On May 7, 2019 Clovis Oncology, Inc. (NASDAQ:CLVS) reported financial results for the quarter ended March 31, 2019, and provided an update on the Company’s clinical development programs and regulatory and commercial outlook for the rest of the year (Press release, Clovis Oncology, MAY 7, 2019, View Source [SID1234535798]).

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"We are pleased with our progress during the first quarter," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "With solid sales performance, an encouraging update of our TRITON prostate cancer data in support of our planned supplemental NDA in late 2019, the expected near-term initiation of two lucitanib combination studies and a successful financing that extends our projected cash runway into 2022, we are very enthusiastic about our progress toward our 2019 goals. In addition, I am pleased to announce that Dan Muehl, our Executive Vice President Finance, has been promoted to Chief Financial Officer. Dan has been with the Company for about four years and this is an extremely well-deserved promotion. "

First Quarter 2019 Financial Results

Clovis reported product revenue for Rubraca of $33.1 million for the first quarter of 2019, which included U.S. product revenue of $31.9 million and ex-U.S. product revenue of $1.2 million, as compared to net product revenue for the quarter ended March 31, 2018 of $18.5 million. During the first quarter, the supply of free drug distributed to eligible patients through the Rubraca patient assistance program in the U.S. was approximately 21 percent of overall commercial supply compared to 22 percent in the first quarter of 2018. This represented $8.4 million in commercial value for the first quarter of 2019 compared to $5.1 million in the first quarter of 2018. Rubraca was initially approved in the ovarian cancer treatment setting in the U.S. in December 2016 and in the EU in May 2018. The Rubraca label was expanded to include the broader and earlier-line maintenance treatment indication in the U.S. in April 2018 and in the EU in January 2019.

Clovis had $406.8 million in cash, cash equivalents and available-for-sale securities as of March 31, 2019. Cash used in operating activities was $98.5 million for the first quarter of 2019, compared with $100.6 million for the first quarter of 2018. This includes product supply costs of $27.5 million in the first quarter of 2019, compared to $31.5 million for the comparable period in 2018. Cash used also includes a $15 million milestone payment in the first quarter of 2019 related to the EU maintenance indication approval. There were no such milestone payments in the first quarter of 2018. Clovis had approximately 53.0 million shares of common stock outstanding as of March 31, 2019.

Clovis reported a net loss for the first quarter of 2019 of $86.4 million, or ($1.63) per share, compared to the net loss for the first quarter of 2018 which was $77.7 million, or ($1.54) per share. Net loss for the first quarter of 2019 included share-based compensation expense of $13.6 million, compared to $11.9 million for the first quarter of 2018.

Research and development expenses totaled $62.0 million for the first quarter of 2019, compared to $43.5 million for the first quarter of 2018. The increase year over year is primarily due to higher research and development costs for rucaparib clinical trials, including increased enrollment in ongoing ovarian and prostate studies, increased costs related to initiating new ovarian and bladder studies during 2018, as well as additional headcount to support these increased rucaparib clinical trial activities.

Selling, general and administrative expenses totaled $47.8 million for the first quarter of 2019, compared to $39.3 million for the comparable period in 2018. The increase year over year is primarily due to higher selling, general and administrative expenses related to the commercialization of Rubraca in the U.S. and the EU, including facility expenses and personnel expenses associated with expanding the EU infrastructure.

Clovis recently entered into an agreement for up to $175 million in non-dilutive clinical trial financing with certain affiliates of TPG Sixth Street Partners to reimburse Clovis’ costs and expenses related to the ATHENA clinical trial. ATHENA is Clovis Oncology’s largest clinical trial, with a planned target enrollment of 1,000 patients across more than 270 sites in at least 25 countries. For further details, please see the Clovis news release and report on Form 8-K, dated May 2, 2019 available on the Company’s website.

Key Milestones and Objectives for Rubraca

Recurrent Ovarian Cancer Maintenance Treatment Indication Approved in the EU and Launched in Germany and UK

In January 2019, the European Commission (EC) approved the use of Rubraca for its second indication, as monotherapy for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. With this approval, Rubraca’s indication is expanded beyond its initial marketing authorization in the EU granted in May 2018, and in this indication Rubraca is available to eligible patients regardless of their BRCA mutation status. Rubraca is the first PARP inhibitor licensed for an ovarian cancer treatment indication in Europe and is the first to be available for both treatment and maintenance treatment among eligible patients with ovarian cancer. Clovis launched Rubraca in Germany and in the private pay market in the UK in March and anticipates launching in other EU countries later in 2019 and 2020.

