On February 6,2018 Redx (AIM: REDX), the drug discovery and development company focused on cancer and fibrosis, reported that it has commenced its Phase 1/2a study for the Porcupine inhibitor RXC004 with the first patient having now been dosed at The Christie in Manchester (Press release, Redx Pharma, FEB 6, 2018, View Source [SID1234524741]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

RXC004 is a novel, oral, potent small molecule Porcupine inhibitor, which targets the Wnt pathway, an embryonic signalling pathway that is implicated in the maintenance of cancer stem cells in multiple cancer types. This pathway is associated with tumorigenesis, metastasis, recurrence and resistance in cancer. RXC004 has now progressed into the dose-finding Phase 1 element of the study in patients with cancer. Once completed, the selected dose will then be used as a monotherapy in a larger number of patients with difficult to treat cancers (Phase 2a). In addition, the Company will look to explore the potential of RXC004 in combination with a PD-1 checkpoint inhibitor following the completion of the safety and tolerability phase of this first in man clinical trial.

As mentioned at the time of the publication of the Company’s strategic update on 6 November 2017, Redx expects initial data from the 1a segment of this trial in H2 2018.

Iain Ross, Chairman of Redx Pharma plc, commented, "We are very excited by the potential of RXC004 to make a major difference in cancer treatment, and intend to progress RXC004 initially as a monotherapy and thereafter in combination with a (PD-1) checkpoint inhibitor through clinical development. We believe that RXC004 has great potential to treat some very challenging cancers that currently have very poor prognosis and we look forward to updating the market on our progress."

On February 6, 2018 MannKind Corporation (NASDAQ:MNKD) reported that David M. Kendall, MD, will join the company as Chief Medical Officer and assume full responsibility for leading MannKind’s scientific research, clinical development, regulatory, and medical affairs activity, effective February 12 (Press release, Mannkind, FEB 6, 2018, View Source [SID1234524353]). Dr. Kendall will report directly to Michael Castagna, Pharm.D., Chief Executive Officer, and will join the company’s executive leadership team. He will be based out of MannKind’s Westlake Village, California headquarters.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"David is a world renowned diabetes expert and represents an important addition to our executive leadership team," said Castagna, Chief Executive Officer of MannKind. "His extensive experience in diabetes research, development, and clinical care in both U.S. and international markets, will be instrumental in helping us achieve the growth potential that we believe Afrezza clearly possesses."

Dr. Kendall’s career includes over 30 years of experience in diabetes and metabolism research, clinical management, research, and policy advocacy. Most recently, he served as Research Physician and Vice President of Global Medical Affairs for Lilly Diabetes, and during that time was responsible for all medical affairs activities and guided research and development strategy across multiple geographies. In this role, he worked to re-establish Lilly Diabetes as a world class medical organization — and added to his extensive experience with both injected and mealtime insulins, as well as devices and continuous glucose monitors. Prior to joining Eli Lilly, Dr. Kendall served as Chief Scientific and Medical Officer at the American Diabetes Association, where he was responsible for all medical affairs, medical education, research, outcomes, and medical policy activities. Earlier in his career, Dr. Kendall served as Medical Director at the International Diabetes Center, and the Park Nicollet Clinic, as well as at Amylin Pharmaceuticals. He received his M.D. and completed his Post Graduate Medical Training at the University of Minnesota, and earned a B.A. in Biology from St. Olaf College.

"The research and clinical response to Afrezza as a mealtime insulin supports ongoing efforts to establish this product as the standard of care for those living with type 1 or type 2 diabetes," said Dr. Kendall. "Afrezza is the only inhaled fast-acting mealtime insulin on the market, and offers the right patients a flexible, safe, and effective treatment option. I’m thrilled to join MannKind, and look forward to being part of a company that has the potential to transform the lives of so many people that are living with diabetes."

On February 6, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been dosed in a phase 1 study evaluating the safety and tolerability of U3-1402, an investigational and potential first-in-class HER3-targeting antibody drug conjugate (ADC), in patients with metastatic or unresectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (C) whose disease has progressed while taking an EGFR tyrosine kinase inhibitor (TKI) (Press release, Daiichi Sankyo, FEB 6, 2018, View Source [SID1234523766]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Treatment with EGFR TKIs such as erlotinib, gefitinib, or afatinib is used as first-line therapy for metastatic EGFR-mutated NSCLC.1,2,3,4 However, patients eventually develop resistance to these treatments, typically experiencing disease progression within a year.1,2,3,4 More than half of these patients develop resistance with a secondary EGFR mutation called T790M, which may be treated with EGFR TKI osimertinib.1,2,3,4 Patients who experience disease progression following EGFR TKI treatment and who have tumors that lack the T790M mutation may be treated with chemotherapy, immunotherapy, or with investigational treatments.3,4

