On July 27, 2018 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported its unaudited financial results for the six months ended June 30, 2018 and updates shareholders on key clinical programs (Press release, Hutchison China MediTech, JUL 27, 2018, https://www.chi-med.com/interim-results-2018/ [SID1234527917]).

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

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

                  Schedule Your 30 min Free Demo!

Fruquintinib made substantial progress through China New Drug Application ("NDA") process, aiming for approval and launch for colorectal cancer ("CRC") this year; we also target to report Phase III top-line results for non-small cell lung cancer ("NSCLC") in Q4 2018;

Savolitinib has two registration studies underway, global Phase III in papillary renal cell carcinoma ("PRCC") and China registration intent Phase II in MET exon 14 mutation/deletion NSCLC; also Tagrisso/savolitinib combination studies in NSCLC indications are in planning, and set to start in late 2018 and early 2019;
Expansion of U.S. and international operations firmly underway, including recruitment of U.S. Chief Medical Officer and Head of International Operations; and
Video webcast presentation at 9:00 a.m. BST and additional conference call at 9:00 a.m. EDT.

Financial Highlights
The points below are selected financial data for the six months ended June 30, 2018. For more details, please refer to "Financial Review", "Operations Review" and "Unaudited Condensed Consolidated Financial Statements" below.

Overall Group

Group revenue of $102.2 million (H1 2017: $126.6m).
Net loss attributable to Chi‑Med of $32.7 million (H1 2017: net profit $1.7m).
Cash resources of $416.9 million at Group level as of June 30, 2018 ($479.6m as of December 31, 2017), including cash and cash equivalents, short-term investments and unutilized bank facilities.
Innovation Platform: increased investment in Research and Development ("R&D") driven by initiation of new trials and ongoing enrollment in existing Phase III programs

Consolidated revenue was $13.6 million mainly from service fee payments from AstraZeneca AB (publ) ("AstraZeneca"), Eli Lilly & Company ("Lilly") and Nutrition Science Partners Limited ("NSP"), our 50/50 joint venture with Nestlé Health Science S.A. ("Nestlé") (H1 2017: $22.7m, which included $9.5m in milestone payments from AstraZeneca and Lilly).
R&D expenses on an as adjusted (non-GAAP) basis increased to $66.7 million (H1 2017: $37.5m), primarily driven by rapid expansion of operations and increased clinical trial expenses on all eight clinical drug candidates.
Net loss attributable to Chi-Med of $52.9 million (H1 2017: -$14.8m).
Commercial Platform: strong net income growth amid shift in revenue model and over-the-counter ("OTC") logistics divestment

Total consolidated sales fell 15% to $88.6 million (H1 2017: $103.9m) due to the implementation of the Two-Invoice System ("TIS") in China, a new government policy that has led to a shift in our revenue recognition for certain third-party drugs from gross sales consolidation to a fee-for-service revenue model.
Total sales of non-consolidated joint ventures, on an as adjusted (non-GAAP) basis excluding the effects of the divestment of certain non-core operations, up 21% to $271.7 million (H1 2017: $224.2m). Strong growth across main product categories.
Total consolidated net income attributable to Chi-Med, unaffected by the TIS implementation, up 19% to $26.9 million (H1 2017: $22.7m), on an as adjusted (non-GAAP) basis which exclude one-time gains in H1 2017.
Innovation Platform — Operating Highlights
The points below summarize some of the pipeline development highlights so far this year. For more details, please refer to "Operations Review – Innovation Platform" below.

Fruquintinib – Highly selective tyrosine kinase inhibitor ("TKI") of vascular endothelial growth factor receptor ("VEGFR") 1/2/3:

FRESCO China Phase III in third-line CRC, potentially best-in-class in terms of both efficacy and safety:
China NDA – substantial progress towards approval: nearing the end of the pre-approval inspection of manufacturing facilities stage of the NDA process, one of the last stages of the NDA process, and aiming to receive an approval in the second half of 2018;
JAMA publication: in June 2018, the full results were published in the Journal of the American Medical Association ("JAMA"), which we believe to be the first China-based novel oncology therapy trial to be published in the JAMA, another landmark achievement.
Two further analyses of FRESCO data presented at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") in June 2018: subgroup analysis by prior anti-VEGF or anti-EGFR target therapy showed that fruquintinib had clinically meaningful benefits regardless of prior target therapy ("PTT") without observed cumulative toxicity; ad-hoc analysis of quality-adjusted time without symptoms or toxicity ("Q-TWiST") showed relative improvement of Q-TWiST with fruquintinib, representing a potentially clinically important quality-of-life benefit for patients;
FALUCA China Phase III in third-line NSCLC: completed enrollment of 527 patients; expect to reach median overall survival ("OS") endpoint maturity and report top-line results in late 2018.
FRUTIGA China Phase III in second-line gastric cancer: recruiting for clinical study in combination with Taxol (paclitaxel) proceeding as planned, with an interim analysis intended in 2019.
U.S. Phase I trial: enrolling as planned and intending to complete at the end of 2018, which would allow us to explore multiple innovative combination studies of fruquintinib and other TKIs, chemotherapy and immunotherapy agents in the U.S.
Savolitinib – Highly selective TKI of mesenchymal epithelial transition factor ("c-MET") – Global Phase III studies underway or in planning:

