On January 22, 2019 Amgen (NASDAQ:AMGN) reported that the European Commission (EC) has approved an expanded indication for BLINCYTO (blinatumomab) monotherapy to include adult patients with Philadelphia chromosome negative (Ph-) CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1 percent (Press release, Amgen, JAN 22, 2019, View Source;p=RssLanding&cat=news&id=2384344 [SID1234532810]). The approval was based on data from the Phase 2 BLAST study in frontline and relapsed/refractory ALL, the largest prospective trial for MRD-positive ALL ever conducted. BLINCYTO, a bispecific CD19-directed CD3 T cell engager (BiTE), is the first BiTE immunotherapy to receive regulatory approval globally.

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MRD refers to the presence of cancer cells that remain detectable, despite a patient having achieved complete remission by conventional assessment.1 MRD is only measurable through the use of highly sensitive testing methods that detect cancer cells in the bone marrow with a sensitivity of at least one cancer cell in 10,000 cells – versus about one in 20 with a conventional microscope-based evaluation.1-3

"This approval represents a paradigm shift in the management of ALL in the European Union, making BLINCYTO the first and only treatment with marketing authorization to include the presence of MRD," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are pleased that the European Commission has seen the value BLINCYTO can bring to people living with ALL and are proud to continue to deliver on our commitment to the pursuit of breakthroughs that can transform the lives of cancer patients."

The EC approval is based on data from the Phase 2 BLAST study, which found that BLINCYTO induced a complete MRD response, or no detectable MRD, in 78 percent of patients within one treatment cycle. Safety results among MRD-positive patients were consistent with the known safety profile of BLINCYTO in relapsed or refractory B-cell precursor ALL.

"Survival rates for patients that achieve MRD-negativity are significantly higher than those for patients that remain MRD-positive, underscoring the critical importance of early testing for and eliminating residual disease in patients with ALL," said Nicola Gökbuget, M.D., principal investigator for the BLAST study and head of the German Multicenter Study Group for Adult ALL located in Frankfurt, Germany. "Data from the BLAST study demonstrated that BLINCYTO is effective in eliminating detectable residual disease and showed the potential to improve relapse-free survival in this patient population. Today’s approval provides physicians across Europe with a much-needed treatment option that can potentially help prevent a relapse, which is associated with a very unfortunate prognosis."

Approval via the centralized procedure allows for obtaining a marketing authorization from the EC, which is valid in all European Union (EU) and European Economic Area (EEA)-European Free Trade Association (EFTA) states (Norway, Iceland and Liechtenstein).

In March 2018, the U.S. Food and Drug Administration (FDA) approved BLINCYTO for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

BLINCYTO is the first immunotherapy from Amgen’s BiTE platform, an innovative approach that helps the body’s immune system target cancer cells. BiTE antibody construct technology, pioneered by Amgen, is an innovative treatment approach that helps the body’s immune system attack cancer cells without the removal of immune cells from the patient. Amgen is studying a number of "off-the-shelf" investigational BiTE immunotherapies, with distinct targets, across a range of hematologic and solid tumors.

About the BLAST Study
The BLAST study is the largest ever prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, single-arm, Phase 2 study evaluating the efficacy, safety and tolerability of BLINCYTO in adult patients with MRD-positive B-cell precursor ALL in complete hematologic remission after three or more cycles of intensive chemotherapy. Patients received continuous IV infusion of BLINCYTO 15 μg/m2/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment and could undergo hematopoietic stem cell transplantation at any time after the first cycle, if eligible. Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). Additional secondary endpoints included incidence and severity of adverse events, overall survival, time to hematological remission and duration of complete MRD response.

Results from the BLAST study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in 2015 and published in Blood in 2018. Long-term overall survival (OS) data results from the BLAST study were also featured in an oral presentation during the ASH (Free ASH Whitepaper) 2018 Annual Meeting & Exposition on Dec. 3, 2018.

