On February 5, 2019 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX & MDAX; NASDAQ: MOR) reported the appointment of David R. Trexler as President and member of the Board of Directors of MorphoSys US Inc., effective February 6, 2019 (Press release, MorphoSys, FEB 5, 2019, View Source [SID1234533085]). Mr. Trexler will lead the ongoing build-up of MorphoSys’s U.S. subsidiary with a focus on establishing the company’s commercial capabilities in preparation for the planned commercialization of MOR208 in the U.S.

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"I am delighted to welcome David Trexler to MorphoSys. With his experience and proven track record in establishing commercial organizations for international pharmaceutical companies as well as successfully executing oncology product launches in the U.S., he is ideally qualified to lead MorphoSys US Inc. We very much look forward to working with him," said Dr. Simon Moroney, Chief Executive Officer of MorphoSys AG and Chairman of the Board of Directors of MorphoSys US Inc. "I would like to thank Jim Hussey for his outstanding contribution as interim president of our U.S. subsidiary over the last five months. Jim will now resume his position as special advisor to me in my role as Chairman of MorphoSys US Inc."

Mr. Trexler has built his career in leadership positions for branded pharmaceuticals in marketing, sales, business development and general management. He joins MorphoSys from EMD Serono, a business of Merck KGaA, Darmstadt, Germany, where he held positions of increasing seniority including most recently positions as Global Brand Lead, Bavencio and Senior Vice President US Oncology Commercial. At EMD Serono, he was responsible for building Merck KGaA’s first commercial oncology footprint in the U.S. and for the successful launch of Bavencio (avelumab) for metastatic Merkel cell carcinoma (mMCC). Prior to EMD Serono, Mr. Trexler worked for 10 years in various marketing roles in oncology for Eisai Inc., in particular as Senior Vice President Americas Oncology, where he was responsible for sales and marketing of Eisai’s oncology portfolio across the U.S. and supported efforts in Canada, Mexico and Brazil. Mr. Trexler previously held leadership roles at Mylan Bertek Pharmaceuticals (2004-2005) and Sanofi-Aventis Pharmaceuticals (1986-2004).

"I am enthused to join MorphoSys US Inc. at this exciting time in the Company’s development," commented David Trexler. "I look forward to working closely with the entire MorphoSys team to build our U.S. organization to enable a successful launch of MOR208 in this country, subject of course to prior FDA approval."

On February 5, 2019 Array BioPharma Inc. (Nasdaq: ARRY) reported results for its second quarter of fiscal 2019 and provided an update on the progress of its key commercial products and clinical development programs (Press release, Array BioPharma, FEB 5, 2019, View Source [SID1234533068]).

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"We continue to be pleased with demand following the U.S. launch of BRAFTOVI + MEKTOVI for patients with BRAF-mutant metastatic melanoma, which delivered $22.7 million in net product sales during the second commercial quarter," said Ron Squarer, Chief Executive Officer. "Separately, we were excited to report an unprecedented 15.3 months mature median overall survival from the safety lead-in of the Phase 3 BEACON CRC trial and we recently completed enrollment of the randomized portion of the trial. We look forward to the interim analysis in the first half of 2019."

MELANOMA
COMMERCIAL
U.S. Sales
BRAFTOVI + MEKTOVI net product sales for the second quarter was $22.7 million, which represents quarter over quarter growth of 62%. Feedback from prescribers continues to be positive.

European Launch
BRAFTOVI + MEKTOVI has launched in Germany, Austria, the Netherlands and the United Kingdom. Preparations for launch in other countries are under way.

Japanese Approval
On January 8, 2019, BRAFTOVI + MEKTOVI received manufacturing and marketing approval in Japan for the indication of unresectable melanoma with a BRAF mutation.

COLORECTAL CANCER (CRC)
BEACON CRC PHASE 3 TRIAL
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 metastatic colorectal cancer (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). Overall response rate 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.
Breakthrough Therapy Designation
On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant 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. [1-8]

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 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 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 (support is for sites outside of North America).

