On December 7, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that the China National Medical Products Administration (NMPA) has approved BLINCYTO (blinatumomab) for injection for the treatment of adult patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, BeiGene, DEC 7, 2020, View Source [SID1234572376]). The biologics license application (BLA) had been submitted by Amgen and received priority review by the Center for Drug Evaluation (CDE) of the NMPA. Developed by Amgen and licensed to BeiGene in China under a strategic collaboration commenced earlier this year, this is the first approval for BLINCYTO in China and BeiGene’s first product licensed from Amgen to be newly approved. With this approval, BLINCYTO has become the first bispecific immunotherapy approved in China.

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"This approval of BLINCYTO provides us with an opportunity to offer adult patients in China with relapsed or refractory B-cell precursor ALL the first approved immunotherapy treatment for their disease. BLINCYTO is the first immunotherapy to demonstrate superior overall survival versus chemotherapy, more than doubling patients’ chances for survival, when used in first salvage R/R ALL in studies outside of China," commented Xiaobin Wu, Ph.D., General Manager of China and President of BeiGene. "We are working to ensure BLINCYTO is available to patients in China as soon as possible. Our commercial organization of more than 1,500 people in China is excited to add BLINCYTO to our product portfolio, which now includes six approved cancer treatments."

The approval of BLINCYTO was based on results from the Phase 3 trial (NCT03476239) in China evaluating the efficacy and safety of BLINCYTO in adult patients with Philadelphia-negative R/R B-cell precursor ALL. Results of the interim analysis of 67 patients showed that the efficacy results in Chinese subjects were generally consistent with those in the global and Japan studies in subjects with Philadelphia-negative R/R ALL. The complete response/complete response with partial recovery of blood cells (CR/CRh) rate within two cycles of BLINCYTO treatment (the primary endpoint) was 47.8% (32 of 67 subjects; 95% CI: 35.4, 60.3). The median overall survival time was 9.6 months (95% CI: 6.4, not estimable). The safety profile observed for Chinese subjects in this study was consistent with that observed in the global studies evaluating BLINCYTO in R/R ALL. No new safety risks were identified based on these interim analyses of adverse events in Chinese subjects.

"Our collaboration with BeiGene is advancing Amgen’s oncology pipeline for patients with significant unmet medical needs. We are confident the approval of BLINCYTO in China has the potential to make a meaningful difference to adult patients with R/R B-cell precursor acute lymphoblastic leukemia," said My Linh Kha, Vice President & General Manager, Amgen Japan Asia-Pacific (JAPAC). "We are deeply committed to continuing to bring therapeutic options to treat debilitating cancers for patients in China, while also actively supporting the Government’s focus on healthy aging through innovative products and initiatives designed to prevent chronic diseases, such as cardiovascular disease and fragility fracture."

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a rapidly progressing cancer of the blood and bone marrow that occurs in both adults and children1. ALL accounts for approximately 20% of all adult leukemia, and in China there were an estimated 82,607 new cases of leukemia in 20182,3. In children, the relapse rate of ALL is nearly 10%, while in adults the relapse rate is closer to 50%4.

About BLINCYTO (blinatumomab)

BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) immuno-oncology molecule that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BiTE molecules are a type of immuno-oncology therapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified molecules are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE immuno-oncology molecules 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 immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

relapsed or refractory B-cell precursor ALL in adults and children.
B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. 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 European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome negative CD19-positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
adults with Philadelphia chromosome negative CD19-positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
paediatric patients age 1 year or older with Philadelphia chromosome-negative CD19-positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.
In China, BLINCYTO is indicated for the treatment of adult patients with relapsed or refractory B-cell precursor ALL.

Important U.S. 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 and treat with corticosteroids 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 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional 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, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
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 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, 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 (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified [39%]), tremor (31%), and chills (28%). 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 adults with relapsed or refractory B-cell precursor ALL 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).

On December 7, 2020 Bristol Myers Squibb (NYSE: BMY) reported new results from the QUAZAR AML-001 study presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, evaluating Onureg (azacitidine tablets; CC-486), an oral hypomethylating agent, as a treatment for adult patients with acute myeloid leukemia (AML) who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy (Press release, Bristol-Myers Squibb, DEC 7, 2020, View Source [SID1234572374]). Results demonstrated treatment with Onureg improved overall survival (OS), the primary endpoint of the study, as well as showed clinical benefit across other key secondary endpoints, compared to placebo, in patients with AML in first remission.

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A longitudinal assessment of measurable residual disease (MRD) status from QUAZAR AML-001 evaluated treatment with Onureg in patients with both MRD positive (MRD+) and MRD negative (MRD-) status at baseline. The MRD evaluable cohort comprised 463/472 randomized patients (Onureg, N=236; placebo, N=227).

Median OS was prolonged with Onureg compared with placebo in patients who were either MRD+ (median 14.6 vs. 10.4 months, respectively; HR: 0.69 [95% CI: 0.51, 0.93]) or MRD- (median 30.1 vs. 24.3 months; HR: 0.81 [0.59, 1.12]) at baseline.
The median duration of MRD negativity was extended with Onureg vs. placebo (11.0 vs. 5.0 months, respectively; HR: 0.62 [95% CI: 0.48, 0.78]). Treatment with Onureg also resulted in a higher rate of MRD response (MRD+ to MRD-) vs. placebo: 37% vs. 19%, respectively.
Median relapse-free survival (RFS) was extended with Onureg for both MRD+ (7.1 vs. 2.7 months, respectively; HR: 0.58 [95% CI: 0.43, 0.78]) and MRD- patients (13.4 vs. 7.8 months; HR: 0.71 [0.52, 0.98]).
The MRD assay used in the QUAZAR AML-001 study is not part of the label recently approved by the U.S. Food and Drug Administration (FDA) for Onureg as a continued treatment for adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy and who are not able to complete intensive curative therapy.
Results from a separate post-hoc analysis evaluated treatment with Onureg in patients from the QUAZAR AML-001 study who had a range of prior consolidation chemotherapy cycles.

472 patients were randomized to Onureg (N=238) or placebo (N=234) and most patients (80%) received consolidation before study entry. Common agents used for consolidation were cytarabine, idarubicin and daunorubicin.
In the cohort where no prior consolidation was administered, median OS with Onureg (N=52) vs. placebo (N=42) was 23.3 vs. 10.9 months, respectively (HR: 0.55 [95% CI: 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 months (0.55 [0.34, 0.88]).
In the cohort of patients who received one cycle of consolidation treatment, median OS was 21.0 vs. 14.3 months with Onureg (N=110) vs. placebo (N=102), respectively (HR: 0.75 [95% CI: 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 months (0.72 [0.53, 0.99]).
In the ≥2 consolidations cohort, median OS was 28.6 months with Onureg (N=76) vs. 17.6 months with placebo (N=90) (HR: 0.75 [95% CI: 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 months (0.59 [0.41, 0.87]).
"These analyses from the QUAZAR AML-001 study provide further insight into the clinical activity of Onureg and its potential role in the treatment paradigm of patients with acute myeloid leukemia in first remission following intensive chemotherapy," said Andrew Wei, MBBS, Ph.D., QUAZAR AML-001 lead investigator, Alfred Hospital and Monash University, Melbourne, Australia. "Persistence of acute myeloid leukemia is frequently measurable after intensive chemotherapy, and these new analyses from the pivotal trial demonstrate that Onureg can improve survival in patients with or without measurable residual disease, and across a range of consolidation cycles."

An additional post-hoc analysis showed treatment with Onureg was associated with reduced risk of hospitalization events and days in hospital, as well as estimated cost savings associated with hospitalizations, compared with placebo. Hospitalization events in the study were collected starting from informed consent signature through 28 days after the last intraperitoneal (IP) dose. Rates of hospitalization and days in hospital were adjusted for duration of Onureg and placebo exposure. 469 patients received Onureg (N=236) or placebo (N=233). In all, 108 patients (45.8%) in the Onureg arm and 118 (50.6%) in the placebo arm were hospitalized. The analysis showed that Onureg reduced exposure-related rate of hospitalization and days in hospital compared to placebo in the QUAZAR AML-001 study. Additionally, the analysis showed that extended remission periods with Onureg compared to placebo may translate into hospitalization-related cost reductions due to reduced rates of hospitalization and days in the hospital.

"New data we’re presenting for Onureg at ASH (Free ASH Whitepaper) highlight its potential to improve long-term outcomes for people living with this aggressive blood cancer," said Samit Hirawat, M.D., executive vice president, chief medical officer, global drug development, Bristol Myers Squibb. "Moreover, oral treatment options like Onureg that can be taken at home are even more important than ever before for patients."

