On May 1, 2019 CStone Pharmaceuticals ("CStone"; HKEX: 2616) and Numab Therapeutics AG ("Numab") reported that they have entered into an exclusive regional licensing agreement for the development and commercialization of ND021, a potential best-in-class monovalent, tri-specific antibody-based molecule targeting PD-L1, 4-1BB, and human serum albumin (HSA) (Press release, CStone Pharmaceauticals, MAY 1, 2019, View Source [SID1234535511]).

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Pursuant to the terms of the licensing agreement, CStone will fund the research and development of ND021 up to completion of an initial Phase Ib clinical trial. In exchange, CStone obtains exclusive rights from Numab to develop and commercialize ND021 in Greater China (including Mainland China, Hong Kong, Macau and Taiwan), South Korea and Singapore. Numab retains all ND021 rights for the rest of the world. Upon completion of CStone’s funding period, no further financial obligations will be owed by either party. This collaboration provides CStone with its first access to Numab’s novel multi-specific technology platform and Numab the opportunity to bring this innovative drug candidate into this region.

Discovered and engineered using Numab’s proprietary λcap technology and MATCH platform, ND021 is a late-preclinical-stage, monovalent, tri-specific antibody-based molecule (scMATCH3) that simultaneously targets PD-L1, 4-1BB, and HSA. ND021 is designed to bind to 4-1BB and activate T cells only when engaging with PD-L1 on the surface of tumor cells, potentially preventing liver toxicities observed in patients treated with conventional 4-1BB-agonistic antibodies.

Compared to other PD-L1/4-1BB bispecific antibody candidates, ND021’s unique monovalent structure and ultra-high-affinity PD-L1-binding is expected to lead to a significantly broader safety window and higher efficacy. Furthermore, half-life extension via the HSA-binding motif in ND021 enables convenient dosing schedules for patients. ND021 is anticipated to be effective against tumors with a wide range of PD-L1 expression-levels and may overcome primary and/or acquired resistance to anti-PD-1/PD-L1 therapies. Therefore, ND021 represents a leading class of next-generation cancer immunotherapies and a new backbone molecule for combinations.

CStone Chairman and CEO, Dr. Frank Jiang, commented: "This collaboration with Numab further strengthens our position as a leading immuno-oncology player in China and commitment to our IO combination strategy. We look forward to joining global simultaneous development to bring this novel therapy to patients in China and beyond as soon as possible."

Dr. David Urech, CEO of Numab, said: "We are very happy to join forces with CStone to accelerate the progress of ND021 in the clinic. In addition to blocking PD-L1-mediated immune-suppression, ND021 has a novel design that tethers potent T cell co-stimulation to the engagement of PD-L1-positive cancer cells, in order to generate focused anti-cancer immune-responses and a favorable risk/benefit profile. We believe this drug candidate has the potential to become an important treatment option for cancer patients around the world."

About ND021

ND021 is a next-generation PD-L1/4-1BB/HSA monovalent, tri-specific scMATCH3 that potently blocks PD-L1/PD-1 signaling while eliciting tumor-restricted co-stimulation of 4-1BB+ cells. In preclinical models, ND021 was well tolerated and induced exquisite antitumoral effects. Its unique, rationally designed molecular architecture and binding properties endow ND021 with several advantageous features that may translate into significant clinical benefit in a broad population of cancer patients.

On May 1, 2019 Celgene Corporation (Nasdaq: CELG) and bluebird bio, Inc. (Nasdaq: BLUE) reported that the New England Journal of Medicine (NEJM) has published interim results from CRB-401, the ongoing phase 1 study of bb2121, the companies’ lead investigational BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy candidate for patients with relapsed and refractory multiple myeloma (Press release, Celgene, MAY 1, 2019, View Source [SID1234535510]).

