On October 30, 2018 Clovis Oncology, Inc. (NASDAQ:CLVS) reported financial results for the quarter ended September 30, 2018, and provided an update on the Company’s clinical development programs and regulatory and commercial outlook for the remainder of 2018 (Press release, Clovis Oncology, OCT 30, 2018, View Source [SID1234530373]).

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"As discussed last quarter, growth remains challenging in the second-line maintenance ovarian cancer setting, but we have efforts underway to address this and we are aggressively moving forward to grow this market and grow our share of this market," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "In addition, our development team continues to make significant progress in moving Rubraca beyond its initial ovarian cancer indications. In particular, we were very pleased with the data from the TRITON studies presented at ESMO (Free ESMO Whitepaper) and at the Prostate Cancer Foundation Scientific Retreat, which also served as the basis for Breakthrough Therapy designation, and we are committed to developing Rubraca in the prostate setting as rapidly as possible to support men with this difficult-to-treat disease."

Third Quarter 2018 Financial Results

Product revenue for the quarter and first nine months ended September 30, 2018 was $22.8 million and $65.0 million, compared to $16.8 million and $38.5 million for the comparable periods in 2017. The supply of free drug distributed to eligible patients through the Rubraca patient assistance program for the three months ended September 30, 2018 was approximately 30 percent of the overall commercial supply, or the equivalent of $9.6 million in commercial value. In the nine months ended September 30, 2018, the supply of this free drug was approximately 26 percent of the overall commercial supply, or the equivalent of $23 million in commercial value. We believe the increase in the free drug percentage not realized as revenue results primarily from an increase in the percentage of patients treated with Rubraca who qualify for our patient assistance program, the majority of whom are on Medicare, following label expansion to include the earlier-line, all-comers maintenance treatment label.

Clovis had $604.4 million in cash, cash equivalents and available-for-sale securities as of September 30, 2018. Cash used in operating activities was $72.5 million for the third quarter of 2018 and $283.3 million for the first nine months of 2018, compared with $45.8 million for the third quarter of 2017 and $195.3 million for the first nine months of 2017. This includes product supply costs of $76.1 million in the first nine months of 2018 related to Clovis’ previously described plan to build additional inventory in advance of the transition to a new manufacturing facility for Rubraca. Additionally, Clovis made one-time milestone payments to Pfizer of $58 million in the first nine months of 2018 related to U.S. product approvals in December 2016 and April 2018 and European product approval in May 2018.

Clovis reported a net loss for the third quarter of 2018 of $89.9 million, or ($1.71) per share, and $268.8 million, or a net loss of ($5.18) per share for the first nine months of 2018. Net loss was $60.7 million, or a net loss of ($1.24) per share for the third quarter of 2017, and $294.5 million, or a net loss of ($6.39) per share for the first nine months of 2017.

The net loss for the nine months ended September 30, 2018 includes a one-time charge of $20 million in the second quarter related to a final settlement reached with the Securities and Exchange Commission which resolves their investigation related to rociletinib, and a charge of $8.0 million in the first quarter related to a legal settlement. The net loss for the nine months ended September 30, 2017 included a charge of $117.0 million related to a legal settlement. The adjusted net loss excluding these items was $240.8 million, or ($4.64) per share for the first nine months of 2018 and $177.5 million, or ($3.85) per share for the first nine months of 2017.

Net loss for the third quarter and first nine months of 2018 included share-based compensation expense of $10.9 million and $37.7 million, compared to $12.6 million and $32.2 million for the comparable periods of 2017.

Clovis had approximately 52.7 million shares of common stock outstanding as of September 30, 2018.

Research and development expenses totaled $63.9 million for the third quarter of 2018 and $160.1 million for the first nine months of 2018, compared to $38.9 million and $104.5 million for the comparable periods in 2017. Research and development expenses will continue to increase compared to prior year as planned Rubraca studies progress.

