On May 25, 2023 Bristol Myers Squibb (NYSE: BMY) reported first results from the Phase 3 COMMANDS study, an open-label, randomized trial evaluating Reblozyl(luspatercept-aamt) versus epoetin alfa, an erythropoiesis-stimulating agent (ESA), for the treatment of anemia in adult patients with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) who require red blood cell (RBC) transfusions and are ESA-naïve (Press release, Bristol-Myers Squibb, MAY 25, 2023, View Source [SID1234632049]). Results from the study will be featured as part of the press program at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 2, 3 p.m. EDT (Abstract #7003), and in an oral presentation of select abstracts during a plenary session at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress on June 10, 2:45 p.m. CEST (Abstract #S102).

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"Chronic anemia, low hemoglobin levels and transfusion dependency are the primary clinical challenges for patients with lower-risk MDS, increasing the risk of death by more than half compared to those who do not require transfusions," said Guillermo Garcia-Manero, M.D., lead investigator and Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center. "Results from the COMMANDS study showed treatment with Reblozyl compared to epoetin alfaled to superior and statistically significant improvements in red blood cell transfusion independence and hemoglobin increase, improvements in response durability, and equal or better outcomes across all subgroups, with acceptable safety and tolerability for patients with ESA-naïve, lower-risk MDS."

The primary endpoint evaluated in the COMMANDS study is RBC transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin increase of ≥1.5 g/dL. Key secondary endpoints include erythroid response (HI-E) of at least 8 weeks during weeks 1-24 of the study, RBC-TI ≥12 weeks and RBC-TI for 24 weeks. Eligible patients were ≥18 years old with lower-risk MDS who require transfusions. Patients were randomized 1:1 to receive subcutaneous Reblozyl (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥24 weeks.

COMMANDS Study Results at ASCO (Free ASCO Whitepaper)
At the time of the interim analysis, 147 evaluable patients received Reblozyl and 154 evaluable patients received epoetin alfa, with median treatment durations of 41.6 and 27 weeks, respectively. Results showed 58.5% (n=86) of patients receiving Reblozyl vs. 31.2% (n=48) of patients receiving epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with concurrent mean hemoglobin (Hb) increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001). HI-E increase of at least 8 weeks was achieved by 74.1% (n=109) of Reblozyl patients vs. 51.3% (n=79) of epoetin alfa patients (p<0.0001). Patients treated with Reblozyl achieved more durable responses vs. epoetin alfa, with a median duration of response of RBC-TI ≥12 weeks (Week 1 to end of treatment) of 126.6 vs. 77 weeks. Within the first 24 weeks of treatment, RBC-TI of at least 24 weeks was achieved by 47.6% (n=70) of Reblozyl patients vs. 29.2% (n=45) of epoetin alfa patients (P=0.0006). Benefit with Reblozyl was also observed in clinically relevant subgroups, and results showed a consistent safety profile and no new safety signals.

COMMANDS Study – ASCO (Free ASCO Whitepaper) Oral Presentation #7003

Safety

Hematology-related treatment emergent adverse events (TEAEs)

Reblozyl

(n=178)

Epoetin alfa

(n=176)

Anemia

9.6% (17)

9.7% (17)

Thrombocytopenia

6.2% (11)

1.7% (3)

Neutropenia

5.1% (9)

7.4% (13)

Most common TEAEs

Fatigue

14.6% (26)

6.8% (12)

Diarrhea

14.6% (26)

11.4% (20)

Peripheral edema

12.9% (23)

6.8% (12)

Efficacy

Reblozyl

(n=147)

Epoetin alfa

(n=154)

Primary Endpoint

Red blood cell transfusion independence (RBC-TI) (≥12 weeks with mean hemoglobin (Hb) increase ≥1.5 g/dL)

58.5% (86)

31.2% (48)

p<0.0001

Secondary Endpoints

Hematologic improvement-erythroid (HI-E) ≥8 weeks

74.1% (109)

51.3% (79)

p<0.0001

RBC-TI, 24 weeks

47.6% (70)