About QUAZAR AML-001

QUAZAR AML-001, is a Phase 3, international, randomized, double-blind study. Eligible patients were ages 55 years or older, had newly diagnosed AML, intermediate or poor cytogenetics, had achieved first CR or CRi following intensive induction chemotherapy with or without consolidation treatment (per investigator preference prior to study entry) within four months before randomization, and were not candidates for hematopoietic stem cell transplant (HSCT) at the time of screening. The study enrolled 472 patients, randomized 1:1 to receive either Onureg 300 mg (N=238) or placebo (N=234) orally, once daily, for 14 days of a 28-day cycle, plus best supportive care.1

About AML

There will be nearly 20,000 new cases of acute myeloid leukemia (AML) in the United States this year, accounting for 1.1% of all cancer cases, with an estimated 11,180 deaths resulting from the disease. There were an estimated 64,500 people living with AML in the United States in 2017.2 AML is one of the most common acute leukemias in adults. AML is characterized by the rapid growth of abnormal cells in the bone marrow and as such interferes with normal blood cell production and function. Because of the impaired production of red blood cells, platelets and white blood cells, it can present with signs of anemia, bleeding and infections.3 AML is a heterogeneous disease associated with diverse genetic mutations, and can rapidly progress and lead to death if not promptly treated.4 AML response to treatment may be of short duration, meaning following patients’ initial response to chemotherapy, there is still a very high risk of relapse, thus representing a significant unmet need for continued treatment options that prolong overall survival.5

About Onureg

Onureg, the first and only FDA-approved continued AML treatment for patients in first remission, is an oral hypomethylating agent that incorporates into DNA and RNA. The main mechanism of action is thought to be hypomethylation of DNA, as well as direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes that are critical for cell differentiation and proliferation.6,7

INDICATION

ONUREG is indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy.
IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.
WARNINGS AND PRECAUTIONS

Risks of Substitution with Other Azacitidine Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment with ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG for intravenous or subcutaneous azacitidine.
Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS): In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG or placebo. 107 received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG for MDS have not been established. Treatment of MDS with ONUREG is not recommended outside of controlled trials.
Embryo-Fetal Toxicity: ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose.
ADVERSE REACTIONS

Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG.
Most common (≥10%) adverse reactions with ONUREG vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).
LACTATION

There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose.
Please see full Prescribing Information for ONUREG.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On December 7, 2020 Treadwell Therapeutics, a clinical-stage biotechnology company developing novel, small molecule therapeutics for highly aggressive cancers, reported two presentations for the Company’s CFI-400945 program, an oral, first-in-class inhibitor of Polo-like Kinase 4 (PLK4) a critical regulator of mitotic progression, at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held virtually from December 5-8, 2020 (Press release, Treadwell Therapeutics, DEC 7, 2020, View Source [SID1234572373]). The first presentation described the efficacy results from an investigator-initiated Phase 1 dose escalation study in AML/MDS. The second was a "Trials in Progress" presentation on the upcoming Treadwell sponsored study in relapsed or refractory AML, MDS or CMML with study initiation planned for the first quarter of 2021.

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"We are very encouraged by the promising preliminary Phase 1 study results which included single agent, durable remissions. This compelling early data supports the continued investigation of CFI-400945 for the potential treatment of patients with acute myeloid leukemia (AML)," said Principal Investigator, Karen W.L. Yee, Leukemia Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

"Abnormal genetics, complex karyotypes, genomic instability characterize poor prognosis in AML. CFI-400945 inhibits PLK4, a highly conserved master regulator of centriole duplication, and is critical for maintenance of genomic integrity, making it an ideal candidate for the potential treatment of AML," said Dr. Mark R. Bray, Chief Scientific Officer at Treadwell Therapeutics. "We are excited by the compelling Phase 1 trial results in AML and look forward to continuing to evaluate the promise of our lead candidate in company sponsored Phase 2 studies."