Selling, general and administrative expenses totaled $42.5 million for the third quarter of 2018 and $126.6 million for the first nine months of 2018, compared to $35.0 million and $100.4 million for the comparable periods in 2017. Selling, general and administrative expenses will continue to increase compared to prior year in support of administrative and commercial activities related to Rubraca in the United States and Europe.

Guidance for Q4 2018; Anticipate Providing 2019 Guidance in Early January

Based on current trends in PARP inhibitor adoption, the Company anticipates Q4 2018 revenues to be consistent with or slightly higher than Q3 2018 reported revenues of $22.8 million. Clovis anticipates providing full-year 2019 guidance in early January.

Key Milestones and Objectives for Rubraca

European Union (EU) Maintenance Treatment Variation Under Review

Following the receipt of the initial Marketing Authorization for Rubraca in late May 2018, Clovis submitted a variation to include the maintenance indication, which was validated by the European Medicines Agency (EMA) in early July. The review is underway and an opinion for the maintenance indication is anticipated from the EMA’s Committee for Medicinal Products for Human Use (CHMP) by the end of 2018, and, if positive, a potential formal European Commission approval could follow in early 2019. Clovis continues to establish its EU organization to support the planned launch of Rubraca in Europe.

TRITON Datasets at ESMO (Free ESMO Whitepaper) and Breakthrough Therapy Designation

Initial data from the Company’s ongoing TRITON studies of Rubraca in advanced prostate cancer were presented at the ESMO (Free ESMO Whitepaper) 2018 Congress (European Society for Medical Oncology) earlier this month. The initial TRITON2 data show a 44% confirmed objective response rate (ORR) by investigator assessment in 25 RECIST1/PCWG3** response-evaluable patients with a BRCA1/2 alteration. The median duration of response in these patients has not yet been reached. In addition, a 51% confirmed prostate specific antigen (PSA) response rate was observed in 45 PSA response-evaluable patients with a BRCA1/2 alteration. Preliminary safety data for Rubraca in men with mCRPC were consistent with those observed in patients with ovarian cancer and other solid tumors.

The TRITON2 results were the basis for Breakthrough Therapy designation for Rubraca as a monotherapy treatment of adult patients with BRCA1/2 mutated mCRPC who have received at least one prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy, which was granted on October 2, 2018 by the U.S. Food and Drug Administration (FDA). The TRITON2 study continues to enroll patients.

Also, a TRITON screening poster presented at ESMO (Free ESMO Whitepaper) provided initial genomic profiling data from the TRITON clinical program. Plasma samples identified alterations in BRCA1 or BRCA2 in approximately 12% of mCRPC patients screened for the TRITON2 study, and data demonstrated that plasma cell-free circulating tumor DNA (cfDNA) samples were highly consistent with tumor tissue in identifying BRCA1 or BRCA2 alterations.

Rubraca Clinical Development

Clovis has a robust clinical development program underway in multiple tumor types, including Clovis-sponsored, partner-sponsored and investigator-initiated trials. The following clinical studies are open for enrollment or are anticipated to open during the next several months:

