On January 15, 2020 BerGenBio ASA (OSE: BGBIO) a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for multiple cancer indications, reported meeting the clinical efficacy endpoint of stage 1 of Cohort B in the phase II trial (BGBC008) evaluating bemcentinib in combination with MSD’s Keytruda (pembrolizumab) in previously treated non-small cell lung cancer (NSCLC) patients with confirmed progression on prior immune checkpoint therapy (Press release, BerGenBio, JAN 15, 2020, View Source [SID1234553244]). The trial will advance into the second stage.

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The company reports that the Cohort B, stage 1 efficacy analysis has met the confirmed response of one or more patients therefore continuation to stage two evaluation is planned.

The second stage will enroll a further 16 patients to confirm the safety and clinical efficacy of the combination in NSCLC patients that have confirmed progression on prior immune checkpoint therapy.

Comprehensive exploratory biomarker studies of tumor and blood samples are ongoing to measure of AXL expression and immune modulation. Further results from the trial are expected during 2020 and will be presented at appropriate scientific conferences.

The BGBC008 trial (ClinicalTrials.gov Identifier: NCT03184571) is being sponsored by BerGenBio. MSD, a tradename of Merck & Co., Inc., Kenilworth, New Jersey, USA, will continue to supply Keytruda for use in the study under a collaboration agreement signed in March 2017.

Richard Godfrey, Chief Executive Officer of BerGenBio, said: "Reversing resistance to immune checkpoint inhibitors in patients who have relapsed on immunotherapy is a highly desirable alternative to the second-line chemotherapy standard-of-care. We are very excited with these early results in this challenging setting and look forward to expanding the study to confirm these findings and reporting comprehensive translational insight. Furthermore, Cohort C in NSCLC patients having failed 1L chemo-checkpoint inhibitor combination is now recruiting, and top line data should be available in the coming months."

About AXL

AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

About Bemcentinib

Bemcentinib (formerly known as BGB324), is a potentially first-in-class selective AXL inhibitor in a broad phase II clinical development programme. Ongoing clinical trials are investigating bemcentinib in multiple solid and haematological tumours, in combination with current and emerging therapies (including immunotherapies, targeted therapies and chemotherapy), and as a single agent. Bemcentinib targets and binds to the intracellular catalytic kinase domain of AXL receptor tyrosine kinase and inhibits its activity. Increase in AXL function has been linked to key mechanisms of drug resistance and immune escape by tumour cells, leading to aggressive metastatic cancers.

On January 15, 2020 Emendo Biotherapeutics, a leader in next-generation gene editing using synthetic biology to address untreatable diseases, reported a Series B investment totaling $61 million led by AnGes, Inc., a Japan-based biopharma, reflecting its strategic interest in partnering with Emendo on the development of specific indications (Press release, Emendo Biotherapeutics, JAN 15, 2020, View Source [SID1234553228]).

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"This financing provides a strong foundation from which we can accelerate our proprietary OMNI gene editing platform towards a broad clinical pipeline for addressing devastating untreatable diseases," said Dr. David Baram, President & CEO, Emendo Biotherapeutics. "We are grateful for such strong support from so many high-quality investors and strategic partners including AnGes, OrbiMed Advisors, OrbiMed Israel Partners and Takeda Ventures who share our vision to translate this powerful science into transformative medicines."

Emendo Biotherapeutics is pioneering OMNI, a next-generation allele-specific gene editing platform that uses synthetic biology to expand what is possible in genome-editing. In 2019, Emendo granted an option to Takeda to use the OMNI nuclease gene editing program for two research and development targets. Emendo received an undisclosed investment from Takeda Ventures that was converted in the Series B.

Emendo’s OMNI technology enables precision gene editing while maintaining high efficiencies, uniquely addressing dominant indications such as Severe Congenital Neutropenia (SCN), caused by mutations in the neutrophil elastase gene ELANE. Dominant indications represent the vast majority of genetic diseases which until now have been untreatable.

On January 15, 2020 Natera, Inc. (NASDAQ: NTRA) reported an agreement with the National Cancer Center (NCC) Japan to launch the CIRCULATE-IDEA trial in Japan, a prospective, multi-center, randomized trial to investigate ctDNA-guided treatment strategies for patients with Stage II-III colon cancer, based on the results of molecular residual disease (MRD) testing with Signatera (Press release, Natera, JAN 15, 2020, View Source [SID1234553245]). The trial is organized by the NCC and national in scope, and it is expected to include approximately 1500 patients from over 100 cancer centers across Japan.

