On May 1, 2018 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on the development of curative therapeutics using CRISPR/Cas9 technology, reported financial results and operational progress for the first quarter of 2018 (Press release, Intellia Therapeutics, MAY 1, 2018, View Source [SID1234525914]).

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John Leonard, M.D., was appointed Intellia’s President and Chief Executive Officer in the first quarter of 2018, and one of his first initiatives was to broaden the Company’s strategy. "We are building the premier CRISPR-based genome editing company with leading in vivo and ex vivo capabilities," said Dr. Leonard. "We are very pleased with the scientific data generated from our in vivo non-human primate (NHP) studies, and the progress with our modular, scalable lipid nanoparticle (LNP) delivery system has allowed us to target a timeframe for our first Investigational New Drug (IND) submission. As we continue to execute on our full spectrum of in vivo and ex vivo genome editing platforms, we will share progress on our differentiated, wholly owned ex vivo approach, starting this month at the American Society of Gene and Cell Therapy Annual Meeting."

The Company announced today that it anticipates submitting an IND application for its lead indication, transthyretin amyloidosis (ATTR), by the end of 2019 and confirms plans to initiate IND-enabling studies in mid-2018. Over the past six months, ongoing NHP studies have demonstrated well-tolerated editing to therapeutically relevant levels of transthyretin (TTR) protein reduction (60 to 80 percent) after a single systemic administration via LNP delivery to NHP hepatocytes. Rates of editing were durable over the six-month period without re-dosing the animals. In support of the proposed IND submission, Intellia has narrowed the field of potential guides to its current development candidate for early human trials. The guide-optimization process used high-throughput screening to evaluate the entire TTR gene for those guides with high levels of activity and undetectable off-target cutting. The Company has completed studies to understand potential dosing regimens and is continuing studies on durability of the effect, both of which may expedite Phase I clinical trials. Intellia has also developed an enhanced LNP formulation through optimization campaigns that is currently being tested for multiple follow-on liver indications, and anticipates that this modular approach may minimize development timelines for each additional and subsequent liver-targeted product candidate.

Intellia has also demonstrated continued progression of its modular liver platform capability to knockout various targets of interest in the livers of mice, including SERPINA1 for alpha-1 antitrypsin deficiency (AATD) and HAO1 for primary hyperoxaluria type 1 (PH1), each of which has resulted in protein expression reductions believed to be therapeutically relevant. This initial knockout edit in AATD lays the groundwork for developing an approach that restores production of the missing protein in AATD, required for the amelioration of the disease.

The table below shows editing rates and corresponding protein reductions in the livers of mice for ATTR, AATD and PH1. ATTR and AATD both produce aberrant proteins hence treatment of these conditions requires reductions in the level of the disease-causing proteins. PH1 results from the low level activity of a particular protein for which treatment requires reducing the levels of substrate for that defective protein to metabolize, achieved by knocking out the gene that encodes HAO1. In each of these three cases, Intellia’s modular LNP delivery system achieved high levels of reduction of the targeted protein. These initial editing rates and corresponding protein reductions are evidence of Intellia’s ability to successfully target monogenic liver diseases by knocking out harmful genetic mutations.

Beyond the liver, the Company continues to advance its application of CRISPR/Cas9 technology to the central nervous system (CNS), including through its collaboration with Beverly Davidson, Ph.D., of the Children’s Hospital of Philadelphia, who will share updated LNP delivery data in a presentation at the American Society of Gene and Cell Therapy Annual Meeting later this month.

In ex vivo applications, Intellia seeks to develop allogeneic cellular therapies, which are cells derived from unmatched tissue donors, which are modified outside of the human body to allow them to be administered to an unrelated patient. This endeavor is supported through multiple efforts, including recently acquired access to intellectual property from researchers at the Karolinska Institutet and Intellia’s collaboration with Ospedale San Raffaele, announced in June of 2017.

In February of 2018, Cell Reports published Intellia’s first peer-reviewed paper entitled "A single administration of CRISPR/Cas9 lipid nanoparticles achieves robust and persistent in vivo genome editing." This landmark paper documented Intellia’s delivery of Cas9 mRNA and single guide RNA using its proprietary LNPs to achieve a 97 percent reduction in mouse TTR protein levels in the liver, which was sustained for at least 12 months.