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The manuscript, "Anti-BCMA CAR T Cell Therapy bb2121 in Relapsed/Refractory Multiple Myeloma", published in NEJM includes key safety and efficacy results from the dose escalation and first expansion cohort, including a minimum of six months follow up on all subjects. As of the data cut-off date of April 30, 2018, manageable safety and deep and durable responses were reported in the first 33 patients infused with bb2121 BCMA-targeted CAR T-cells. Patients in the study were heavily pre-treated, with a median of seven prior multiple myeloma treatment regimens (range, 3 to 23), which included prior treatment with immunomodulatory drugs, proteasome inhibitors and daratumumab in the majority of patients. All but one patient had previously received an autologous stem cell transplant.

"CAR T-cell therapy is an important area of research for relapsed/refractory multiple myeloma patients where there remains a need for new options. We are encouraged by the expansion and persistence of the CAR T-cells, as well as the deep and durable responses with a manageable safety profile we’ve seen for bb2121 to date," said senior author and principal investigator James N. Kochenderfer, M.D., Experimental Transplantation and Immunology Branch, National Cancer Institute Center for Cancer Research.

For the first 33 patients, the most common grade ≥3 events were hematologic toxicities, including neutropenia (85%), leukopenia (58%), anemia (45%) and thrombocytopenia (45%). Neurotoxicity all-grades occurred in 14 (42%) patients; 13 (39%) were grade ≤2 and one patient (3%) had grade 4 neurotoxicity which resolved within one month. Twenty-five (76%) patients experienced cytokine release syndrome; 23 (70%) were grade ≤2 events and two (6%) were grade 3 events; all events were reversible. Infection occurred in 14 (42%) patients; two were grade 3 (6%) and there were no grade 4 events. Peak CAR T cell expansion was higher in patients with cytokine release syndrome and CAR T-cells remained detectable in the blood in 57% of patients at six months following infusion.

Treatment with bb2121 resulted in an 85% objective response rate (ORR) with 45% of patients achieving a complete response (CR) (n=15) and an additional 27% of patients (n=9) achieving a very good partial response (VGPR) to yield a ≥ VGPR rate of 73%. Sixteen responding patients were evaluable for assessment of minimal residual disease (MRD) and all tested MRD negative at one or more time points.

Responses to bb2121 CAR T-cell infusion occurred early, with a median time to first partial response or better of 1.0 month (range, 0.5 to 3.0), and responses were durable, with a median duration of response of 10.9 months (95% CI, 7.2 to not estimable). Researchers observed that greater CAR T-cell expansion occurred in responding patients. Responses were observed independent of tumor or serum BCMA levels. Median progression-free survival among all 33 patients was 11.8 months (95% CI, 6.2–17.8).

"These data from CRB-401 demonstrate that BCMA is a promising target in the treatment of patients with multiple myeloma. We continue to be encouraged by the potential of bb2121 as a first-in-class BCMA-targeted CAR T-cell therapy," said Alise Reicin, M.D., President, Global Clinical Development for Celgene. "The compelling data in these heavily pre-treated relapsed/refractory patients has provided important insights in the development of bb2121 as we continue the follow up of patients in our recently fully enrolled pivotal KarMMa trial. We are also evaluating the potential for bb2121 in earlier lines of multiple myeloma treatment in the other KarMMa trials."

"The data published in NEJM from CRB-401 provide the foundation for advancing the development of bb2121, which is currently being assessed in multiple clinical studies across different patient populations within multiple myeloma," said Dave Davidson, M.D., chief medical officer, bluebird bio. "We hope that this potentially first-in-class BCMA-targeted CAR T-cell therapy may provide a new treatment option for patients living with multiple myeloma."

In November 2017, bb2121 was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration and PRIority Medicines (PRIME) eligibility by the European Medicines Agency based on preliminary clinical data from the phase 1 CRB-401 study.

bb2121 is being developed as part of a Co-Development, Co-Promote and Profit Share Agreement between Celgene and bluebird bio.

Potential approval of bb2121 in the U.S. is anticipated in the second half of 2020. bb2121 is an investigational therapy; safety and efficacy have not yet been established. bb2121 has not been approved for use by any health authority.