Expression of HER3, a member of the HER family of receptor tyrosine kinases, is believed to play a role in tumor growth and proliferation in many different types of cancer including NSCLC.5 Studies have shown that HER3 overexpression in lung cancer can also be associated with acquired resistance to other EGFR family targeted interventions such as TKIs and anti-EGFR antibody therapies.5 Patients with NSCLC with high levels of HER3 may face a significantly worse prognosis and decreased survival.5,6,7 Currently, there are no approved HER3-targeted therapies.

"While the treatment of metastatic EGFR-mutated NSCLC has significantly improved over the past decade, new treatments are needed that work to overcome resistance associated with current EGFR TKIs," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "In this study, we are exploring whether the smart delivery of chemotherapy with U3-1402 to cancer cells that express HER3 – a known feature of resistance in pre-treated EGFR-mutated NSCLC – could become a new treatment strategy for these patients."

About the Study

The global, phase 1, open label, two-part study will enroll patients with metastatic or unresectable EGFR-mutated NSCLC whose disease has progressed while taking an EGFR TKI. This includes patients who experienced disease progression during treatment with erlotinib, gefitinib, or afatinib and whose tumors have tested negative for the T790M mutation and patients who experienced disease progression during treatment with osimertinib regardless of T790M status. The primary objectives of the study are to assess the safety and tolerability of U3-1402 and determine the recommended dose for the dose expansion part of the study. The secondary objectives are to characterize the pharmacokinetics of U3-1402 and to evaluate preliminary efficacy by measuring antitumor activity of U3-1402. The study is expected to enroll more than 60 patients at approximately 17 sites globally. For more information about the study, visit ClinicalTrials.gov.

About U3-1402

Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, U3-1402 is an investigational and potential first-in-class ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, U3-1402 is a smart chemotherapy comprised of a human anti-HER3 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

U3-1402 is currently being evaluated in two phase 1 clinical studies including a phase 1/2 study for HER3-expressing metastatic or unresectable breast cancer and a phase 1 study for metastatic or unresectable EGFR-mutated NSCLC. U3-1402 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The vision of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science Franchise, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. Compounds in pivotal stage development include: DS-8201, an antibody drug conjugate (ADC) for HER2-expressing breast, gastric and other cancers; quizartinib, an oral selective FLT3 inhibitor, for newly-diagnosed and relapsed/refractory acute myeloid leukemia (AML) with FLT3-ITD mutations; and pexidartinib, an oral CSF-1R inhibitor, for tenosynovial giant cell tumor (TGCT). For more information, please visit: www.DSCancerEnterprise.com.

On February 6, 2018 Celgene Corporation (NASDAQ:CELG) reported that the Phase III, randomized, open-label, international clinical study, OPTIMISMM, achieved its primary endpoint, showing a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for the pomalidomide arm versus the comparator arm (Press release, Celgene, FEB 6, 2018, View Source [SID1234523754]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

OPTIMISMM evaluated the efficacy and safety of POMALYST/IMNOVID (pomalidomide) plus bortezomib and low-dose dexamethasone (PVd) versus bortezomib and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. It is the only phase III trial to investigate a triplet combination in patients who have all received prior lenalidomide (REVLIMID), a population for which there is a growing unmet medical need.

"The OPTIMISMM results confirm the expanding role of pomalidomide in previously treated multiple myeloma patients," said Paul Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at the Dana Farber Cancer Institute, RJ Corman Professor of Medicine, Harvard Medical School and principal investigator of the study. "We see the PVd combination as an important step in improving care, and especially for patients previously treated with lenalidomide in this setting."

In the study, the safety profile was consistent with previously reported data. Detailed data from OPTIMISMM will be presented at future medical meetings.

The combination of POMALYST/IMNOVID, bortezomib and low-dose dexamethasone is not currently approved for use.

About POMALYST/IMNOVID

Indication

POMALYST (pomalidomide) is a thalidomide analogue indicated, in combination with dexamethasone, for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.
Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution program called POMALYST REMS.

Venous and Arterial Thromboembolism

Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with POMALYST. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.

