Press Release Details

THOUSAND OAKS, Calif., Feb. 14, 2018 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced that the Oncologic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) will review data supporting the BLINCYTO^® (blinatumomab) supplemental Biologics License Application (sBLA) for the treatment of patients with minimal residual disease (MRD)-positive B-cell precursor acute lymphoblastic leukemia (ALL) at a meeting on March 7, 2018.

MRD refers to the presence of a small amount of detectible cancer cells that remain in the patient after treatment.

"After achieving remission, the presence of MRD is the strongest prognostic factor for relapse in acute lymphoblastic leukemia. However, today up to half of patients remain MRD-positive after induction treatments and receive limited clinical benefit from treatments like chemotherapy or stem cell transplantation as a result of failure to identify and treat this residual disease," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "Currently there are no approved therapies for patients with MRD-positive ALL, representing a significant unmet need. This sBLA for BLINCYTO is the first application to ever be submitted for an MRD positive indication, and we look forward to discussing the supporting data with members of the Committee."

The Committee will review results from clinical studies in support of this potential new indication, including results from the Phase 2 BLAST study evaluating patients with B-cell precursor ALL and persistent or recurrent MRD after at least three cycles of intensive chemotherapy.

BLINCYTO is the first-and-only approved bispecific CD19-directed CD3 T cell engager (BiTE^®) immunotherapy. It is also the first bispecific antibody construct from Amgen's BiTE^® platform, which helps the body's immune system target cancer cells and represents an entirely new area of oncology research. 

The sBLA for BLINCYTO was accepted by the FDA for priority review, and a Prescription Drug User Fee Act (PDUFA) target action date of March 29, 2018 has been set. 

About BLINCYTO^® (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE^®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. BLINCYTO was granted breakthrough therapy and priority review designations by the FDA in 2014 for the treatment of relapsed or refractory B-cell precursor ALL in adults and children, and is now approved in the U.S. for this indication.

In November 2015, BLINCYTO was granted conditional marketing authorization in the European Union for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL. Additional regulatory applications for BLINCYTO are underway and have been submitted to health authorities worldwide.

About the BLAST Study
The BLAST study is the largest prospective trial in patients with MRD-positive ALL. It is an open-label, multicenter, confirmatory 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 treatments and a presence of MRD. Patients received continuous IV infusion of 15 μg/m²/d for four weeks, followed by two weeks off. Patients received up to four cycles of treatment, or could undergo a hematopoietic stem cell transplantation (HSCT) at any time after the first cycle, if eligible. The primary endpoint was the rate of complete MRD response within the first treatment cycle. The key secondary endpoint was relapse-free survival at 18 months. Additional secondary endpoints include incidence and severity of adverse events, overall survival (OS), time to hematological remission and duration of complete MRD response. Results from the BLAST study were presented at the 57^th Annual Meeting and Exposition of the American Society of Hematology in 2015.  

About ALL and MRD
ALL is a rare and rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children.^1,2 Many adult patients with ALL relapse, often within one year of their diagnosis, from which the median survival is only 4 to 8 months.³  Poor outcomes have been observed in patients who relapse after achieving a complete response but have persistent MRD, with 5-year OS rates as high as 75 percent for patients that achieve MRD-negative status, compared with 33 percent among patients that remain MRD-positive.⁴ In pediatric patients, MRD-positive status after treatment is associated with a 15-times higher risk of relapse compared with those with undetectable residual disease.⁵

About BiTE^® Technology
Bispecific T cell engager (BiTE^®) antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body's immune system to detect and target malignant cells. The modified antibodies are designed to bridge T cells to tumor cells, using the patient's own immune system to eradicate their cancer. BiTE^® antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE^® antibody constructs are currently being investigated for their potential to treat a wide variety of cancers. For more information, visit www.biteantibodies.com.

BLINCYTO^® U.S. Product Safety Information

Indication and Important Safety Information, including Boxed WARNINGS, for BLINCYTO^® (blinatumomab) for injection, for intravenous use

INDICATION

BLINCYTO^® is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children.

IMPORTANT SAFETY INFORMATION

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^®. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO® as outlined in the Prescribing Information (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 and interrupt or discontinue BLINCYTO^® as outlined in the PI.
• Infections: Approximately 25% of patients receiving BLINCYTO^® experienced serious 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): 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 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 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 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 in Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) (≥ 20%) in the BLINCYTO^® arm 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 increased (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).

Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide, for BLINCYTO^®.

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.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world's leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

Forward-Looking Statements 
This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen, including our most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and current reports on  Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project.  Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints we have selected. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products, including our devices, after they are on the market.

Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In addition, sales of our products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, our research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. Our business may be impacted by government investigations, litigation and product liability claims. In addition, our business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. Further, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors, or we may fail to prevail in present and future intellectual property litigation. We perform a substantial amount of our commercial manufacturing activities at a few key facilities, including in Puerto Rico, and also depend on third parties for a portion of our manufacturing activities, and limits on supply may constrain sales of certain of our current products and product candidate development. In addition, we compete with other companies with respect to many of our marketed products as well as for the discovery and development of new products. Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have substantial purchasing leverage in their dealings with us. The discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to acquire other companies or products and to integrate the operations of companies we have acquired may not be successful. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all. We are increasingly dependent on information technology systems, infrastructure and data security. Our stock price is volatile and may be affected by a number of events. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock.

The scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses.

CONTACT: Amgen, Thousand Oaks
Kristen Davis, 805-447-3008 (Media)
Kristen Neese, 805-313-8267 (Media)
Arvind Sood, 805-447-1060 (Investors)

References:

1. Cancer Research UK. About acute lymphoblastic leukaemia (ALL). http://www.cancerresearchuk.org/about-cancer/acute-lymphoblastic-leukaemia-all/about. Accessed Dec. 5, 2017. 
2. Mayo Clinic. Acute lymphocytic leukemia. http://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/basics/definition/con-20042915. Accessed Dec. 5, 2017.
3. Katz A, Chia V, Schoonen M, et al. Acute lymphoblastic leukemia: an assessment of international incidence, survival, and disease burden. Cancer Causes Control. 2015;26:1627-1642.
4. Bassan R, Spinelli O, Oldani E, et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009:113: 4153-4162.
5. Cavé H, van der Werff ten Bosch J, Suciu S, et al. Clinical Significance of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia. N Engl J Medicine.1998:339: 591-598.

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