During the course of 2018, Intellia plans to share additional preclinical data on its TTR genome editing program, including the achievement of a near ten-fold reduction in the required dose, derived via improvements in potency, as well as other knockout targets and data on delivery via LNPs to the CNS of NHPs. Additionally, Intellia plans to share preclinical data on both immuno-oncology and autoimmune disease targets in 2018.

First Quarter 2018 Financial Results

Collaboration Revenue

Collaboration revenue was $7.5 million for the first quarter of 2018, compared to $6.2 million during the first quarter of 2017. The increase in collaboration revenue in 2018 was primarily driven by amounts recognized under Intellia’s collaboration agreement with Regeneron.

Since inception through March 31, 2018, the Company has received $112.1 million in funding from the collaborations with Novartis and Regeneron, excluding amounts received for equity investments, and had an accounts receivable balance of $7.5 million at March 31, 2018.

Operating Expenses

Research and development expenses increased by $9.1 million to $22.5 million during the first quarter of 2018, compared to $13.4 million during the first quarter of 2017. This increase was driven primarily by the advancement of Intellia’s research programs, research personnel growth to support these programs, as well as the expansion of the development organization, and includes laboratory supplies and research materials such as reagents.

General and administrative expenses increased by $1.7 million to $7.4 million during the first quarter of 2018, compared to $5.7 million during the first quarter of 2017. This increase was driven primarily by increased salary and related headcount-based expenses to support Intellia’s larger research and development organization, public company compliance, and administrative obligations.

The Company’s net loss was $21.4 million for the first quarter of 2018, compared to $12.6 million during the first quarter of 2017.

Balance Sheet

Cash and cash equivalents at March 31, 2018, were $327.8 million, compared to $340.7 million at December 31, 2017.

Financial Guidance

The Company’s primary uses of capital will continue to be for research and development programs, laboratory and related supplies, compensation costs for current and future employees, consulting, legal and other regulatory expenses, patent prosecution filing and maintenance costs for Intellia’s licensed intellectual property, and general overhead costs.

As of March 31, 2018, the Company had an accumulated deficit of $137.0 million. The Company expects losses to increase as it continues to incur significant research and development expenses related to the advancement of Intellia’s therapeutic programs and ongoing operations. Based on Intellia’s research and development plans and expectations related to the progress of the Company’s programs, the Company expects that the cash and cash equivalents as of March 31, 2018, as well as technology access and research funding from Novartis and Regeneron, will enable Intellia to fund operating expenses and capital expenditures through mid-2020, excluding any potential milestone payments or extension fees that could be earned and distributed under the collaboration agreements with Novartis and Regeneron or any strategic use of capital not currently in the base-case planning assumptions.

On May 1, 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 first quarter ending March 31, 2018, and provided a corporate update (Press release, VBI Vaccines, MAY 1, 2018, View Source [SID1234525932]).

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"Following the completion of the $71.9 million financing in October 2017, we have made strong progress across our development programs, highlighted by the recent completion of enrollment of more than 1,600 participants in our Phase 3 PROTECT study of Sci-B-Vac, our Hepatitis B vaccine," said Jeff Baxter, President and CEO of VBI. "With data readouts from both our congenital cytomegalovirus (CMV) and glioblastoma (GBM) programs expected mid-year and in the second half of 2018, respectively, our goal for 2018 is to capitalize on the recent momentum and continue to create value, advancing all three of our lead clinical programs towards significant clinical milestones."

Recent Highlights and Upcoming Milestones
Sci-B-Vac for Hepatitis B
VBI initiated a pivotal Phase 3 clinical program for Sci-B-Vac, the Company’s Hepatitis B vaccine, in December 2017 in the U.S., Europe, and Canada. This program consists of two concurrent Phase 3 studies, the PROTECT study and the CONSTANT study.