In MET Exon 14 mutation/deletion first-line NSCLC: while continuing to enroll patients in Phase II in China, we have reached an agreement with regulators regarding the conditions under which the existing trial could be sufficient for an NDA submission in China.
In EGFR mutation-positive NSCLC, following ongoing encouraging data in the TATTON Phase Ib/II trials of combinations with Tagrisso, AstraZeneca is proceeding to:
In third-generation EGFR TKI-refractory (principally second-line and third-line after Tagrisso) NSCLC: initiate the next stage of global clinical trials around the end of 2018;
In first-/second-generation EGFR TKI-refractory (principally second-line after Iressa/ Tarceva) NSCLC: initiate the next stage of global clinical trials in early 2019.
SAVOIR global Phase III study in c-MET-driven PRCC enrolling patients at all sites now following its initiation in June 2017.
PRCC molecular epidemiology study ("MES") progressing: 200+ patient tissue-sample diagnostic analysis likely to yield data by end of 2018, which we hope will highlight for regulatory authorities an unmet medical need in c-MET-driven PRCC.
CALYPSO Phase II combinations with Imfinzi programmed death-ligand 1 ("PD-L1") inhibitor: enrolled rapidly in H1 2018 and may complete enrollment in late 2018 and in mid-2019 in PRCC and clear cell renal cell carcinoma ("ccRCC") patients, respectively.
Sulfatinib – Unique angio-immuno kinase inhibitor of VEGFR, fibroblast growth factor receptor ("FGFR") 1, and colony stimulating factor-1 receptor ("CSF-1R"):

Phase IIIs in neuroendocrine tumor ("NET"): enrollment continuing in the two Phase III studies in NET patients in China, with interim analysis expected for 2019; if results are positive, this could potentially be our first novel drug candidate to be launched by our own commercial team.
U.S. Phase Ib/IIa expansion: enrolling pancreatic NET and biliary tract cancer ("BTC") patients, following the completion of the U.S. dose escalation stage and based on preliminary efficacy and safety data observed in these two indications in China.
Further progress in early/proof-of-concept clinical trials, including:

Epitinib Phase Ib/II in EGFR gene amplified glioblastoma: trial initiated in China in the first quarter of 2018 with epitinib, our unique EGFR inhibitor that has demonstrated the ability to penetrate the blood-brain barrier.
HMPL-523 U.S. investigational new drug ("IND") clearance: The U.S. Food and Drug Administration ("FDA") approved our highly selective spleen TKI ("Syk") to progress into clinical trials in June 2018, which we plan to initiate in early 2019.
HMPL004-6599 Australia Phase I initiated: proprietary botanical drug being developed by our 50/50 joint venture with Nestlé initiated and completed the single ascending dose study in the first half of 2018. Phase II enabling non-clinical studies are being initiated.
Expansion of U.S. and international operations, and recruitment of key personnel:

New office in New Jersey: U.S./ex-Asia operations expanded to support our unpartnered compounds through proof-of-concept, registration trials, and market launch in territories outside of Asia.
Key personnel recruited, including the U.S. Chief Medical Officer and Head of International Operations.
Key potential pipeline milestones anticipated in the next 6-12 months

Savolitinib:
Third-generation (Tagrisso) EGFR-TKI refractory, c-MET gene amplified, NSCLC (both second-line and third-line): initiation of global study of savolitinib in combination with Tagrisso in this rapidly growing patient population.
First-/second-generation (Iressa/Tarceva) EGFR-TKI refractory, c-MET gene amplified, T790M negative NSCLC (second-line): initiation of a global randomized, controlled study of savolitinib in combination with Tagrisso along with multiple supporting clinical studies.
Presentation of preliminary Phase II data for savolitinib monotherapy in c-MET gene amplified gastric cancer and first-line MET Exon 14 mutation/deletion NSCLC.
Release of results of global PRCC MES and review of the potential Breakthrough Therapy opportunity in c-MET-driven PRCC.
Fruquintinib:
Aim to receive NDA approval in advanced CRC and launch in China, with our partner Lilly.
Release of top-line results for the FALUCA Phase III study in third-line NSCLC.
Epitinib: initiation of Phase III China registration study in first-line NSCLC patients with EGFR activating mutations and brain metastasis.
HMPL-523: presentation of preliminary safety and efficacy data from Phase I dose escalation study in hematological cancer in Australia and China.
Immunotherapy combinations: aim to take first steps to develop our VEGFR inhibitors, fruquintinib and sulfatinib, in combination with various programmed cell death protein-1 ("PD-1") antibodies in several solid tumor settings.
Commercial Platform — Operating Highlights
The points below summarize some of the operational and financial highlights of our Commercial Platform in the first half of 2018. For more details, please refer to "Operations Review — Commercial Platform" below.

