for mouse survival time was 19 days for the immune checkpoint inhibitor and 27.5 days for FF-10850. Meanwhile, when administered as a combination therapy, the median value for mouse survival time exceeded 40 days, demonstrating a statistically significant difference when compared with the monotherapies. Mouse survival rates for the combination therapy were 75% at 40 days after administration, which was higher than the monotherapies.
Even when administered as a combination therapy, noticeable side effects such as weight loss were not observed, and there were no issues with tolerability.
[Chart] Survival rates and median survival time when administered in combination with an immune checkpoint inhibitor
Based on the above, FF-10850 is expected to further suppress tumor proliferation through administration with an immune checkpoint inhibitor and prolong survival time.

Fujifilm will present its research results on FF-10850 at the "30th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) SYMPOSIUM", one of the world’s most prominent cancer related conferences, to be held in Dublin, Ireland from November 13th to 16th, 2018.

Fujifilm is harnessing its advanced technologies such as the nano-dispersion technology and ability to synthesize and design compounds to undertake the development of new drugs in the key areas of cancer, central nervous system diseases, and infectious diseases. The company is also focusing on developing drug delivery system (DDS) technologies including liposome drugs, undertaking research and development to apply DDS technologies not only to low-molecular-weight drugs but also to next-generation drugs such as nucleic acid drugs and gene therapy drugs. Going forward, the company will contribute to the resolution of social issues by developing and delivering innovative, high value-added pharmaceutical products.

* An anti-cancer agent (generic name: topotecan, product name: Hycamtin) developed by GlaxoSmithKline plc. Currently, the drug is distributed by Novartis. It is used as a treatment for ovarian cancer, small-cell lung cancer, and cervical cancer.
** The general term for drugs that have an effect by enabling activated immune cells to attack cancer cells by inhibiting the mechanism (immune checkpoints) that weakens the action of immune cells. Widely used in the treatment of malignant melanomas, lung cancer, stomach cancer, and kidney cancer. The immune checkpoint inhibitor used in the combination therapy with FF-10850 was an anti-PD-1 antibody.
*** An anti-cancer drug (generic name: gemcitabine, product name: Gemzar) developed by the U.S. company Eli Lilly and Company. It is used as a drug of first choice for the treatment of pancreatic cancer, and is also indicated for the treatment of a wide range of other cancers (such as lung cancer and ovarian cancer).
*4 As they grow, tumors generate surrounding blood vessels, but these newly generated blood vessels are not fully developed and have large gaps that are much smaller in normal blood vessels. When liposomes and polymers are retained within the blood, they do not permeate the walls of normal blood vessels, which have small gaps, permeating only the vascular walls around the tumor. In addition, as lymphatic vessels are not fully developed in tumors, the liposomes and polymers that have permeated are not easily eliminated, resulting in the accumulation of these liposomes and polymers in the tumor. This is called the EPR (enhanced permeability and retention) effect.
*5 The time required for the concentration of a drug in the blood to be reduced to half.
*6 The state where production of white blood cells, platelets, and red blood cells in the bone marrow is reduced, leading to increased risk of infection and bleeding and symptoms such as anemia.

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.

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"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.

On November 13, 2018 Rubius Therapeutics, Inc. (Nasdaq: RUBY), a biotechnology company developing an entirely new class of allogeneic cellular therapies, reported third quarter 2018 financial results and operational progress (Press release, Rubius Therapeutics, NOV 13, 2018, View Source [SID1234531334]).

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"During the third quarter, we remained focused on advancing our first program, RTX-134, for the treatment of phenylketonuria. We are on track to file an Investigational New Drug application during the first quarter of 2019," said Pablo J. Cagnoni, M.D., chief executive officer of Rubius Therapeutics. "We are also continuing to advance our earlier pipeline, which we believe holds broad therapeutic potential across cancer, autoimmune disease and additional enzyme deficiencies. In order to successfully bring our medicines to patients, we are ensuring that we will have state-of-the-art manufacturing capabilities in place, as shown through the purchase, in July, of our 135,000-square foot manufacturing facility in Smithfield, RI."