Regulatory Path for Supplemental NDA in BRCA-mutant Advanced Prostate Cancer

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) in October 2018. The initial TRITON2 data showed a 44 percent confirmed objective response rate (ORR) by investigator assessment in 25 RECIST1/PCWG3** response-evaluable patients with a BRCA1/2 alteration, and results by independent assessment were consistent. The median duration of response in these patients had not yet been reached. In addition, a 51 percent 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 mutant mCRPC who have received at least one prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy, which was granted on October 1, 2018 by the U.S. Food and Drug Administration (FDA). Both studies in the TRITON program, TRITON2 and TRITON3, continue to enroll patients.

As a result of Rubraca’s breakthrough therapy status, Clovis agreed to provide regular updates to FDA on the Company’s advanced prostate cancer development program on a regular basis. At the end of April 2019, Clovis provided an update to FDA on 52 patients with BRCA-mutant mCRPC that showed a RECIST response rate and PSA response highly consistent with the data presented at ESMO (Free ESMO Whitepaper) 2018. Clovis expects to discuss this update with FDA in the next several weeks. Clovis intends to file the planned supplemental NDA by the end of 2019.

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 Clovis-sponsored clinical studies are open for enrollment or are anticipated to open during the next several months:

ARIEL4, a confirmatory study in the ovarian cancer 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.
ATHENA is a Phase 3 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.
TRITON3 is a Phase 3 comparative study in 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 castration-resistant setting. TRITON3 compares Rubraca to physician’s choice of AR-targeted therapy or chemotherapy in these patients. This study is currently enrolling patients.
TRITON2 is a Phase 2 single-arm study in mCRPC in patients with BRCA mutations (inclusive of germline and somatic), which is also enrolling patients with deleterious mutations of other homologous recombination (HR) repair genes. 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. Updated data from the ongoing TRITON2 study are anticipated at a Fall 2019 medical meeting.
RUCA-J study is a Phase 1 study which has identified the 600mg BID dose of rucaparib as the recommended dose in Japanese patients; this 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.
ARIES is a Phase 2, open-label, multi-cohort study evaluating the combination of Rubraca and Opdivo in patients with relapsed ovarian cancer. This study is expected to begin enrolling patients in the first half of 2019.
SEASTAR is a Phase 1b/2 study comprised of multiple single-arm rucaparib combination studies, which currently includes the following planned combinations:
Rubraca and lucitanib, Clovis’ investigational inhibitor of multiple tyrosine kinases including VEGFR, for the treatment of ovarian cancer, expected to begin in mid-2019;
Rubraca and sacituzumab govitecan, an antibody drug conjugate, for the treatment of advanced metastatic triple-negative breast cancer, relapsed platinum-resistant ovarian cancer and potentially advanced metastatic urothelial cancers, is expected to begin enrolling patients in 2019;
And a planned Phase 2 pan-tumor study in patients with multiple tumor types with a mutation in certain genes likely to confer sensitivity to Rubraca, which is expected to begin by year-end 2019.
Also, a Phase 2 combination study of Opdivo with Rubraca for the treatment of mCRPC is underway. This study, sponsored by Bristol-Myers Squibb, is being conducted as an arm in the CHECKMATE 9KD prostate cancer study, and is currently enrolling patients. Exploratory studies in other tumor types are also underway, as well as active discussions with Bristol-Myers Squibb regarding additional potential combination studies.

Lucitanib Clinical Development

Lucitanib is an investigational, 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.

Recent data for a drug that inhibits these same three pathways – when combined with a PD-1 inhibitor – are extremely encouraging and represent a scientific rationale for the development of lucitanib in combination with a PD-1 inhibitor, and a Clovis-sponsored study of lucitanib in combination with Opdivo is planned in gynecologic and other tumor types. Clovis also intends to initiate a study of lucitanib in combination with rucaparib in ovarian cancer as an arm of the SEASTAR study mentioned above, based on encouraging data of VEGF and PARP inhibitors in combination. Each of these Phase 1b/2 studies is expected to initiate in mid-2019.