29.2% (45)

p=0.0006

RBC-TI ≥12 weeks

66.7% (98)

46.1% (71)

p=0.0002

Association of Baseline Characteristics

Reblozyl

n/N (%)

Epoetin alfa

n/N (%)

Risk Difference

(95% CI)

Serum erythropoietin (sEPO) ≤200 U/L

74/118 (62.7%)

44/121 (36.4%)

26.35 (12.78 to 38.41)

sEPO >200 U/L

12/29 (41.4%)

4/33 (12.1%)

29.26 (6.35 to 50.83)

Ring sideroblast +

70/108 (64.8%)

29/112 (25.9%)

38.92 (25.87 to 50.70)

Ring sideroblast –

16/39 (41.0%)

19/41 (46.3%)

-5.32 (-27.71 to 16.74)

SF3B1 mutated

64/92 (69.6%)

27/88 (30.7%)

38.88 (24.13 to 51.91)

SF3B1 non-mutated

22/53 (41.5%)

20/62 (32.3%)

9.25 (-8.73 to 26.87)

COMMANDS Study Results at EHA (Free EHA Whitepaper)
Data to be presented at EHA (Free EHA Whitepaper) included both efficacy and safety consistent with results at ASCO (Free ASCO Whitepaper), and showed Reblozyl demonstrated favorable outcomes compared to epoetin alfa across common MDS mutations (SF3B1, SF3B1a, ASXL1, TET2, DNMT3A, EZH2, IDH2, U2AF1) and had a higher probability of achieving clinical benefit, regardless of overall mutational burden.

COMMANDS Study – EHA (Free EHA Whitepaper) Oral Presentation #S102

Association of MDS-Related Mutations

Reblozyl

n/N

Epoetin alfa

n/N

Risk Difference

95% CI

ASXL 1

15/31

3/29

0.38 (0.17 to 0.59)

CBL

0/5

2/5

-0.40 (-0.85 to 0.05)

DNMT3A

19/28

11/25

0.24 (-0.02 to 0.50)

DTA.SF3B1.n

12/31

12/40

0.09 (-0.14 to 0.31)

EZH2

5/10

2/9

0.28 (-0.13 to 0.69)

IDH2

3/6

1/5

0.30 (-0.23 to 0.83)

RUNX1

1/4

0/9

0.25 (-0.17 to 0.67)

SF3B1

64/92

27/90

0.40 (0.26 to 0.53)

SF3B1.alpha

41/55

16/55

0.45 (0.29 to 0.62)

SF3B1.beta

1/4

0/8

0.25 (-0.18 to 0.68)

SRSF2

5/14

2/14

0.21 (-0.10 to 0.53)

TET2

30/48

16/53

0.32 (0.14 to 0.51)

U2AF1

6/16

4/19

0.16 (-0.14 to 0.46)

A supplemental Biologics License Application for Reblozyl is currently under Priority Review with the U.S. Food and Drug Administration (FDA)for treatment of anemia in ESA-naïve adult patients with very low- to intermediate-risk MDS who may require RBC transfusions with an assigned Prescription Drug User Fee Act (PDUFA) goal date of August 28, 2023. The European Medicines Agency has also validated the Type II Variation for Reblozyl in this patient population. Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021.

"Clinical experience has demonstrated that just one in three patients with low-risk myelodysplastic syndromes experience responses to erythroid stimulating agents over 6-18 months, leaving a significant need for more effective options to address chronic anemia," said Matteo Giovanni Della Porta, study investigator and head of Leukemia Unit at Humanitas Cancer Center in Milan, Italy. "In the COMMANDS study, the median duration of red blood cell transfusion independence was nearly one year longer with Reblozyl than with epoetin alfa and showed safety consistent with its known profile, demonstrating its potential as a first-line treatment in patients with transfusion-dependent, very low- to intermediate-risk MDS."

"Results being presented at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) reinforce the notion that Reblozyl should be used as the initial treatment of anemia in patients with lower- to intermediate-risk myelodysplastic syndromes," said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. "As a potentially more effective and durable upfront treatment option, Reblozyl could shift the paradigm for standard of care among these patients."