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The CIRCULATE-IDEA trial was unveiled in September 2019 at the annual congress of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper),1 introduced as a sequel to the pivotal IDEA collaboration of 2007-2017 which compared outcomes from 3 months vs. 6 months of adjuvant chemotherapy in patients with Stage III colon cancer. The CIRCULATE-IDEA trial picks up where the IDEA trial left off, with groups across Japan, the U.S. and Europe collaborating to explore optimal treatment strategies in the era of personalized, tumor-informed MRD testing.

There will be multiple investigational arms in the Japanese CIRCULATE-IDEA trial, including treatment escalation (experimental therapies) in patients who test MRD-positive after surgery, and treatment de-escalation (no chemotherapy at all) in patients who test MRD-negative after surgery. The study’s primary objective is to demonstrate that MRD-negative patients derive no significant clinical benefit from adjuvant chemotherapy and thus may safely avoid it. This outcome, if achieved, would result in a significant change to current medical practice, in which adjuvant chemotherapy is standard for all Stage III patients despite the fact that most patients are cured by surgery alone.

In Japan, CIRCULATE-IDEA is the centerpiece of a new platform study called SCRUM-Japan MONSTAR-SCREEN. If successful, the platform study is expected to support widespread adoption and reimbursement of MRD testing in Japan.

"There are many thousands of colon cancer patients each year who receive unnecessary chemotherapy," said the study’s Principal Investigator, Dr. Takayuki Yoshino of the NCC East, Kashiwa, Japan. "We believe the Signatera technology offers a breakthrough solution to differentiating which patients need further treatment and which do not."

In a published validation study, Signatera detected relapse in patients with Stage II-III colorectal cancer up to 16.5 months earlier (average 8.7 months earlier) than standard diagnostic tools including CT imaging and CEA. Patients who remained MRD-negative throughout the study had significantly reduced risk of relapse, as low as 3%.2

"We are proud to partner with the NCC and the Japanese oncology community on this important trial," said Alexey Aleshin, M.D., M.B.A., Natera’s Senior Medical Director for Oncology. "Helping patients avoid unnecessary treatment is a cornerstone of our vision for Signatera across many cancer types, and we believe this collaboration is an early example of how that story will unfold globally."

About Signatera
Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. The test is available for clinical and research use, and in 2019 it was granted Breakthrough Device Designation by the FDA. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood. Unlike a standard liquid biopsy, Signatera is not intended to match patients with any particular therapy; rather it is intended to detect and quantify how much cancer may be left in the body, to detect recurrence earlier, and to help optimize treatment decisions. Signatera test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers.

Signatera was developed by Natera, Inc. a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). This test has not been cleared or approved by the U.S. Food and Drug Administration (FDA). Although FDA does not currently clear or approve laboratory-developed tests in the U.S., certification of the laboratory is required under CLIA to ensure the quality and validity of the tests.

On January 15, 2020 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for Rubraca (rucaparib) and granted priority review status to the application with a Prescription Drug User Fee Act (PDUFA) date of May 15, 2020. Clovis submitted the sNDA submission for rucaparib as a monotherapy treatment of adult patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer in November 2019 (Press release, Clovis Oncology, JAN 15, 2020, View Source [SID1234553229]).

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"Recently presented data suggests that Rubraca may play a meaningful role in the treatment of patients withBRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer, and this filing represents an important milestone for Clovis as it brings us one step closer to potentially making this valuable therapy available," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We are encouraged by the FDA’s decision to grant priority review to the Rubraca application, which focuses on eligible patients with advanced prostate cancer, for whom new treatment options are very much needed."

A priority review designation is granted to proposed medicines that the FDA has determined have the potential, if approved, to offer a significant improvement in the safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. Priority designation shortens the review period from the standard 10 months to six months.

About Prostate Cancer

The American Cancer Society estimated that more than 175,000 men in the United States would be diagnosed with prostate cancer in 2019, and the GLOBOCAN Cancer Fact Sheets estimated that approximately 450,000 men in Europe were diagnosed with prostate cancer in 2018. Castrate-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castrate-resistant prostate cancer, or mCRPC, is an incurable disease, usually associated with poor prognosis. Approximately 43,000 men in the U.S. are expected to be diagnosed with mCRPC in 2020. According to the American Cancer Society, the five-year survival rate for mCRPC is approximately 30 percent. Up to 12 percent of patients with mCRPC harbor a deleterious germline and/or somatic mutation in the genes BRCA1 and BRCA2.These molecular markers may be used to select patients for treatment with a PARP inhibitor.