2020 ASH (Free ASH Whitepaper) Poster Presentations and Details:

Preliminary Results from a Phase 1 Study of CFI-400945, a PLK4 Inhibitor, in Patients with Acute Myeloid Leukemia and High Risk MDS
Publication Number: 1050
Session: 616; Poster I
Date and Time: December 5, 2020, 7:00 AM-3:30 PM
A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of CFI-400945 as a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia
Publication Number: 1974
Session: 616; Poster II
Date and Time: Sunday, December 6 th, 7:00 AM-3:30 PM
In the presentation titled, "Preliminary Results from a Phase 1 Study of CFI-400945, a PLK4 Inhibitor, in Patients with Acute Myeloid Leukemia and High Risk MDS," CFI-400945 demonstrated promising activity as a monotherapy in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and a tolerable safety profile in an open-label, dose escalation, safety and pharmacokinetic study. Data showed that of six patients evaluable for response, two (33%) achieved complete remission (CR) as best response with 3 patients achieving stable disease (SD). Onset of response tended to be within 1 or 2 cycles. One CR occurred in a complex karyotype patient with a p53 mutation who previously failed 7+3 induction and had a durability of ~90 days. The second CR was in a previously untreated AML patient with a 5q deletion who is still in response after >200 days. One subject achieving SD as best response with duration of > 200 days was a previously untreated AML patient with a p53 mutation and had blast reduction from 38% to 9%, but complete blood counts remained below PR criteria. The most common non-hematological drug related toxicities of any grade, which occurred in over 20%, were diarrhea (44%), headache (44%), colitis (33%), vomiting (33%), bilirubin increase (22%), dizziness (22%), fatigue (22%), and nausea (22%).

A second presentation titled, "A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of CFI-400945 as a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia," details the study design for a Treadwell sponsored trial examining CFI-400945 in AML, MDS and chronic myelomonocytic leukemia (CMML). The study will use a standard 3 + 3 design and have four parts: Part 1A (1A), a single agent dose optimization lead-in, Part 1B (1B), a food effect portion once the MTD of 1A is determined, and Part 2, combinations with azacitidine (2A), and decitabine (2B). The efficacy endpoints for AML, MDS, and CMML include the overall response rate, and the CR rate per standard criteria.

About CFI-400945

CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, polo-like kinase 4 (PLK4). PLK4 is a highly conserved master regulator of centriole duplication and is critical for maintenance of genomic integrity. PLK4 is overexpressed in a variety of solid tumors and elevated expression is associated with poor clinical outcomes. Depletion of PLK4 expression in cancer cells by RNA interference leads to mitotic defects and cell death. PLK4 was identified as a drug target based on functional screening to identify vulnerabilities of genomically unstable breast cancers.

Anti-tumor activity of CFI-400945 has been shown in mice bearing human cancer xenografts, including robust tumor growth inhibition and durable tumor regression in primary tumor xenografts from breast cancer. CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, polo-like kinase 4 (PLK4). CFI-400945 is currently in multiple investigator-initiated studies in solid and liquid malignancies, with a company sponsored trial in relapsed or refractory leukemia to commence in the first quarter of 2021.

On December 7, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new data from the randomised Phase 2 GRIFFIN study showing that the addition of DARZALEX▼ (daratumumab) to lenalidomide, bortezomib and dexamethasone (D-RVd), followed by daratumumab plus lenalidomide (D-R) maintenance therapy, resulted in deeper and improved responses, including minimal residual disease (MRD) negativity, compared to RVd followed by R alone, in newly diagnosed, stem cell transplant-eligible patients with multiple myeloma (Press release, Janssen Pharmaceuticals, DEC 7, 2020, View Source [SID1234572372]).1 These data investigating the use of daratumumab in combination with RVd, which were shared in separate oral and poster presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting, provide further evidence that this regimen may provide greater efficacy for transplant-eligible, newly diagnosed multiple myeloma (NDMM) patients than standard therapy. This morning’s oral presentation (Abstract #549) shared longer-term follow-up data, and the poster presentation (Abstract #3243) featured additional data from the safety run-in cohort.1,2

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"The long-term GRIFFIN data show that maintenance therapy with daratumumab in combination with lenalidomide (D-R) resulted in deeper and longer responses compared to R alone in patients with multiple myeloma who are newly diagnosed and transplant-eligible," said Peter Voorhees, M.D.,* Atrium Health’s Levine Cancer Institute and GRIFFIN study investigator. "These data indicate that the addition of daratumumab to RVd followed by R maintenance results in improved response rates and depth of response during induction, consolidation and maintenance treatment cycles."