Third quarter highlights include:

· On track to submit first IND for lead program, RTX-134, during the first quarter of 2019, and an additional three to four INDs during 2019 and 2020

· Closed initial public offering (IPO) in July 2018, raising $254.3 million in net proceeds

· Acquired and initiated renovations on manufacturing facility in Smithfield, RI; facility is expected to be operational by the end of 2020

· Continued to generate promising preclinical data in support of additional pipeline programs; data expected to be published during 2019

· Strengthened internal capabilities in discovery, platform development and manufacturing and grew the organization to 110 employees to predominantly support research and development (R&D) activities

Third Quarter Financial Results

Net loss for the third quarter of 2018 was $26.4 million or $0.42 per common share, compared to $11.9 million or $1.48 per common share in the third quarter of 2017.

In the third quarter of 2018, Rubius invested $14.4 million in R&D related to its novel RED PLATFORM and towards expanding and advancing its product pipeline, compared to $6.1 million in the third quarter of 2017. The year-over-year increase was due to an additional $2.9 million of costs incurred in preparation for the Phase 1/2a clinical trial for RTX-134, and $3.6 million was associated with personnel costs and stock-based compensation driven by increases in R&D headcount to support Rubius’ goal of delivering four to five IND’s during 2019 and 2020.

G&A expenses were $13.2 million during the third quarter of 2018, as compared to $5.8 million for the third quarter of 2017. The higher costs were primarily driven by a $4.6 million increase in stock-based compensation and a $1.9 million increase in personnel costs and professional fees to support the Company’s growth and to operate as a public company.

Nine Month Financial Results

Net loss for the first nine months of 2018 was $62.0 million or $2.33 per common share, compared to $27.0 million or $3.42 per common share in the first nine months of 2017.

In the nine months ended September 30, 2018, Rubius invested $35.2 million in R&D related to its novel RED PLATFORM and towards expanding and advancing its product pipeline, compared to $14.6 million in the first nine months of 2017. The year-over-year increase was due to an increase of $5.8 million of costs incurred in preparation for the Phase 1/2a clinical trial for RTX-134, and $6.6 million in personnel costs and stock-based compensation driven by increases in R&D headcount to support Rubius’ goal of delivering four to five IND’s during 2019 and 2020.

G&A expenses were $27.3 million during the first nine months of 2018, as compared to $11.2 million for the same period in 2017. The higher costs were primarily driven by a $8.7 million increase in stock-based compensation and a $6.0 million increase in personnel costs and professional fees to support the Company’s growth and to operate as a public company.

During the third quarter of 2018, the Company adopted new guidance for the accounting for stock-based payments to nonemployees, effective as of January 1, 2018. As a result of this adoption, previously reported amounts for the six months ended June 30, 2018 for R&D expenses and G&A expenses were reduced by $0.7 million and $8.0 million, respectively.

Cash Position

As of September 30, 2018, cash, cash equivalents and investments grew significantly to $408.9 million as compared to $104.3 million as of December 31, 2017, providing Rubius with a cash runway into 2021. The increase in cash reflects $254.3 million of net proceeds from the company’s IPO during the third quarter of 2018 and $101.0 million of net proceeds received from its Series C preferred stock financing during the first quarter of 2018. The proceeds received from the financings were offset by $38.6 million used in operations during the nine-month period and $11.7 million of capital purchases, including $8.0 million to acquire the manufacturing facility in Smithfield, Rhode Island.

About Phenylketonuria and RTX-134

Phenylketonuria (PKU) is an inherited, rare enzymatic disorder characterized by the body’s inability to effectively metabolize the amino acid phenylalanine. The accumulation of phenylalanine in the blood causes damage to the central nervous system and a range of symptoms, including intellectual disability, delayed development and impaired cognitive function. RTX-134 is an allogeneic cellular therapy for the treatment of PKU, which expresses the enzyme phenylalanine ammonia lyase (PAL) inside the cell. In preclinical studies, phenylalanine was shown to diffuse into RTX-134, where PAL converted phenylalanine into ammonia and trans-cinnamic acid, metabolites that are cleared by the body. Compared to current therapeutic interventions, RCT product candidates may have a longer and more sustained treatment duration given the 120-day half-life of red blood cells and may avoid immune-driven adverse events and reduction in efficacy, which result from antibody formation.

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.