During the second quarter, Clovis and Alkermes initiated a preclinical research collaboration to evaluate ALKS 4230, Alkermes’ investigational engineered interleukin-2 (IL-2) variant immunotherapy, in combinations with rucaparib and lucitanib.

Conference Call Details

Clovis will hold a conference call to discuss First Quarter 2019 results this morning, May 7, at 8:30am 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 877.698.7048, International participants 647.689.5448, conference ID: 8567356.

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, and lung 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.

In the EU, Rubraca is approved for the maintenance treatment of adults with platinum-sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. This expands rucaparib’s indication beyond its initial marketing authorization in the EU granted in May 2018 and with this label expansion, rucaparib is now available to patients regardless of their BRCA mutation status. Rubraca is also approved in the EU for the treatment of adult patients with platinum sensitive, relapsed or progressive, BRCA mutated (germline and/or somatic), high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have been treated with two or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy.

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

On May 7, 2019 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology, reported that the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug (IND) application for AGI-134, a novel immunotherapy anti-cancer vaccine for solid tumors (Press release, BioLineRx, MAY 7, 2019, View Source;p=RssLanding&cat=news&id=2397449 [SID1234535797]).

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"We are pleased with the FDA’s IND approval, which will enable us to expand our ongoing Phase 1/2a study, currently being carried out in the UK and Israel, to the US by the first half of 2020," said Philip Serlin, Chief Executive Officer of BioLineRx. "Pre-clinical studies have demonstrated that treatment with AGI-134 leads to complete regression of primary tumors, prevents growth of untreated distal secondary tumors, and triggers a vaccine effect that may prevent the development of future metastases. Furthermore, preclinical studies have also shown that, in addition to the monotherapy effect, the combination of AGI-134 with an anti-PD-1 immune checkpoint inhibitor demonstrates a synergistic effect in protection from secondary tumor growth. We look forward to the initial safety results of the trial in the second half of this year and anticipate initial efficacy results by the end of 2020."

The ongoing Phase 1/2a study is a multicenter, open-label study expected to take place at approximately 15 sites in the US, UK and Israel. The study is primarily designed to evaluate the safety and tolerability of AGI-134, given both as monotherapy and in combination with an immune checkpoint inhibitor, in solid tumors. Additional objectives include a wide array of biomarker endpoints, as well as validation of AGI-134’s mechanism of action. Furthermore, efficacy will be assessed by clinical and pharmacodynamic parameters.

The study is comprised of two parts: (i) the ongoing accelerated dose-escalation part to assess the safety and tolerability of intratumorally injected AGI-134 as a monotherapy, as well as to determine the maximum tolerated dose and the recommended dose for part 2 of the study; and (ii) a dose expansion part at the recommended dose, comprised of three cohorts and designed to assess the safety, tolerability and anti-tumor activity of AGI-134 as a monotherapy in a basket cohort of multiple solid tumor types, as well as in two additional cohorts in combination with an immune checkpoint inhibitor – in metastatic colorectal cancer and in head and neck squamous cell carcinoma.

About AGI-134

AGI-134 is a synthetic alpha-Gal glycolipid in development for solid tumors that is highly differentiated from other cancer immunotherapies. AGI-134 is designed to label cancer cells with alpha-Gal via intratumoral administration, thereby targeting the body’s pre-existing, highly abundant anti-alpha-Gal (anti-Gal) antibodies and redirecting them to treated tumors. Binding of anti-Gal antibodies to the treated tumors results in activation of the complement cascade, which destroys the tumor cells and creates a pro-inflammatory tumor microenvironment that also induces a systemic, specific anti-tumor (vaccine) response to the patient’s own tumor neo-antigens.

AGI-134 has been evaluated in numerous pre-clinical studies. In a mouse melanoma model, treatment with AGI-134 led to regression of established primary tumors and suppression of secondary tumor (metastases) development. Synergy has also been demonstrated in additional pre-clinical studies when combined with an anti-PD-1 immune checkpoint inhibitor, offering the potential to broaden the utility of such immunotherapies, and improve the rate and duration of responses in multiple cancer types. AGI-134 was obtained by BioLineRx through the acquisition of Agalimmune Ltd.

On May 7, 2019 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology, reported it will release its unaudited financial results for the quarter ended March 31, 2019 on Tuesday, May 14, 2019, before the US markets open (Press release, BioLineRx, MAY 7, 2019, View Source;p=RssLanding&cat=news&id=2397480 [SID1234535796]).