Key Findings from GRIFFIN (Abstract #549):
The GRIFFIN oral presentation featured updated safety and efficacy data based on longer follow-up for D-RVd and evaluated the potential role of D-R for maintenance therapy in patients with NDMM.1

Initial findings of GRIFFIN:
At the end of post-transplant consolidation (median follow-up, 13.5 months) in the response-evaluable population, the stringent complete response (sCR) rate favoured D-RVd vs. RVd (42.4 percent vs. 32.0 percent, P=0.0253).1
The complete response (CR) or better rate also favoured D-RVd vs. RVd (51.5 percent vs. 42.3 percent; P=0.0014).1
No new safety concerns were observed in the D-RVd arm receiving D-R maintenance therapy.1
The most common Grade 3/4 treatment-emergent adverse events (TEAEs) in the D-RVd arm receiving D-R maintenance therapy were neutropenia (43 percent), lymphopenia (23 percent), leukopenia (16 percent) and thrombocytopenia (15 percent).1
With an additional 12 months of D-R or R maintenance therapy (median follow up of 27.4 months), responses continued to deepen and remained higher for the daratumumab-containing arm.1
At the clinical cutoff date, the sCR rate favoured the daratumumab-containing arm (63.6 percent vs. 47.4 percent; P=0.0253).1
The CR or better rate continued to favour D-RVd vs. RVd (81.8 percent vs. 60.8 percent; P=0.0014).1
MRD negativity favoured D-RVd vs. RVd (62.5 percent vs. 27.2 percent, P=0.0001).1
No new safety concerns were observed with the D-R maintenance therapy.1
The 24-month progression-free survival (PFS) rate was 94.5 percent for D-RVd and 90.8 percent for RVd.1
Key Findings from GRIFFIN (Abstract #3243):
The poster presentation shared final results of the safety run-in cohort (n=16 patients) of the GRIFFIN study. These additional data showed that maintenance therapy with daratumumab and lenalidomide (D-R) improved both the sCR rate and MRD negativity rate in patients with NDMM who underwent D-RVd induction, autologous stem cell transplant (ASCT) and D-RVd consolidation. This deepening of responses was associated with durable remissions, and no new safety signals were observed with maintenance therapy.2

Initial findings from the safety run-in cohort for GRIFFIN:
By the end of post-transplant consolidation, the sCR rate was 56 percent.2
MRD negativity (10-5) at the end of consolidation was observed in 50 percent of patients, and no patients were MRD negative at 10-6.2
New findings:
The sCR rate improved to 94 percent by the end of both 12 and 24 months of D-R maintenance therapy.2
By the end of 24 months of D-R maintenance therapy, 81 percent of patients were MRD negative at 10-5, with five patients (31 percent) MRD negative at 10-6.2
At a median follow-up of 40.8 months, three of 16 patients had progressed, with estimated 24-month and 36-month PFS rates of 94 percent and 78 percent, respectively.2
With longer follow-up including two years of D-R maintenance therapy, no new safety concerns were identified.2
"The stringent complete response and minimal residual disease negativity rates with daratumumab combination maintenance therapy for transplant-eligible patients further solidify daratumumab as a foundational treatment for multiple myeloma," said Dr Catherine Taylor, Vice President, Medical Affairs Therapeutic Area Strategy, Europe, Middle East and Africa (EMEA), Janssen-Cilag Ltd., Middle East. "At Janssen, we remain focused on pursuing effective treatment combinations and investigating different endpoints, such as minimal residual disease, in order to provide effective treatments to patients across the spectrum of multiple myeloma."

"We continue to be encouraged by the GRIFFIN data showing deeper and improved responses in patients with newly diagnosed, ASCT-eligible multiple myeloma," said Andree Amelsberg, M.D., MBA, Vice President, U.S. Medical Affairs, Oncology Medical Affairs, Janssen Scientific Affairs, LLC. "These data show promising results for patients with newly diagnosed multiple myeloma and we remain committed to exploring the full potential of daratumumab and daratumumab subcutaneous formulation."

*Peter Voorhees is lead investigator of the GRIFFIN study and was not compensated for any media work.

#ENDS#

About the GRIFFIN Study3
The Phase 2 GRIFFIN (NCT02874742) study has enrolled and treated more than 200 adults ages 18-70 years with NDMM and who are eligible for high-dose therapy/autologous stem cell therapy (ASCT).