About MDS

Myelodysplastic syndromes (MDS) are a group of closely related blood cancers characterized by ineffective production of healthy red blood cells (RBC), white blood cells and platelets, which can lead to anemia and frequent or severe infections.1,2 People with MDS who develop anemia often require regular blood transfusions to increase the number of healthy red blood cells in circulation.3 Frequent transfusions are associated with an increased risk of iron overload, transfusion reactions and infections.4 Patients who become RBC transfusion-dependent have a significantly shorter overall survival than those who are not dependent on transfusions, partially due to iron overload or to more severe bone marrow disease than in non-transfusion dependent patients.5

About Reblozyl(luspatercept-aamt)

Reblozyl, a first-in-class therapeutic option, promotes late-stage red blood cell maturation in animal models.6 Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. Reblozyl is currently approved in the U.S. for the treatment of:

anemia in adult patients with beta thalassemia who require regular red blood cell transfusions, and
anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndrome with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
Reblozyl is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia. In the U.S., Reblozyl is not indicated for use in patients with non-transfusion-dependent beta thalassemia.

U.S. Important Safety Information

WARNINGS AND PRECAUTIONS

Thrombosis/Thromboembolism

In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.

Hypertension

Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.

Extramedullary Hematopoietic Masses (EMH)

In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study).

In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double- blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia.

Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses.

Embryo-Fetal Toxicity

REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post- implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.

ADVERSE REACTIONS

Beta Thalassemia

Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML).

Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%).

Myelodysplastic Syndromes

Grade ≥3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients.

The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection.

LACTATION

It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.

Please see full Prescribing Information and Summary of Product Characteristics for REBLOZYL.

On May 25, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported updated results from Phase 2 (Part A segment) of the RINGSIDE study evaluating AL102 in desmoid tumors (Press release, Ayala Pharmaceuticals, MAY 25, 2023, View Source [SID1234632048]). The results are summarized in an abstract published today for the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. More detailed results will be featured in a poster session at ASCO (Free ASCO Whitepaper) on Saturday, June 3. AL102 is a once-daily, potent, selective, oral gamma-secretase inhibitor (GSI).

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"This latest data cut includes data from all 42 patients enrolled in the Phase 2 study portion of this trial and shows compelling evidence of anti-tumor activity for all tested dose regimens of AL102 across multiple measures, including RECIST-based response rate, disease control rate and reduction in tumor volume per blinded independent central review," said Andres Gutierrez, MD, PhD, Executive Vice President & Chief Medical Officer of Ayala. "In addition, there appears to be a consistent pattern of deeper and faster responses in the 1.2 mg once-daily group, the selected Phase 3 dose, versus the biweekly regimen groups. We are also encouraged to see that AL102 continues to be generally well tolerated and has a manageable safety profile as seen in all three dose arms. There have been no new safety signals, and the safety results appear consistent with the GSI class. Overall, the data continuing to emerge from RINGSIDE support our belief that AL102 has the potential to become a valuable treatment option for people living with desmoid tumors as it may have important clinical advantages along with convenient once-daily dosing, which may improve treatment adherence and patient satisfaction."

RINGSIDE Study Highlights

The ongoing Phase 2/3 RINGSIDE clinical trial is a randomized, global multi-center study evaluating AL102 in patients with progressing desmoid tumors. The study consists of two parts: Phase 2 (Part A) is an open-label, dose regimen finding study, and Phase 3 (Part B) is a double blind, placebo-controlled study and Open Label Extension utilizing the 1.2 mg once daily dose regimen selected based on data from Phase 2.

Enrollment of all 42 patients into Phase 2 was completed as of March 2022. Patients were randomized to one of three dose regimens of AL102 (n=14 each), including 1.2 mg once-daily (QD), 4 mg twice a week (BIW) or 2 mg BIW. As of January 3, 2023, median time on study was 10.3 months (range 0.8 – 14.7) and 30 patients were still on study,10 of whom rolled over to the open label extension.