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The Company will host a conference call on Tuesday, May 14, 2019 at 10:00 a.m. EDT featuring remarks by Philip Serlin, Chief Executive Officer. The conference call will be available via webcast and can be accessed through the Investor Relations page of BioLineRx’s website. Please allow extra time prior to the call to visit the site and download any necessary software to listen to the live broadcast.

To dial into the conference call, please dial +1-888-281-1167 from the U.S. or +972-3-918-0644 internationally. A replay of the conference call will be available approximately two hours after completion of the live conference call on the Investor Relations page of BioLineRx’s website. A dial-in replay of the call will be available until May 16, 2019; please dial +1-888-782-4291 from the U.S. or +972-3-925-5925 internationally.

On May 7, 2019 Array BioPharma Inc. (Nasdaq: ARRY) reported results for its third quarter of fiscal 2019 and provided an update on the progress of its key commercial products and clinical development programs (Press release, Array BioPharma, MAY 7, 2019, View Source [SID1234535795]).

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"U.S. demand for BRAFTOVI + MEKTOVI for patients with BRAF-mutant metastatic melanoma continues to be strong with over $35 million in net product sales during the third commercial quarter," said Ron Squarer, Chief Executive Officer. "We are also pleased the combination of BRAFTOVI, MEKTOVI and cetuximab or panitumumab was recommended by NCCN guidelines as a treatment option for patients with advanced BRAFV600E-mutant colorectal cancer. We look forward to reporting topline results from the BEACON CRC interim analysis this quarter."

MELANOMA
U.S. Sales
BRAFTOVI + MEKTOVI net product sales for the third quarter were $35.1 million.

Japanese Launch
On February 26, 2019, BRAFTOVI + MEKTOVI was launched in Japan and is indicated for unresectable melanoma with a BRAF mutation.

COLORECTAL CANCER (CRC)
BEACON CRC PHASE 3 TRIAL
National Comprehensive Cancer Network (NCCN) Recommendation
On March 18, 2019, Array announced that the National Comprehensive Cancer Network (NCCN) updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and ERBITUX (cetuximab) or panitumumab as a Category 2A treatment for patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after one or two prior lines of therapy for metastatic disease. The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial evaluating the triplet combination of BRAFTOVI in combination with MEKTOVI and ERBITUX (cetuximab) in 29 patients with BRAFV600E-mutant mCRC.

Safety Lead-in Median Overall Survival (OS) Data Presented at ASCO (Free ASCO Whitepaper) 2019 Gastrointestinal Cancers Symposium

Array announced updated safety and efficacy results from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of BRAFTOVI, MEKTOVI, and ERBITUX in patients with BRAFV600E-mutant mCRC.

Mature median OS was 15.3 months (95% CI, 9.6–not reached) for patients treated with the triplet.
Updated median progression-fee survival (mPFS) and updated confirmed overall response rate (ORR) results for patients treated with the triplet in the safety lead-in remain the same, as previously reported, with 8 months mPFS (95% CI, 5.6-9.3) and a 48% ORR (95% CI, 29.4–67.5). ORR by central assessment, 41% (95% CI 24%–61%), was consistent with local assessment.
The triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities continued to be lower than generally observed with ERBITUX in mCRC.
Regulatory Update
Following consultation with the FDA and European Medicines Agency, Array 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 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 this quarter. 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 has completed enrollment.

ANCHOR CRC TRIAL
ANCHOR CRC, an international trial designed to assess the efficacy and safety of the combination of BRAFTOVI, MEKTOVI, and ERBITUX in patients with BRAFV600E-mutant mCRC in the first-line setting, is advancing. 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 for sites outside of North America.

IMMUNO-ONCOLOGY COLLABORATIONS
Array is investigating MEKTOVI 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 mCRC patients with microsatellite stable tumors (BMS and Merck), and patients with non-small cell lung cancer and pancreatic cancer (Pfizer).

BRAFTOVI + MEKTOVI LIFE-CYCLE TRIAL MANAGEMENT
POLARIS (NCT03911869), an open-label Phase 2 trial designed to assess the efficacy and safety of the combination of BRAFTOVI + MEKTOVI in patients with BRAFV600-mutant melanoma brain metastasis, has been active since April 2019.