In the safety run-in cohort, patients received 25 mg of lenalidomide orally on Days 1-14; 1.3 mg/m2 of bortezomib subcutaneously on Days 1, 4, 8 and 11; and 20 mg of dexamethasone on Days 1, 2, 8, 9, 15 and 16, every 21 days during the induction and consolidation phases (Cycles 1-6). Daratumumab 16 mg/kg IV was given on Days 1, 8 and 15 of Cycles 1-4 and on Day 1 of Cycles 5-6.

During maintenance phase (Cycles 7-32), patients received 10 mg daily of lenalidomide (15 mg beginning at Cycle 10 if tolerated) on Days 1-21 every 28 days and daratumumab 16 mg/kg IV every 56 days; this was amended to every 28 days based upon emerging clinical pharmacokinetic data demonstrating improved target saturation with every 4-week maintenance dosing. Maintenance therapy with lenalidomide may be continued beyond Cycle 32 in both arms, per local standard of care.

In the subsequent randomised Phase 2 portion of the study, approximately 200 patients were randomised and received treatment with RVd, induction and consolidation, ASCT and maintenance therapy with lenalidomide; or daratumumab and RVd, ASCT and maintenance therapy with daratumumab and lenalidomide.

About daratumumab and daratumumab SC
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, it is estimated that more than 154,000 patients have been treated with daratumumab worldwide.4 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.5

CD38 is a surface protein that is highly expressed across multiple myeloma cells, regardless of the stage of disease. Daratumumab SC binds to CD38 and induces myeloma cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.6

Data across nine Phase 3 clinical trials in multiple myeloma and light chain (AL) amyloidosis, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival.7,8,9,10,11,12,13,14 Additional studies are underway to assess the efficacy and safety of daratumumab SC in the treatment of other malignant and pre-malignant haematologic diseases in which CD38 is expressed, including smouldering myeloma and AL amyloidosis.15,16

For further information on daratumumab, please see the Summary of Product Characteristics at View Source

About Multiple Myeloma
Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.17 In Europe, more than 48,200 people were diagnosed with MM in 2018, and more than 30,800 patients died.18 Around 50 percent of newly diagnosed patients do not reach five-year survival,19,20 and almost 29 percent of patients with multiple myeloma will die within one year of diagnosis.21

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.22 Relapsed and refractory myeloma is defined as disease that is nonresponsive while on salvage therapy, or progresses within 60 days of last therapy in patients who have achieved minimal response (MR) or better at some point previously before then progressing in their disease course.23 While some patients with MM have no symptoms at all, others are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.24 Patients who relapse after treatment with standard therapies, including proteasome inhibitors and immunomodulatory agents, have poor prognoses and require new therapies for continued disease control.25

On December 7, 2020 CEL-SCI Corporation (NYSE American: CVM) reported that the Phase 3 study is in the final stage of review which involves statistical analysis of all study data (Press release, Cel-Sci, DEC 7, 2020, View Source [SID1234572371]).. Data lock has already been completed.

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Since the required number of events to allow statistical analysis of CEL-SCI’s Phase 3 study in head and neck cancer was reached earlier this year, the Clinical Research Organizations (CROs) managing CEL-SCI’s Phase 3 study, Ergomed and ICON, had been performing data base lock of the study results. Data base lock is a very important and time intensive process that needs to be completed to ensure any study’s data are accurate and as complete as possible before the results of the study can be statistically evaluated and reliable conclusions drawn regarding the study’s outcome(s). This process was particularly complicated for CEL-SCI’s Phase 3 study because the study was conducted in over 20 countries on three continents, and many of these countries had, and still have, severe shutdowns due to the COVID-19 pandemic.

The statistical analysis of our Phase 3 study data is being performed according to a statistical analysis plan that was approved in advance of data lock. The analysis is being conducted by independent unbiased contractors. CEL-SCI is not involved in this process. Once the analysis has been completed, CEL-SCI will become privy to the study results. At that time, shareholders will be advised of the results through a public announcement. CEL-SCI also plans to publish the results in peer reviewed scientific journals.

"Our goal has been to create a cancer drug that is both non-toxic and works with the body’s immune system to increase the ‘intent to cure’ success rate of the first-line cancer treatment. We believe that immunotherapy should be administered before, not after, surgery, radiation and chemotherapy have damaged the immune system. We further believe that success in head and neck cancer should lead to many new ways of helping cancer patients." said Geert Kersten, CEO of CEL-SCI Corporation. "We are grateful to our shareholders for believing in us and supporting us during the very long Phase 3 study."