IMMUNO-ONCOLOGY COLLABORATIONS
TRIALS ADVANCING WITH BRISTOL-MYERS SQUIBB, MERCK AND PFIZER
Array is developing 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 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

Second Quarter of Fiscal 2019 Compared to First Quarter of Fiscal 2019

Net Product Sales for BRAFTOVI + MEKTOVI for the second quarter of fiscal 2019 was $22.7 million, compared to $14.0 million for the first quarter of fiscal 2019.
Total Revenue for the second quarter of fiscal 2019 was $82.5 million, compared to $56.9 million for the prior quarter. The increase was primarily due to higher product sales and recognition of $40 million of milestone revenue from Loxo Oncology, which was partially offset by reduced reimbursement revenue from Novartis and milestones earned in the previous quarter.
Cost of Goods Sold related to our product revenues for the second quarter of fiscal 2019 was $0.8 million which represents 3.5% of net sales, compared to $0.2 million for the prior quarter.
Research and development expense for proprietary programs for the second quarter of fiscal 2019 was $62.1 million, compared to $55.6 million for the prior quarter. The increase was primarily driven by proprietary trial activities including the BEACON CRC trial, which was partially offset by lower activity on the Novartis transitioned studies.
Selling, General and Administrative for the second quarter of fiscal 2019 was $30.5 million, compared to $24.9 million for the prior quarter. The increase was mostly driven by costs associated with BRAFTOVI + MEKTOVI commercial and sales activities.
Net loss for the second quarter of fiscal 2019 was $11.4 million, or ($0.05) per share, compared to $24.8 million, or ($0.12) per share, for the prior quarter. The decrease in net loss was primarily due to increased product sales and increased milestone revenue from Loxo Oncology, which was partially offset by increased operating expenses and reduced reimbursement revenue from Novartis.
Cash, cash equivalents and marketable securities as of December 31, 2018 were $478 million.
CONFERENCE CALL INFORMATION
Array will hold a conference call on Tuesday, February 5, 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, February 5, 2019

Time:

9:00 a.m. Eastern Time

Toll-Free:

(844) 464-3927

Toll:

(765) 507-2598

Pass Code:

9778144

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. [9,10] 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. [9-13]

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 BRAFV600mutation, as detected by a validated test.

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 exclusive rights to commercialize both products in Israel and Pierre Fabre 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 U.S., 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. [14,15] 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. [16] 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. [17] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [1-3, 18-19] 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. [8,18] 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. [1-7,20] BRAF V600E-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. 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 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 (support is 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 January 31, 2019, Gritstone Oncology, Inc. (the "Company") reported that it has entered into an Office/Laboratory Lease (the "New Lease"), effective as of January 28, 2019, with Emery Station West, LLC (the "Landlord") to lease approximately 34,469 square feet of office and laboratory space located at 5959 Horton Street, Emeryville, California 94608 (the "Premises") for the Company’s new principal executive offices (Press release, Gritstone Oncology, FEB 5, 2019, View Source [SID1234533086]).

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The term of the New Lease (the "Lease Term") commences on the earlier of (i) the date on which the Landlord delivers the newly constructed Premises, substantially completed, and tenders possession to the Company of, the Premises or (ii) the date upon which the Company, with the Landlord’s consent, takes possession of any portion of the Premises to commence construction of certain tenant improvements (the "Commencement Date"). Beginning on the earlier of (x) 270 days after the Commencement Date or (y) the date on which the Company opens for business in any portion of the Premises (the "Rent Commencement Date"), the New Lease provides for annual base rent of approximately $1.7 million, which increases on a yearly basis up to approximately $2.6 million for the final 12 months of the initial Lease Term (the "Initial Lease Term"). In addition, the Company deposited with the Landlord a security deposit of approximately $0.6 million, equal to three months base rent.

The Initial Lease Term terminates on the last day of the 120th calendar month following the Rent Commencement Date, unless terminated earlier in accordance with the New Lease. The Company has the option to extend the Lease Term for two consecutive additional five year terms (the "Renewal Terms"). The New Lease provides for the base rent during the applicable Renewal Term to be calculated based on the fair market rental value of the Premises at such time, as described in the New Lease. The Company will also be obligated to pay to the Landlord for certain costs, taxes and operating expenses related with the New Lease and the Premises, subject to certain exclusions.