PHAROS (NCT03915951), an open-label Phase 2 trial designed to assess the efficacy and safety of the combination of BRAFTOVI + MEKTOVI in patients with BRAFV600E-mutant metastatic non-small cell lung cancer, has been active since April 2019.

FINANCIAL HIGHLIGHTS

Third Quarter of Fiscal 2019 Compared to Second Quarter of Fiscal 2019

Net Product Sales for BRAFTOVI + MEKTOVI for the third quarter of fiscal 2019 were $35.1 million, compared to $22.7 million for the second quarter of fiscal 2019.
Total Revenue for the third quarter of fiscal 2019 was $64.7 million, compared to $82.5 million for the prior quarter. The decrease was primarily due to the recognition of the Vitrakvi milestones in the prior quarter.
Research and Development Expense for the third quarter of fiscal 2019 was $65.5 million, compared to $62.1 million for the prior quarter. The increase was primarily driven by proprietary trial activities including the BEACON CRC trial, as well as other BRAFTOVI + MEKTOVI life-cycle trials initiated in the quarter, POLARIS and PHAROS.
Selling, General and Administrative for the third quarter of fiscal 2019 was $35.5 million, compared to $30.5 million for the prior quarter. The increase was mostly driven by costs associated with BRAFTOVI + MEKTOVI commercial and sales activities, as well as general corporate expenses.
Net loss for the third quarter of fiscal 2019 was ($37.5 million), or ($0.17) per share, compared to ($11.4 million), or ($0.05) per share, for the prior quarter.
Cash, cash equivalents and marketable securities as of March 31, 2019 were $479 million.
CONFERENCE CALL INFORMATION
Array will hold a conference call on Tuesday, May 7, 2019, 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, May 7, 2019

Time:

9:00 a.m. Eastern Time

Toll-Free:

(844) 464-3927

Toll:

(765) 507-2598

Pass Code:

3638409

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. [1,2] 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. [1-5]

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. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co. Ltd., exclusive rights to commercialize both products in Japan and South Korea, Medison Pharma Ltd. exclusive rights to commercialize both products in Israel and Pierre Fabre Médicament exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

BRAFTOVI + MEKTOVI have received regulatory approval in the United States, European Union, Australia and Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

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. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Warnings and Precautions
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. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. 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. 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. Patients with cardiovascular risk factors should be monitored closely.

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. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

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. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. 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 ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-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), and 0.5% for alkaline phosphatase. 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 and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. 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. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal 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. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. [6-7] 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 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. [8] In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year. [9] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [10-14] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [10,15] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published 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 2 to 3 months and median OS of 4 to 6 months. [12-14,16-20] BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [21-23] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX 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 ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. Microsatellite instability high, 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 ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). 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. Ltd., Pierre Fabre and Merck KGaA, Darmstadt, Germany for sites outside of North America.

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

On May 7, 2019 AMAG Pharmaceuticals, Inc. (NASDAQ: AMAG) reported unaudited consolidated financial results for the first quarter ended March 31, 2019 and provided a business update (Press release, AMAG Pharmaceuticals, MAY 7, 2019, View Source [SID1234535793]).

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Total revenue for the first quarter of 2019 was $75.8 million, compared with $117.4 million in the same period last year. Makena (hydroxyprogesterone caproate injection) revenues were $31.3 million in the first quarter, compared with $90.0 million in the same period last year. This decline was primarily due to the mid-2018 entry of generic competition to the Makena intramuscular (IM) product, as well as IM supply constraints in the quarter (described below). Feraheme (ferumoxytol injection) first quarter 2019 revenues increased to a record $40.0 million, or 59%, over the same period last year. Intrarosa (prasterone) realized significant growth in net price as well as volume growth in the first quarter of 2019, as compared to the prior year period.