CONTRAINDICATIONS

Pregnancy: POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If POMALYST is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.
WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS
Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm.
Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of POMALYST therapy because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST.
POMALYST REMS Program: See Boxed WARNINGS
Prescribers and pharmacies must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive POMALYST. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements.
Further information about the POMALYST REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Venous and Arterial Thromboembolism: See Boxed WARNINGS. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient’s underlying risk factors.
Increased Mortality with Pembrolizumab: In clinical trials in patients with multiple myeloma, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.
Hematologic Toxicity: Neutropenia (46%) was the most frequently reported Grade 3/4 adverse reaction in patients taking POMALYST in clinical trials, followed by anemia and thrombocytopenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification.
Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly. Stop POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
Hypersensitivity Reactions: Angioedema and severe dermatologic reactions have been reported. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe dermatologic reactions, and do not resume therapy.
Dizziness and Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with POMALYST. Patients at risk are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
ADVERSE REACTIONS

Nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). The most common adverse reactions (≥15%) included neutropenia (51.3%), fatigue and asthenia (46.7%), upper respiratory tract infection (31%), thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%), diarrhea (22%), constipation (21.7%), back pain (19.7%), cough (20%), pneumonia (19.3%), bone pain (18%), edema peripheral (17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15%) included neutropenia (48.3%), thrombocytopenia (22%), and pneumonia (15.7%).

DRUG INTERACTIONS

Avoid concomitant use of POMALYST with strong inhibitors of CYP1A2. Consider alternative treatments. If a strong CYP1A2 inhibitor must be used, reduce POMALYST dose by 50%.

USE IN SPECIFIC POPULATIONS

Pregnancy: See Boxed WARNINGS. If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a POMALYST pregnancy exposure registry that monitors pregnancy outcomes in females exposed to POMALYST during pregnancy as well as female partners of male patients who are exposed to POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.
Lactation: There is no information regarding the presence of pomalidomide in human milk, the effects of POMALYST on the breastfed infant, or the effects of POMALYST on milk production. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from POMALYST, advise a nursing woman to discontinue breastfeeding during treatment with POMALYST.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients > 65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
Renal Impairment: Reduce POMALYST dose by 25% in patients with severe renal impairment requiring dialysis. Take dose of POMALYST following hemodialysis on hemodialysis days.
Hepatic Impairment: Reduce POMALYST dose by 25% in patients with mild to moderate hepatic impairment and 50% in patients with severe hepatic impairment.
Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of pomalidomide by 32% by CYP1A2 induction.

Please see full Prescribing Information, including Boxed WARNINGS.

On February 6, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported results for its second quarter of fiscal 2018 and provided an update on the progress of its key clinical development programs (Press release, Array BioPharma, FEB 6, 2018, View Source [SID1234523740]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

COLUMBUS PHASE 3 TRIAL

Treatment with the combination of encorafenib 450 mg daily and binimetinib 45 mg twice daily (COMBO450) reduced the risk of death compared to treatment with vemurafenib 960 mg daily [hazard ratio (HR) of 0.61, (95% CI 0.47, 0.79, p<0.001)] in patients with BRAF-mutant melanoma in the Phase 3 COLUMBUS trial.

Phase 3 trial showed mOS of 33.6 months for patients treated with COMBO450, compared to 16.9 months for patients treated with vemurafenib as a monotherapy.
As previously announced, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT) (9%), increased blood creatine phosphokinase (CK) (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK-inhibitor treatments for patients receiving the combination of encorafenib and binimetinib included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.

The FDA:

Continues review of Array’s New Drug Applications (NDAs) to support use of the encorafenib and binimetinib combination for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma
Set a target action date under Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications
Informed Array that, based on its preliminary review of the applications, it has not identified any potential review issues, and that it is not currently planning to hold an advisory committee meeting to discuss these NDAs
The regulatory submissions were based on findings from the pivotal Phase 3 COLUMBUS trial.

“We believe the strength of the COLUMBUS data, with a remarkable median overall survival of 33.6 months and median progression-free survival of 14.9 months, highlights the potential of the encorafenib and binimetinib combination for patients with BRAF-mutant melanoma,” said Ron Squarer, Chief Executive Officer. “These data, together with our impressive, recently presented results in BRAF-mutant colorectal cancer, and our strong cash balance, position us well to advance our innovative therapies for patients with cancer.”

BEACON CRC PHASE 3 TRIAL

Updated results from the 30 patient safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, binimetinib and cetuximab, an EGFR antagonist, in patients with BRAF-mutant CRC whose disease has progressed after one or two prior regimens were presented at the ASCO (Free ASCO Whitepaper) 2018 Gastrointestinal Cancers Symposium.