Under the New Lease, the Landlord will provide the Company with an improvement allowance of up to approximately $4.0 million in the aggregate for costs relating to the design, permitting and construction of improvements that are permanently affixed to the Premises.

Lease Termination Agreement

On January 31, 2019, the Company also entered into a Lease Termination Agreement (the "Termination Agreement"), effective as of January 28, 2019, with Emery Station Joint Venture, LLC (the "Current Landlord"), pursuant to which the Company and the Current Landlord agreed to early terminate the Company’s lease, dated November 23, 2015, as subsequently amended (the "Current Lease"), of the premises located at 5858 Horton Street, Emeryville, California 94608 (the "Current Premises"). Pursuant to the Termination Agreement, the Current Lease will terminate effective no later than 60 days after the Rent Commencement Date under the New Lease. In the event that the Company is deemed to hold over in possession of the Current Premises, the Company will be liable for 150% of the monthly base rent under the Current Lease and 100% of any increases for rent adjustments, as reasonably determined by the Current Landlord.

The foregoing descriptions of the New Lease and the Termination Agreement do not purport to be complete and are subject to, and qualified in their entirety by reference to, the full terms of the New Lease and the Termination Agreement, copies of which are filed as Exhibits 10.1 and 10.2 to this Current Report on Form 8-K, and are incorporated by reference herein.

On February 5, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported completing the submission of a supplemental Biologics License Application to the U.S. Food and Drug Administration (FDA) for Kadcyla (ado-trastuzumab emtansine) for adjuvant (after surgery) treatment of people with HER2-positive early breast cancer (EBC) with residual disease after neoadjuvant (before surgery) treatment (Press release, Genentech, FEB 5, 2019, View Source [SID1234533069]). The FDA is reviewing the application under the Real-Time Oncology Review and Assessment Aid pilot programs, which aim to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. For this indication, Kadcyla was also granted Breakthrough Therapy Designation, which is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases.

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"Kadcyla was granted Breakthrough Therapy Designation and is also the first Genentech medicine to be reviewed under the FDA’s Real-Time Oncology Review pilot program; both FDA initiatives aim to expedite reviews and bring medicines to patients sooner," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We are working closely with the FDA to bring Kadcyla to people with HER2-positive early breast cancer who have residual disease after neoadjuvant therapy as early as possible."

This application is based on results of the Phase III KATHERINE study showing Kadcyla significantly reduced the risk of invasive breast cancer recurrence or death from any cause (invasive disease-free survival; iDFS) by 50 percent (HR=0.50, 95% CI 0.39-0.64, p<0.0001) compared to Herceptin (trastuzumab) as an adjuvant treatment in people with HER2-positive EBC who have residual disease present following neoadjuvant treatment. People who have residual disease after neoadjuvant treatment have a worse prognosis than those with no detectable disease. At three years, 88.3 percent of people treated with Kadcyla did not have their breast cancer return compared to 77.0 percent treated with Herceptin, an absolute improvement of 11.3 percent.

The most common Grade 3-4 side effects (≥1 percent) with Kadcyla in the KATHERINE study were decreased platelet count; high blood pressure; radiation-induced skin injury; numbness, tingling or pain in the hands or feet; decreased neutrophil count; low blood potassium level; fatigue and decrease in red blood cells.

About the KATHERINE study

KATHERINE is an international, multi-center, two-arm, randomized, open-label, Phase III study evaluating the efficacy and safety of Kadcyla versus Herceptin as an adjuvant therapy in people with HER2-positive EBC who have pathological invasive residual disease in the breast and/or axillary lymph nodes following neoadjuvant therapy that included Herceptin and taxane-based chemotherapy. The primary endpoint of the study is iDFS, which in this study is defined as the time from randomization free from invasive breast cancer recurrence or death from any cause. Secondary endpoints include disease-free survival and overall survival.