Scaled, high-performance drug marketing and distribution platform covering ~300 cites/towns in China with approximately 3,400 sales personnel. Targeting multiple indications with many household-name brands:

Sales of our non-consolidated Prescription Drugs joint venture, Shanghai Hutchison Pharmaceuticals Limited ("SHPL") grew by 18% to $152.7 million (H1 2017: $129.7m). SHPL’s main product, She Xiang Bao Xin ("SXBX") pill, an oral vasodilator and pro-angiogenesis prescription therapy approved to treat coronary artery disease, saw sales increase by 18% to $129.8 million.
Our consolidated Prescription Drugs business, operated through Hutchison Whampoa Sinopharm Pharmaceuticals (Shanghai) Company Limited ("Hutchison Sinopharm"), saw sales decrease by 21% to $68.0 million (H1 2017: $85.8m) as a result of the Chinese government’s implementation of the new TIS, pursuant to which we had converted to earning service fees from the commercialization of certain third-party products instead of recognizing the gross sales from these products in our revenue as we had done prior to implementation of TIS in October 2017; despite the TIS change, service fees earned from key third-party products, such as anti-psychotic Seroquel, grew rapidly, up 75% to $9.6 million (H1 2017: $5.5m).
Sales of our non-consolidated Consumer Health joint venture, Hutchison Whampoa Guangzhou Baiyunshan Chinese Medicine Company Limited ("HBYS"), grew by 26% to $119.0m (H1 2017: $94.4m, excluding divested operations), driven by the elimination of production capacity constraints.
Our consolidated Consumer Health sales increased by 14% to $20.6 million (H1 2017: $18.1m), resulting from higher volume in infant nutrition products.

Simon To, Chairman of Chi-Med, said: "Chi-Med continues to deliver on its clear strategy of developing its broad pipeline and cultivating and growing its capabilities in global drug discovery and development, while maintaining an over a decade-and-a-half long track record of earnings growth in its Commercial Platform.

During the first half of 2018, we have focused on navigating the China NDA process for fruquintinib, which we believe is now nearing completion. We are optimistic that we will see fruquintinib approved and launched by year end. We also look forward, around year end, to reporting the top-line results for the pivotal Phase III, the FALUCA study, of fruquintinib in third-line NSCLC in China.

Our collaboration with AstraZeneca continues to gather momentum, and we are currently enrolling registration studies in both kidney and lung cancer indications for savolitinib monotherapy. We are also in the process of planning and preparing to initiate multiple additional studies in lung and gastric cancers, which we believe may ultimately serve as registration studies.

Our un-partnered assets have also made good progress, with sulfatinib in two Phase III studies in China that could produce readout next year in NETs. In addition, we have worked with key opinion leaders and the regulatory authorities in China to agree on a Phase III pathway for epitinib and aim to initiate a pivotal study around year end. On our Syk, phosphoinositide 3-kinase delta ("PI3Kδ") and FGFR compounds, all of which are in proof-of-concept, we have made meaningful progress in enrollment thereby acquiring a preliminary understanding of efficacy and safety for each compound. We expect to present some of these data at scientific conferences over the next twelve months.

We are now looking closely into multiple opportunities to combine our highly selective TKIs with both PD-1 and PD-L1 immunotherapy agents and will strive to make progress during the second half of 2018, via collaboration, in this very high potential arena.

We have expanded our U.S./ex-Asia operations, including our office in New Jersey, and continue to recruit seasoned talent to manage the progress of our unpartnered compounds through proof-of-concept, registration trials, and market launch in territories outside of Asia.

Chi-Med has a clear and ambitious aim to bring three of our drugs through approval over the next approximately three years. We believe we are adequately structured and resourced to support this aim. In the longer term, we intend to continue to emerge as a world-class innovator based in China, bringing our assets to both the China and global markets. We have confidence in our ability to achieve these aims."

Use of Non-GAAP Financial Measures – References in this announcement to adjusted R&D expenses, adjusted consolidated net income attributable to Chi-Med from our Commercial Platform, adjusted consolidated operating profit from our Commercial Platform, adjusted consolidated net income attributable to Chi-Med from our Prescription Drugs business and adjusted revenue of HBYS and non-consolidated joint ventures are based on non-GAAP financial measures. Please see the "Use of Non-GAAP Financial Measures and Reconciliation" below for further information relevant to the interpretation of these financial measures and reconciliations of these financial measures to the most comparable GAAP measures, respectively.

FINANCIAL GUIDANCE:
Our updated guidance for 2018, compared to the most recent guidance in our full year results announcement for the year ended December 31, 2017 dated March 12, 2018, includes a $20 million increase in expected full year Innovation Platform R&D expense to $130-140 million. This increase reflects a rise in clinical trial spending as well as broadening of organizational scale and new middle management share-based incentive grants. These costs are all driven by the heightened competitive environment in China biotech, resulting from the step-change increase interest and investment in the sector over the past two years.