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA Approved Indications

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated as monotherapy for the treatment of adult patients with deleterious BRCA mutations (germline and/or somatic) associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies and selected for therapy based on an FDA-approved companion diagnostic for Rubraca.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long-term follow-up. Of these, five occurred during treatment or during the 28-day safety follow-up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA-damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1).

Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose (see Dosage and Administration [2.2] in full Prescribing Information) and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample cytogenetic analysis. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1–4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%) and neutropenia (20%).

Most common laboratory abnormalities in ARIEL3 (≥ 25%; Grade 1–4) were increase in creatinine (98%), decrease in hemoglobin (88%), increase in cholesterol (84%), increase in alanine aminotransferase (ALT) (73%), increase in aspartate aminotransferase (AST) (61%), decrease in platelets (44%), decrease in leukocytes (44%), decrease in neutrophils (38%), increase in alkaline phosphatase (37%) and decrease in lymphocytes (29%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1–4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%) and thrombocytopenia (21%).

Most common laboratory abnormalities in Study 10 and ARIEL2 (≥ 35%; Grade 1–4) were increase in creatinine (92%), increase in alanine aminotransferase (ALT) (74%), increase in aspartate aminotransferase (AST) (73%), decrease in hemoglobin (67%), decrease in lymphocytes (45%), increase in cholesterol (40%), decrease in platelets (39%) and decrease in absolute neutrophil count (35%).

Co-administration of Rubraca can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring. Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose. You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Clovis Oncology, Inc. at 1-844-258-7662.

On January 15, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported that the first patient has been dosed in a Phase 2 study evaluating the investigational agent alvocidib, a potent CDK9 inhibitor, in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with a hypomethylating agent (HMA) (Press release, Tolero Pharmaceuticals, JAN 15, 2020, View Source [SID1234553246]). The open-label, randomized study has two parts and will evaluate the safety and efficacy of alvocidib in monotherapy or in combination with low-dose cytarabine.

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"Patients with AML who are resistant to or progressed following treatment with the BCL-2 inhibitor venetoclax in combination with an HMA have limited treatment options, and it has been well established in the literature that a key potential mechanism of resistance to BCL-2 targeted therapy is the switch to a dependence on MCL-1," said David J. Bearss, Ph.D., Chief Executive Officer of Tolero Pharmaceuticals, Inc. "The initiation of this study marks an important step toward understanding the potential of alvocidib as a monotherapy or in combination with low-dose cytarabine for these patients. We believe that patients whose cancers have progressed following treatment with venetoclax may be sensitive to alvocidib and this trial will help us to better understand this hypothesis."

The primary objective of the Phase 2 study is to determine the rate of combined complete remission (CR) and CR with incomplete hematological recovery (CRi), of alvocidib and alvocidib in combination with low-dose cytarabine in patients with AML. Secondary objectives include establishing the recommended treatment regimen for the second part of the study and evaluating the median overall survival (mOS) and CR rate. Additional secondary outcome measures include evaluating event-free survival (EFS), duration of composite CR (CRc), safety and tolerability of the regimen and mortality.

In the first part of the study, patients who are refractory to or have relapsed on venetoclax in combination with an HMA will be randomized into two arms. In Arm 1 of the study, patients will receive combination therapy of alvocidib and low-dose cytarabine. In Arm 2 of the study, patients will receive alvocidib monotherapy. In the second part of the study, patients will receive the regimen based on the outcome of the first part.

The trial is being conducted at sites in the United States. Additional information on this trial, including comprehensive inclusion and exclusion criteria, can be accessed at www.ClinicalTrials.gov (NCT03969420).

About Alvocidib
Alvocidib is an investigational small molecule inhibitor of cyclin-dependent kinase 9 (CDK9) currently being evaluated in the Phase 2 studies, Zella 202 in patients with acute myeloid leukemia (AML) who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine (NCT03969420) and Zella 201 in patients with relapsed or refractory MCL-1 dependent AML, in combination with cytarabine and mitoxantrone (NCT02520011). Alvocidib is also being evaluated in Zella 101, a Phase 1 clinical study evaluating the maximum tolerated dose, safety and clinical activity of alvocidib in combination with cytarabine and daunorubicin (7+3) in newly diagnosed patients with AML (NCT03298984), and Zella 102, a Phase 1b/2 study in patients with myelodysplastic syndromes (MDS) in combination with decitabine (NCT03593915). In addition, alvocidib is being evaluated in a Phase 1 study in patients with relapsed or refractory AML in combination with venetoclax (NCT03441555).

About CDK9 Inhibition and MCL-1
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.1 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.2 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.1,3 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).4,5 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.4 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.1