About HER2-positive breast cancer

Breast cancer is the most common cancer among women worldwide. According to the American Cancer Society, approximately 271,000 people in the United States will be diagnosed with breast cancer, and more than 42,000 will die from the disease in 2019. Breast cancer is not one, but many diseases based on the biology of each tumor. In HER2-positive breast cancer, there is excess HER2 protein on the surface of tumor cells. Approximately 15-20 percent of breast cancers are HER2-positive based on the result of a diagnostic test.

About Kadcyla

Kadcyla is an antibody-drug conjugate (ADC) engineered to deliver potent chemotherapy directly to HER2-positive cells. It is designed to limit damage to healthy tissues, although it can still affect them. Kadcyla can cause serious side effects. It combines two anti-cancer agents using a stable linker: the HER2-targeting trastuzumab (the active ingredient in Herceptin) and the chemotherapy agent DM1. Kadcyla is the only ADC approved for the treatment of HER2-positive metastatic breast cancer. In the U.S., Genentech licenses technology for Kadcyla under an agreement with ImmunoGen, Inc.

Kadcyla Indication Statement

Kadcyla, as a single agent, is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:

Received prior therapy for metastatic disease, or
Developed disease recurrence during or within six months of completing adjuvant therapy.
Important Safety Information

Most important safety information about Kadcyla

Kadcyla is not the same medicine as trastuzumab (Herceptin).

Liver problems

Kadcyla may cause severe liver problems that can be life-threatening. Symptoms of liver problems may include vomiting, nausea, eating disorder (anorexia), yellowing of the skin (jaundice), stomach pain, dark urine or itching.
Heart problems

Kadcyla may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). Symptoms may include swelling of the ankles or legs, shortness of breath, cough, rapid weight gain of more than five pounds in 24 hours, dizziness or loss of consciousness, or irregular heartbeat.
Pregnancy

Receiving Kadcyla during pregnancy can result in the death of an unborn baby and birth defects. Birth control should be used while receiving Kadcyla and for seven months after a patient’s last dose of Kadcyla.
If a patient thinks she may be pregnant, she should contact her healthcare provider immediately.
If a patient is exposed to Kadcyla during pregnancy, or becomes pregnant within seven months following her last dose of Kadcyla, she is encouraged to report Kadcyla exposure to Genentech at (888) 835-2555.
If a male patient has a female partner that could become pregnant, birth control should be used during treatment and for four months following his last dose of Kadcyla.
A patient should not breastfeed during treatment and for seven months after the last dose of Kadcyla.
A patient should contact their doctor right away if they experience symptoms associated with these side effects.

Additional possible serious side effects of Kadcyla

Lung problems

Kadcyla may cause lung problems, including inflammation of the lung tissue, which can be life-threatening. Signs of lung problems may include trouble breathing, cough, tiredness and fluid in the lungs.
Infusion-related reactions

Symptoms of an infusion-related reaction may include one or more of the following: the skin getting hot or red (flushing), chills, fever, trouble breathing, low blood pressure, wheezing, tightening of the muscles in the chest around the airways or a fast heartbeat. A patient’s doctor will monitor the patient for infusion-related reactions.
Serious bleeding

Kadcyla can cause life-threatening bleeding. Taking Kadcyla with other medications used to thin the blood (antiplatelet) or prevent blood clots (anticoagulation) can increase the risk of bleeding. A patient’s doctor should provide additional monitoring if the patient is taking one of these other drugs while on Kadcyla. Life-threatening bleeding may also happen with Kadcyla, even when blood thinners are not also being taken.
Low platelet count

Low platelet count may happen during treatment with Kadcyla. Platelets help the blood to clot. Signs of low platelets may include easy bruising, bleeding, and prolonged bleeding from cuts. In mild cases there may not be any symptoms.
Nerve damage

Symptoms may include numbness and tingling, burning or sharp pain, sensitivity to touch, lack of coordination, muscle weakness, or loss of muscle function.
Skin reactions around the infusion site

Kadcyla may leak from the vein or needle and cause reactions such as redness, tenderness, skin irritation, or pain or swelling at the infusion site. If this happens, it is more likely to happen within 24 hours of the infusion.
HER2 testing and Kadcyla

A patient must have a HER2 test to determine if their breast cancer is HER2-positive before taking Kadcyla, because benefit has been shown only in patients whose tumors are HER2-positive.

