On December 7, 2020 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, reported data from two ongoing Phase 2 studies evaluating parsaclisib, an Incyte-discovered, potent, highly selective, next-generation oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), for the treatment of patients with relapsed or refractory follicular (CITADEL-203) and marginal zone (CITADEL-204) lymphomas (Press release, Innovent Biologics, DEC 7, 2020, View Source [SID1234572379]). These data were accepted for presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH 2020), held virtually from December 5–8, 2020.

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The primary endpoint for the CITADEL-203, and -204 studies is objective response rate (ORR); duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and tolerability are among the secondary endpoints. All radiology-based endpoints are based on independent review committee (IRC) assessment.

Eligible patients received parsaclisib 20 mg once daily for eight weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg once daily (daily-dosing group [DG]). Subsequently, daily dosing was selected as the preferred regimen and patients initially enrolled in the WG were allowed to switch to DG. Data are presented for the DG and all patients.

Key results from the CITADEL studies include:

ORR(95%CI), %

mDOR(95%CI),
months

mPFS(95%CI),
months

CITADEL-203: R/R Follicular Lymphoma

DG (N=95)

75(65-83)

14.7(12.0-17.5)

15.8(13.8-19.1)

All (N=118)

73(64-81)

15.9(12.0-NE)

15.8(13.2-19.3)

CITADEL-204: R/R Marginal Zone Lymphoma

DG (N=72)

56.9(44.7-68.6)

NR(8.1-NE)

NR(11.0-NE)

All N=100)

57.0(46.7-66.9)

12.0(9.3-NE)

19.4(13.7-NE)

R/R: relapsed or refractory; ORR: objective response rate; mDOR: median duration
of response (reported for responders); mPFS: median progression-free survival;
DG:daily dosing group.

Parsaclisib was generally well tolerated in all studies with a manageable safety profile.

"We are glad that data from the CITADEL studies presented at ASH (Free ASH Whitepaper) 2020 appear promising, and they highlight the potential of parsaclisib to become a meaningful treatment for patients with relapsed or refractory B-cell non-Hodgkin lymphomas," said Dr. Hui Zhou, Vice President of Oncology Strategy and Medical Sciences of Innovent, "A pivotal Phase 2 registrational trial to evaluate the efficacy and safety of parsaclisib in patients with recurrent and refractory follicular lymphoma or marginal zone lymphoma in China is also recruiting now, and, if successful, the results of this study may help benefit patients with recurrent or refractory indolent B-cell lymphoma and potentially provide more treatment options to the clinicians that treat them."

Presentations are available on the ASH (Free ASH Whitepaper) website at
View Source; #338 (Oral presentation, CITADEL-204), #2935 (Poster, CITADEL-203).

In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates, including parsaclisib (PI3Kδ inhibitor). Under the terms of the agreement, Innovent has received the rights to develop and commercialize the parsaclisib and two other assets in Mainland China, Hong Kong, Macau and Taiwan. Currently Innovent is conducting a pivotal Phase 2 registrational trial in China to evaluate the efficacy and safety of parsaclisib in patients with recurrent and refractory follicular lymphoma or marginal zone lymphoma.

About Follicular and Marginal Zone Lymphomas

Follicular lymphoma is a B-cell cancer that originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. Although it is classified as indolent lymphoma, and the current immunochemotherapy has achieved good efficacy, it still often relapses following by aggressive diseases, which may lead to death within 1 to 2 years. There is an unmet medical need for treatment options for recurrent/refractory follicular lymphoma.

Marginal zone lymphoma is also a group of indolent B-cell lymphoma. Although BTK inhibitors have been approved in the United States to treat recurrent/refractory marginal zone lymphoma, the reported disease free survival after treatment with BTK inhibitors is short, so new treatments need to be developed on the basis of BTK inhibitors.

About Parsaclisib

Parsaclisib is a potent, highly selective, next-generation investigational novel oral inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ). It is currently under evaluation as a monotherapy in several ongoing Phase 2 trials as a treatment for non-Hodgkin lymphomas (follicular, marginal zone and mantle cell); and autoimmune hemolytic anemia. Pivotal trials of parsaclisib in combination with ruxolitinib for the treatment of patients with myelofibrosis are underway; and there are plans to initiate a trial to evaluate parsaclisib in combination with tafasitamab for B-cell malignancies.

In December 2018, Innovent and Incyte entered into a strategic collaboration for three clinical-stage product candidates, including parsaclisib (PI3Kδ inhibitor). Under the terms of the agreement, Innovent has received the rights to develop and commercialize parsaclisib and two other assets in Mainland China, Hong Kong, Macau and Taiwan.

On December 7, 2020 Ascentage Pharma (6855.HK), a globally focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported positive data from two pivotal Phase II clinical trials of HQP1351 (olverembatinib) in an oral presentation at the 62nd ASH (Free ASH Whitepaper) Annual Meeting (Press release, Ascentage Pharma, DEC 7, 2020, View Source [SID1234572378]). These results were presented by the principal investigator of the study, Qian Jiang, MD, Deputy Chief of the Hematology Department at Peking University People’s Hospital. Following oral presentations in 2018 and 2019, this is the third consecutive year in which clinical study results of HQP1351 were selected for oral presentation at the ASH (Free ASH Whitepaper) Annual Meetings, signifying the recognition of HQP1351’s safety and efficacy from the international hematology community.

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HQP1351 is a novel third-generation BCR-ABL tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma for the treatment of patients with CML resistant to first- and second-generation TKIs, including those with the T315I mutation. Based on results from two pivotal Phase II trials, Ascentage Pharma submitted a New Drug Application (NDA) for HQP1351 for the treatment of patients with T315I-mutated CML in chronic-phase (CML-CP) or accelerated-phase (CML-AP) in China this year, and the NDA was subsequently granted Priority Review status.

At 12:30 PST, December 7, during the session "Chronic Myeloid Leukemia: Therapy: CML: New and Beyond", Dr. Qian Jiang delivered an oral presentation on results from the pivotal Phase II studies of HQP1351, in an address titled "Novel BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) HQP1351 (Olverembatinib) Is Efficacious and Well Tolerated in Patients with T315I-Mutated Chronic Myeloid Leukemia (CML): Results of Pivotal (Phase II) Trials".

Highlights of the results:

Two pivotal Phase II trials of HQP1351 in patients with TKI-resistant and T315I-mutated CML-CP or CML-AP were conducted in China. Patients in the studies were administered HQP1351 at 40 mg once every other day (QOD).
As of the data cut-off date of March 23, 2020, pivotal Phase II study HQP1351-CC201 had enrolled 41 patients with CML-CP. Across a median follow-up of 7.9 months, the mean 3-month progression-free survival (PFS) was 100%, and the 6-month PFS was 96.7%. A total of 75.6% of evaluable patients achieved a major cytogenetic response (MCyR), including 65.9% with a complete cytogenetic response (CCyR) and 48.8% with a major molecular response (MMR).
As of the data cut-off date of February 11, 2020, pivotal Phase II study HQP1351-CC202 had enrolled 23 patients with CML-AP. Across a median follow-up of 8.2 months, the 3-month PFS was 100% and the 6-month PFS was 95.5%. A total of 78.3% of evaluable patients achieved a major hematologic response (MaHR), including 60.9% of patients with a complete hematologic response (CHR). A further 52.2% of patients achieved MCyR, including 39.1% with CCyR and 26.1% with MMR.
In study HQP1351-CC201, the most frequent treatment-related adverse event (TRAE) of Grade 3-4 was thrombocytopenia (48.8%), and there were no treatment-related deaths.
In study HQP1351-CC202, the most frequent TRAE of Grade 3-4 was also thrombocytopenia (52.2%).
Results from the two studies show that HQP1351 was efficacious and well tolerated in patients with T315I-mutated and TKI-resistant CML-AP or CML-CP, and the probability and depth of clinical response is expected to increase with prolonged treatment period.
"Once T315I mutation occurs in patients with CML-CP or CML-AP, first- and second-generation TKIs are no longer effective. Currently, there is no approved treatment for these TKI-resistant patients in China, thus representing an urgent unmet medical need," said presenting author Dr. Qian Jiang. "Results from these two pivotal Phase II studies of HQP1351 in patients with T315I-mutated and TKI-resistant CML-AP or CML-CP have demonstrated promising efficacy and tolerability profiles. We remain steadfast to continuing the clinical development of this China-developed innovative therapy and bringing it to patients as early as possible."

"We are very pleased that results from the Phase II studies of HQP1351, a third-generation BCR-ABL inhibitor, have demonstrated encouraging efficacy and tolerability," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "For this drug candidate to be selected for oral presentation at the ASH (Free ASH Whitepaper) annual meeting in three consecutive years really shows the recognition of HQP1351 as a potential treatment for CML from the international hematology community. The release of these results marks another major milestone for the development of HQP1351, following the NDA submission and Priority Review designation in China. We hope HQP1351 will soon obtain its market authorizations so that patients with drug-resistant CML in China and around the world may start benefiting from this novel therapy."

About HQP1351 (Olverembatinib)

Being developed by Ascentage Pharma, HQP1351 is a novel, orally active, potent third-generation BCR-ABL tyrosine kinase inhibitor (TKI) designed to effectively target a spectrum of BCR-ABL mutants, including T315I, and the first China-developed third-generation BCR-ABL TKI targeting drug-resistant chronic myeloid leukemia (CML). At present, a New Drug Application (NDA) for HQP1351 has been submitted in China, and the application was subsequently granted the Priority Review status. In July 2019, HQP1351 was cleared by the US Food and Drug Administration (FDA) to enter a Phase Ib clinical study. In May 2020, the drug candidate was granted an Orphan Drug Designation (ODD) and a Fast Track Designation (FTD) by the US FDA. Furthermore, a Phase Ib trial of HQP1351 in patients with gastrointestinal stromal tumor (GIST) is also ongoing in China.

On December 7, 2020 InnoCare Pharma (HKEX: 09969), a leading biopharmaceutical company, reported three presentations of the most recent clinical data with orelabrutinib, its BTK inhibitor, at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, InnoCare Pharma, DEC 7, 2020, View Source [SID1234572377]). These data, contained in the three poster sessions described below, highlight both favorable objective response rates (ORR) and complete response rates (CR) as demonstrated in patients with relapsed or refractory Mantle Cell Lymphoma (MCL) and patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) /Small Cell Leukemia (SLL).

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Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia

Abstract Number：1320

This study was designed to evaluate safety and efficacy following oral daily administration. The primary endpoint was ORR. The duration of response (DOR), progression-free survival (PFS) and safety were chosen as secondary endpoints.

A total of 80 patients were enrolled, most with advanced stage disease. The median follow-up time was 14.3 months. As evaluated by an independent review committee, the ORR was 91.3%, including 10.0% of patients with CR, 63.8% with partial response (PR) and 17.5% with PR-L. Median time to first response following treatment initiation was 1.87 months. The median DOR and PFS were not reached.

Most adverse events were mild to moderate. Extended follow-up analysis did not reveal new safety concerns. The most frequent adverse events (AEs) include thrombocytopenia, neutropenia, anemia, upper respiratory tract infection, pneumonia and hypokalemia.

Dr. Wei Xu, Deputy Director of Department of Hematology, Jiangsu Province Hospital, said, "These updated data, based upon longer follow up periods, further confirm that orelabrutinib is active in treating r/r CLL/SLL patients with a higher CR rate, deeper response and improved safety profiles. As a highly selective BTK inhibitor with novel pharmacokinetic and pharmacodynamic properties, orelabrutinib provides a favorable therapeutic choice for patients with r/r CLL/SLL and a potential best candidate for combination therapy."

Long-Term Safety and Efficacy of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Mantle Cell Lymphoma: A Multicenter, Open-Label, Phase II Study

Abstract Number：2048

This study is aimed at evaluating its safety and efficacy. The primary endpoint was ORR assessed per Lugano criteria (2014). Safety and other efficacy (DOR, PFS) evaluations were chosen as secondary endpoints.

A total of 106 patients, most with advanced stage disease, were enrolled in this study, with median follow up time of 16.4 months. As per protocol analysis, ORR was 87.9% and disease control rate was 93.9%.

The CR rate, by conventional CT method, reached 34.3%. The median DOR and PFS were not reached.

Orelabrutinib demonstrated a good safety profile in r/r MCL patients. Adverse events included thrombocytopenia, neutropenia, leukopenia, and hypertension.

Dr. Yuqin Song, deputy director of the Lymphoma Department at Peking University Cancer Hospital, Beijing, said, "Orelabrutinib showed continued activity in treating patients with r/r MCL over an extended period. In addition, orelabrutinib was observed to be safe, with no treatment related grade 3 or higher diarrhea, atrial fibrillation/flutter or severe bleeding in this study. These results support orelabrutinib as a better selection for BTKi therapy for r/r MCL patients."

Pooled Analysis of Safety Data from Clinical Trials of Orelabrutinib Monotherapy in Hematologic Malignancies

Abstract Number: 1140

Safety data of 266 patients from the five ongoing orelabrutinib monotherapy studies were pooled and analyzed.

Orelabrutinib was observed to have a lower frequency of BTK off-target related adverse events, such as atrial fibrillation/flutter and diarrhea, compared with other BTK inhibitors. Among all 266 patients, one patient was reported with one episode of transient grade 1 atrial fibrillation, and no grade ≥3 atrial fibrillation was observed. One case (0.4%) was reported as grade 3 diarrhea. The second primary malignancies were reported in one patient (0.4%) with r/r MCL. Most of the adverse events occurred early in treatment and the frequency of new event occurrence was significantly decreased during the later cycles.

Dr. Song said, "Orelabrutinib shows good safety profile in long-term treatment. These data suggest that orelabrutinib may be a favorable treatment choice as a single agent for B-cell malignancies."

About Orelabrutinib

Orelabrutinib is a selective BTK inhibitor under development for the treatment of cancers and autoimmune diseases. Currently, multi-center, multi-indication clinical trials are underway in the US and China with orelabrutinib as monotherapy or in combination therapies. Current clinical data have demonstrated orelabrutinib’s robust efficacy and safety profile. Orelabrutinib’s two indications have been included in priority review by the NMPA.

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.

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