The Clovis-sponsored ARIEL4 confirmatory study in the treatment setting is a Phase 3 multicenter, randomized study of Rubraca versus chemotherapy in relapsed ovarian cancer patients with BRCA mutations who have failed two prior lines of therapy. This study is currently enrolling patients.
The Clovis-sponsored Phase 3 ATHENA study in advanced ovarian cancer in the first-line maintenance treatment setting evaluating Rubraca plus Opdivo (PD-1 inhibitor), Rubraca, Opdivo and placebo in newly diagnosed patients who have completed platinum-based chemotherapy. This study, as part of a broad clinical collaboration with Bristol-Myers Squibb, is currently enrolling patients
The Clovis-sponsored TRITON3 study, a Phase 3 comparative study in metastatic castration-resistant prostate cancer (mCRPC) enrolling BRCA mutant and ATM mutant (both inclusive of germline and somatic) patients who have progressed on androgen-receptor (AR)-targeted therapy and who have not yet received chemotherapy in the castrate-resistant setting. TRITON3 compares Rubraca to physician’s choice of AR-targeted therapy or chemotherapy in these patients. This study is currently enrolling patients.
The Clovis-sponsored TRITON2 study in mCRPC, a Phase 2 single-arm study in patients with BRCA mutations (inclusive of germline and somatic) and also enrolling patients with deleterious mutations of other homologous recombination (HR) repair genes, including ATM. All patients will have progressed after receiving one line of taxane-based chemotherapy and one or two lines of AR-targeted therapy. This study is currently enrolling patients.
The Clovis-sponsored single-arm Phase 2 open-label monotherapy study of Rubraca in recurrent, metastatic bladder cancer titled ATLAS: A Study of Rucaparib in Patients with Locally Advanced or Metastatic Urothelial Carcinoma. This study is currently enrolling patients.
The Phase 1 RUCA-J study, sponsored by Clovis, is a Phase 1 study to identify the recommended dose of rucaparib in Japanese patients, which will enable development of a bridging strategy and potential inclusion of Japanese sites in planned or ongoing global studies. This study is currently enrolling patients.
The Phase 2, open-label, multi-cohort study evaluating the combination of Rubraca and Opdivo in patients with relapsed ovarian cancer and in patients with locally advanced or metastatic bladder carcinoma. This study is sponsored by Clovis and is expected to begin in early 2019.
The Phase 1/2 combination study of sacituzumab govitecan and Rubraca for the treatment of advanced metastatic TNBC, relapsed platinum-resistant ovarian cancer and metastatic urothelial cancers is sponsored by Clovis and is expected to begin enrolling patients in the first half of 2019.
The Phase 3 pivotal study in advanced triple-negative breast cancer (TNBC) to evaluate Opdivo and Rubraca in combination. This study is sponsored by Bristol-Myers Squibb. The protocol for this study is in development.
The Phase 2 combination study of Opdivo with Rubraca for the treatment of mCRPC. This study, sponsored by Bristol-Myers Squibb, is being conducted as an arm of a larger sponsored prostate cancer study. This study is currently enrolling patients.
The Phase 1b combination study of the cancer immunotherapy Tecentriq (atezolizumab; anti-PDL1) and Rubraca for the treatment of ovarian and triple-negative breast cancers. This study is sponsored by Roche and is currently enrolling patients.
Exploratory studies in other tumor types are also underway.

________________________________

1 Response Evaluation Criteria in Solid Tumors (RECIST) is a standardized methodology for determining therapeutic response to anticancer therapy using changes in lesion appearance on imaging studies.

** Prostate Cancer Working Group (PCWG3) is an international expert committee of prostate cancer clinical investigators who have recommended modifications to RECIST for use in the conduct of trials in metastatic castration-resistant prostate cancer (mCRPC) which were adopted in the TRITON2 protocol.

Lucitanib Clinical Development

Lucitanib is an oral, potent inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3), platelet-derived growth factor receptors alpha and beta (PDGFRα/β) and fibroblast growth factor receptors 1 through 3 (FGFR1-3), which was previously evaluated in breast and lung cancers in partnership with Servier. Clovis has global rights (excluding China) for lucitanib.

Lucitanib was originally developed by Clovis and Servier with the hypothesis of activity in FGFR driven tumors; data in breast and lung cancer were insufficient to move the program forward. Recent data for a similar drug that inhibits these same three pathways – when combined with a PD-1 inhibitor – are extremely encouraging and represent a validated and alternative hypothesis for the development of lucitanib in combination with a PD-(L)1 inhibitor, and a Clovis-sponsored combination study is now being planned. Clovis also intends to initiate a study of lucitanib in combination with rucaparib, based on encouraging data of VEGF and PARP inhibitors in combination. Each of these studies is expected to initiate before the end of Q1 2019.