Most common side effects of Kadcyla

The most common side effects seen in people taking Kadcyla are:

Tiredness
Nausea
Pain that affects the bones, muscles, ligaments and tendons
Bleeding
Low platelet count
Headache
Liver problems
Constipation
Nosebleeds
Patients are encouraged to report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

On February 5, 2019 Neurocrine Biosciences, Inc. (NASDAQ: NBIX) reported its financial results for the quarter ended December 31, 2018 and provided an update on the launch of INGREZZA (valbenazine) and its clinical development programs (Press release, Neurocrine Biosciences, FEB 5, 2019, View Source [SID1234533104]).

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"We are extremely proud of what we have accomplished since INGREZZA was approved in 2017 and the impact INGREZZA is having on the lives of many patients with tardive dyskinesia. Our field sales team expansion and educational efforts position us to further help patients struggling with tardive dyskinesia," said Kevin Gorman, Ph.D., Chief Executive Officer of Neurocrine Biosciences. "Beyond INGREZZA, we are gearing up to file an NDA for opicapone to treat Parkinson’s disease and anticipating the Phase IIa data readout for our congenital adrenal hyperplasia program. And now, our pipeline includes the collaboration programs with Voyager in Parkinson’s disease and Friedreich’s ataxia. These efforts, along with AbbVie’s anticipated mid-year NDA submission for elagolix in uterine fibroids, put Neurocrine in an exciting position to have the potential of three approved drugs in four indications in 2020 with a robust and highly diversified pipeline."

Financial Results

Total revenue was $131.5 million for the fourth quarter of 2018, compared to $94.5 million for the same period in 2017. For the year ended December 31, 2018, total revenue was $451.2 million, compared to $161.6 million for the same period in 2017.

INGREZZA was made available for commercial distribution on May 1, 2017 and ORILISSA (elagolix) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of endometriosis with associated moderate to severe pain during the third quarter of 2018, with AbbVie sales beginning in August 2018. With the FDA approval of ORILISSA, the Company recognized a $40 million event-based milestone as revenue under the Company’s collaboration agreement with AbbVie during the third quarter of 2018. Total revenue for 2017 was inclusive of milestone revenue of $45 million recognized pursuant to the Company’s collaboration agreements with AbbVie and Mitsubishi Tanabe Pharma Corporation (MTPC).

The Company reported net income of $18.1 million, or $0.19 diluted net income per share, for the fourth quarter of 2018, compared to $6.9 million, or $0.07 diluted net income per share, for the same period in 2017. For the year ended December 31, 2018, the Company reported net income of $21.1 million, or $0.22 diluted net income per share, compared to a net loss of $142.5 million, or $1.62 net loss per share, for the same period in 2017. The increase in net income across both periods is primarily due to increased INGREZZA net product sales.

Research and development (R&D) expenses increased to $39.1 million for the fourth quarter of 2018, from $25.6 million for the same period in 2017. For the year ended December 31, 2018, R&D expenses increased to $160.5 million from $121.8 million for the same period in 2017. The increase in R&D expenses across both periods is primarily due to advancement of the Company’s clinical programs, including congenital adrenal hyperplasia (CAH), a vesicular monoamine transporter 2 (VMAT2) inhibitor, and a first-in-class central nervous system (CNS) compound, as well as activities to prepare for the Company’s intended opicapone new drug application (NDA) submission in the second quarter of 2019.

Sales, general and administrative (SG&A) expenses increased to $69.0 million for the fourth quarter of 2018, from $56.3 million for same period in 2017. For the year ended December 31, 2018, SG&A expenses increased to $248.9 million from $169.9 million for the same period in 2017. The increase in SG&A expenses across both periods is primarily due to the hiring of the Company’s sales force, including the third quarter 2018 sales force expansion, and commercialization activities for INGREZZA, which launched in the third quarter of 2017.