The company reported an operating loss of $117.7 million in the first quarter of 2019, compared with an operating loss of $50.8 million in the first quarter of 2018. Included in the loss in the first quarter of 2019 was a $74.9 million accounting impact related to the acquisition of Perosphere Pharmaceuticals Inc., which closed in the quarter. Consistent with its strategic plan and 2019 financial guidance, the company reported negative adjusted EBITDA of $26.6 million in the first quarter of 2019, compared with positive adjusted EBITDA of $30.0 million in the first quarter of 2018.1

"While total Makena revenues in the first quarter were adversely impacted by a number of non-recurring charges, we are encouraged by the strong underlying demand for the subcutaneous auto-injector, and the progress made to replace our previous primary supplier of Makena IM with new inventory from two suppliers this second quarter," said William Heiden, AMAG’s president and chief executive officer. "We’re also proud of our Feraheme team and the continued growth that product has realized. The significant cash flow from these products helps fund the development of our novel pipeline assets, which we believe are the future value drivers of the company."

"In the first quarter, our development pipeline continued to progress nicely. We are eagerly awaiting a decision on the upcoming PDUFA date for VyleesiTM (bremelanotide) and the mid-year initiation of the Phase 3a clinical studies for ciraparantag," continued Mr. Heiden. "We look forward to discussing more about AMAG’s future at our Analyst Day that will be held on May 22 in New York, which will include panels for AMAG-423, Vyleesi and ciraparantag of key opinion leaders who will provide their expert views on the opportunity for and value of these new product candidates."

1 See summaries of GAAP to non-GAAP adjustments at the conclusion of this press release.

1

First Quarter 2019 and Recent Business Highlights:
•
Promoted Tony Casciano to chief commercial officer; Mr. Casciano led the successful launches of the Makena SC auto-injector and the Feraheme broad label
•
Achieved 59% growth in Feraheme net sales year-over-year
•
Makena SC auto-injector achieved 40% volume growth and captured 54% market share of all FDA-approved hydroxyprogesterone caproate prescription volume over the fourth quarter of 2018
•
Improved first quarter 2019 Intrarosa gross-to-net price by more than 30% over the fourth quarter of 2018; successfully combined and cross trained the women’s health and maternal health sales forces into one team of approximately 125 sales representatives
•
Acquired Perosphere Pharmaceuticals, including ciraparantag, a development-stage drug candidate to reverse the anticoagulant effects of novel oral anticoagulants (NOACs) and low molecular weight heparin (LMWH)
•
Completed the study and submitted ambulatory blood pressure data to the FDA and continued activities supporting the potential launch of Vyleesi (PDUFA date: June 23, 2019)
•
Data presentations:
–
New and encore data related to Vyleesi for the treatment of hypoactive sexual desire disorder (HSDD) at the International Society for the Study of Women’s Sexual Health (ISSWSH)/International Society for Sexual Medicine (ISSM) joint meeting
–
New data related to Vyleesi for the treatment of HSDD and Feraheme related to iron deficiency anemia (IDA) resulting from abnormal uterine bleeding at the American College of Obstetricians and Gynecologists (ACOG) Annual Clinical and Scientific Meeting
•
Reaffirmed 2019 financial guidance

First Quarter Ended March 31, 2019 (unaudited)
Total revenues for the first quarter of 2019 were $75.8 million, compared with $117.4 million in the first quarter of 2018. First quarter 2019 net product sales of Makena were $31.3 million, which were lower than the $90.0 million reported in the first quarter of 2018, primarily due to the mid-2018 entry of generic competition to the Makena IM product, as well as IM supply constraints. Makena revenues in the first quarter of 2019 were further impacted by a number of gross-to-net charges, including: (i) $3.5 million of failure-to-supply penalties related to a temporary authorized generic (AGx) IM out of stock situation that occurred during the first quarter, (ii) approximately $5.0 million of increased Medicaid rebates related to the IM supply constraints in the quarter and best price implications, and (iii) $6.0 million change in estimate for Medicaid liability for prior period sales of the Makena IM product. The company expects to resolve its Makena IM supply constraints in the second quarter of 2019 and, therefore, believes charges (i) and (ii) described above are non-recurring in nature. During the first quarter of 2019, the company did not record any branded Makena IM revenues, and revenues for the AGx were adversely impacted by IM supply constraints. Sales of the Makena SC auto-injector totaled $37.8 million in the first quarter of 2019, which is net of the $5.0 million additional Medicaid rebates referenced above. Sales of Feraheme and MuGard increased 59% to $40.1 million in the first quarter of 2019, compared with $25.2 million in the first quarter of 2018. Intrarosa contributed $4.4 million in net sales during the first quarter of 2019, compared with $2.2 million in the same period last year.