The PROTECT study is designed to evaluate the safety and immunogenicity of Sci-B-Vac in more than 1,600 adults. The primary endpoints, which are stratified by age cohort, include assessment of the seroprotection rate after three doses of Sci-B-Vac Engerix-B. The secondary endpoint will evaluate speed to seroprotection, including assessment after two doses of Sci-B-Vac vs. three doses of Engerix-B.
In April 2018, VBI completed enrollment in the PROTECT study.
The CONSTANT study is designed to demonstrate lot-to-lot consistency for immune response in approximately 3,200 adults, as measured by geometric mean concentration (GMC) of antibodies across three independent, consecutively manufactured lots of Sci-B-Vac. The secondary endpoint will evaluate safety of Sci-B-Vac Engerix-B.
Enrollment is ongoing in the CONSTANT study.

Topline data are expected mid-year 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)
VBI-1501 is currently being evaluated in 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.
In July 2017, VBI announced positive interim immunogenicity data from this Phase I study. After two of the three planned vaccinations, antibody responses against the CMV gB antigen were observed with clear evidence of dose-dependent boosting, seroconversion in 100% of subjects who received the highest dose, and clear benefit of the adjuvant alum.
VBI plans to report final safety and immunogenicity data from the study mid-year 2018, which will inform next steps for the clinical development of VBI-1501.
VBI-1901 for Glioblastoma (GBM)
In January 2018, VBI commenced patient dosing in a Phase 1/2a clinical study of VBI-1901 for the treatment of recurrent glioblastoma (rGBM).
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.
In April 2018, VBI announced that the independent Data and Safety Monitoring Board (DSMB) unanimously recommended continuation of the Phase 1/2a clinical study without modification after review of all safety data from the fully enrolled, low-dose patient cohort.
Following this recommendation, VBI initiated patient enrollment in the intermediate-dose arm of the dose-escalation phase of the study.
Two additional, pre-specified DSMB reviews are planned to occur following the completion of enrollment in the intermediate-dose study arm and the high-dose study arm, respectively.
Extensive biomarker testing and tumor imaging is built into this clinical protocol, such that VBI expects to generate immunologic data that will show whether VBI-1901 is inducing an immune response as expected.
In the second half of 2018, VBI hopes to be able to correlate this immunologic and biomarker data with initial clinical outcomes, and in early 2019, 6-month overall survival (OS) and progression-free survival (PFS) data are expected.
First Quarter 2018 Financial Results
VBI ended the first quarter of 2018 with $58.1 million in cash and cash equivalents compared with $67.7 million as of December 31, 2017. Net cash used in operations for the three months ended March 31, 2018 was $8.6 million.
Revenue for the first quarter of 2018 was $0.2 million, compared with $0.1 million for the same period in 2017. The increase was primarily due to named-patient sales of Sci-B-Vac in Europe.
Research and development expenses were $7.0 million for the first quarter of 2018, as compared to $4.7 million for the same period in 2017. The increase was primarily due to the initiation of the Phase 3 program for Sci-B-Vac and the Phase 1/2a clinical study for VBI-1901 in recurrent GBM patients, but was partially offset by the reduction in research expenses as VBI-1901 moved from pre-clinical activity to clinical activity.
General and administrative expenses were $3.4 million for the first quarter of 2018, as compared to $3.0 million for the same period in 2017. The increase was primarily due to expanded headcount and facilities.
Net loss and net loss per share for the first quarter of 2018 were $12.3 million and $0.19, respectively, compared to a net loss of $8.6 million and a net loss per share of $0.22 for the first quarter of 2017.

On April 30, 2018 Crescendo Biologics Ltd (Crescendo) the developer of multi-functional biologics with a focus on novel targeted T-cell engagers, reported that it has completed a $70 million (€57 million) Series B financing(Press release, Crescendo Biologics, APR 30, 2018, View Source [SID1234525829]). The funds will be used to advance the development of its lead programme, CB307, which stimulates local activation of tumour-specific T-cells, into the clinic and further expand its internal pipeline of products.

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Crescendo Biologics is developing potent, multi-functional Humabody therapeutics in oncology. It is pursuing novel Humabody-based product opportunities, through in-house development and strategic partnerships. To date, it has a collaboration with Takeda Pharma worth up to $790m.