The Company’s balance sheet at December 31, 2018, reflected total assets of $993.2 million, including cash and investments of $866.9 million, compared to total assets of $817.6 million at December 31, 2017.

2019 Financial Guidance

Revenue milestones under the AbbVie agreement for 2019 are expected to be $20 million contingent on FDA’s acceptance of the NDA submission of elagolix for uterine fibroids. Ongoing SG&A and R&D expenses for 2019, excluding upfront expenses associated with the recently announced Voyager Therapeutics collaboration, should approximate $550 to $600 million. The 2019 anticipated expenses include an estimated $80 million of share-based compensation expense. The increase in expenses is largely attributable to the Voyager collaboration’s ongoing program costs, increased investment in INGREZZA patient education, sales and marketing activities, opicapone NDA submission and increased R&D pipeline activities.

Pipeline Highlights

INGREZZA (valbenazine) Update

INGREZZA received FDA approval on April 11, 2017, becoming the first medicine approved in the United States for the treatment of adults with tardive dyskinesia.

In March 2015, the Company announced that it had entered into an exclusive collaboration and licensing agreement for the development and commercialization of INGREZZA in Japan and other select Asian markets with MTPC. In 2017, MTPC initiated a pivotal trial of INGREZZA in Japan for the treatment of tardive dyskinesia.

ORILISSA (elagolix) Update

On July 24, 2018, AbbVie, in collaboration with Neurocrine, announced FDA approval and in October 2018 Health Canada approval for ORILISSA for the management of endometriosis with associated moderate to severe pain. The FDA granted priority review to ORILISSA. The FDA grants priority review designation to medicines that, if approved, would provide a significant improvement in the safety or effectiveness of treatment of a serious condition. AbbVie began commercialization of ORILISSA in the United States in August 2018.

AbbVie provided positive top-line efficacy data from two Phase III studies in women with uterine fibroids in the first quarter of 2018 and from the associated six-month safety extension during the third quarter of 2018. The ELARIS UF-I and UF-II studies of elagolix met all primary and ranked secondary endpoints at month six. These replicate Phase III studies were randomized, parallel, double-blind, placebo-controlled clinical trials evaluating elagolix alone or in combination with low-dose hormone (add-back) therapy in women with heavy uterine bleeding associated with uterine fibroids. The studies enrolled approximately 400 patients each for an initial six-month placebo-controlled dosing period. At the end of the six months of placebo-controlled evaluation, patients were eligible to enter an additional six-month safety extension study. The primary efficacy endpoint of the study was an assessment of the change in menstrual blood loss utilizing the alkaline hematin method comparing baseline to month six. Additional secondary efficacy endpoints were evaluated including the change in fibroid volume and hemoglobin. Bone mineral density was assessed via dual-energy x-ray absorptiometry (DEXA) scan at baseline at the conclusion of dosing and at six months post-dosing. Results from these studies will form the basis for an anticipated NDA submission to the FDA for the approval of elagolix in the treatment of uterine fibroids in the middle of 2019.

Opicapone Update

In February 2017, the Company entered into an exclusive licensing agreement with BIAL – Portela & CA, S.A. (BIAL) for the development and commercialization of opicapone in the United States and Canada. Opicapone is a once-daily, oral, peripherally-acting, highly-selective catechol-O-methyltransferase inhibitor, being developed as an adjunct therapy to preparations of levodopa/DOPA decarboxylase inhibitors for adult patients with Parkinson’s disease and motor fluctuations. The Company met with the FDA in January 2018 and based upon the BIPARK-I and BIPARK-II pivotal Phase III studies conducted by BIAL, the FDA did not require additional Phase III trials to form an NDA submission. The Company is in the process of preparing for an NDA submission which it anticipates will occur during the second quarter of 2019.

CAH Program (NBI-74788) Update

In the second quarter of 2017, the Company successfully completed the Phase I investigational new drug (IND)-opening study of NBI-74788 in healthy volunteer participants. The study was a randomized, open-label, two-period crossover study to evaluate the pharmacokinetics, the effect of food on pharmacokinetics, and the safety of NBI-74788 in a total of 16 healthy adults.

The Company began a Phase II proof-of-concept study examining the pharmacokinetics, pharmacodynamics, and safety of NBI-74788 in adult males and females with classic 21-hydroxylase deficiency CAH in November of 2017. This study will evaluate the safety and tolerability of NBI-74788 in patients with CAH together with the relationship between exposure and specific steroid hormone levels in these patients. Initial results from this trial are expected during the first quarter of 2019.

New VMAT2 Inhibitor

The Company has filed an IND and completed dosing in the single ascending dose portion of a Phase I study designed to assess initial safety, tolerability and pharmacokinetics of a novel, internally discovered VMAT2 inhibitor. This compound has the potential to be used in the treatment of several neurology and/or psychiatry disorders. The multiple dosing portion of this Phase I study is ongoing and is expected to be completed during the first half of 2019.

New CNS Compound

The Company has filed an IND and completed dosing in a Phase I single ascending dose study for an internally discovered first-in-class CNS compound with potential use in the treatment of several neurology and/or psychiatry disorders. The study is a randomized, double-blind, single ascending dose study to evaluate the safety, tolerability, and pharmacokinetic profile of the compound in healthy participants. The Company is currently analyzing the data from this study to inform the design of future clinical studies for the program.

Voyager Collaboration

Neurocrine Biosciences formed a strategic collaboration with Voyager Therapeutics focused on the development and commercialization of Voyager’s gene therapy programs, VY-AADC for Parkinson’s disease and VY-FXN01 for Friedreich’s ataxia, as well as rights to two programs to be determined. This collaboration combines Neurocrine Biosciences’ expertise in neuroscience, drug development and commercialization with Voyager’s innovative gene therapy programs targeting severe neurological diseases. This transaction is anticipated to close in the first quarter subject to standard Hart-Scott-Rodino waiting periods

Conference Call and Webcast Today at 4:30 PM Eastern Time

Neurocrine will hold a live conference call and webcast today at 4:30 p.m. Eastern Time (1:30 p.m. Pacific Time). Participants can access the live conference call by dialing 877-876-9174 (US) or 785-424-1669 (International) using the conference ID: NBIX. The webcast can also be accessed on Neurocrine’s website under Investors at www.neurocrine.com. A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived for approximately one month.

About INGREZZA (valbenazine) Capsules

INGREZZA, a selective VMAT2 inhibitor, is the first FDA-approved product indicated for the treatment of adults with tardive dyskinesia, a condition associated with uncontrollable, abnormal and repetitive movements of the face, torso, and/or other body parts.

INGREZZA is thought to work by reducing the amount of dopamine released in a region of the brain that controls movement and motor function, helping to regulate nerve signaling in adults with tardive dyskinesia. VMAT2 is a protein in the brain that packages neurotransmitters, such as dopamine, for transport and release from presynaptic neurons. INGREZZA, developed in Neurocrine’s laboratories, is novel in that it selectively inhibits VMAT2 with no appreciable binding affinity for VMAT1, dopaminergic (including D2), serotonergic, adrenergic, histaminergic, or muscarinic receptors. Additionally, INGREZZA can be taken for the treatment of tardive dyskinesia as one capsule, once-daily, together with psychiatric medications such as antipsychotics or antidepressants.

Important Safety Information

Contraindications

INGREZZA is contraindicated in patients with a history of hypersensitivity to valbenazine or any components of INGREZZA. Rash, urticaria, and reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth) have been reported.

Warnings & Precautions

Somnolence

INGREZZA can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by INGREZZA.

QT Prolongation

INGREZZA may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. INGREZZA should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.

Adverse Reactions

The most common adverse reaction (≥5% and twice the rate of placebo) is somnolence. Other adverse reactions (≥2% and >placebo) include: anticholinergic effects, balance disorders/falls, headache, akathisia, vomiting, nausea, and arthralgia.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.