About CRB-401

The open-label phase 1 CRB-401 study (NCT02658929) is evaluating the preliminary safety and efficacy of bb2121 BCMA-targeted CAR T-cell therapy in patients with relapsed/refractory multiple myeloma. The primary endpoint of the study is safety. The first portion of the study included a dose-escalation phase in which cohorts of patients received ascending doses of bb2121 to determine the maximum tolerated dose; these findings established the recommended dose of the phase 2 KarMMa trial. The second portion of the study was a dose expansion phase where patients received bb2121 to further evaluate the safety, tolerability and clinical activity at the recommended phase 2 dose. All patients have been treated in the study and follow-up is ongoing. Complete data from the additional expansion cohorts will be published at a later date.

Patients in the dose escalation cohort and first expansion cohort of the study were heavily pre-treated, with a median of seven prior multiple myeloma treatment regimens (range: 3-14) in the dose escalation cohort (n=21) and eight prior regimens (range: 3-23) in the dose expansion cohort (n=12). Patients in the dose escalation phase had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. In addition, patients in the expansion cohorts had received a CD38 antibody and were refractory to their last regimen. All but one patient had previously received an autologous stem cell transplant. As of the data cut-off, patients had at least six months of follow-up or had disease progression, and there was one patient death unrelated to study treatment.

Patients received a lymphodepleting conditioning regimen of fludarabine and cyclophosphamide, followed by an infusion of bb2121 anti-BCMA CAR T-cells. The CAR T-cells were produced from each patient’s own blood cells, which were modified using a proprietary lentiviral vector encoding the anti-BCMA CAR.

Patients were enrolled and dosed in either the dose-escalation cohort of the study, at four target dose levels (50 x 106, 150 x 106, 450 x 106 and 800 x 106 CAR+ T cells), or in the dose expansion cohort in a target dose range between 150-450 x 106 CAR+ T cells.

On May 1, 2019 Physicians’ Education Resource (PER), a worldwide leading resource for continuing medical education (CME), reported that it will present an in-studio video broadcast titled, "Rapid Reviews in Oncology from Chicago: Practice-Changing Data in Breast Cancer" on Wednesday, June 19 at 8 p.m. EDT (Press release, Physicians’ Education Resource, MAY 1, 2019, View Source [SID1234535509]).

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The live activity will be chaired by renowned breast cancer expert and leading clinical researcher Dr. Joyce O’Shaughnessy, who is the Celebrating Women Chair in Breast Cancer Research at Texas Oncology-Baylor Charles A. Sammons Cancer Center, and co-chair of the breast cancer research program at The US Oncology Network.

"We look forward to presenting this live-stream interactive broadcast to physicians after this year’s ASCO (Free ASCO Whitepaper) Annual Meeting to cover recent data in breast cancer," said Phil Talamo, president of PER. "PER’s Rapid Reviews in Oncology legacy program features highlights of practice-changing data in breast cancer, with expert faculty interpretation, along with audience Q&A sessions immediately following the Annual Meeting."

This live CME-certified interactive webcast is designed to rapidly update medical oncologists and fellows who treat patients with breast cancer with emerging data that has recently been presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. O’Shaughnessy will be joined by a panel of experts who will highlight the implications and applications of these data for physicians’ practice, helping them optimize care for their patients with breast cancer. Attendees will also have the opportunity to learn how experts in breast cancer research place emerging data into clinical context for the treatment and management of patients with breast cancer and stay up-to-date on the latest data pertaining to treatment and management of breast cancer across the spectrum of disease.

This live webcast is accredited by the Accreditation Council for Continuing Medical Education for 2.0 AMA PRA Category 1 Credits for physicians. For more information and to register, click here.

On May 1, 2019 Exelixis, Inc. (NASDAQ: EXEL) reported that it is initiating COSMIC-313, a phase 3 pivotal trial of cabozantinib (CABOMETYX) in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) versus nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma (RCC) with intermediate- or poor-risk disease per the International Metastatic Renal Cell Carcinoma Database Consortium (Press release, Exelixis, MAY 1, 2019, View Source [SID1234535508]). The primary endpoint of the trial is progression-free survival, and the secondary endpoints are overall survival and objective response rate.

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"Clinical observations suggest cabozantinib promotes an immune-permissive environment, which could present an opportunity for additive or synergistic effects with immune checkpoint inhibitors," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "The mechanisms of action of single agent cabozantinib and the combination of nivolumab and ipilimumab are complementary, and each has demonstrated efficacy in advanced renal cell carcinoma. The further combination of these agents as a triplet regimen may offer promise to previously untreated patients with intermediate- or poor-risk disease, who are known to have poor treatment outcomes."

COSMIC-313 is a multicenter, randomized, double-blinded, controlled phase 3 pivotal trial that aims to enroll approximately 676 patients at 150 sites globally. Patients will be randomized 1:1 to the experimental arm of cabozantinib in combination with nivolumab and ipilimumab and to the control arm of nivolumab and ipilimumab in combination with matched placebo.

Design of this phase 3 pivotal trial was informed by results from the ongoing phase 1b study of cabozantinib plus nivolumab with or without ipilimumab in patients with previously treated advanced genitourinary cancers, including RCC. The phase 1b trial is being conducted by the U.S. National Cancer Institute and includes centers from its Experimental Therapeutics Clinical Trials Network.

Bristol-Myers Squibb is providing nivolumab and ipilimumab for use in this trial.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About RCC

The American Cancer Society’s 2019 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.1 Approximately 32,000 patients in the U.S. and 70,000 globally require treatment, and an estimated 15,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.3

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.4,5 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.6,7,8,9 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.5,6

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC and for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan.

The combination of CABOMETYX with nivolumab and ipilimumab is not indicated for previously untreated advanced RCC.

U.S. Important Safety Information

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: GastrointestinaI (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 28 days prior to scheduled dental surgery or invasive dental procedures. Withhold CABOMETYX for development of ONJ until complete resolution.
Wound Complications: Wound complications were reported with CABOMETYX. Stop CABOMETYX at least 28 days prior to scheduled surgery. Resume CABOMETYX after surgery based on clinical judgment of adequate wound healing. Withhold CABOMETYX in patients with dehiscence or wound healing complications requiring medical intervention.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On May 1, 2019 Exelixis, Inc. (Nasdaq: EXEL) reported financial results for the first quarter of 2019 and provided an update on progress toward fulfilling its key corporate objectives, as well as commercial and clinical development milestones (Press release, Exelixis, MAY 1, 2019, View Source [SID1234535507]).

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"The first quarter of 2019 was a very productive start to the year, with strong execution across all aspects of our business," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "We continued our efforts to maximize the commercial and clinical potential of cabozantinib through the U.S. launch in advanced hepatocellular cancer in January, as well as the initiation of the COSMIC-313 study announced today."

Dr. Morrissey continued: "The financial stability provided by our growing revenue base across product and collaboration revenue provides Exelixis with an effective foundation upon which to pursue long-term growth. We have ambitious plans for the rest of 2019: we intend to start additional cabozantinib pivotal trials, bring new assets into our development organization through internal drug discovery and external business development, and advance our early-stage pipeline, including XL092. As we move through our 25th anniversary year, not only is our commitment to helping patients with cancer stronger than ever, but our ability to do so is notably stronger as well."

First Quarter 2019 Financial Results

Total revenues for the quarter ended March 31, 2019 were $215.5 million, compared to $213.7 million for the comparable period in 2018.

Total revenues included net product revenues of $179.6 million for the quarter ended March 31, 2019, compared to $134.3 million for the comparable period in 2018. The increase in net product revenues reflected the continued growth of CABOMETYX (cabozantinib) in the U.S. for the treatment of patients with advanced renal cell carcinoma (RCC), as well as the U.S. launch of CABOMETYX for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib, following its approval by the U.S. Food and Drug Administration (FDA) in January 2019.