About ALL and MRD
ALL is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.4,5 Poor outcomes have been observed in patients who achieve first or second complete hematologic remission but have persistent MRD, which remains detectable at the molecular level after treatment.1,6 For more information about MRD, please visit AmgenOncology.com.

About BiTE Technology
Bispecific T cell engager (BiTE) antibody construct is an innovative technology that can be engineered to target any tumor antigen expressed by any type of cancer. The protein molecules are designed to kill malignant cells using the patient’s own immune system by bridging T cells to tumor cells. The BiTE antibody construct helps connect the T cells to the targeted cell, with the intent of causing T cells to inject toxins which trigger cancer cell death (apoptosis). Amgen is developing BiTE antibody constructs to uniquely (or specifically) target numerous hematologic malignancies and solid tumors.

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) immunotherapy that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the FDA in 2014, and carries full approval in the U.S. for the treatment of relapsed or refractory B-cell precursor ALL in adults and children. In the U.S., BLINCYTO is also approved for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In the EU, BLINCYTO is indicated for the treatment of adults with Ph- relapsed or refractory B-precursor ALL and for the treatment of Ph- CD19 positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1 percent.

BLINCYTO is now approved in 57 countries, including all member countries in the EU and EEA, Canada, Japan and Australia.

Important EU BLINCYTO (blinatumomab) Safety Information

This product is subject to additional monitoring in the EU. All suspected adverse reactions should be reported in accordance with the national reporting system.

The adverse reactions described in this section were identified in clinical studies of patients with B-precursor ALL (N = 843). The most serious adverse reactions that may occur during blinatumomab treatment include: infections (24.8%), neurologic events (13.8%), neutropenia/febrile neutropenia (10.1%), cytokine release syndrome (3.3%), and tumour lysis syndrome (0.7%). The most common adverse reactions were: pyrexia (69.2%), infusion-related reactions (43.4%), infections – pathogen unspecified (42.1%), headache (32.9%), anaemia (22.8%), thrombocytopenia (20.9%), febrile neutropenia (20.2%), oedema (20.0%), neutropenia (19.7%), rash (16.7%), increased liver hepatic enzymes (16.1%), bacterial infectious disorders (15.4%), tremor (15.2%), cough (15.1%), leukopenia (13.4%), back pain (13.3%), chills (13.0%), hypotension (12.8%), viral infectious disorders (12.7%), decreased immunoglobulins (12.5%), cytokine release syndrome (11.6%), tachycardia (11.3%), insomnia (10.7%), fungal infectious disorders (10.6%) and pain in extremity (10.2%).

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

Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS is 2 days after the start of infusion. Closely monitor patients for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). In clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL and in 7% of patients with MRD-positive ALL. Interrupt or discontinue BLINCYTO for evidence of CRS, as outlined in the PI.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment, and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life‐threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms of neurological toxicity and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia, infusion related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increase (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).

On January 22, 2019 Johnson & Johnson (NYSE: JNJ) reported sales of $20.4 billion for the fourth quarter of 2018, an increase of 1.0% as compared to the fourth quarter of 2017 (Press release, Johnson & Johnson, JAN 22, 2019, View Source [SID1234532806]).

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Operational sales results increased 3.3% and the negative impact of currency was 2.3%. Domestic sales increased 1.5%. International sales increased 0.4%, reflecting operational growth of 5.1% and a negative currency impact of 4.7%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales for the fourth quarter of 2018 increased 5.3%, domestic sales increased 2.6% and international sales increased 8.3%.*

Worldwide sales for the full-year 2018 were $81.6 billion, an increase of 6.7% versus 2017. Operational results increased 6.3% and the positive impact of currency was 0.4%. Domestic sales increased 5.1%. International sales increased 8.5%, reflecting operational growth of 7.7% and a positive currency impact of 0.8%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales for the full-year 2018 increased 5.5%, domestic sales increased 3.4% and international sales increased 7.8%.*