The Series B round was led by Andera Partners (formerly Edmond de Rothschild Investment Partners) with Europe’s largest life science fund Biodiscovery V, and joined by Quan Capital with its leading life sciences fund, Quan Venture Fund I, and Crescendo’s existing investors Sofinnova Partners, IP Group, EMBL and Takeda Ventures. This is the largest disclosed Series B biotech financing in Europe in 2018.

Gilles Nobécourt, Partner at Andera Partners and lead investor said: "We have been very impressed with the high quality of the novel biology behind multi-functional Humabodies and Crescendo’s growing development portfolio. Crescendo is a true pioneer in the development of targeted T-cell engagement and we are looking forward to working with the team."

Graziano Seghezzi, Managing Partner at Sofinnova Partners added: "We have been supporting Crescendo since its seed round in 2009, and then through the Series A together with IP Group, the substantial size of the round and the participation of new investors of the Series B underlines the
potential and success of VH-based Humabodies."

Marietta Wu, Managing Director of Quan Capital which invested a significant amount in the round, explained: "We have been especially drawn to the Humabody platform that offers multiple potential advantages over the current antibody (IgG) approaches and could enable the Company to quickly build a
substantial portfolio of impactful therapeutics. We look forward to joining our partners to rapidly advance Crescendo’s portfolio into clinical development where we can improve patient lives."

Peter Pack CEO of Crescendo said: "We appreciate the strong support – past and present – from our current investors, who have enabled us to grow the Company to this point. In this round, we are also welcoming two new investors, Andera Partners and Quan Capital. We look forward to taking our leadprogramme, CB307 into the clinic and further exploit our technology platform with new products."

On April 30, 2018 Amgen (NASDAQ:AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending a label variation for KYPROLIS (carfilzomib) to include the final overall survival (OS) data from the Phase 3 ASPIRE trial (Press release, Amgen, APR 30, 2018, View Source;p=RssLanding&cat=news&id=2345533 [SID1234525847]). The ASPIRE trial demonstrated that the addition of KYPROLIS to lenalidomide and dexamethasone (KRd) reduced the risk of death by 21 percent versus lenalidomide and dexamethasone alone (Rd) and extended OS by 7.9 months in patients with relapsed or refractory multiple myeloma (median OS 48.3 months for KRd versus 40.4 months for Rd, HR = 0.79, 95 percent CI, 0.67 – 0.95; 1-sided p=0.0045).

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"This latest positive CHMP opinion marks the second time Amgen will add overall survival data from a Phase 3 study to the label, further validating the fundamental role of KYPROLIS in treating patients with relapsed or refractory multiple myeloma," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "This is a major step towards advancing KYPROLIS-based regimens as standard of care, and we look forward to the European Commission’s decision later this year."

KYPROLIS is approved in the European Union (EU) for use in combination with lenalidomide and dexamethasone or with dexamethasone alone (Kd) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The Kd regimen of twice-weekly KYPROLIS administered at 56 mg/m2 and the KRd regimen of twice-weekly KYPROLIS administered at 27 mg/m2 are the first and only therapeutic combinations to demonstrate consistently improved OS versus recent standards of care in two Phase 3 trials in relapsed or refractory multiple myeloma patients (Kd versus bortezomib and dexamethasone [Vd] and KRd versus Rd).

Since its approval in 2012, approximately 80,000 patients worldwide have received KYPROLIS. The KYPROLIS clinical program continues to focus on providing treatment options for physicians and patients for this frequently relapsing and difficult-to-treat cancer.

About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated KYPROLIS in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed or refractory multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was progression-free survival, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included OS, overall response rate, duration of response, disease control rate, health-related quality of life and safety. Patients were randomized to receive KYPROLIS (20 mg/m2 on days 1 and 2 of cycle one, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, seven days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel. The study results were published in the Journal of Clinical Oncology.

The safety data from ASPIRE was consistent with the known safety profile of KYPROLIS. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were diarrhea, anemia, neutropenia, fatigue, upper respiratory tract infection, pyrexia, cough, hypokalemia, thrombocytopenia, muscle spasms, pneumonia, nasopharyngitis, nausea, constipation, insomnia and bronchitis.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.2,3 In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.4

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.6 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.5,6

KYPROLIS is approved in the EU for use in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three lines of therapy.

KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the United States. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

Important EU KYPROLIS (carfilzomib) Safety Information
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

KYPROLIS treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during KYPROLIS treatment include: Cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute renal failure, tumor lysis syndrome, infusion reactions, thrombocytopenia, hemorrhage, hepatic toxicity, venous thromboembolism, posterior reversible encephalopathy syndrome (PRES) and thrombotic microangiopathy including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). The most common side effects are anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough, and neutropenia.

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important U.S. KYPROLIS (carfilzomib) Safety Information

In the United States, KYPROLIS (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. It is recommended to control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
Please see full US prescribing information at www.kyprolis.com.

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

On April 30, 2018 Provectus Biopharmaceuticals, Inc. (OTCQB: PVCT, www.provectusbio.com), ("Provectus" or the "Company"), a clinical-stage biotechnology company developing PV-10 as the first small molecule oncolytic immunotherapy for solid tumor cancers, reported that the open-access journal PLOS ONE published results from an H. Lee Moffitt Cancer Center and Research Institute ("Moffitt") study investigating cancer combination therapy with intralesional ("IL") PV-10 and immune checkpoint blockade (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) in murine melanoma models.1,2 The authors also examined the role of specific immune cell populations in eliciting and controlling tumor-specific response (Press release, Provectus Pharmaceuticals, APR 30, 2018, View Source [SID1234525865]).

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The Moffitt authors noted, "In this study, we have shown the impact of combining systemic checkpoint blockade (PD-1, PD-L1) with the tumor-specific immune response induced by IL PV-10. Treatment with IL PV-10 and anti-PD-1 antibody resulted in a delay in tumor growth and enhanced T cell activation in the M05 tumor model. Similar effects were observed with IL PV-10 and anti-PD-L1 antibody in the B16 tumor model. The effect of combination therapy with IL PV-10 and PD-1 blockade is mediated by CD8+ T cells, and depletion of either CD4+ T cells or CD4+CD25+ Tregs enhances anti-tumor immunity in the M05 melanoma model. Together these results support further development of clinical trials to assess safety and anti-tumor T cell responses in patients after IL injection of PV-10 in combination with checkpoint blockade."

Dominic Rodrigues, Vice Chair of the Company’s Board of Directors, said, "We are grateful to our research collaborators, like those at Moffitt, who continue to independently establish PV-10 as an oncolytic immunotherapy in both monotherapy and combination therapy settings."

Mr. Rodrigues added, "This PLOS ONE work established the rational clinical foundation for our ongoing Phase 1b/2 study PV-10 in combination with anti-PD-1 drug KEYTRUDA for patients with Stage IV melanoma. Moffit’s work also builds on the foundation for future combinations of PV-10 and anti-PD-L1 agents as well as other potential combinations and permutations of cancer therapies that include PV-10 as a key element."

About our Phase 1b/2 Study of PV-10 + KEYTRUDA for Stage IV Melanoma

The Phase 1b portion of the study continues to enroll patients with metastatic melanoma at clinical sites in the U.S. (NCT02557321). Stage IV patients with at least one injectable lesion who are candidates for KEYTRUDA are eligible. A total of up to 24 patients would receive the combination of IL PV-10 and KEYTRUDA every three weeks for five cycles (i.e., for up to 12 weeks, with no further PV-10 administered after week 12), followed by only KEYTRUDA every three weeks for up to 24 months. The primary endpoint for the Phase 1b trial is safety and tolerability; objective response rate and progression-free survival are key secondary endpoints (both assessed via RECIST 1.1 after five treatment cycles, and then every 12 weeks thereafter).

About PV-10

Provectus’ lead investigational oncology drug product, PV-10, the first small molecule oncolytic immunotherapy, can induce immunogenic cell death. PV-10 is undergoing clinical study for adult solid tumor cancers, like melanoma and cancers of the liver, and preclinical study for pediatric cancers.