CABOMETYX net product revenues for the quarter ended March 31, 2019 were $175.9 million, compared to $171.6 million for the quarter ended December 31, 2018. CABOMETYX net product revenues, as compared to the preceding quarter, were impacted by higher discounts and allowances of $7.2 million, driven by increased uptake in the government payor channel. In addition, as of March 31, 2019, the quantity of CABOMETYX inventory in the U.S. wholesaler distribution channel was approximately $2.3 million lower than it was as of December 31, 2018.

Total revenues for the quarter ended March 31, 2019 also include collaboration revenues of $35.9 million, compared to $79.4 million for the comparable period in 2018. The decrease in collaboration revenues was primarily the result of a decrease in revenues from milestones recognized from Exelixis’ collaboration agreements, which was partially offset by increases in royalty revenues on net sales of cabozantinib by Ipsen Pharma SAS (Ipsen) outside of the U.S. and Japan, and development cost reimbursements by Ipsen and Takeda Pharmaceutical Company Ltd. (Takeda).

Research and development expenses for the quarter ended March 31, 2019 were $63.3 million, compared to $37.8 million for the comparable period in 2018. The increase in research and development expenses was primarily related to increases in clinical trial costs, personnel expenses and stock-based compensation. The increase in clinical trial costs was primarily due to costs associated with the expanding clinical trial program for cabozantinib that now includes four phase 3 pivotal studies (CheckMate 9ER, COSMIC-311, COSMIC-312 and COSMIC-313), as well as the multi-cohort phase 1b study, COSMIC-021. The increases in personnel expenses and stock-based compensation were primarily due to increases in headcount to support Exelixis’ expanded discovery and development efforts.

Selling, general and administrative expenses for the quarter ended March 31, 2019 were $60.1 million, compared to $54.0 million for the comparable period in 2018. The increase in selling, general and administrative expenses was primarily related to increases in consulting and outside services, personnel expenses, marketing costs and stock-based compensation. The increases in personnel expenses and stock-based compensation were primarily due to increases in general and administrative headcount to support the company’s commercial and research and development organizations. The increase in consulting and outside services and marketing expenses was primarily due to increases in marketing activities in support of the CABOMETYX launch in HCC and continued support of the product in an increasingly competitive RCC market.

Provision for income taxes for the quarter ended March 31, 2019 was $14.9 million and Exelixis’ effective tax rate was 16.4%, compared to $2.5 million and 2.1%, respectively, for the comparable period in 2018. The provision for income taxes relating to Exelixis’ pre-tax income for the three months ended March 31, 2018 was largely offset by a valuation allowance against its net operating loss carryforwards and other deferred tax assets. At December 31, 2018, Exelixis released substantially all of the remaining valuation allowance against Exelixis’ deferred tax assets, after Exelixis determined that it was more likely than not that these deferred tax assets would be realized.

GAAP net income for the quarter ended March 31, 2019 was $75.8 million, or $0.25 per share, basic and $0.24 per share, diluted, compared to GAAP net income of $115.9 million, or $0.39 per share, basic and $0.37 per share, diluted, for the comparable period in 2018. The decrease in net income was primarily related to the decrease in milestone-related revenues and the increases in research and development expenses, selling, general and administrative expenses and the provision for income taxes; those changes were partially offset by the increases in net product revenues and royalty revenues recognized from Exelixis’ collaboration agreements.

Non-GAAP net income for the quarter ended March 31, 2019 was $85.5 million, or $0.28 per share, basic and $0.27 per share, diluted, compared to non-GAAP net income of $125.0 million, or $0.42 per share, basic and $0.40 per share, diluted, for the comparable period in 2018. Non-GAAP net income excludes stock-based compensation and adjusts for the related income tax effect.