Conference Call Details

Clovis will hold a conference call to discuss Q3 2018 results this afternoon, October 30, at 4:30pm ET. The conference call will be simultaneously webcast on the Company’s web site at www.clovisoncology.com, and archived for future review. Dial-in numbers for the conference call are as follows: US participants 866.393.4306, International participants 734.385.2616, conference ID: 5885294.

About Rubraca (rucaparib)

Rubraca is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in ovarian cancer as well as several additional solid tumor indications. Studies open for enrollment or under consideration include ovarian, prostate, breast, gastroesophageal, pancreatic, lung and bladder cancers. Clovis holds worldwide rights for Rubraca.

In the United States, Rubraca is approved 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 also approved in the United States for the treatment of adult patients with deleterious BRCA mutation (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.

Rubraca is an unlicensed medical product outside of the U.S. and EU.

On October 30, 2018 BioTime, Inc. (NYSE American and TASE: BTX), a clinical-stage biotechnology company focused on degenerative diseases, reported that it will report its third quarter 2018 financial and operating results on Thursday, November 8th, 2018, following the close of the U.S. financial markets (Press release, BioTime, OCT 30, 2018, View Source;p=RssLanding&cat=news&id=2374117 [SID1234530372]). BioTime management will also host a conference call and webcast on Thursday, November 8th, 2018, at 4:30 p.m. Eastern Time/1:30 p.m. Pacific Time to discuss its third quarter 2018 financial results and to provide a business update.

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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

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Interested parties may access the conference call by dialing (866) 888-8633 from the U.S. and Canada and (636) 812-6629 from elsewhere outside the U.S. and should request the "BioTime Inc. Call". A live webcast of the conference call will be available online in the Investors section of BioTime’s website. A replay of the webcast will be available on BioTime’s website for 30 days and a telephone replay will be available through November 15th, 2018, by dialing (855) 859-2056 from the U.S. and Canada and (404) 537-3406 from elsewhere outside the U.S. and entering conference ID number 8658619.

On October 30, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported results for its first quarter of fiscal 2019 and provided an update on the progress of its key commercial products and clinical development programs (Press release, Array BioPharma, OCT 30, 2018, View Source [SID1234530370]).

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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

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"We have received positive feedback from the melanoma community and our team continues to execute a robust U.S. launch of BRAFTOVI + MEKTOVI for patients with BRAF-mutant melanoma. We were also delighted BRAFTOVI + MEKTOVI received European Commission approval in September," said Ron Squarer, Chief Executive Officer. "Our BEACON CRC Phase 3 trial continues to advance and is supported by Breakthrough Therapy Designation. We look forward to the interim analysis of the BEACON CRC trial in the first half of 2019."

MELANOMA
COMMERCIAL
BRAFTOVI + MEKTOVI U.S. Approval and Launch
BRAFTOVI + MEKTOVI were available for sale beginning on July 2, 2018, and patients began receiving the combination therapy that same week.

Net product sales for the first quarter was $14 million. Array has seen strong demand for BRAFTOVI + MEKTOVI and continues to receive positive feedback from healthcare providers, payers and the melanoma community regarding the combination.

BRAFTOVI + MEKTOVI European Approval
On September 20, 2018, the European Commission approved BRAFTOVI in combination with MEKTOVI for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. This approval is applicable to all 28 European Union member states, as well as Liechtenstein, Iceland and Norway.

COLUMBUS PHASE 3 TRIAL OVERALL SURVIVAL (OS) RESULTS PUBLISHED IN THE LANCET ONCOLOGY
Detailed OS results of the pivotal COLUMBUS trial were published online on September 12, 2018 by The Lancet Oncology.