On July 27, 2018 AbbVie (NYSE:ABBV) reported its financial results for the second quarter ended June 30, 2018 (Press release, AbbVie, JUL 27, 2018, View Source [SID1234527921]).

"We are extremely pleased with the strong momentum of our business in the quarter and progress year-to-date. We’ve driven strong commercial, operational and R&D execution, resulting in top- and bottom-line results once again ahead of our expectations," said Richard A. Gonzalez, chairman and chief executive officer, AbbVie. "This outstanding performance was driven by growth from several assets across our portfolio, including significant contributions from HUMIRA, IMBRUVICA, and MAVYRET. Based on our performance in the first half of the year and the tremendous confidence we have in our business, we are raising our full year 2018 EPS guidance for the third time."

Second-Quarter Results

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

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

                  Schedule Your 30 min Free Demo!

Worldwide GAAP net revenues were $8.278 billion in the second quarter, up 19.2 percent year-over-year. Worldwide adjusted net revenues of $8.258 billion increased 17.1 percent on an operational basis, excluding a 1.8 percent favorable impact from foreign exchange.

Second-Quarter Results (continued)

Global HUMIRA sales increased 10.0 percent on a reported basis, or 8.2 percent operationally, excluding a 1.8 percent favorable impact from foreign exchange. In the U.S., HUMIRA sales grew 10.0 percent in the quarter. Internationally, HUMIRA sales grew 4.4 percent, excluding a 5.4 percent favorable impact from foreign exchange.

Second-quarter global IMBRUVICA net revenues were $850 million, with U.S. sales of $693 million and international profit sharing of $157 million for the quarter, reflecting growth of 35.6 percent.

Second-quarter global HCV net revenues were $973 million.

On a GAAP basis, the gross margin ratio in the second quarter was 76.6 percent. The adjusted gross margin ratio was 80.5 percent.

On a GAAP basis, selling, general and administrative expense was 21.3 percent of net revenues. The adjusted SG&A expense was 19.9 percent of net revenues.

On a GAAP basis, research and development expense was 16.0 percent of net revenues. The adjusted R&D expense was 15.3 percent, reflecting funding actions supporting all stages of our pipeline.

On a GAAP basis, the operating margin in the second quarter was 33.4 percent. The adjusted operating margin was 45.3 percent.

On a GAAP basis, net interest expense was $272 million. On a GAAP basis, the tax rate in the quarter was 1.5 percent. The adjusted tax rate was 9.0 percent.

Diluted EPS in the second quarter was $1.26 on a GAAP basis. Adjusted diluted EPS, excluding specified items, was $2.00, up 40.8 percent.

Recent Events

AbbVie, in cooperation with Neurocrine Biosciences, announced the U.S. Food and Drug Administration (FDA) approved, under Priority Review, ORILISSA (elagolix) for the management of moderate to severe pain associated with endometriosis. ORILISSA represents the first FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over a decade and is expected to be available in U.S. retail pharmacies in early August 2018.

At the American College of Obstetricians and Gynecologists (ACOG) Annual Clinical and Scientific Meeting, AbbVie, in cooperation with Neurocrine Biosciences, presented new data highlighting the company’s research in endometriosis and uterine fibroids. Presentations for elagolix included long-term safety and efficacy data from two extension Phase 3 studies, as well as new data highlighting rescue analgesic use, fatigue scores, and pain burden from pivotal Phase 3 studies of elagolix in women with moderate to severe pain associated with endometriosis. New data from a Phase 2b study highlighting the impact of elagolix on productivity in women with uterine fibroids was also presented.

Recent Events (continued)

AbbVie announced FDA approval, under Priority Review, of VENCLEXTA in combination with rituximab as a treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. The approval is based on data from the Phase 3 MURANO trial, which demonstrated a significant improvement in progression-free survival (PFS) for relapsed/refractory (R/R) CLL patients, reducing the risk of disease progression or death by 81 percent when compared to bendamustine in combination with rituximab, a standard of care chemoimmunotherapy regimen. The FDA also approved expansion of the indication of VENCLEXTA as monotherapy for CLL or SLL patients, with or without 17p deletion, who have received one prior therapy. Outside of the U.S., regulatory submissions to and reviews with health authorities are underway. VENCLEXTA is being developed by AbbVie and Roche; it is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

AbbVie announced submission of a supplemental new drug application (sNDA) to the FDA for VENCLEXTA in combination with a hypomethylating agent (HMA) or in combination with low dose cytarabine (LDAC) for the treatment of newly diagnosed patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. VENCLEXTA has received two Breakthrough Therapy Designations from the FDA for combination treatments of patients with untreated AML not eligible for standard induction chemotherapy.

At the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, AbbVie presented new data from several investigational studies of VENCLEXTA as monotherapy or in combination for the management of a number of difficult-to-treat blood cancers. Multiple studies investigating VENCLEXTA in CLL, AML, multiple myeloma (MM), and acute lymphoblastic leukemia (ALL) were presented, including results from a new analysis of undetectable minimal residual disease (uMRD) rates from the Phase 3 MURANO trial of VENCLEXTA in combination with rituximab in patients with R/R CLL.

