On December 7, 2020 Sierra Oncology, Inc. (SRRA), a late-stage biopharmaceutical company on a quest to deliver targeted therapies that treat rare forms of cancer, reported an updated efficacy analyses of momelotinib in myelofibrosis patients with thrombocytopenia (Press release, Sierra Oncology, DEC 7, 2020, View Source [SID1234572324]). The data were presented in a poster presentation at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Jean-Jacques Kiladjian, MD, PhD, Consultant Hematologist, Head, Clinical Investigation Center, Saint Louis Hospital, Paris, France.

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"This retrospective analysis of the two Phase 3 SIMPLIFY studies demonstrate that the relative benefit-risk profile of momelotinib and ruxolitinib is influenced by baseline platelet count. What we show in this analysis is that momelotinib’s safety and activity profile do not appear to be affected by baseline platelet count, while in contrast, activity with ruxolitinib declined in patients with lower baseline platelet counts," said Dr. Kiladjian. "These updated data analyses complement previous findings that demonstrate the ability to initiate and maintain near-maximal momelotinib dose intensity regardless of baseline platelet count, suggesting that this durable dosing contributes to its efficacy profile."

"These exciting data provide a novel insight into a patient population where momelotinib’s unique receptor inhibition profile—JAK1, JAK2 & ACVR1—may be particularly relevant. The observation of preserved activity in patients with reduced platelet counts is provocative and potentially differentiating. The wealth of information contained in the SIMPLIFY studies will enable further analyses and potentially identify additional populations of interest to be presented at future scientific meetings," said Stephen Dilly, MBBS, PhD, Chief Executive Officer at Sierra Oncology. "We now look forward to completing enrollment in the pivotal Phase 3 MOMENTUM study and subsequent topline data to support our plan to file for regulatory approval of momelotinib for the treatment of myelofibrosis."

Momelotinib’s Spleen, Symptom and Anemia Efficacy is Maintained in Intermediate/High Risk Myelofibrosis Patients with Thrombocytopenia (Abstract #3086)

Dr. Kiladjian presented comparative efficacy data for momelotinib and ruxolitinib in patients with low platelets from the SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) Phase 3 studies. Results from the updated analyses include:

In S1 (JAKi-naïve), patients whose baseline platelet counts were:
<150 x 109/L, momelotinib achieved substantially higher TI (62% vs. 42%) and splenic response rates (23% vs. 4%) and a similar symptomatic response (28% vs. 33%) relative to ruxolitinib
150-300 x 109/L, generally similar splenic (35% vs. 32%) and symptom response rates (33% vs. 41%) and a higher TI response rate (72% vs. 54%) were achieved with momelotinib relative to ruxolitinib
>300 x 109/L, ruxolitinib achieved higher splenic (44% vs. 19%) and symptom response rates (46% vs. 23%) at week 24 than with momelotinib; the Week 24 TI rate remained higher with momelotinib (63% vs. 51%)
In S2 (JAKi-exposed patients):
Momelotinib’s response rates for the 3 response parameters remain very consistent with overall ITT response rates in patients whose baseline platelets were <150 x 109/L
Momelotinib’s symptomatic and anemia benefit were also preserved in patients whose baseline platelet counts were <50 and >50-100 x 109/L
In both S1 and S2, rates of TEAEs on momelotinib were generally similar between the overall safety population and subjects with baseline platelets <150 x 109/L
Patients were randomized 1:1 (S1) and 2:1 (S2) to receive momelotinib (200 mg QD) versus ruxolitinib (20 mg BID) or best available therapy (88.5% RUX/RUX+) for 24 weeks followed by extended momelotinib treatment. A baseline platelet limit of >50 x 109/L was required in S1 while there was not lower platelet limit for S2. Both trials had primary endpoints of Splenic Response Rate and secondary endpoints of Total Symptom Score and Transfusion Independence Rate.

About Momelotinib

Momelotinib is a selective and orally bioavailable JAK1, JAK2 and ACVR1 inhibitor currently under investigation for the treatment of myelofibrosis. Myelofibrosis results from dysregulated JAK-STAT signaling and is characterized by constitutional symptoms, splenomegaly (enlarged spleen) and progressive anemia.

Momelotinib is currently under investigation in the MOMENTUM clinical trial, a global, randomized, double-blind Phase 3 study for symptomatic and anemic myelofibrosis patients. Top-line data are anticipated in H1 2022. The U.S. Food & Drug Administration has granted Fast Track designation for momelotinib.

On December 7, 2020 Celyad Oncology SA (Brussels:CYAD) (Paris:CYAD) (NASDAQ:CYAD) (Euronext & Nasdaq: CYAD), a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer, reported updates from the company’s shRNA-based anti-B cell maturation antigen (BCMA) allogeneic CAR T candidate, CYAD-211, and autologous NKG2D receptor-based CAR T candidates, CYAD-01 and CYAD-02 (Press release, Celyad, DEC 7, 2020, View Source [SID1234572341]). These updates were virtually presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, held from December 5-8, 2020.

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"The recent announcement of the dosing of our first patient with CYAD-211 in the IMMUNICY-1 trial was a major milestone for the organization as we continue to strategically focus on next-generation allogeneic CAR T cell therapies underpinned by our innovative shRNA technology platform that we took from concept to clinic in just two years," said Filippo Petti, Chief Executive Officer of Celyad Oncology. "With IMMUNICY-1, we’re not only looking to offer patients with refractory multiple myeloma an option where few exist, but also to use this as an opportunity to validate the use of our shRNA platform as a novel allogeneic technology in what we believe could greatly expand our potential to develop best-in-class, off-the-shelf CAR T cell therapies."

Mr. Petti added, "While we are disappointed by the latest update from the Phase 1 THINK trial for CYAD-01, we are encouraged by the initial clinical results from our next-generation CYAD-02 candidate for the treatment of patients with relapsed or refractory AML and MDS and look forward to future updates from the CYCLE-1 trial. With greater perspective on our autologous programs, the organization will remain steadfast in our commitment to patients with cancer by continuing to concentrate on the discovery and development of novel, allogeneic CAR T candidates."

CYAD-211 and IMMUNICY-1 Phase 1 Trial Update

Background

CYAD-211 is a first-in-class, allogeneic CAR T candidate engineered to co-express a BCMA targeting chimeric antigen receptor and a single shRNA, which interferes with the expression of the CD3ζ component of the T cell receptor complex.
IMMUNICY-1 will evaluate the safety and clinical activity of a single infusion of CYAD-211 following preconditioning chemotherapy cyclophosphamide and fludarabine in patients with relapsed/refractory multiple myeloma (r/r MM).
The trial seeks to determine the recommended dose of CYAD-211 in r/r MM patients for further development as well as to establish proof-of-principle that single shRNA-mediated knockdown can generate allogeneic CAR T cells in humans without inducing Graft-versus-Host Disease (GvHD).
On December 4, 2020, the company announced dosing of the first patient in the CYAD-211 Phase 1 IMMUNICY-1 trial.
Preclinical Results

CYAD-211 demonstrated robust anti-tumor activity in vitro and in vivo concurrent with lack of alloreactivity in preclinical MM models.
No demonstrable evidence of GvHD was observed with CYAD-211 in preclinical models confirming efficient inhibition of alloreactivity.
Study Design

The IMMUNICY-1 trial is a first-in-human, open-label dose-finding study evaluating three dose levels of CYAD-211, including 3×107, 1×108 and 3×108 cells per infusion, in patients with r/r MM.
Next Steps

Proof-of-principle data from the initial dose cohorts are expected during first half 2021.
Clinical activity data from the full dose-escalation trial are expected during second half 2021.
CYAD-01 and THINK Phase 1 Trial Update

Background

The company’s first generation NKG2D receptor-based CAR T clinical candidate CYAD-01 was evaluated for the treatment of patients with r/r acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in the Phase 1 THINK trial.
In 2019, the company implemented the OptimAb manufacturing process within the CYAD-01 program, to be evaluated in the study expansion cohort of the THINK trial. The trial intended to assess the safety and clinical activity of CYAD-01 when produced with the OptimAb process following no preconditioning chemotherapy.
Latest Clinical Data

Overall, eight of the eleven patients planned per protocol in the THINK trial were treated with OptimAb-produced CYAD-01 cells.
No dose-limiting toxicities were reported from patients treated with OptimAb-produced CYAD-01 cells.
Stable disease (SD) was achieved in two of eight patients treated with OptimAb-produced CYAD-01 cells (one MDS and one AML patient); an additional MDS patient became eligible for an allogeneic stem cell transplantation after treatment with CYAD-01 and achieved a complete response. No objective responses were observed following treatment with OptimAb-produced CYAD-01 cells.
Next Steps

Based on clinical futility observed to date of CYAD-01 from the Phase 1 THINK trial the company has decided to discontinue the development of CYAD-01 for the treatment of r/r AML / MDS. No additional patients will be enrolled in the CYAD-01 program.
CYAD-02 and CYCLE-1 Phase 1 Trial Update

Background

In November 2019, the company initiated the dose-escalation Phase 1 CYCLE-1 trial, evaluating the safety and clinical activity of the next-generation, autologous NKG2D receptor-based CAR T candidate CYAD-02 following preconditioning chemotherapy in patients with r/r AML / MDS.
The next-generation, NKG2D receptor-based CAR T candidate CYAD-02 incorporates shRNA to target the NKG2D ligands MICA and MICB. In preclinical models, shRNA-mediated knockdown of MICA and MICB expression on NKG2D receptor-based CAR T cells has shown enhanced in vitro expansion, as well as enhanced in vivo engraftment and persistence of the CAR T cells, as compared to first-generation NKG2D receptor-based CAR T cells.
Preliminary Clinical Data

To date, nine patients have received treatment with CYAD-02: three patients at dose level 1, three patients at dose level 2 and three patients at dose level 3.
CYAD-02 was generally well-tolerated, with one grade 4 infusion reaction (dose level 1) and one grade 3 cytokine release syndrome (dose level 3). Both patients recovered rapidly following the appropriate treatment.
To date, seven patients were evaluable for clinical activity:
Of the five very high-risk MDS patients: (i) three patients demonstrated anti-leukemic activity (at least 50% bone marrow blasts decrease) with the single patient evaluated at dose level 3 achieved a marrow complete response (mCR) at first assessment (ongoing); (ii) two additional patients exhibited a durable SD of more than five months (one of two ongoing).
Of the two adverse AML patients, one patient demonstrated anti-leukemic activity with a SD of four months (ongoing).
Next Steps

The dose level 3 cohort of the CYCLE-1 trial is ongoing. Additional safety and efficacy data from the trial are expected during the first half of 2021.
Conference Call and Webcast Details

Celyad Oncology will host a conference call to discuss the update from ASH (Free ASH Whitepaper) on Monday, December 7, 2020 at 1 p.m. CET / 7 a.m. ET. The conference call can be accessed through the following numbers:

United States: +1 877 407 9716
International: +1 201 493 6779

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events" section of the company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.

About CYAD-211

CYAD-211 is an investigational, short hairpin RNA (shRNA)-based allogeneic CAR T candidate for the treatment of relapsed or refractory multiple myeloma (r/r MM). CYAD-211 is engineered to co-express a BCMA targeting chimeric antigen receptor and a single shRNA, which interferes with the expression of the CD3ζ component of the T cell receptor (TCR) complex. In July 2020, Celyad Oncology announced FDA Clearance of its IND application for CYAD-211.

About CYAD-01

CYAD-01 is an investigational CAR T therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) based on NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells.

About CYAD-02

CYAD-02 is an investigational CAR T therapy that engineers an all-in-one vector approach in patient’s T cells to express both (i) the NKG2D chimeric antigen receptor (CAR), a receptor expressed on natural killer cells that binds to eight stress-induced ligands expressed on tumor cells, and (ii) short hairpin RNA (shRNA) SMARTvector technology licensed from Horizon Discovery to knockdown the expression of NKG2D ligands MICA and MICB on the CAR T cells. In preclinical models, shRNA-mediated knockdown of MICA and MICB expression on NKG2D CAR T cells has shown enhanced in vitro expansion, as well as enhanced in vivo engraftment and persistence, of the CAR T cells, as compared to first-generation NKG2D receptor based CAR T cells.

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 clinical data on its BTK inhibitor BRUKINSA (zanubrutinib) in two posters at the 62nd American Society for Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, including results from a Phase 2 trial in patients with relapsed/refractory (R/R) B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib and the first results from a pivotal Phase 2 trial in patients with R/R Waldenström’s Macroglobulinemia (WM) that were included in a supplemental new drug application of BRUKINSA currently under priority review in China (Press release, BeiGene, DEC 7, 2020, View Source [SID1234572357]).

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"Tolerability of treatments for B-cell malignancies is an important consideration with BTK inhibition, and BRUKINSA was designed with that in mind to maximize BTK occupancy and minimize off-target effects. Following on the results of the Phase 3 ASPEN trial, in which BRUKINSA demonstrated advantages in safety and tolerability compared to ibrutinib in patients with WM, we’re excited to learn from the Phase 2 trial that BRUKINSA was tolerable and showed activity in patients who discontinued treatment with ibrutinib and/or acalabrutinib due to adverse events," said Jane Huang, M.D., Chief Medical Officer, Hematology at BeiGene. "Additionally, we reported data from our pivotal Phase 2 trial in China in patients with relapsed/refractory WM, which showed deep responses in a difficult-to-treat patient population. With a growing clinical development team across the globe, we look forward to continuing to advance our clinical program for BRUKINSA."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual booth at this year’s ASH (Free ASH Whitepaper) Annual Meeting at View Source

Phase 2 Trial of Zanubrutinib in Patients with Previously Treated B-Cell Malignancies Intolerant to Ibrutinib and/or Acalabrutinib

Abstract 2947

This single-arm, open-label, multicenter Phase 2 trial in the U.S. (NCT04116437) was designed to evaluate the safety and efficacy of BRUKINSA in patients with previously treated B-cell malignancies who were intolerant to prior treatment with ibrutinib and/or acalabrutinib. The primary endpoint of safety was assessed by the recurrence and the change in severity of adverse events (AEs) compared to patients’ intolerance AE profile to ibrutinib and/or acalabrutinib. Secondary endpoints included investigator-assessed overall response rate (ORR), investigator-assessed progression-free survival (PFS) and patient-reported outcomes. A total of 60 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), WM, mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL) intolerant to ibrutinib and/or acalabrutinib were enrolled in this trial.

"BTK inhibitors are an emerging standard of care in B-cell malignancies, but off-target effects have been implicated in adverse events – the most common reason for treatment discontinuation. Data from 32 evaluable patients in this trial demonstrated that some intolerable adverse events that patients experienced on other BTK inhibitors did not recur with zanubrutinib treatment, and that it was generally well-tolerated among these patients," commented Mazyar Shadman, M.D., MPH, Associate Professor of Clinical Research Division at Fred Hutchinson Cancer Research Center and Assistant Professor of Oncology at University of Washington.

At the data cutoff on August 28, 2020, with a median zanubrutinib exposure of 3.5 months, safety results from 32 evaluable patients included:

In 32 patients previously treated with and intolerant to ibrutinib, there were 66 intolerant events, 58 (88%) of which did not recur with zanubrutinib treatment; of the eight intolerant events that recurred, seven recurred at a lower grade in severity and one at the same grade;
In two patients previously treated with and intolerant to acalabrutinib, there were four intolerant events, two of which did not recur (both arthralgia) with zanubrutinib treatment; of the two intolerant events that recurred, one recurred at a lower grade in severity and one at the same grade;
Of the 25 Grade 3 intolerant events on ibrutinib and/or acalabrutinib, 23 did not recur with zanubrutinib treatment;
Of the four Grade 4 intolerant events, which were neutropenia (n=2), increased alanine aminotransferase (ALT) (n=1), and increased aspartate aminotransferase (AST) (n=1), none recurred with zanubrutinib treatment;
26 patients experienced at least one AE of any grade on zanubrutinib, with the most common (≥10.0%) being myalgia (21.9%), contusion (18.8%), cough (15.6%), dizziness (15.6%), and fatigue (12.5%);
Eight patients experienced bleeding events on zanubrutinib, all in low-grade severity;
Atrial fibrillation did not recur in six patients who were intolerant to ibrutinib due to atrial fibrillation. Atrial fibrillation and flutter recurred in one patient (3.1%) who was previously treated with and intolerant to ibrutinib at a lower severity (Grade 2 on zanubrutinib vs. Grade 3 on ibrutinib) with a shorter duration (3 days on zanubrutinib vs. 14 days on ibrutinib);
Three patients experienced at least one Grade ≥3 AE, including neutropenia (n=2) and syncope (n=1); and
No serious adverse events (SAEs) or treatment discontinuation due to AEs were reported.
Among the 18 patients who were evaluable for response at the time of data cutoff (13 for CLL, 4 for SLL and 1 for MCL), 17 maintained (n=8) or improved (n=9) responses on zanubrutinib. With the median time to first response being 12.6 weeks, the ORR was 50%, including six (33.3%) PRs and three (16.7%) PRs with lymphocytosis.

Pivotal Phase 2 Trial of Zanubrutinib in Patients with R/R WM in China

Abstract 2940

Data from this single-arm, open-label, multicenter, pivotal Phase 2 trial (NCT03332173) showed that R/R WM patients in China were able to achieve deep, quick, and durable responses on zanubrutinib. A total of 44 patients were enrolled in the trial, including 20 with high risk and 13 with intermediate risk based on WM prognostic scoring, and 43 patients were evaluable for efficacy.

"From the results of the BGB-3111-210 trial, we were encouraged to see a major response rate of nearly 70 percent and a median time to major response under three months, which means zanubrutinib was able to quickly induce deep responses in these WM patients, most of whom were determined to have intermediate to high risks based on the prognostic score," said Lugui Qiu, M.D., Director at Department of Lymphoma in Chinese Academy of Medical Sciences Blood Diseases Hospital and leading Principal Investigator of the trial. "Zanubrutinib also demonstrated a safety profile consistent with previous reports in WM. We hope this BTK inhibitor will become a new effective treatment option for WM patients in China in the near future."

At the data cutoff on August 31, 2019, 27 patients remained on study treatment. With a median follow-up time of 18.58 months, results included:

Major response rate (MRR), defined as partial response or better, was 69.8% (95% CI: 53.9, 82.8), including 32.6% very good partial responses (VGPRs) and 37.2% partial responses (PRs); ORR, defined as minor response or better, was 79.1% (95% CI: 64.0, 90.0);
The median time to VGPR and overall response was 2.87 months and 2.76 months, respectively;
Median progression free survival (PFS) and duration of major response (DOMR) were not reached;
The most common (≥20.0%) treatment-emergent adverse events (TEAEs) of any grade were decreased neutrophil count (56.8%), decreased platelet count (29.5%), decreased white blood cell count (27.3%), upper respiratory tract infection (27.3%), diarrhea (25.0%), weight increase (20.5%), and arthralgia (20.5%);
72.7% of patients experienced at least one Grade ≥3 TEAE, with the most common (≥10.0%) being decreased neutrophil count (31.8%), decreased platelet count (20.5%), lung infection (13.6%), and decreased white blood cell count (11.4%);
50.0% of patients experienced at least one serious TEAE and 11.4% of patients discontinued treatment due to TEAEs; and
4.5% of patients experienced a fatal TEAE, with one patient caused by multiple organ dysfunction syndrome and acute hepatitis B, and the other one being death with unknown reason, which was considered by investigator to be caused by progression of WM and accompanying respiratory failure.
About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK), discovered by BeiGene scientists, that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA was approved by the U.S. FDA in November 2019 to treat adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

BRUKINSA was approved in China in June 2020 for the treatment of MCL in adult patients who have received at least one prior therapy and the treatment of CLL/SLL in adult patients who have received at least one prior therapy. A supplemental new drug application (sNDA) of BRUKINSA in patients with relapsed/refractory Waldenström’s macroglobulinemia (WM) has been accepted by the Center for Drug Evaluation (CDE) of the NMPA and is currently under priority review.

A marketing authorization application (MAA) for BRUKINSA for the treatment of patients with WM who have received at least one prior therapy or as first-line treatment for patients unsuitable for chemo-immunotherapy has been accepted by the European Medicines Agency (EMA).

In addition, multiple regulatory filings of BRUKINSA have been accepted in other countries and are currently under review.

BRUKINSA is not approved outside of the United States and China.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%), and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for at least 1 week after the last dose. Advise men to avoid fathering a child during treatment and for at least 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Of the 118 patients with MCL treated with BRUKINSA, 8 (7%) patients discontinued treatment due to adverse reactions in the trials. The most frequent adverse reaction leading to treatment discontinuation was pneumonia (3.4%). One (0.8%) patient experienced an adverse reaction leading to dose reduction (hepatitis B).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For co-administration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid co-administration with moderate or strong CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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 Oncopeptides AB (publ) (Nasdaq Stockholm: ONCO), a pharmaceutical company focused on the development of targeted therapies for difficult-to-treat hematological diseases reported updated efficacy and safety data from the ongoing phase 2 ANCHOR combination study, following an oral presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) virtual annual meeting (Press release, Oncopeptides, DEC 7, 2020, View Source [SID1234572395]). The data showed that a triplet regimen with melflufen (INN melphalan flufenamide) plus dexamethasone in combination with daratumumab or bortezomib in heavily pretreated patients with relapsed refractory multiple myeloma, demonstrated encouraging activity, was well tolerated and had a similar safety profile as when used as a doublet regimen with only melflufen plus dexamethasone. The severe treatment related adverse events reported were primarily hematologic and were clinically manageable with dose reduction.

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The primary objective of the phase 2 ANCHOR study is overall response rate, and a secondary objective is progression free survival. The data represents an analysis of both treatment arms, with a cut-off date of October 19, 2020. The overall response rate for melflufen plus dexamethasone was 73% in combination with daratumumab and 62% in combination with bortezomib. The median progression free survival was 12.9 months when combined with daratumumab. The recommended dose of melflufen for future studies with daratumumab shall be 30 mg. Since the bortezomib arm of ANCHOR still is recruiting, progression free survival has not been reported and the recommended phase 2 dose is yet to be determined. The recruitment is expected to be completed in 2021.

"The ANCHOR data are very promising: both combinations are well tolerated and demonstrated encouraging activity. The data support further development of melflufen in triplet regimens", says Klaas Bakker, MD, PhD, Chief Medical Officer, Oncopeptides AB. "This provides a clear rational for our larger randomized phase 3 LIGHTHOUSE study, which compares melflufen and dexamethasone with subcutaneous daratumumab vs. subcutaneous daratumumab alone. We are preparing study start in close dialogue with relevant authorities and expect to enroll the first patient during the first quarter of 2021".

ANCHOR is a phase 1/2 open label multicenter study evaluating the safety and efficacy of melflufen plus dexamethasone in combination with either daratumumab or bortezomib in patients with relapsed refractory multiple myeloma, who have undergone 1-4 prior lines of therapy. The patients are refractory to an immunomodulatory drug and/or a proteasome inhibitor. They have not received any prior anti-CD38 monoclonal antibody therapy.