The median OS was 33.6 months for patients treated with BRAFTOVI + MEKTOVI, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. The combination reduced the risk of death compared to treatment with vemurafenib [hazard ratio (HR) of 0.61, (95% CI 0.47-0.79, p <0.0001)] in the planned analysis of OS.
Observed grade 3 or 4 adverse events seen in more than 5% of patients with BRAFTOVI + MEKTOVI were increased gamma-glutamyltransferase (9%), increased blood creatine phosphokinase (7%) and hypertension (6%). Additional safety information can be found in the manuscript and in the Important Safety Information and the full Prescribing Information for BRAFTOVI and MEKTOVI below.
COLORECTAL CANCER (CRC)
BEACON CRC PHASE 3 TRIAL
Breakthrough Therapy Designation
On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and cetuximab for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease. BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no therapies specifically approved for this high unmet need population. [1-6]

Regulatory Update
Following consultation with the FDA and European Medicines Agency, Array has initiated an amendment to the BEACON CRC protocol to allow for an interim analysis of trial endpoints. Should a planned analysis based primarily on confirmed overall response rate (ORR) and durability of response be supportive, the Company plans to use it to seek accelerated approval in the U.S. The interim analysis may also support regulatory submissions in other regions. The Company anticipates topline results from this analysis in the first half of 2019. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated.

The BEACON CRC trial continues to enroll well and Array expects to complete enrollment of the trial around the end of 2018.

ANCHOR CRC TRIAL
In October 2018, ANCHOR CRC, an international trial designed to assess the efficacy and safety of the combination of encorafenib, binimetinib and cetuximab in patients with BRAFV600E-mutant mCRC in the first-line setting, was posted to clinicaltrials.gov. This trial was designed in partnership with top global key opinion leaders and Array is excited by the potential of this combination therapy to benefit patients in the first-line setting. The ANCHOR CRC trial is being conducted in collaboration with Pierre Fabre and Ono Pharmaceutical Co.,Ltd., and with support from Merck KGaA, Darmstadt, Germany.

IMMUNO-ONCOLOGY COLLABORATIONS
TRIALS ADVANCING WITH BRISTOL-MYERS SQUIBB, MERCK AND PFIZER
Array is developing binimetinib in combination with PD-1/PD-L1 checkpoint inhibitors and previously announced separate, strategic collaborations with Bristol-Myers Squibb, Merck and Pfizer. Each collaboration is pursuing a different rationally designed clinical approach in several solid tumor populations including metastatic colorectal cancer patients with microsatellite stable tumors (BMS and Merck), and patients with non-small cell lung and pancreatic cancer (Pfizer). These approaches are characterized by their focus on earlier lines of therapy and the addition of a third regimen.

FINANCIAL HIGHLIGHTS

First Quarter of Fiscal 2019 Compared to First Quarter of Fiscal 2018

Net Product Sales for BRAFTOVI + MEKTOVI for the first quarter of fiscal 2019 was $14.0 million. The Company has seen strong demand for BRAFTOVI + MEKTOVI during the quarter and continues to receive positive feedback from the melanoma community.
Total Revenue for the first quarter of fiscal 2019 increased by $27.2 million compared to the same quarter of fiscal 2018. The increase was primarily due to new product sales and increased milestone revenue from Pierre Fabre and Loxo Oncology, which was partially offset by reduced reimbursement revenue from Novartis as those underlying trials continue to decrease and certain reimbursement limits are met.
Cost of Goods Sold related to our product revenues was $0.2 million which represents 1.4% of net sales. The Company expects the percentage of net sales in subsequent quarters to increase as the initial launch inventory was mostly expensed prior to approval.
Research and development expense for proprietary programs increased by $2.3 million, compared to the first quarter of fiscal 2018. The increase was primarily driven by activities related to the BEACON CRC trial, which was partially offset by lower activity on the Novartis transitioned studies.
Selling, General and Administrative increased by $12.8 million compared to first quarter of fiscal 2018, primarily driven by commercialization activities for the BRAFTOVI and MEKTOVI launch.
Net loss for the first quarter of fiscal 2019 was $24.8 million, or ($0.12) per share, compared to $38.0 million, or ($0.22) per share, for the same quarter in fiscal 2018. The decrease in net loss was primarily due to new product sales and increased milestone revenue from Pierre Fabre and Loxo Oncology, which was partially offset by reduced reimbursement revenue from Novartis.
Cash, cash equivalents and marketable securities as of September 30, 2018 were $415 million.
CONFERENCE CALL INFORMATION
Array will hold a conference call on Tuesday, October 30, 2018, at 9:00 a.m. Eastern Time to discuss these results and provide an update on the progress of its key commercial products and clinical development programs. Ron Squarer, Chief Executive Officer, will lead the call.

Date:

Tuesday, October 30, 2018

Time:

9:00 a.m. Eastern Time

Toll-Free:

(844) 464-3927

Toll:

(765) 507-2598

Pass Code:

5559328

Webcast, including Replay and Conference Call Slides:
View Source

About BRAF-mutant Metastatic Melanoma
Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumors. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [7,8] There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. 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. [7,9-11]

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test.

The Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA) are currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is currently reviewing the Manufacturing and Marketing Approval applications submitted by Ono Pharmaceutical Co, Ltd.

Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted.

Warnings and Precautions New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or BRAFV600Kmutation prior to initiating BRAFTOVI.

Cardiomyopathy: In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis, was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmic evaluation at regular intervals and for any visual disturbances.

Interstitial Lung Disease (ILD): ILD, including pneumonitis, occurred in 0.3% of patients with BRAFmutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST). Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK periodically and as clinically indicated.

QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial) were: fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS trial, the most common laboratory abnormalities (≥20%, all Grades) included: increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information [12,13]. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. The primary endpoint of the trial was PFS; all secondary efficacy analyses, including the prospectively planned analysis of OS, are descriptive in nature. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial.

About Colorectal Cancer
Worldwide, colorectal cancer 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. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [14] 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. [15] In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients. [5,6,16,17] The risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [18] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established clinical activity benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8% ,mPFS of 1.8 to 2.5 months and median OS of 4 to 6 months. [1-6,19]

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and cetuximab in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAFV600E mutation. 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 BRAFTOVI in combination with cetuximab with or without MEKTOVI compared to cetuximab and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and cetuximab) or the control arm (irinotecan-based therapy and cetuximab). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination 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, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

On October 30, 2018 Amgen (NASDAQ:AMGN) reported financial results for the third quarter of 2018 (Press release, Amgen, OCT 30, 2018, View Source [SID1234530368]). Key results include:

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Total revenues increased 2 percent versus the third quarter of 2017 to $5.9 billion.

Product sales grew 1 percent globally. New and recently launched products including Repatha (evolocumab), Prolia (denosumab), KYPROLIS (carfilzomib) and XGEVA (denosumab) showed double-digit growth.

GAAP earnings per share (EPS) increased 4 percent to $2.86 driven by higher total revenues, a lower tax rate and lower weighted-average shares outstanding.

GAAP operating income decreased 5 percent to $2.3 billion and GAAP operating margin decreased 2.5 percentage points to 42.2 percent.

Non-GAAP EPS increased 13 percent to $3.69 driven by higher total revenues, a lower tax rate and lower weighted-average shares outstanding.

Non-GAAP operating income decreased 2 percent to $3.0 billion and non-GAAP operating margin decreased 1.7 percentage points to 53.9 percent.

2018 EPS guidance revised to $12.23-$12.55 on a GAAP basis and $14.00-$14.25 on a non-GAAP basis; total revenues guidance revised to $23.2-$23.5 billion.

The Company generated $3.1 billion of free cash flow in the third quarter of 2018 versus $3.3 billion in the third quarter of 2017.

Product Sales Performance

Total product sales increased 1 percent for the third quarter of 2018 versus the third quarter of 2017.

Repatha sales increased 35 percent driven primarily by higher unit demand, offset partially by lower net selling price.

Prolia sales increased 15 percent driven by higher unit demand.

KYPROLIS sales increased 12 percent driven by higher unit demand, offset partially by lower net selling price.

XGEVA sales increased 12 percent driven by higher unit demand.

BLINCYTO (blinatumomab) sales increased 12 percent driven by higher unit demand.

Nplate (romiplostim) sales increased 11 percent driven by higher unit demand.

Vectibix (panitumumab) sales increased 8 percent driven by higher unit demand, offset partially by lower net selling price.

Parsabiv (etelcalcetide) was launched in the U.S. in the first quarter of 2018 and sales grew 40 percent sequentially in the third quarter.

Aimovig (erenumab-aooe) was launched in the U.S. in the second quarter of 2018 and generated $22 million in sales in the third quarter.

EPOGEN (epoetin alfa) sales decreased 5 percent driven by lower net selling price.

Enbrel (etanercept) sales decreased 5 percent driven by lower unit demand and, to a lesser extent, lower net selling price, offset partially by favorable changes in accounting estimates.

Neulasta (pegfilgrastim) sales decreased 6 percent driven by lower net selling price, lower unit demand and favorable prior-period changes in accounting estimates.

Aranesp (darbepoetin alfa) sales decreased 8 percent driven primarily by the impact of competition on unit demand.

Sensipar/Mimpara (cinacalcet) sales decreased 11 percent driven primarily by lower unit demand, which was due to continued adoption of Parsabiv in the U.S.

NEUPOGEN (filgrastim) sales decreased 38 percent driven by lower unit demand and, to a lesser extent, lower net selling price, which the Company believes is a function of competition.

Operating Expense, Operating Margin and Tax Rate Analysis
On a GAAP basis:

Total Operating Expenses increased 7 percent. All expense categories reflect savings from our transformation and process improvement efforts. Cost of Sales margin increased by 0.6 points due to higher manufacturing costs and higher acquisition-related intangibles amortization, offset partially by lower royalty cost and the favorable comparison to Hurricane Maria-related charges in Q3 2017. Research & Development (R&D) increased 6 percent driven by spending in late and early-stage programs, offset partially by decreased spending to support marketed products. Selling, General & Administrative (SG&A) expenses increased 11 percent due to investments in product launches and marketed product support. Other operating expenses increased primarily due to higher impairment-related charges associated with intangible assets acquired in business combinations.

Operating Margin decreased by 2.5 percentage points to 42.2 percent.

Tax Rate decreased by 3.9 percentage points due to the impacts of U.S. corporate tax reform.
On a non-GAAP basis:

Total Operating Expenses increased 7 percent. All expense categories reflect savings from our transformation and process improvement efforts. Cost of Sales margin increased by 0.3 points due to higher manufacturing cost, offset partially by lower royalty cost and the favorable comparison to Hurricane Maria-related charges in Q3 2017. R&D increased 6 percent driven by spending in late and early-stage programs, offset partially by decreased spending to support marketed products. SG&A expenses increased 11 percent due to investments in product launches and marketed product support.

AMGEN REPORTS THIRD QUARTER 2018 FINANCIAL RESULTS

Operating Margin decreased by 1.7 percentage points to 53.9 percent.

Tax Rate decreased by 6.4 percentage points due to the impacts of U.S. corporate tax reform

Cash Flow and Balance Sheet

The Company generated $3.1 billion of free cash flow in the third quarter of 2018 versus $3.3 billion in the third quarter of 2017 with the decrease driven by timing of tax payments.

The Company’s third quarter 2018 dividend of $1.32 per share was declared on July 31, 2018, was paid on Sept. 7, 2018, to all stockholders of record as of Aug. 17, 2018.

During the third quarter, the Company repurchased 8.7 million shares of common stock at a total cost of $1.7 billion. At the end of the third quarter, the Company had $3.7 billion remaining under its stock repurchase authorization.

AMGEN REPORTS THIRD QUARTER 2018 FINANCIAL RESULTS
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2018 Guidance
For the full year 2018, the Company now expects:

Total revenues in the range of $23.2 billion to $23.5 billion.

Previously, the Company expected total revenues in the range of $22.5 billion to $23.2 billion.

On a GAAP basis, EPS in the range of $12.23 to $12.55 and a tax rate in the range of 12.5 percent to 13.5 percent.

Previously, the Company expected GAAP EPS in the range of $11.83 to $12.62. Tax rate guidance is unchanged.

On a non-GAAP basis, EPS in the range of $14.00 to $14.25 and a tax rate in the range of 13.5 percent to 14.5 percent.

Previously, the Company expected non-GAAP EPS in the range of $13.30 to $14.00. Tax rate guidance is unchanged.

Capital expenditures to be approximately $700 million.

Third Quarter Product and Pipeline Update
The Company provided the following updates on selected product and pipeline programs:
KYPROLIS

In October, the U.S. Food and Drug Administration (FDA) approved the supplemental New Drug Application to expand the Prescribing Information to include a once-weekly dosing option for KYPROLIS (20/70 mg/m2) in combination with dexamethasone for patients with relapsed or refractory multiple myeloma.
BLINCYTO

In September, the Japanese Ministry of Health, Labour and Welfare granted marketing approval for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

In August, the European Commission (EC) approved an expanded indication for BLINCYTO as monotherapy for the treatment of pediatric patients aged one year or older with Philadelphia chromosome-negative CD19 positive B-cell precursor ALL, which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
Aimovig

In July, the EC approved Aimovig for the prevention of migraine in adults experiencing four or more migraine days per month.
Repatha

In July, the National Drug Administration of China approved Repatha for the treatment of adults and adolescents over 12 years old with homozygous familial hypercholesterolemia.
Tezepelumab

In September, the FDA granted Breakthrough Therapy Designation for tezepelumab in patients with severe asthma without an eosinophilic phenotype.

Aimovig is developed in collaboration with Novartis.
Tezepelumab is developed in collaboration with AstraZeneca.

AMGEN REPORTS THIRD QUARTER 2018 FINANCIAL RESULTS

Non-GAAP Financial Measures
In this news release, management has presented its operating results for the third quarters of 2018 and 2017, in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on a non-GAAP basis. In addition, management has presented its full year 2018 EPS and tax rate guidance in accordance with GAAP and on a non-GAAP basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, restructuring and certain other items from the related GAAP financial measures. Reconciliations for these non-GAAP financial measures to the most directly comparable GAAP financial measures are included in the news release. Management has also presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the third quarters of 2018 and 2017. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP.
The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor’s overall understanding of the financial performance and prospects for the future of the Company’s ongoing business activities by facilitating comparisons of results of ongoing business operations among current, past and future periods. The Company believes that FCF provides a further measure of the Company’s liquidity.
The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning internally to evaluate the performance of the business, including to allocate resources and to evaluate results relative to incentive compensation targets. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP

On October 30, 2018 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported that it will report financial results for the third quarter ending September 30, 2018 on Wednesday, November 7, 2018, before the U.S. financial markets open (Press release, Alnylam, OCT 30, 2018, View Source;p=RssLanding&cat=news&id=2374231 [SID1234530367]).

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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

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Management will provide an update on the Company and discuss third quarter 2018 results as well as expectations for the future via conference call on Wednesday, November 7, 2018 at 8:30 am ET. To access the call, please dial 800-667-5617 (domestic) or 334-323-0509 (international) five minutes prior to the start time and refer to conference ID 7650424. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 888-203-1112 (domestic) or 719-457-0820 (international) and refer to conference ID 7650424.

A live audio webcast of the call will be available on the Investors section of the Company’s website, www.alnylam.com. An archived webcast will be available on the Alnylam website approximately two hours after the event.