Efficacy Results

In the evaluable patient population, partial responses were observed in 50% of patients (i.e., 6 out of 12) in the 1.2 mg QD group, 23.1% of patients (3/13) in the 4 mg BIW group, and 45.5% of patients (5/11) in the 2 mg BIW group. Responses were assessed by blinded independent central review (BICR).
In the intention-to-treat (ITT) population, partial responses were observed in 43% of patients (i.e., 6/14) in the 1.2 mg QD group, 21.4% of patients (3/14) in the 4 mg BIW group, and 36% (5/14) in the 2 mg BIW group. Responses were assessed by BICR.
Median volume changes, assessed by BICR, from baseline to week 16 were -51.9% for 1.2 mg QD, -9.5% for 4 mg BIW, and -15.2% for 2 mg BIW.
Median tumor volume changes from baseline to week 28 were -76.4%, -35.5%, and -51.2%, respectively, for the 1.2 mg QD, 4 mg BIW and 2 mg BIW dose groups.
Similar patterns were observed for percentage changes from baseline in T2 signal intensity, suggesting reduction of cell density within the tumor.
Disease control rates (partial response + stable disease) were 100%, 91%, and 97% in the evaluable patients in the 1.2mg QD, 4 mg BIW and 2 mg BIW dose groups, respectively.
Safety

AL102 was generally well tolerated with a manageable safety profile across all dose arms. The safety profile was consistent with the GSI class of drugs.
Regardless of dose regimen, adverse events (AEs) were predominantly Grade 1 (~70%) or Grade 2 (~20%). There were no Grade 4 or Grade 5 related AEs. Serious AEs were reported in 6 of 42 patients (14%) and assessed as unrelated to AL102 by investigators. There were no new safety signals.
Discontinuation due to AEs occurred in 6 of 42 (14%) patients. These were due to Grade 2 rash, keratitis, stomatitis, diarrhea, ALT elevation. All occurred within 3 months of treatment initiation.
Ovarian dysfunction was reported in 11 of 23 (48%) women of childbearing potential across all dose arms, but in only 3 of 9 (33%) women who received the 1.2 mg once-daily dose.
The registration-enabling Phase 3 segment is enrolling patients globally. For more information on RINGSIDE, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

Poster Presentation Details

The poster (abstract # 11515, Poster Bd # 449 in Hall A) will be available for viewing 1.15pm – 4:15pm CT Saturday, June 3, 2023. In addition to the presentation of the study in the poster hall, Elizabeth J. Davis, M.D. of Vanderbilt University Medical Center, will highlight and discuss this and other selected abstracts in the Poster Discussion Session S404 Primary track: Sarcoma, 4:30 pm CT on the same day. The focus of this session will be on how the findings apply to clinical practice and future research. Dr. Davis and the abstract presenters will answer questions during a moderated panel discussion.

A copy of the poster will be available on the Ayala corporate website, under Events & Presentations, following the presentation at ASCO (Free ASCO Whitepaper).

About Desmoid Tumors

Desmoid tumors, also called aggressive fibromatosis or desmoid-type fibromatosis, are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, mesenteric root, and chest wall, or other parts of the body. Desmoid tumors do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. People living with desmoid tumors are often limited in their daily life due to chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. Desmoid tumors have an annual incidence of approximately 1,700 patients in the United States and typically occur in patients between the ages of 15 and 60 years. They are most commonly diagnosed in young adults between 30-40 years of age and are more prevalent in females. Today, surgery is no longer regarded as the cornerstone treatment of desmoid tumors due to surgical morbidity and a high rate of recurrence post-surgery. There are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

About AL102

AL102 is an investigational small molecule gamma secretase inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in the Phase 2/3 RINGSIDE clinical studies in patients with progressing desmoid tumors. AL102 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL102 from Bristol-Myers Squibb Company in November 2017. AL102 was granted U.S. FDA Fast Track Designation for the treatment of DT.