Operating expenses, including cost of product sales, were aligned with expectations, totaling $193.5 million in the first quarter of 2019, compared with $168.2 million for the same period in 2018. This increase was primarily due to: (i) the $74.9 million acquired in-process research and development charge related to the acquisition of Perosphere, (ii) a one-time restructuring charge of $7.4 million related to combining the company’s women’s health and maternal health sales forces, and (iii) higher research and development costs of $7.3 million related to the company’s ongoing clinical development programs. These increases in operating expenses were partially off-set by a $45.4 million reduction in cost of product sales, driven primarily by lower intangible amortization expense.

2

The company reported an operating loss from continuing operations in the first quarter of 2019 of $117.7 million, compared with an operating loss of $50.8 million for the same period last year, largely due to the Perosphere acquisition described above. The company reported a net loss from continuing operations of $122.1 million, or $3.54 loss per basic and diluted share, for the first quarter of 2019, compared with a net loss from continuing operations of $58.1 million, or $1.70 loss per basic and diluted share, for the same period in 2018. The net loss reported during the first quarter on 2019 was favorably impacted by a reduction in interest expense incurred, as compared to the prior year period. This was the result of the company retiring $475 million in high-yield bonds in the third quarter of 2018.

Non-GAAP adjusted EBITDA from continuing operations for the first quarter of 2019 was ($26.6) million, compared with $30.0 million in the first quarter of 2018.

Balance Sheet Highlights
As of March 31, 2019, the company’s cash and investments totaled $266.5 million, and long-term total debt totaled $320.0 million (representing the principal amounts outstanding of the 2022 convertible notes). Cash used during the first quarter of 2019 included: (i) $70.8 million related to the acquisition of Perosphere Pharmaceuticals, (ii) $21.4 million for the repayment of the balance of the company’s 2019 Convertible Note, and (iii) $13.7 million for the repurchase of approximately 1.1 million shares of common stock.

2 See reconciliations of 2019 GAAP to non-GAAP financial guidance at conclusion of this press release.
3 As previously reported, the 2019 operating loss guidance range issued in January 2019 excluded the potential accounting impact for the acquisition of Perosphere, which had not closed at that time. The operating loss guidance range has now been adjusted to incorporate the $74.9 million accounting impact of the Perosphere acquisition, which was recorded in the first quarter of 2019.

"We’re pleased with the market uptake of the Makena SC auto-injector, which captured more than 50 percent share of patients treated with FDA-approved hydroxyprogesterone caproate in the first quarter, underscoring continued strong physician demand of this differentiated product and the sustainability of the Makena franchise," said Ted Myles, AMAG’s chief financial officer. "With the expected return of Makena IM supply in the second quarter, continued strong underlying demand for the SC auto-injector, impressive performance from Feraheme, as well as encouraging leading indicators from our Intrarosa direct-to-consumer campaign, we are reiterating our full year guidance for 2019."

Conference Call and Webcast Access
AMAG Pharmaceuticals, Inc. will host a conference call and webcast today at 8:00 a.m. ET to discuss the company’s first quarter 2019 financial results, recent business highlights and 2019 outlook.

Dial-in Number
U.S./Canada dial-in number: (877) 412-6083
International dial-in number: (702) 495-1202
Conference ID: 6850648

Replay dial-in number: (855) 859-2056
Replay International dial-in number: (404) 537-3406
Conference ID: 6850648

A telephone replay will be available from approximately 11:00 a.m. ET on May 7, 2019 through midnight on May 14, 2019. The webcast with slides will be accessible through the Investors section of AMAG’s website at www.amagpharma.com. A replay of the webcast will be archived on the website for 30 days.

Use of Non-GAAP Financial Measures
AMAG has presented certain non-GAAP financial measures, including non-GAAP costs and expenses and non-GAAP adjusted EBITDA (earnings before income taxes, depreciation and amortization). These non-GAAP financial measures exclude certain amounts, expenses or income, from the corresponding financial measures determined in accordance with accounting principles generally accepted in the U.S. (GAAP). Management believes this non-GAAP information is useful for investors, taken in conjunction with AMAG’s GAAP financial statements, because it provides greater transparency regarding AMAG’s operating performance. Management uses these measures, among other factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of AMAG’s operating results as reported under GAAP, not as a substitute for GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures are included in the tables accompanying this press release after the unaudited condensed consolidated financial statements.