At the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), AbbVie presented data from studies evaluating IMBRUVICA (ibrutinib) and VENCLEXTA across multiple hematologic malignancies, including positive data from the Phase 2 CAPTIVATE study evaluating IMBRUVICA in combination with VENCLEXTA in previously-untreated CLL/SLL patients. Also featured at ASCO (Free ASCO Whitepaper) were data from late-stage investigational products, including rovalpituzumab tesirine (Rova-T), depatuxizumab mafodotin (Depatux-M) and veliparib, as well as data from early-stage investigational compounds, including ABBV-075 (Mivebresib) and ABT-165.

AbbVie announced the FDA has accepted for Priority Review a supplemental NDA for IMBRUVICA in combination with rituximab as a new treatment option for Waldenström’s macroglobulinemia (WM), a rare and incurable form of blood cancer. The filing is based on data from the Phase 3 iNNOVATE study, which demonstrated a significant improvement in progression-free survival (PFS) with IMBRUVICA plus rituximab compared to rituximab alone. Patients taking IMBRUVICA plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab. If approved, the sNDA would expand the prescribing information of IMBRUVICA in WM beyond its current approved use as a single agent for all lines of therapy to include combination use with rituximab. Data from the Phase 3 iNNOVATE study was featured as an oral presentation at ASCO (Free ASCO Whitepaper). IMBRUVICA is jointly developed and commercialized with Janssen Biotech, Inc.

AbbVie announced positive top-line results from the Phase 3 iLLUMINATE trial, which evaluated IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL patients. The study met its primary endpoint for a clinically and statistically significant difference in PFS for patients treated with IMBRUVICA plus obinutuzumab versus those who received chlorambucil plus obinutuzumab. Regulatory submissions to health authorities are planned for the second half of 2018 based on iLLUMINATE results for this chemotherapy-free CD20 combination in first-line CLL.

Recent Events (continued)

AbbVie announced topline results from the Phase 3 PHOENIX trial (DBL3001) evaluating the investigational use of IMBRUVICA in the treatment of newly diagnosed non-Germinal Center B-cell (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL). The DBL3001 study evaluated the addition of IMBRUVICA to a chemotherapy regimen consisting of five different agents used in combination – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) – versus R-CHOP plus placebo. The DBL3001 study targeted a subtype of DLBCL disease that typically has poorer treatment outcomes. At the conclusion of the study, data collected found that IMBRUVICA plus R-CHOP, was not superior to R-CHOP alone, and that the study did not meet its primary endpoint of improving event-free survival (EFS) in the targeted patient population. Full results from this study will be submitted for presentation at a future medical meeting.

AbbVie announced positive top-line results from the Phase 3 SELECT-EARLY trial, which evaluated the company’s investigational oral JAK1-selective inhibitor, upadacitinib, as a monotherapy treatment compared to methotrexate (MTX) monotherapy in adult patients with moderate to severe rheumatoid arthritis (RA) who were MTX-naïve. The results showed that both once-daily doses of upadacitinib monotherapy (15mg and 30mg) met the primary endpoints of ACR50 at week 12 and clinical remission at week 24 versus MTX monotherapy. Additionally, all ranked secondary endpoints were met with both doses. Both doses of upadacitinib monotherapy also significantly inhibited radiographic progression (mTSS) from baseline at week 24 compared to MTX. The safety profile of upadacitinib was consistent with previously reported Phase 3 SELECT trials and Phase 2 studies, with no new safety signals detected. The company expects to submit regulatory applications in the fourth quarter of 2018.

AbbVie presented new patient-reported outcome data at the Annual European Congress of Rheumatology (EULAR) from three Phase 3 trials evaluating upadacitinib in adult patients with moderate to severe RA. New data highlighted improvements in pain, physical function and morning joint stiffness after 12 weeks of treatment with upadacitinib (15 mg and 30 mg, once-daily) in SELECT-NEXT and SELECT-BEYOND and after 14 weeks of treatment in SELECT-MONOTHERAPY. Additionally, improvements were reported in fatigue and work instability in SELECT-NEXT and patients’ physical component of health-related quality of life in SELECT-NEXT and SELECT-BEYOND at 12 weeks. In SELECT-MONOTHERAPY, upadacitinib monotherapy demonstrated improvements in patients’ physical function and health-related quality of life, as well as reductions in the duration of morning joint stiffness compared to patients receiving methotrexate.

AbbVie submitted a Biologics License Application (BLA) to the FDA and a marketing authorization application (MAA) to the European Medicines Agency (EMA) for risankizumab for the treatment of patients with moderate to severe plaque psoriasis. The BLA and MAA are supported by data from the global risankizumab Phase 3 psoriasis program evaluating more than 2,000 patients with moderate to severe plaque psoriasis across four pivotal Phase 3 studies: ultIMMa-1, ultIMMa-2, IMMhance and IMMvent. Risankizumab is being developed in collaboration with Boehringer Ingelheim.

AbbVie announced a collaboration with Calibr, a nonprofit drug discovery division of Scripps Research, to develop T-cell therapies aimed primarily at cancer. Calibr’s novel cell therapy program is designed to enhance safety, versatility and efficacy through a proprietary modular "switchable" CAR-T cell that uses antibody-based switch molecules to control the activation and antigen specificity of CAR-T cells. Calibr’s proprietary technology may enable the development of universal CAR-T-based treatments across several types of hematological and solid tumor indications. This collaboration broadens AbbVie’s oncology research to access advanced precision medicine technology to expand the development of potentially life-changing treatments for patients with cancer.

Recent Events (continued)

AbbVie announced an extension of its collaboration with Calico, an Alphabet-backed life sciences company, to discover, develop and bring to market new therapies for patients with age-related diseases, including neurodegeneration and cancer. Working together with AbbVie, Calico is pursuing discovery-stage research and development. AbbVie provides scientific and clinical development support and will lend its commercial expertise to lead future development and commercialization activities. Since 2014, the collaboration between the two companies has produced more than two dozen early-stage programs addressing disease states across oncology and neuroscience and has yielded new insights into the biology of aging.

AbbVie announced patent license agreements with Mylan over its proposed biosimilar adalimumab product. Under the terms of the agreements, AbbVie will grant Mylan a non-exclusive license on specified dates to AbbVie’s intellectual property relating to HUMIRA in the United States and in various other countries around the world in which AbbVie has intellectual property, excluding Europe. Mylan’s U.S. license will begin on July 31, 2023. Mylan will pay royalties to AbbVie for licensing its HUMIRA patents once its biosimilar product is launched.

AbbVie made charitable contributions totaling $120 million in the second quarter. These donations are part of AbbVie’s plan to make an additional $350 million in charitable contributions to U.S. not-for-profit organizations in 2018. The contributions will provide AbbVie with the opportunity to support charities creating long-term impact in communities in need, including Puerto Rico, North Chicago and cities across America.

Full-Year 2018 Outlook

AbbVie is updating its GAAP diluted EPS guidance for the full-year 2018 to $6.47 to $6.57. AbbVie is raising its adjusted EPS guidance range for the full-year 2018 from $7.66 to $7.76 to $7.76 to $7.86. The midpoint of this guidance reflects year-over-year growth of 39.5 percent. The company’s 2018 adjusted diluted EPS guidance excludes $1.29 per share of intangible asset amortization expense, changes in the fair value of contingent consideration, a one-time net tax benefit related to the timing of the phase in of provisions of the U.S. tax reform legislation on certain subsidiaries, and other specified items.

AbbVie’s adjusted EPS guidance range reflects an effective tax rate approaching 9 percent in 2018. In 2018, AbbVie will experience a one-time net tax benefit related to the timing of the phase in of provisions of the new legislation on certain subsidiaries. This benefit has been excluded from the adjusted EPS guidance, and included in the GAAP guidance range.

AbbVie continues to anticipate the company’s adjusted effective tax rate to increase to 13 percent over the next five years as a result of increased domestic income and investment.

On July 26, 2018 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA, Merck’s anti-PD-1 therapy, has been approved by the China National Drug Administration (CNDA) for the treatment of adult patients with unresectable or metastatic melanoma following failure of one prior line of therapy (Press release, Merck & Co, JUL 26, 2018, View Source [SID1234527880]). This is the first and only approval of an anti-PD-1 therapy for advanced melanoma in China.

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

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

                  Schedule Your 30 min Free Demo!

"Over the past decades, we have had limited effective options in the treatment of patients with advanced melanoma," Professor Jun Guo, M.D., Ph.D, director of the Department of Melanoma & Renal Cancer, Peking University Cancer Hospital and Institute Secretary-General of the Chinese Society of Clinical Oncology, primary investigator, KEYNOTE-151. "Advanced melanoma is one of the cancers that has been most responsive to immunotherapy, and outside of China, anti-PD-1 therapies such as pembrolizumab have become the standard therapy for this disease. With the approval of pembrolizumab in China, the treatment of advanced melanoma will now be aligned with international standards."

The approval of KEYTRUDA in China was based on overall response rate (ORR) data from the Phase 1b KEYNOTE-151 study, which evaluated KEYTRUDA monotherapy in Chinese patients with previously treated locally advanced or metastatic melanoma who received one prior line of systemic therapy. In 2018, the CNDA granted priority review status to KEYTRUDA, which accelerated the approval process by allowing for simultaneous clinical validation for the first time – creating an industry leading approval turnaround time for imported cancer medicine in China.

"Merck is committed to bringing new treatment advances, like KEYTRUDA, to cancer patients in China," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "The approval of KEYTRUDA in China, for this first indication, was made possible through extensive collaborative effort with the Chinese patients and investigators who participated in KEYNOTE-151, as well as the regulatory and government authorities who prioritized this filing. We appreciate their commitment to bringing forward the first anti-PD-1 therapy for advanced melanoma in China."

"The approval of our anti-PD-1 therapy reflects the Chinese government’s strong commitment to expedite the introduction of innovative therapies to Chinese patients," said Joseph Romanelli, president of MSD China. "The approval of KEYTRUDA in advanced melanoma marks the sixth new product approval for MSD China in 2018. We are encouraged that our scientific advancements are leading to new options for patients and their families."

About Melanoma in China

Malignant melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. Melanoma is one of the fastest growing malignant cancers in China, increasing at an annual rate of 3-5 percent, which makes it one of the deadliest diseases in the country. Research data has shown that once the disease metastasizes, the five-year survival rate for metastatic melanoma in Chinese patients is only 4.6 percent.

About KEYNOTE-151

KEYNOTE-151 is an open-label, single-arm, multi-center, Phase 1b trial evaluating KEYTRUDA monotherapy in 103 Chinese patients with previously treated locally advanced or metastatic melanoma who received one prior line of systemic therapy. Patients were enrolled to receive KEYTRUDA at a dose of 2 mg/kg every three weeks. The primary efficacy outcome measure was ORR as assessed by Blinded Independent Central Review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were duration of response (DOR) and progression-free survival (PFS; as assessed by BICR per RECIST 1.1 and irRECIST), ORR (as assessed by BICR per irRECIST) and overall survival (OS).

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 750 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA (pembrolizumab) Indications and Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy. In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10], or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC, occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA. While immune-mediated adverse reactions usually occur during treatment with PD-1/PD-L1 blocking antibodies, they may occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 developed graft-versus-host disease (GVHD) (one fatal case), and two developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (one fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

In KEYNOTE-021(G1), when KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem) in advanced nonsquamous NSCLC, KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction.

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL, and treatment was interrupted due to adverse reactions in 26% of patients. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock. The most common adverse reactions (occurring in ≥20% of patients) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL, and treatment was interrupted due to adverse reactions in 15%. Twenty-five percent (25%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 26% of patients and included: arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (occurring in ≥20% of patients) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reactions (in ≥20% of patients) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%). Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with KEYTRUDA experienced sepsis which led to death, and 3 patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of KEYTRUDA occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients, the most frequent (≥2%) of which were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (≥20%) in patients who received KEYTRUDA vs those who received chemotherapy were fatigue (38% vs 56%), musculoskeletal pain (32% vs 27%), pruritus (23% vs 6%), decreased appetite (21% vs 21%), nausea (21% vs 29%), and rash (20% vs 13%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients, the most frequent (≥2%) of which were urinary tract infection, pneumonia, anemia, and pneumonitis.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients (in Cohort E) with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (occurring in ≥20% of patients) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

There is limited experience in pediatric patients. In a study, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).

On July 26, 2018 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, reported that Genentech, a member of the Roche Group, has dosed the first patient in a Phase 3 study of a fixed-dose combination of pertuzumab (Perjeta) and trastuzumab (Herceptin) for subcutaneous administration using Halozyme’s proprietary ENHANZE drug-delivery technology in combination with chemotherapy (Press release, Halozyme, JUL 26, 2018, View Source [SID1234527902]).

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

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

                  Schedule Your 30 min Free Demo!

The global Phase 3 study is investigating the combination as a single fixed-dose in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the neoadjuvant and adjuvant settings. The estimated administration time for the initial loading dose of the combination is 7 to 8 minutes and subsequent maintenance doses are approximately 5 minutes.

"We are excited to support the initiation by Genentech of the first Phase 3 study exploring a fixed-dose combination of two therapeutics," said Dr. Helen Torley, president and CEO of Halozyme. "For breast cancer patients and healthcare professionals, the approach of administering pertuzumab and trastuzumab subcutaneously in a single injection with ENHANZE offers the potential for a new treatment administration option."

The Phase 3 study follows a Phase 1b clinical trial that assessed the safety, tolerability and pharmacokinetics of the same fixed-dose combination presented at the 2017 San Antonio Breast Cancer Symposium.

Perjeta (pertuzumab) and Herceptin (trastuzumab) are registered trademarks of Genentech, a member of the Roche Group.

About ENHANZE Technology
Halozyme’s proprietary ENHANZE drug-delivery technology is based on its patented recombinant human hyaluronidase enzyme (rHuPH20). rHuPH20 has been shown to remove traditional limitations on the volume of biologics that can be delivered subcutaneously (just under the skin). By using rHuPH20, some biologics and compounds that are administered intravenously may instead be delivered subcutaneously. ENHANZE technology may also benefit subcutaneous biologics by reducing the need for multiple injections. This delivery method has been shown in studies to reduce health care practitioner time required for administration and shorten time for drug administration.

On July 26, 2018 VBI Vaccines Inc. (NASDAQ: VBIV) ("VBI"), a commercial-stage biopharmaceutical company developing next-generation infectious disease and immuno-oncology vaccines, reported financial results for the second quarter ending June 30, 2018, and provided a corporate update (Press release, VBI Vaccines, JUL 26, 2018, View Source [SID1234527881]).

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

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

                  Schedule Your 30 min Free Demo!

"We continue to make strong progress in all three of our lead clinical programs," said Jeff Baxter, President and CEO of VBI. "Our pivotal Phase 3 program of Sci-B-Vac, our hepatitis B vaccine, is advancing well towards topline data from the PROTECT study expected mid-year 2019. Our eVLP technology-based pipeline showed exciting results in the clinic in May, when we reported positive final safety and immunogenicity data from our Phase 1 randomized study of VBI-1501 for CMV. This study was the first in-human study of a vaccine developed with our eVLP technology. We were excited to be able to demonstrate a robust immunologic response at a dose that is one-tenth the amount of other organizations’ CMV vaccine candidates. For our immuno-oncology pipeline, also developed with our eVLP technology, we look forward to reporting initial immunologic data from the Phase 1/2a study of VBI-1901 in recurrent GBM patients, which we expect in the second half of this year."

Recent Highlights and Upcoming Milestones
Sci-B-Vac for Hepatitis B
Sci-B-Vac, the Company’s Hepatitis B vaccine, is currently being studied in a pivotal Phase 3 clinical program in the U.S., Europe, and Canada. This program consists of two concurrent Phase 3 studies, the PROTECT study and the CONSTANT study.
Topline data from the PROTECT study are expected mid-year 2019, with topline data from the CONSTANT study expected in the second half of 2019.
The results from this pivotal Phase 3 program are intended to support future regulatory filings in the U.S., Europe, and Canada.

VBI-1501 for Congenital Cytomegalovirus (CMV)
In May 2018, VBI reported positive safety and immunogenicity data from a Phase 1 randomized, observer-blind, placebo-controlled study designed to evaluate the safety, tolerability, and immunogenicity of VBI-1501 in 128 CMV-negative, healthy adults aged 18-40 years.

Subjects were randomized into five arms to receive various dose levels of a modified form of the CMV gB antigen, gB-g, with or without the adjuvant alum, or to receive placebo. The highest does of antigen tested was 2.0μg of gB-g content with alum (VBI-1501A 2.0μg).
The final Phase 1 study results demonstrated that VBI-1501A was safe and well-tolerated at all doses.
VBI-1501A 2.0μg elicited CMV-neutralizing antibodies against fibroblast cell infection in 100% of subjects after the third vaccination (85% after two vaccinations), inducing titers comparable to those observed in patients protected as a result of natural infection (CMV-positive controls).
In epithelial cells, which have historically been the much harder cell type to protect against infection, VBI-1501A 2.0μg demonstrated a 31% neutralizing antibody seroconversion rate after three vaccinations, up from 17% after two vaccinations.
Discussions with regulatory bodies are planned for the second half of 2018 to discuss the next stage of development for VBI-1501A.

VBI-1901 for Glioblastoma (GBM)
A Phase 1/2a Clinical Study of VBI-1901 for the treatment of recurrent glioblastoma (rGBM) is ongoing.
The multi-center, open-label, two-part study will enroll up to 28 patients and is designed to evaluate safety, tolerability, and the optimal therapeutic dose level of VBI-1901.
Extensive biomarker testing and tumor imaging is built into this clinical protocol to enable the Company to assess the robustness of the immune response induced by VBI-1901.
In the second half of 2018, VBI hopes to be able to correlate this immunologic and biomarker data with initial clinical outcomes from the low and mid dose cohorts, and expects 6-month overall survival (OS) and progression-free survival (PFS) data in the first half of 2019.

First Quarter 2018 Financial Results
VBI ended the second quarter of 2018 with $41.1 million in cash and cash equivalents compared with $67.7 million as of December 31, 2017. Net cash used in operations for the six months ended June 30, 2018 was $24.5 million.
Revenue for the second quarter of 2018 was $0.2 million and was primarily attributable to sales of Sci-B-Vac in Israel and in Europe, on a named-patient basis. Revenue for the second quarter of 2017 was $0.3 million and was primarily attributable to sales of Sci-B-Vac in Israel and to a services agreement that was completed during that time frame.
Research and development expenses were $10.9 million for the second quarter of 2018, as compared to $4.5 million for the same period in 2017. The increase was primarily due to the continuation of the Phase 3 program for Sci-B-Vacand the Phase 1/2a clinical study for VBI-1901 in recurrent GBM patients, but was partially offset by the reduction in research expenses due to the advancement of VBI-1901 into clinical development from pre-clinical development.

General and administrative expenses were $4.0 million for the second quarter of 2018, as compared to $2.8 million for the same period in 2017. The increase was primarily due to human resources expenses, stock-based compensation expenses, and impairment related to leasehold improvements and manufacturing equipment no longer being utilized in the business as a result of the renovation and capacity increases of our manufacturing facility in Rehovot, Israel.

Net loss and net loss per share for the second quarter of 2018 were $16.7 million and $0.26, respectively, compared to a net loss of $9.0 million and a net loss per share of $0.22 for the second quarter of 2017.