On May 25, 2023 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported the presentation of new data showcasing the range of BeiGene’s research expertise and the productivity of one of the industry’s largest research and development teams at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, BeiGene, MAY 25, 2023, View Source [SID1234632046]). These results include data for BeiGene’s cornerstone therapies, BRUKINSA (zanubrutinib) and tislelizumab, as well as early results for BeiGene’s OX40 agonist and BCL-2 inhibitor.

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"The data presented at ASCO (Free ASCO Whitepaper) demonstrate the strength of BeiGene’s oncology portfolio, from early data supporting the differentiated biological hypotheses for our BCL-2 inhibitor and OX40 agonist and continuing results from the global development programs for our innovative medicines, BRUKINSA and tislelizumab, as monotherapies and in combination regimens," said Lai Wang, Ph.D., Global Head of R&D at BeiGene. "At BeiGene, we believe the patients we serve come first, and we will continue to partner with patients to advance innovative potential best- and first-in-class medicines."

For more information on BeiGene’s clinical program and company updates, please visit BeiGene’s virtual ASCO (Free ASCO Whitepaper) booth: www.BeiGeneVirtualExperience.com.

Cornerstone Medicines Continue to Demonstrate Consistent Safety and Efficacy Profile

In a risk factor analysis of RATIONALE-301, a Phase 3 study of tislelizumab vs sorafenib as first-line treatment of unresectable hepatocellular carcinoma, tislelizumab demonstrated numerically longer median overall survival (OS) versus sorafenib in the biomarker subgroups of ALBI grade 1 (19.9 months vs. 16.9 months), PLR ≤141 (19.4 months vs. 14.5 months), and NLR ≤3 (20.9 months vs. 15.2 months), suggesting the potential for prognostic value.

In a European/North American (EU/NA) subgroup analysis of RATIONALE-301, numerically longer median OS, median duration of response, and a higher objective response rate (ORR) were seen with tislelizumab versus sorafenib. Notably, the EU/NA subgroup had a higher rate of patients with non-viral etiology and a slightly lower number of patients with advanced-stage disease (BCLC Stage C) compared with the overall population from RATIONALE-301.

Additionally, incidence of grade ≥3 treatment-emergent adverse events (TEAEs; 46% vs 66%), grade ≥3 treatment-related TEAEs (TRAEs; 17% vs 50%), and TRAEs leading to discontinuation (9% vs 15%) were lower with tislelizumab versus sorafenib in the EU/NA subgroup respectively and similar to incidences observed in the overall study population.

These results will be presented on Monday, June 5, as poster presentations from 8:00-11:00 a.m. CT. (Abstracts #4082 and #4083).
In an updated analysis of the ROSEWOOD study, BRUKINSA in combination with obinutuzumab demonstrated clinically meaningful activity and manageable safety profile in patients with heavily pretreated relapsed/refractory (R/R) follicular lymphoma (FL). The combination of BRUKINSA and obinutuzumab represents a potentially new therapy for patients with R/R FL.

Demonstrating a commitment to developing rigorous evidence for potential new treatments for rare hematologic malignancies, BeiGene will detail the trial design of its ongoing Phase 3 MAHOGANY study of BRUKINSA plus obinutuzumab versus lenalidomide plus rituximab in R/R FL or marginal zone lymphoma during the Trials in Progress session.

These posters will be presented on Monday, June 5 from 8:00-11:00 a.m. CT (Abstracts #7545 and #TPS7590).
First-in-Human Results Show Promise for Key Pipeline Assets

BeiGene’s investigational BGB-A445 is a novel monoclonal antibody OX40 agonist that does not compete with endogenous OX40 ligand binding. The molecule is being studied as a single agent or in combination with tislelizumab in patients with advanced solid tumors in an ongoing, Phase 1 dose escalation and expansion study.

In first-in-human results presented at ASCO (Free ASCO Whitepaper), BGB-A445 monotherapy or in combination with tislelizumab was generally well-tolerated across all doses with no dose-limiting toxicities and demonstrated preliminary antitumor activity in patients with advanced solid tumors.