Net earnings and diluted earnings per share for the fourth quarter of 2018 were $3.0 billion and $1.12, respectively. Fourth-quarter 2018 net earnings included after-tax intangible amortization expense of approximately $1.0 billion and a net charge for after-tax special items of approximately $1.4 billion. Fourth-quarter 2017 net earnings included after-tax intangible amortization expense of approximately $0.9 billion and a net charge for after-tax special items of approximately $14.6 billion. Included in these special items was the provisional amount of approximately $13.6 billion associated with the enactment of tax legislation. Excluding after-tax intangible amortization expense and special items, adjusted net earnings for the current quarter were $5.4 billion and adjusted diluted earnings per share were $1.97, representing increases of 12.5% and 13.2%, respectively, as compared to the same period in 2017.* On an operational basis, adjusted diluted earnings per share increased 16.1%.* A reconciliation of non-GAAP financial measures is included as an accompanying schedule.

Net earnings and diluted earnings per share for the full-year 2018 were $15.3 billion and $5.61, respectively. Full-year net earnings included after-tax intangible amortization expense of approximately $3.9 billion and a net charge for after-tax special items of approximately $3.1 billion. Full-year 2017 net earnings included after-tax intangible amortization expense of approximately $2.5 billion and a charge for after-tax special items of approximately $16.2 billion. Included in these special items was a provisional amount of approximately $13.6 billion associated with the enactment of tax legislation. Excluding after-tax intangible amortization expense and special items, adjusted net earnings for the full-year of 2018 were $22.3 billion and adjusted diluted earnings per share were $8.18, representing increases of 11.4% and 12.1%, respectively, as compared to the same period in 2017.* On an operational basis, adjusted diluted earnings per share also increased 10.4%.* A reconciliation of non-GAAP financial measures is included as an accompanying schedule.

"Johnson & Johnson delivered another year of strong operational sales growth of 6.3% and achieved our 35th consecutive year of adjusted operational earnings growth at 9.8% in 2018. This can be attributed to accelerated underlying sales performance across each of our businesses, where we also leveraged our scale across the enterprise to improve margins," said Alex Gorsky, Chairman and Chief Executive Officer. "Looking ahead, the strength of our broad-based business and disciplined approach to portfolio management positions us to continue to fuel investments in innovation that enable us to capitalize on strategic opportunities and deliver strong performance over the long-term."

Mr. Gorsky continued, "Our performance is the result of our talented Johnson & Johnson colleagues and their extraordinary dedication to help advance health and well-being for patients and customers around the world."

In December, the Company announced a share repurchase program of up to $5.0 billion of the Company’s common stock. Repurchases may be made at management’s discretion from time to time on the open market or through privately negotiated transactions. The repurchase program has no time limit and may be suspended for periods or discontinued at any time.

The Company announced its 2019 full-year guidance for sales of $80.4 billion to $81.2 billion reflecting expected operational growth in the range of 0.0% to 1.0% and expected adjusted operational growth in the range of 2.0% to 3.0%. The Company also announced adjusted earnings guidance for full-year 2019 of $8.50 to $8.65 per share reflecting expected operational growth in the range of 5.7% to 7.6%.* Adjusted earnings guidance excludes the impact of after-tax intangible amortization expense and special items.

Segment Sales Performance
Worldwide Consumer sales of $13.9 billion for the full-year 2018 represented an increase of 1.8% versus the prior year, consisting of an operational increase of 2.2% and a negative impact from currency of 0.4%. Domestic sales increased 3.5%; international sales increased 0.7%, which reflected an operational increase of 1.4% and a negative currency impact of 0.7%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 3.2%, domestic sales increased 3.1% and international sales increased 3.3%*.

Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by growth in over-the-counter products, including TYLENOL and MOTRIN analgesics and digestive health products; NEUTROGENA and OGX beauty products; and LISTERINE oral care products. Subsequent to the quarter, the Company announced the completion of the acquisition of Ci:z Holdings Co., Ltd., which markets the DR.CI:LABO, LABO LABO and GENOMER line of skincare products.

Worldwide Pharmaceutical sales of $40.7 billion for the full-year 2018 represented an increase of 12.4% versus the prior year with an operational increase of 11.8% and a positive impact from currency of 0.6%. Domestic sales increased 8.4%; international sales increased 18.0%, which reflected an operational increase of 16.5% and a positive currency impact of 1.5%. Sales included the impact of Actelion Ltd which contributed 3.4%, to worldwide operational sales growth. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 8.4%, domestic sales increased 4.9% and international sales increased 13.5%.*

Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by STELARA (ustekinumab) and SIMPONI/SIMPONI ARIA (golimumab), biologics for the treatment of a number of immune-mediated inflammatory diseases, ZYTIGA (abiraterone acetate), an oral, once-daily medication for use in combination with prednisone for the treatment of metastatic, castration-resistant prostate cancer, DARZALEX (daratumumab), for the treatment of patients with multiple myeloma, IMBRUVICA (ibrutinib), an oral, once-daily therapy approved for use in treating certain B-cell malignancies, a type of blood or lymph node cancer, TREMFYA (guselkumab), for the treatment of adults living with moderate to severe plaque psoriasis, INVEGA SUSTENNA/XEPLION/INVEGA TRINZA/TREVICTA (paliperidone palmitate), a long-acting, injectable atypical antipsychotics for the treatment of schizophrenia in adults, partially offset by declines in REMICADE (infliximab), a biologic approved for the treatment of a number of immune-mediated inflammatory diseases, due to biosimilar entrants.

During the quarter, the U.S. Food and Drug Administration (FDA) approved an additional indication for INVOKANA (canagliflozin) to reduce the risk of major adverse cardiovascular (CV) events, including heart attack, stroke or death due to a cardiovascular cause in adults with type 2 diabetes who have established CV disease. In addition, the European Commission approved apalutamide, a next generation oral androgen receptor inhibitor for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease.

A supplemental Biologics License Application was submitted to the FDA and a Type II Variation Application was submitted to European Medicines Agency (EMA) seeking approval of STELARA (ustekinumab) for the treatment of adults with moderately to severely active ulcerative colitis. A supplemental New Drug Application was submitted to the FDA seeking to broaden the use of XARELTO (rivaroxaban) for the prevention of venous thromboembolism (VTE), or blood clots, in medically ill patients. Two Type II Variation Applications were submitted to EMA for the expanded use of IMBRUVICA (ibrutinib) in combination with obinutuzumab in previously untreated adults with chronic lymphocytic leukemia and in combination with rituximab for the treatment of previously untreated and relapsed/refractory adults with Waldenström’s macroglobulinemia.

Additionally, the Company entered into a worldwide collaboration and license agreement with argenx BVBA and argenx SE to develop and commercialize cusatuzumab (ARGX-110), an investigational therapeutic antibody that targets CD70, an immune checkpoint implicated in numerous cancers, including hematological malignancies.

Worldwide Medical Devices sales of $27.0 billion for the full-year 2018 represented an increase of 1.5% versus the prior year consisting of an operational increase of 1.1% and a positive currency impact of 0.4%. Domestic sales increased 0.1%; international sales increased 2.8%, which reflected an operational increase of 1.9% and a positive currency impact of 0.9%. Sales included the impact of the divestiture of its Lifescan business which negatively impacted worldwide operational sales growth by 1.4%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 2.6%, domestic sales increased 1.0% and international sales increased 4.0%.*

Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by electrophysiology products in the Interventional Solutions business; ACUVUE contact lenses and surgical products in the Vision business; wound closure products in the General Surgery business; along with endocutters and biosurgicals in the Advanced Surgery business.

On January 21, 2019 BerGenBio ASA (OSE:BGBIO), reported that the first patient has been dosed in a phase I clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumour efficacy of ADCT-601, an AXL-targeting antibody drug conjugate (ADC), in patients with advanced solid tumours (Press release, BerGenBio, JAN 21, 2019, View Source [SID1234532796]).

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ADCT-601 is composed of a humanised monoclonal antibody against human AXL (BGB601) discovered by BerGenBio, conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. BGB601 was out-licensed for ADC development to ADC Therapeutics SA (ADCT). In preclinical studies, ADCT-601 has demonstrated potent and specific anti-tumour activity in multiple in vivo models and was stable and well tolerated, as reported by ADCT at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual congress in 2018.

The open-label, multi-centre, single arm phase I trial will enrol approximately 75 patients with selected tumour types and will be managed and sponsored by license partner ADC Therapeutics. For more information see View Source (accessing trial identifier NCT03700294).

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "We congratulate ADC Therapeutics on reaching this important milestone. We are pleased to now see three of our AXL-targeting modalities in clinical development with the potential to address large patient populations. Our focus remains on completing our ongoing oncology phase II programme with bemcentinib, a first-in-class highly selective oral AXL inhibitor, and start randomised, potentially pivotal trials later this year. In the meantime, we look forward to providing updates on the development of BGB149, a therapeutic AXL antibody, and ADCT-601, an anti-AXL ADC, as they progress through phase I testing."

END

About ADCT-601
BerGenBio out-licensed two novel and proprietary anti-AXL monoclonal antibodies invented by the Company to ADC Therapeutics SA (ADCT) for the development of an antibody drug conjugate (ADC).

ADCT-601 is composed of BGB601, a humanised monoclonal antibody that binds to human AXL, conjugated using GlycoConnect technology to a linker with a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to an AXL-expressing cell, ADCT-601 is internalised into the cell where enzymes release the PBD-based warhead. The PBD-based warhead has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and ultimately killing the cancer cell. ADCT-601 is currently undergoing Phase I clinical testing (NCT03700294).

Under the license, a series of development, regulatory and sales-based milestones are due to BerGenBio from ADCT upon the achievement of certain specified events. The first milestone payment is triggered during the phase I clinical study.

About AXL
AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

On January 21, 2019 ISA Pharmaceuticals B.V., a clinical-stage company dedicated to the development of rationally designed immunotherapeutics, reported randomization of the first patient in a Phase 2 combination trial of its lead compound ISA101b and Regeneron´s (NASDAQ: REGN) anti-PD-1 antibody cemiplimab (REGN2810) (Press release, ISA Pharmaceuticals, JAN 21, 2019, View Source [SID1234532797]).

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This double blind, placebo-controlled, randomized, phase 2 study (NCT03669718) will enroll approximately 164 patients with HPV16-positive oropharyngeal cancer (OPC), who have failed first-line chemotherapy. Patients will be randomly allocated on a 1:1 basis to the combination of cemiplimab/ISA101b or cemiplimab/placebo. In both study arms, patients will receive treatment in cycles of 3 weeks for up to 24 months. The primary efficacy objective of this trial is to assess whether the addition of ISA101b to cemiplimab will elicit a higher Overall Response Rate (ORR, as per RECIST 1.1 criteria) compared to cemiplimab plus placebo. Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS), as well as safety and tolerability of cemiplimab plus ISA101b (as compared to cemiplimab plus placebo). The study will be conducted at approximately 50 investigative sites in the USA and Europe.

ISA Pharmaceuticals´ lead compound ISA101 is a clinical-stage SLP immunotherapy targeting HPV16-induced diseases such as cervical cancer and head–and-neck cancer. It induces specific immune responses to the oncogenic E6 and E7 antigens of HPV16. Cemiplimab, also known as REGN2810, is currently under review by EMA and was approved by the U.S. Food and Drug Administration in September 2018 under the brand name Libtayo as monotherapy for patients with advanced cutaneous squamous cell carcinoma. Regeneron, in collaboration with Sanofi, is developing cemiplimab both alone and in combination with other therapies for the treatment of various cancers.

"We are excited about this new clinical trial with ISA101b and cemiplimab," said Dr. Leon Hooftman, CMO of ISA Pharmaceuticals. "ISA101b has already demonstrated very promising results when combined with nivolumab in a previous study in advanced HPV16-positive cancers. Particularly in patients with relapsed head-and-neck cancer the percentage of patients with a meaningful tumor response appeared to be twice as high as achieved with nivolumab alone. The objective of the current randomized trial is to confirm such clinical benefit of ISA101b in a controlled setting."

"In our collaboration with Regeneron that was announced in December 2017, this is the first of two indications in which we jointly aim to develop novel combination immunotherapies for cervical cancer and head-and-neck cancer," said Gerben Moolhuizen, CEO of ISA Pharmaceuticals. "I am very proud of the efforts of the joint team that allowed us to advance quickly to this stage. We look forward to the first read-out from the trial, which is expected in the second half of 2020."

Oropharyngeal cancer, a subtype of head-and-neck cancer, affects tissues of the throat (oropharynx), e.g. the base of the tongue, the tonsils, the soft palate, and the walls of the pharynx. Oropharyngeal cancers can be divided into two types: HPV-positive, which are related to human papillomavirus infection, and HPV-negative cancers, which are usually linked to alcohol or tobacco use.

On January 21, 2019 Achilles Therapeutics ("Achilles"), a biopharmaceutical company developing personalised cancer immunotherapies, reported that its Clinical Trial Application (CTA) to conduct a Phase I/II study with its lead product, a tumour-derived T cell therapy targeting clonal neoantigens, in development for the treatment of advanced Non-Small Cell Lung Cancer (NSCLC), has been approved by the UK regulatory authority, the Medicines and Healthcare products Regulatory Agency (MHRA) (Press release, Achilles Therapeutics, JAN 21, 2019, View Source [SID1234532798]). The study, an open-label, multi-centre Phase I/II trial evaluating the safety and clinical activity of clonal neoantigen T cells (cNeT) in patients with advanced NSCLC, is expected to enrol the first patient in 2H 2019.

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"Approval of our first CTA represents an important validation of our approach and a significant milestone for Achilles," said Dr Iraj Ali, CEO of Achilles Therapeutics. "Achilles was founded by world-leading experts in cancer evolution, bioinformatics and the delivery of cell-based immunotherapies and we are bringing together these disciplines to develop next-generation, patient-specific T cell therapies that harness the immune system to destroy cancer cells."

"The Achilles approach is a technological step forward in the immune-oncology space with the potential to bring the next wave of revolutionary new immunotherapies to cancer patients," said Dr Martin Forster, Chief Investigator for the study at University College London Hospitals (UCLH), the lead clinical site. "We are excited to be part of the study and look forward to enrolling patients into the clinical trial."

Achilles is developing personalised T cell therapies for solid tumours targeting clonal neoantigens: protein markers unique to each patient that are present on the surface of a cancer cell. Using its PELEUS bioinformatics platform, Achilles can identify clonal neoantigens from each patient’s unique tumour profile which are present on every cancer cell and can be recognised by the immune system. Achilles uses its proprietary process to manufacture clonal neoantigen T cells (cNeT) which exquisitely target the specific set of clonal neoantigens in each patient. The starting material for cNeT are tumour infiltrating lymphocytes (TILs) which are isolated from the patient’s own tumour sample. These T cells are already programmed to invade and attack the tumour, and previous clinical studies have shown that expanded TILs can debulk solid tumours with durable and potent responses. Targeting multiple clonal neoantigens that are present on all cancer cells, but not on healthy cells, reduces the risk that new mutations can induce immune evasion and therapeutic resistance, and allows individualised treatments to target and destroy tumours without harming healthy tissue.

A second clinical study in patients with metastatic or recurrent melanoma is anticipated to open later in 2019.

– Ends –

Further information:

Achilles Therapeutics
Dr Iraj Ali – Chief Executive Officer
+44 (0)1438 906 906
[email protected]

Julia Wilson – Head of Communications
+44 (0)7818 430877
[email protected]

Consilium Strategic Communications
Mary-Jane Elliott, Sukaina Virji, Melissa Gardiner
Tel: +44 (0) 203 709 5000
Email: [email protected]