Cash and cash equivalents, short- and long-term investments and long-term restricted cash and investments totaled $1,019.4 million at March 31, 2019, compared to $851.6 million at December 31, 2018.

Non-GAAP Financial Measures

To supplement Exelixis’ financial results presented in accordance with GAAP, Exelixis uses certain non-GAAP financial measures in this press release. In particular, Exelixis presents non-GAAP net income (and the related per share measures), which exclude from GAAP net income (and the related per share measures) stock-based compensation expense and adjust for the related income tax effect of this non-GAAP adjustment.

Exelixis believes that the presentation of these non-GAAP financial measures provides useful supplementary information to, and facilitates additional analysis by, investors. In particular, Exelixis believes that each of these non-GAAP financial measures, when considered together with its financial information prepared in accordance with GAAP, can enhance investors’ and analysts’ ability to meaningfully compare Exelixis’ results from period to period, and to identify operating trends in Exelixis’ business. Exelixis has excluded stock-based compensation expense because it is a non-cash expense that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. Exelixis also regularly uses these non-GAAP financial measures internally to understand, manage and evaluate its business and to make operating decisions.

These non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. Exelixis encourages investors to carefully consider its results under GAAP, as well as its supplemental non-GAAP financial information and the reconciliation between these presentations, to more fully understand Exelixis’ business. Reconciliations between GAAP and non-GAAP results are presented in the tables of this release.

2019 Financial Guidance

Exelixis is maintaining the following financial guidance for 2019. Cost of goods sold is expected to be between 4% and 5% of net product revenues. Research and development expenses are expected to be between $285 million and $315 million and include non-cash expenses related to stock-based compensation of $20 million. Selling, general and administrative expenses are expected to be between $220 million and $240 million and include non-cash expenses related to stock-based compensation of $35 million. Guidance for the effective tax rate in 2019 is between 21% and 23%.

Cabozantinib Highlights

Strong Growth in Cabozantinib Franchise Net Revenues and Royalties. Net product revenues generated by the cabozantinib franchise were $179.6 million during the quarter ended March 31, 2019, an increase of 34% year-over-year. During the first quarter of 2019, CABOMETYX generated $175.9 million in net product revenues and COMETRIQ (cabozantinib) capsules for the treatment of patients with progressive, metastatic medullary thyroid cancer generated an additional $3.7 million in net product revenues. Based upon our partner Ipsen’s cabozantinib-related revenues in the first quarter of 2019 of approximately $63 million, Exelixis earned $14.0 million in royalty revenues at the 22% royalty rate. CABOMETYX continues to expand its global footprint, where it is currently approved and commercially available in 41 and 28 countries, respectively.

FDA Approval of CABOMETYX Tablets for Previously Treated HCC. In January, Exelixis announced the FDA approval of CABOMETYX for the treatment of patients with HCC who have been previously treated with sorafenib. The FDA’s approval of CABOMETYX was based on results from the CELESTIAL phase 3 pivotal trial.

Cabozantinib Data at the 2019 American Society for Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI). In January, data from clinical trials of cabozantinib were featured in five presentations at ASCO (Free ASCO Whitepaper)-GI in San Francisco, including further analyses from the CELESTIAL trial.

Takeda’s Application to the Japanese Ministry of Health, Labour and Welfare (MHLW) for CABOMETYX as a Treatment for Advanced RCC. In April, Takeda, Exelixis’ partner in cabozantinib’s development and commercialization in Japan, announced that it applied to the Japanese MHLW for approval to manufacture and sell CABOMETYX as a treatment for unresectable and metastatic RCC in Japan. Per the terms of the exclusive licensing agreement the two companies entered into in 2017, Exelixis will receive a $10.0 million milestone payment as a result of this regulatory filing. Exelixis is eligible for additional development, regulatory and first-sales milestone payments, as well as royalties on sales of cabozantinib in Japan.

Completion of Enrollment in CheckMate 9ER. In April, CheckMate 9ER, the phase 3 pivotal trial evaluating the combination of cabozantinib and nivolumab versus sunitinib in patients with previously untreated advanced or metastatic RCC completed enrollment, including in Japan where the last few patients are in the process of being randomized. CheckMate 9ER is sponsored by Bristol-Myers Squibb Company (BMS) and co-funded by Exelixis, and Exelixis’ partners Ipsen and Takeda.

Initiation of COSMIC-313, Phase 3 Pivotal Trial Evaluating the Triplet Combination of Cabozantinib, Nivolumab and Ipilimumab Versus the Combination of Nivolumab and Ipilimumab in Patients with Previously Untreated Advanced Intermediate- or Poor-Risk RCC. Today, Exelixis announced the initiation of COSMIC-313, a multicenter, randomized, double-blinded, controlled phase 3 pivotal trial that aims to enroll approximately 676 patients at 150 sites globally. The primary endpoint of the trial is progression-free survival, and the secondary endpoints are overall survival and objective response rate. COSMIC-313 will be conducted in collaboration with BMS, which is providing nivolumab and ipilimumab for use in this trial.

Corporate Highlights

MINNEBRO Receives Regulatory Approval for the Treatment of Hypertension in Japan. In January, Exelixis’ partner Daiichi Sankyo Company, Limited (Daiichi Sankyo) announced that MINNEBRO (esaxerenone) tablets had received approval from the Japanese MHLW as a treatment for patients with hypertension. MINNEBRO is a compound identified during the prior research collaboration between Exelixis and Daiichi Sankyo, which the companies entered into in March 2006, and has been subsequently developed by Daiichi Sankyo. Per the collaboration agreement, Exelixis will receive a $20.0 million milestone payment upon the first commercial sale of MINNEBRO in Japan. Exelixis is eligible for additional commercialization milestone payments, as well as low double-digit royalties on sales of MINNEBRO.

Start of Phase 1 Development for XL092. In February, Exelixis announced it had submitted an investigational new drug (IND) application to the FDA for XL092, a next-generation small molecule tyrosine kinase inhibitor targeting VEGF receptors, MET and other kinases implicated in cancer’s growth and spread. Following the FDA’s acceptance of the IND filing, Exelixis initiated a phase 1 dose escalation trial evaluating the pharmacokinetics, safety and tolerability of XL092 in patients with advanced solid tumors, with the primary objective of determining a dose for daily oral administration of XL092 suitable for further evaluation. Assuming positive data from the initial phase of the trial, the expansion phase is designed to further explore the selected dose of XL092 in individual tumor cohorts, where safety, tolerability and initial clinical activity would be evaluated. XL092 is the first clinical candidate to emerge from Exelixis’ in-house laboratories since Exelixis resumed drug discovery activities.

Basis of Presentation

Exelixis has adopted a 52- or 53-week fiscal year that generally ends on the Friday closest to December 31st. For convenience, references in this press release as of and for the fiscal periods ended March 29, 2019, December 28, 2018 and March 30, 2018 are indicated as being as of and for the periods ended March 31, 2019, December 31, 2018 and March 31, 2018, respectively.

Conference Call and Webcast

Exelixis management will discuss the company’s financial results for the first quarter of 2019 and provide a general business update during a conference call beginning at 5:00 p.m. EDT / 2:00 p.m. PDT today, Wednesday, May 1, 2019.

To access the webcast link, log onto www.exelixis.com and proceed to the News & Events / Event Calendar page under the Investors & Media heading. Please connect to the company’s website at least 15 minutes prior to the conference call to ensure adequate time for any software download that may be required to listen to the webcast. Alternatively, please call 855-793-2457 (domestic) or 631-485-4921 (international) and provide the conference call passcode 4774486 to join by phone.

A telephone replay will be available until 8:00 p.m. EDT on May 3, 2019. Access numbers for the telephone replay are: 855-859-2056 (domestic) and 404-537-3406 (international); the passcode is 4774486. A webcast replay will also be archived on www.exelixis.com for one year.