As further evaluation, the dose expansion phase is currently enrolling patients into non-small cell lung cancer and head and neck squamous cell carcinoma cohorts.

These results will be presented on Saturday, June 3, as a poster presentation from 8:00 – 11:00 a.m. CT (Abstract #2574).
BGB-11417 is a potent and highly selective BCL-2 inhibitor, and a dose-finding results showed that single agent treatment was well tolerated at all tested doses up to 640 mg/d as monotherapy in B-cell malignancies, with no dose-dependent toxicity increase. BGB-11417 monotherapy also showed promising initial efficacy results in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma, with patients achieving responses at lower dose levels.

These results will be presented on Monday, June 5, as a poster presentation from 8:00-11:00 a.m. CT (Abstract #7558).
More details on BeiGene’s abstracts are available on the ASCO (Free ASCO Whitepaper) website.

About BRUKINSA (zanubrutinib)
BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease relevant tissues.

BRUKINSA is supported by a broad clinical program which includes more than 4,900 subjects in 35 trials across 29 markets. To date, BRUKINSA is approved in more than 65 markets around the world, including the United States, China, the European Union, Great Britain, Canada, Australia, South Korea, and Switzerland.

About Tislelizumab
Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors. In pre-clinical studies, binding to Fcγ receptors on macrophages has been shown to compromise the antitumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells.

The global development program for tislelizumab includes more than 12,000 patients and encompasses more than 20 potentially registration-enabling clinical trials in more than 30 countries and regions. More information on the clinical trial program for tislelizumab can be found at: View Source

Tislelizumab is approved in 11 indications in China, including a recent approval for use in combination with chemotherapy, for the treatment of patients with previously untreated advanced or metastatic esophageal squamous cell carcinoma. Tislelizumab is not currently approved for use outside of China.

About BGB-11417
BGB-11417 is a highly potent and selective Bcl-2 inhibitor designed to produce deeper and more sustained target inhibition.

Compared with venetoclax, BGB-11417 exhibited greater potency (>10-fold) and higher target selectivity and showed signs of overcoming treatment resistance in pre-clinical studies and tumor models. i

About BGB-A445
BGB-A445 is an investigational agonistic antibody directed to the OX40 antigen. BGB-A445 is a non-ligand competing antibody that does not disrupt OX40 to OX40 ligand engagement. Preclinical experiments showed that BGB-A445 had increasing effectiveness at higher doses versus an antibody that was ligand-competing, which showed falling effectiveness at higher doses.

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

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration 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 infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii 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 (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

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 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 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

In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).

Drug Interactions

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

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations

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

INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see full Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf

ON May 25, 2023 Be Biopharma, Inc. ("Be Bio"), a company pioneering the discovery and development of Engineered B Cell Medicines (BeCMs), reported that Chief Executive Officer, Joanne Smith-Farrell, Ph.D., will present at the Jefferies Healthcare Conference being held in New York, NY, June 7-9, 2023 (Press release, Be Biopharma, MAY 25, 2023, View Source [SID1234632045]). Company management will also be available for one-on-one meetings.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Presentation Details:

Thursday, June 8, 2023
9:30-9:55 a.m. EST
Track 3
About B Cells – A New Class of Cellular Medicines

Imagine what could "Be?" In nature, a single B cell engrafts in the bone marrow and can produce thousands of proteins per second at constant levels over decades. B cells are nature’s exquisite medicine factories, manufacturing proteins to fight disease and maintain health. Unleashing the power of B cells is driving a new class of cellular medicines – Engineered B Cell Medicines (BeCMs). BeCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BeCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas.