The estimated mPFS at the time of analysis was 8 months in 29 patients with BRAFV600E-mutant CRC.
The confirmed overall response rate (ORR) was 48% with 3 complete responses in patients with BRAFV600E-mutant CRC. Further, the ORR was 62% in the 16 patients who received only one prior line of therapy.
These data represent improvements compared to several separate historical published standard of care benchmarks for this population which range between 4% to 8% ORR and 1.8 and 2.5 months mPFS.
The triplet combination was generally well-tolerated. Two patients discontinued treatment due to AEs with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue, urinary tract infection, increased aspartate aminotransferase (AST) and increased blood CK.
Enrollment in the randomized portion of BEACON CRC is ongoing. BRAF mutations are estimated to occur in 10% to 15% of patients with CRC and represent a poor prognosis for these patients.
“Media progression-free survival of 8 months in the BEACON CRC safety lead-in represents an exciting result relative to historical benchmarks and is an encouraging signal for the success of the randomized portion of this trial,” said Victor Sandor, M.D., Chief Medical Officer.

Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

IMMUNO-ONCOLOGY COLLABORATIONS: TRIAL ADVANCING WITH BRISTOL-MYERS SQUIBB, TRIAL INITIATED WITH MERCK AND NEW COLLABORATION ANNOUNCED WITH PFIZER
Array is developing binimetinib in combination with PD-1 / PD-L1 checkpoint inhibitors. We have announced separate, strategic collaborations with Bristol-Myers Squibb, Merck and Pfizer, but in each case, are pursuing a unique trial design to explore different clinical approaches.

Bristol-Myers Squibb

The clinical trial with Bristol-Myers Squibb continues to advance and is designed to investigate the safety, tolerability and efficacy of binimetinib in combination with nivolumab (anti-PD-1 therapy), with and without ipilimumab (CTLA-4 antibody), in patients with advanced metastatic microsatellite stable (MSS) CRC and the presence of a RAS mutation who have received one or two prior regimens.
The trial is jointly supported by Array and Bristol-Myers Squibb and sponsored by Array.
Merck

The clinical trial with Merck is designed to investigate the safety, tolerability and efficacy of binimetinib in combination with pembrolizumab (anti-PD-1 therapy), with and without FOLFOX or FOLFIRI (chemotherapy) in patients with CRC whose tumors are not microsatellite instability-high (MSI-H).
After establishing combinability in separate Phase 1 cohorts, the trial will enroll expansion cohorts of 1st and 2nd-line CRC patients onto these novel triplet combinations to determine effectiveness.
The trial will be sponsored and funded by Merck, with Array providing binimetinib supply.
Pfizer

The clinical trial with Pfizer is designed to investigate the safety, tolerability and efficacy of several novel anti-cancer combinations, including binimetinib, avelumab (anti-PD-L1 therapy) and talazoparib (PARP inhibitor) across various tumor types.
The multi-arm Phase 1b clinical trial is designed to establish recommended doses of different regimens combining the drugs.
Initially, the focus will be in non-small cell lung cancer (NSCLC) and pancreatic cancer, with additional indications being explored at a later stage.
The study is expected to begin by the third quarter of 2018, and results will be used to determine optimal approaches to further clinical development of these combinations.
The trial will be sponsored and funded by Pfizer, with Array providing binimetinib supply.
NEW SUBSIDIARY FORMED TO ADVANCE ARRY-797
Array formed a wholly-owned subsidiary, Yarra Therapuetics, LLC, to further develop and commercialize therapeutics targeted towards rare diseases, including ARRY-797, an oral, selective p38 mitogen-activated protein kinase inhibitor. A Phase 3 trial of ARRY-797 in patients with LMNA A/C-related dilated cardiomyopathy is planned to begin this quarter. LMNA A/C-related dilated cardiomyopathy is a rare, degenerative cardiovascular disease caused by mutations in the LMNA gene and characterized by a poor prognosis.

FINANCIAL HIGHLIGHTS
Novartis Financial Commitment
Novartis continues to substantially fund all ongoing trials with encorafenib and binimetinib that were active or planned as of the close of the Novartis Agreements in 2015, including the COLUMBUS Phase 3 trial. Reimbursement revenue from Novartis was approximately $88.5 million for the 12 months ended December 31, 2017, of which $22.4 million was recorded in the quarter ended December 31, 2017. Total revenue and upfront payment collected from Novartis since the start of the 2015 agreement is $348.7 million.

Second Quarter of Fiscal 2018 Compared to First Quarter of Fiscal 2018 (Sequential Quarters Comparison)

Revenue for the second quarter of fiscal 2018 was $42.2 million, compared to $29.7 million for the prior quarter. The increase was primarily due to recognition of the remaining $7.9 million deferral of the Asahi Kasei Pharma upfront payment resulting from completion of all remaining material obligations under the Collaboration and License Agreement, as well as higher Novartis reimbursement revenue.
Cost of partnered programs for the second quarter of fiscal 2018 was $13.7 million, compared to $11.8 million for the prior quarter. The increase was primarily due to higher costs incurred for the BEACON CRC trial as it continues to advance, as well as additional resources engaged on collaborations.
Research and development expense was $42.6 million, compared to $41.4 million in the prior quarter. The increase was driven by costs related to the increased activity on Novartis transitioned studies, and is partially offset by the non-recurring expense related to commercial and clinical supply from the previous quarter.
Loss from Operations for the quarter was $25.7 million, compared to a loss from operations of $35.5 million in the previous quarter. The decrease in net loss was primarily due to increased revenue, which was partially offset by increased research and development.
Net loss for the second quarter was $34.1 million, or ($0.17) per share, compared to $38.0 million, or ($0.22) per share, in the prior quarter.
Cash, Cash Equivalents and Marketable Securities as of December 31, 2017 were $420 million.
Second Quarter of Fiscal 2018 Compared to Second Quarter of Fiscal 2017 (Prior Year Comparison)

Revenue for the second quarter of fiscal 2018 decreased $2.3 million compared to the same quarter of fiscal 2017. The decrease was primarily due to decreased reimbursement revenue for the Novartis transitioned studies, which was partially offset by revenue from new and expanded collaborations.
Cost of partnered programs increased $4.7 million compared to the second quarter of fiscal 2017. The increase was primarily due to higher costs incurred for the BEACON CRC trial, as well as more resources engaged on collaborations.
Research and development expense decreased $3.9 million, compared to the second quarter of fiscal 2017. The decrease was due to expenses associated with the Novartis transitioned studies.
Net loss for the second quarter of fiscal 2018 was $34.1 million, or ($0.17) per share, compared to $23.3 million, or ($0.14) per share, for the same quarter in fiscal 2017. The increase in net loss was primarily due to a decrease in reimbursement revenue from Novartis and one-time costs to convert and extinguish Array’s convertible debt.
CONFERENCE CALL INFORMATION
Array will hold a conference call on Tuesday, February 6, 2018 at 9:00 a.m. Eastern Time to discuss these results and provide an update on the progress of its key clinical development programs. Ron Squarer, Chief Executive Officer, will lead the call.

Webcast, including Replay and Conference Call Slides:
View Source

About COLUMBUS
The COLUMBUS trial, (NCT01909453), is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive COMBO450, ENCO300, or vemurafenib 960 mg alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was an mPFS comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of ENCO300 to that of the COMBO450 arm and a comparison of OS for the COMBO450 arm to that of vemurafenib alone. Results from Part 1 of the COLUMBUS trial previously presented at the 2016 Society for Melanoma Research Annual Congress, showed that COMBO450 more than doubled mPFS)\ in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR 0.54, (95% CI 0.41-0.71, p<0.001)]. In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months [HR 0.75, (95% CI 0.56-1.00, p=0.051)].
In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg plus binimetinib 45 mg (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.
As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the planned analysis of mOS is descriptive.

About Melanoma
Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4]

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of encorafenib, binimetinib and cetuximab in patients with BRAF-mutant metastatic CRC whose disease has progressed after one or two prior regimens. Thirty patients were treated in the safety lead-in and received the triplet combination of encorafenib 300 mg daily, binimetinib 45 mg twice daily and cetuximab per label. Of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H), resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial.

The randomized portion of the BEACON CRC trial is designed to assess the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (encorafenib and cetuximab) or the control arm (irinotecan-based therapy and cetuximab). The primary endpoint of the trial is mOS of the triplet combination compared to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, ORR, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAF-mutant advanced CRC. Phase 2 trial results were presented at the 2016 ASCO (Free ASCO Whitepaper) annual meeting. [5] In the doublet arm of encorafenib and cetuximab, mOS exceeded one year, which is more than double several separate historical published standard of care benchmarks for this population. [5-11] Further, the ORR was 22% and the mPFS was 4.2 months. [5] Historical published ORR and mPFS benchmarks in this patient population using standard of care regimens range between 4% to 8% and 1.8 and 2.5 months, respectively. [9-12]

About Colorectal Cancer
Worldwide, CRC is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. [13] Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. [14] Globally in 2012, approximately 694,000 deaths were attributed to CRC. [13] In the U.S. alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. [13] In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with CRC and represent a poor prognosis for these patients. [7, 8, 16, 17] Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) to 18% in a recent Southwestern Oncology Group (SWOG) randomized Phase 2 trial. [11]