On May 25, 2023 Aulos Bioscience, an immuno-oncology company working to revolutionize cancer care through the development of potentially best-in-class IL-2 therapeutics, reported interim results from an ongoing Phase 1/2 trial of AU-007, as detailed in the online publication of Abstract e14507 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting (Press release, Aulos Bioscience, MAY 25, 2023, View Source [SID1234632044]). The data indicate that AU-007 is well tolerated in patients with unresectable locally advanced or metastatic cancer. AU-007 is a human IgG1 monoclonal antibody designed using artificial intelligence to harness the power of interleukin-2 (IL-2) to eradicate solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These new interim data support our belief that AU-007 offers a novel mechanism of action among IL-2 therapeutics in development, as demonstrated by AU-007’s pharmacodynamic and safety profile to date," said Aron Knickerbocker, Aulos Bioscience’s chief executive officer. "In addition, we are further encouraged that, since the data cutoff date, we are seeing early signs of anti-tumor activity in patients, which is consistent with preclinical findings that demonstrate AU-007’s unique ability to bind to IL-2 and redirect it from regulatory T cells, which suppress the immune system, to effector T cells and natural killer cells that can kill tumor cells. AU-007 is the only IL-2 therapy in development that precisely binds to IL-2 instead of the IL-2 receptor, and that turns an immunosuppressive negative feedback loop into a positive feedback loop. This gives AU-007 distinct mechanistic advantages as a potential new cancer therapeutic. As the study continues and we expand the number of trial sites in the United States and Australia, we look forward to presenting additional clinical data in the future."

AU-007 is the first computationally designed human monoclonal antibody in a human clinical trial. Created by Biolojic Design, the antibody binds with exquisite precision to IL-2, preventing IL-2 from binding to the CD25 subunit contained in trimeric IL-2 receptors expressed on immunosuppressive regulatory T cells (Tregs), vascular and pulmonary endothelium, and eosinophils. While AU-007 prevents IL-2 from attaching to Tregs, it doesn’t affect IL-2’s ability to bind to dimeric IL-2 receptors expressed on effector T cells (Teff) and natural killer (NK) cells. This allows Teff and NK cells to expand and kill tumor cells.

The Phase 1/2 clinical trial of AU-007 is a two-part, open label, first-in-human study evaluating the safety, tolerability, immunogenicity and clinical activity of AU-007 in patients with unresectable locally advanced or metastatic cancer. Data shared in the ASCO (Free ASCO Whitepaper) abstract show that AU-007 at doses up to 4.5 mg/kg every two weeks is well tolerated in eight patients (as of the data cutoff date of February 1, 2023), with no dose-limiting toxicities and all treatment-related adverse events mild (Grade 1). Three of the four tumor evaluable patients had a best response of stable disease, and two patients continue treatment as of the data cutoff date.

In addition, all seven patients with available pharmacodynamic data demonstrate overall decreasing Tregs (percentage change and absolute) and eosinophils. This finding is in stark contrast to data from other IL-2 therapeutics, which show increases in Tregs that cannot be controlled and may result in immune suppression instead of activation. Initial pharmacokinetic data (0.5 and 1.5 mg/kg) from the AU-007 trial also demonstrate continued dose proportional serum concentrations of the compound, with characteristics similar to IgG1 therapeutic human monoclonal antibodies. This indicates the antibody is behaving predictably and has a half-life that will allow for dosing every two weeks.

The Phase 1/2 trial of AU-007 consists of three dose escalation arms evaluating AU-007 either as a monotherapy, in combination with a single loading dose of recombinant human IL-2 (aldesleukin), or with both AU-007 and aldesleukin administered once every two weeks. The aldesleukin will be administered subcutaneously, at much lower doses and much less frequently than the approved regimen of intravenously administered aldesleukin. The Phase 2 portion of the trial will evaluate a dosing regimen selected from dose escalation for expansion in specified tumor types to further define the safety and initial efficacy of AU-007. The trial is currently enrolling patients at multiple site locations in the U.S. and Australia.

To learn more about the AU-007 clinical trial program, please visit ClinicalTrials.gov (identifier: NCT05267626). For patients and providers in the U.S., please visit www.solidtumorstudy.com. For patients and health professionals in Australia, please visit www.solidtumourstudy.com.

About AU-007

AU-007 is a computationally designed, human IgG1 monoclonal antibody that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 leverages IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to trimeric receptors on vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy.