On June 11, 2021 Caelum Biosciences and Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported new Phase 2 safety and tolerability data for CAEL-101, a potentially first-in-class amyloid fibril targeted therapy, in combination with standard-of-care (SoC) therapy in patients with AL amyloidosis (Press release, Caelum Biosciences, JUN 11, 2021, View Source [SID1234583848]). The data, presented in two e-posters at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress 2021, strengthen the safety and tolerability profile of CAEL-101, further support the dose selection for the ongoing Phase 3 study, and suggest possible cardiac and renal response. An e-poster featuring the first data from a new arm of the study demonstrated that CAEL-101 administered in combination with cyclophosphamide-bortezomib-dexamethasone (CyBorD) plus daratumumab was generally safe and well-tolerated in the first four weeks of treatment. Data presented in a second e-poster showed longer-term evidence that CAEL-101 in combination with CyBorD was generally well-tolerated for a median treatment duration of 49 weeks, and exploratory clinical biomarker data suggesting possible cardiac disease improvements and renal response among patients with cardiac or renal impairment at baseline, respectively.

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"AL amyloidosis is a relentless disease that is particularly devastating when it impacts the heart, with some of these patients facing a median survival of less than one year following diagnosis. Current treatments for AL amyloidosis are designed to prevent or suppress the formation of new amyloids, but they do not address the existing amyloid buildup in the involved organs like the heart and kidneys, which can result in continued organ damage and can ultimately be fatal," said Michael Spector, President and Chief Executive Officer of Caelum. "Understanding that CAEL-101 has the potential to be the first therapy to address the devastating organ damage caused by AL amyloidosis, we are urgently working to advance the ongoing CARES Phase 3 program in collaboration with Alexion."

Safety and Tolerability of CAEL-101 in Combination with Cyclophosphamide-Bortezomib-Dexamethasone and Daratumumab in Patients with AL amyloidosis (#EP1017)

As was previously announced, the Phase 2 study of CAEL‑101 in combination with CyBorD met its primary objectives, supporting the safety and tolerability of CAEL-101 and the selection of the 1000 mg/m2 dose for the ongoing Phase 3 study. Results presented from an additional study arm that included 11 patients receiving CAEL-101 (1000 mg/m2 dose) in combination with CyBorD plus daratumumab suggested that treatment with this combination was generally well-tolerated in the first four weeks of treatment. Specifically, adding daratumumab to the CAEL-101 and CyBorD regimen did not result in any new safety signals, nor did it alter the pharmacokinetic (PK) exposure to CAEL-101. The most common adverse events (AEs) reported in the first four weeks in the additional arm were nausea, constipation, and insomnia.

Safety and Tolerability of CAEL-101 in Patients with AL Amyloidosis in a Phase 2 Study for a Median of 49 Weeks (#EP1018)

Additional longer-term data presented from the Phase 2 study demonstrated that CAEL-101 in combination with CyBorD in patients with AL amyloidosis (N=13) was generally well tolerated up to a median treatment duration of 49 weeks (range 12-57 weeks), with most patients having received more than 20 infusions of CAEL-101. The most common AEs reported were diarrhea, nausea, fatigue, rash, and anemia. In addition, exploratory clinical biomarker evaluations showed early signals suggesting possible cardiac and renal response. Specifically, median percent changes for biomarkers of cardiac disease (cTnT and NT-proBNP) were lower at each subsequent time point measured, suggesting improvement in cardiac function among eight patients with active cardiac disease at baseline. Additionally, seven patients with active renal impairment at baseline demonstrated renal response, as defined by a decrease of at least 30 percent in proteinuria (an excess of protein in the urine) following treatment.

"We are grateful to clinical trial participants who are essential to advancing our work towards new treatment options for AL amyloidosis," said John Orloff, M.D., Executive Vice President and Head of Research and Development at Alexion. "We remain committed to working together with the AL amyloidosis community and Caelum to evaluate the potential of CAEL-101 as a potentially first-in-class treatment option for patients who are living with this devastating disease."

As was previously announced, the Cardiac Amyloid Reaching for Extended Survival (CARES) Phase 3 clinical program to evaluate CAEL-101 in combination with SoC therapy in AL amyloidosis has begun. Enrollment is underway in two parallel Phase 3 studies – one in patients with Mayo stage IIIa disease (ClinicalTrials.gov Identifier: NCT04512235) and one in patients with Mayo stage IIIb disease (ClinicalTrials.gov Identifier: NCT04504825) – and will collectively enroll approximately 370 patients globally.

About the CAEL-101 Phase 2 Study

The Phase 2 multicenter, open-label, dose-selection study (ClinicalTrials.gov Identifier: NCT04304144) is designed to evaluate the safety and tolerability of CAEL-101 in combination with standard of care (SoC) therapy for patients with AL amyloidosis and determine the recommended dose for Phase 3 studies. The study is divided into two parts: Part A examined CAEL-101 in combination with cyclophosphamide-bortezomib-dexamethasone (CyBorD) and employed a 3+3 dose escalation design (cohort 1 – 500 mg/m2; cohort 2 – 750 mg/m2 ; cohort 3 1000 mg/m2); Part A patients were subsequently up titrated to 1000mg/m2, once this was identified as the Phase 3 dose. Part B is examining CAEL-101 at the 1000 mg/m2 dose in combination with CyBorD plus daratumumab. Patients from Parts A and B receive CAEL-101 therapy weekly for the four-week observation period followed by CAEL-101 doses every other week thereafter, all while continuing to receive SoC therapy. Patients continue to receive CAEL-101 per protocol until the end of the study or discontinuation.

About CAEL-101

CAEL-101 is a first-in-class monoclonal antibody (mAb) designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients with AL amyloidosis. The antibody is designed to bind to misfolded light chain proteins and amyloid and shows binding to both kappa and lambda subtypes. In a Phase 1a/1b study, CAEL-101 demonstrated improved organ function, including cardiac and renal function, in 27 patients with relapsed and refractory AL amyloidosis who had previously not had an organ response to standard of care therapy. CAEL-101 has received Orphan Drug Designation from both the U.S. Food and Drug Administration and European Medicine Agency as a potential therapy for patients with AL amyloidosis.

About AL Amyloidosis

AL amyloidosis is a rare systemic disorder caused by an abnormality of plasma cells in the bone marrow. Misfolded immunoglobulin light chains produced by plasma cells aggregate and form fibrils that deposit in tissues and organs. This deposition can cause widespread and progressive organ damage and high mortality rates, with death most frequently occurring as a result of cardiac failure. Current standard of care includes plasma cell directed chemotherapy and autologous stem cell transplant, but these therapies do not address the organ dysfunction caused by amyloid deposition, and up to 80 percent of patients are ineligible for transplant.

AL amyloidosis is a rare disease but is the most common form of systemic amyloidosis. There are approximately 22,000 patients across the United States, France, Germany, Italy, Spain and the United Kingdom. AL amyloidosis has a one-year mortality rate of 47 percent, 76 percent of which is caused by cardiac amyloidosis.

On June 11, 2021 Bristol Myers Squibb (NYSE: BMY) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported the first data from the Phase 2 BEYOND study evaluating Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, plus best supportive care in adult patients with non-transfusion dependent (NTD) beta thalassemia, were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress as part of its Presidential Symposium (Abstract #S101) (Press release, Bristol-Myers Squibb, JUN 11, 2021, View Source [SID1234583847]). Results demonstrated that 77.7% of patients treated with Reblozyl achieved a hemoglobin increase (≥1.0 gram/deciliter) compared to 0% of patients in the placebo arm. Changes in patient-reported outcomes also correlated with increases in hemoglobin. NTD beta thalassemia is a term used to describe patients who do not require lifelong regular red blood cell (RBC) transfusions for survival, although they may require occasional or even frequent transfusions, usually for defined periods of time.

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"Patients with non-transfusion dependent beta thalassemia experience chronic anemia and iron overload, which may lead to a range of clinical complications, and treatment options are greatly needed," said Ali Taher, M.D., Ph.D., FRCP, of American University of Beirut and BEYOND study investigator. "Results from the BEYOND study show the clinical potential of luspatercept to sustain the elevation of hemoglobin levels in a majority of patients regardless of their baseline hemoglobin status, and improvements were noted in quality of life outcomes in adults with non-transfusion dependent beta thalassemia."

Reblozyl is the first and only erythroid maturation agent approved in the European Union, United States and Canada to address anemia-associated beta thalassemia and lower-risk myelodysplastic syndromes, representing an important class of therapy for eligible patients.1,2,3

"We are very encouraged by the magnitude of improvement seen among Reblozyl-treated patients in the BEYOND trial," said Habib Dable, President and Chief Executive Officer of Acceleron. "These data further strengthen our confidence in Reblozyl’s potential to become a meaningful option for this important, underserved patient population around the world."

"The results we are presenting at EHA (Free EHA Whitepaper) continue to highlight multiple benefits observed with Reblozyl to treat anemia and achieve transfusion independence, as well as show its potential for patients with non-transfusion dependent disease who face a range of serious, often lifelong health complications," said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. "Along with our partners at Acceleron, we are committed to advancing our clinical program for Reblozyl for patients living with anemia-associated blood disorders."

BEYOND Study Results

BEYOND is a Phase 2, randomized, double-blind, placebo-controlled multi-center study to determine the efficacy and safety of Reblozyl versus placebo in adults with non-transfusion dependent (NTD) beta thalassemia. Eligible patients were ≥18 years with beta thalassemia or hemoglobin (Hb) E beta thalassemia and received ≤5 red blood cell (RBC) units in the 24 weeks prior to randomization, with mean baseline Hb ≤10.0 gram/deciliter (g/dL).4

In the study, 145 patients were randomized 2:1 to receive Reblozyl, 1 milligram/kilogram (titration up to 1.25 mg/kg) or placebo subcutaneously every 3 weeks for ≥48 weeks. Patients in both arms continued to receive best supportive care, including RBC transfusions as indicated and iron chelation therapy. The primary endpoint was achievement of ≥1.0 g/dL mean Hb increase from baseline over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions. Secondary endpoints included proportion of patients who remained transfusion free over weeks 1-24, who achieved mean Hb increase of ≥1.5 g/dL from baseline to weeks 13-24, and mean change in NTD beta thalassemia patient-reported outcome tiredness and weakness (NTDT-PRO T/W) domain scores (higher scores reflect worse quality of life; QoL).4

Over a continuous 12-week interval from weeks 13-24 in the absence of RBC transfusions, 74 of 96 (77.1%) patients in the Reblozyl treatment arm achieved the study’s primary endpoint, ≥1.0 g/dL mean Hb increase from baseline, versus 0 of 49 (0%) patients in the placebo arm (P<0.0001). The primary endpoint was achieved by 40 of 55 (72.7%) patients in the Reblozyl arm with mean baseline Hb of <8.5 g/dL versus 0 (0%) of patients in the placebo arm (P<0.0001), and 34 of 41 patients (82.9%) with mean baseline Hb of ≥8.5 g/dL versus 0 patients (0%) in the placebo arm (P<0.0001). In a key secondary endpoint of the study, during weeks 13-24, 50 of 96 patients (52.1%) in the Reblozyl arm achieved mean Hb increase of ≥1.5 g/dL compared to baseline versus 0 patients (0%) in the placebo arm (P<0.0001). 89.6% of patients in the Reblozyl arm remained transfusion free at weeks 1-24 versus 67.3% of patients in the placebo arm (P=0.0013). Improvements in patient-reported QoL outcomes (tiredness and weakness) were also observed to correlate with Hb increases.

The most common treatment-emergent adverse events of any grade occurring in ≥5% of patients were bone pain (36.5% Reblozyl versus 6.1% placebo), headache (30.2% versus 20.4%), and arthralgia (29.2% versus 14.3%). No malignancies or thromboembolic events were reported in patients treated with Reblozyl.

About Beta Thalassemia

Beta thalassemia is an inherited blood disorder caused by a genetic defect in hemoglobin. It is one of the most common autosomal recessive disorders, and the total annual incidence of symptomatic individuals is estimated at 1 in 100,000 people globally and 1 in 10,000 people in the European Union.5 The disease is associated with ineffective erythropoiesis, which results in the production of fewer and less healthy red blood cells (RBCs), often leading to severe anemia—a condition that can be debilitating and can lead to other complications for patients—as well as other serious health issues. Treatment options for anemia associated with beta thalassemia are limited, consisting mainly of frequent RBC transfusions that have the potential to contribute to iron overload, which can cause serious complications such as organ damage.5 Non-transfusion dependent thalassemia is a term used to describe patients who do not require lifelong regular transfusions for survival, although they may experience a range of clinical complications and require occasional or even frequent transfusions, usually for defined periods of time.6

About Reblozyl

Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, promotes late-stage red blood cell maturation in animal models. Bristol Myers Squibb and Acceleron are jointly developing Reblozyl as part of a global collaboration. 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 syndromes 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.

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%) 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.

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

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

Bristol Myers Squibb is inspired by a single vision—transforming patients’ 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.

Four-year follow-up analysis from the Phase III CLL14 study showed progression-free survival rate of 74.0% in previously untreated patients with chronic lymphocytic leukemia (CLL) three years after completion of a one-year fixed-duration treatment with Venclexta plus Gazyva New Phase III MURANO study data suggested certain genetic risk factors may help tailor treatments for patients with previously treated CLL A post-hoc analysis from the Phase III VIALE-A study in newly diagnosed acute myeloid leukemia indicated increased duration of response, event-free survival and overall survival in patients who achieved undetectable minimal residual disease.

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the latest data from three pivotal Phase III studies of Venclexta^® (venetoclax) – CLL14, MURANO and VIALE-A – to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress, June 9-17 (EHA2021). Long-term follow-up data from the CLL14 and MURANO studies support the primary analysis of Venclexta in chronic lymphocytic leukemia (CLL) and the possibility of tailoring treatment approaches based on genetic risk factors. Furthermore, the latest research shows the potential of minimal residual disease (MRD) as a key measure of disease response in CLL and acute myeloid leukemia (AML).
“The data from these Venclexta combinations support our continued commitment to provide valuable therapeutic options for patients with hard-to-treat blood cancers,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. “These data also advance our understanding of minimal residual disease, which we believe is a useful endpoint that may help identify patients more quickly who are in need of additional treatment.”

Four-Year Follow-Up Analysis of the Phase III CLL14 Study

This four-year post-hoc analysis of investigator-assessed progression-free survival (PFS) had a median follow-up of 52.4 months (interquartile range: 49.5-56.2 months). The fixed treatment duration (12 months) study indicated that the chemotherapy-free Venclexta plus Gazyva^® (obinutuzumab) regimen had an estimated PFS rate of 74.0% vs 35.4% for Gazyva plus chlorambucil. Importantly, the time to next treatment (TTNT) was significantly longer among patients treated with the Venclexta plus Gazyva regimen versus the comparator (four-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p<0.0001). Abstract #S146, oral presentation.
Furthermore, 30 months after the end of treatment, 26.9% of the Venclexta-treated patients still had undetectable MRD (uMRD) compared with 3.2% of those treated with the comparator. Undetectable MRD, sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes. Undetectable MRD is emerging as a measure of disease response that may be useful to consider in treatment decision-making.
Common grade 3-4 adverse events with Venclexta and Gazyva at 28 months follow-up were low white blood cell count and infections.

Substudy from the Phase III MURANO Study

Results from this substudy suggested that increased prevalence of certain unfavorable genetic risk factors negatively impacted the MRD response of patients who were retreated with Venclexta plus Rituxan^® (rituximab) after progression on treatment with that regimen. These data indicate the potential to tailor treatment approaches for patients with previously treated CLL based on genetic risk factors. Abstract #EP599, poster presentation.

Post-Hoc Analysis of the Phase III VIALE-A Study

Additionally, a post-hoc analysis from the Phase III VIALE-A study suggested the value of continued research to understand the role of MRD monitoring in AML. In the analysis, patients who achieved a composite complete remission and uMRD following treatment with Venclexta and azacitidine, a hypomethylating agent, had improved survival outcomes compared with those who were MRD-positive following treatment. The 12-month estimates for duration of response, overall survival and event-free survival for both groups are listed below:

	Achieved composite complete remission and uMRD (MRD<10 -3)	Did not achieve composite complete remission and uMRD (MRD≥10 -3)
Duration of response	81.2% (95% CI 69.3-88.9)	46.6% (95% CI 35.6-56.8)
Overall survival	94.0% (95% CI 84.7-97.7)	67.9% (95% CI 57.6-76.2)
Event-free survival	83.2% (95% CI 71.6-90.3)	45.4% (95% CI 35.2-55.0)

Adverse events of grade ≥3 (MRD<10^-3/MRD≥10^-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%) and thrombocytopenia (44%/44%), similar to the overall population. Abstract #S137, oral presentation.
Genentech is collaborating with regulatory authorities and others in the industry to advance understanding of MRD. The company continues to investigate Venclexta in a robust clinical development program, including in the Phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.
Venclexta is approved in the United States and European Union in combination with Rituxan for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.
Venclexta is also approved in the United States in combination with azacitidine, decitabine or low dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. In the European Union, Venclexta is approved in combination with a hypomethylating agent for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

About the CLL14 Study

CLL14 [View Source">NCT02242942] is a randomized Phase III study evaluating the combination of fixed-duration Venclexta^® (venetoclax) plus Gazyva^® (obinutuzumab) compared to Gazyva plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukemia (CLL) and co-existing medical conditions. 432 patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta alongside six-month duration of Gazyva (Arm A) or six-month duration of Gazyva alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva followed by a five-week Venclexta dose ramp-up to help reduce the risk of tumor burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints included PFS assessed by independent review committee, minimal residual disease (MRD) status, overall response rate, complete response rate, and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About the MURANO Study

MURANO [View Source">NCT02005471] is a Phase III open-label, international, multicenter, randomized study evaluating the efficacy and safety of fixed-duration Venclexta (venetoclax) in combination with Rituxan^® (rituximab) compared to bendamustine in combination with Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta patients on the Venclexta plus Rituxan arm received six cycles of Venclexta plus Rituxan followed by Venclexta monotherapy for up to two years total. The study included 389 patients with chronic lymphocytic leukemia (CLL), with or without 17p deletion, who had been previously treated with at least one line of therapy. A substudy from 2018 onward enrolled 34 relapsed or refractory CLL patients who progressed after initial treatment to receive Venclexta plus Rituxan as retreatment (n=25) or who crossed-over from the BR arm (n=9). The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the VIALE-A Study

VIALE-A [View Source">
NCT02993523] is a Phase III, randomized, double-blind, placebo-controlled multicenter study evaluating the efficacy and safety of Venclexta^® (venetoclax) plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukemia who are ineligible for intensive chemotherapy. Two-thirds of patients (n=286) received 400 mg Venclexta daily, in combination with azacitidine, and the remaining patients (n=145) received placebo tablets in combination with azacitidine. Patients enrolled in the study had a range of mutational subtypes, including IDH1/2 and FLT3. VIALE-A met its primary and key secondary endpoints.

About Venclexta

Venclexta is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumors, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States. Together, the companies are committed to research with Venclexta, which is currently being studied in clinical trials across several types of blood cancers.

In the United States, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. Food and Drug Administration (FDA): one for previously untreated CLL, two for relapsed or refractory CLL and two for previously untreated acute myeloid leukemia.

Venclexta Indications

Venclexta is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:

‒ are 75 years of age or older, or

‒ have other medical conditions that prevent the use of standard chemotherapy.

It is not known if Venclexta is safe and effective in children.

Important Safety Information


What is the most important information patients should know about Venclexta?


Venclexta can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. The patient’s doctor will do tests to check their risk of getting TLS before they start taking Venclexta. The patient will receive other medicines before starting and during treatment with Venclexta to help reduce the risk of TLS. The patient may also need to receive intravenous (IV) fluids into their vein.

The patient’s doctor will do blood tests to check for TLS when the patient first starts treatment and during treatment with Venclexta. It is important for patients to keep appointments for blood tests. Patients should tell their doctor right away if they have any symptoms of TLS during treatment with Venclexta, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Patients should drink plenty of water during treatment with Venclexta
to help reduce the risk of getting TLS.

Patients should drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before the first dose on the day of the first dose of Venclexta, and each time a dose is increased.

The patient’s doctor may delay, decrease the dose, or stop treatment with Venclexta if the patient has side effects. When restarting Venclexta after stopping for 1 week or longer, the patient’s doctor may again check for the risk of TLS and change the patient’s dose.

What patients should not take Venclexta?


Certain medicines must not be taken when the patient first starts
taking Venclexta and while the dose is being slowly increased because
of the risk of increased TLS.
 

• 
  Patients should tell their doctor about all the medicines they take
  , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Venclexta and other medicines may affect each other causing serious side effects.
• Patients must not start new medicines during treatment with Venclexta without first talking with their doctor.

Before taking Venclexta, patients must tell their doctor about all of
their medical conditions, including if they:

• Have kidney or liver problems.
• Have problems with body salts or electrolytes, such as potassium, phosphorus, or calcium.
• Have a history of high uric acid levels in the blood or gout.
• Are scheduled to receive a vaccine. Patients should not receive a “live vaccine” before, during, or after treatment with Venclexta, until the patient’s doctor tells them it is okay. If the patient is not sure about the type of immunization or vaccine, the patient should ask their doctor. These vaccines may not be safe or may not work as well during treatment with Venclexta.
• Are pregnant or plan to become pregnant. Venclexta may harm an unborn baby. If the patient is able to become pregnant, the patient’s doctor should do a pregnancy test before the patient starts treatment with Venclexta, and the patient should use effective birth control during treatment and for at least 30 days after the last dose of Venclexta. If the patient becomes pregnant or thinks they are pregnant, the patient should tell their doctor right away.
• Are breastfeeding or plan to breastfeed. It is not known if Venclexta passes into the patient’s breast milk. Patients are instructed to not breastfeed during treatment with Venclexta and for 1 week after the last dose.

What to avoid while taking Venclexta:

Patients should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while they are taking Venclexta. These products may increase the amount of Venclexta in the patient’s blood.

What are the possible side effects of Venclexta?

Venclexta can cause serious side effects, including:

• Low white blood cell counts (neutropenia). Low white blood cell counts are common with Venclexta, but can also be severe. The patient’s doctor will do blood tests to check their blood counts during treatment with Venclexta and may pause dosing.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with Venclexta. The patient’s doctor will closely monitor and treat the patient right away if they have a fever or any signs of infection during treatment with Venclexta.

Patients should tell their doctor right away if they have a fever or any signs of an infection during treatment with Venclexta.

The most common side effects of Venclexta when used in combination with
obinutuzumab or rituximab or alone in people with CLL or SLL include
low white blood cell count; low platelet count; low red blood cell count; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of arms, legs, hands, and feet.

The most common side effects of Venclexta in combination with
azacitidine or decitabine or low-dose cytarabine in people with AML
include
nausea; diarrhea; low platelet count; constipation; low white blood cell count; fever with low white blood cell count; tiredness; vomiting; swelling of arms, legs, hands, or feet; fever; infection in lungs; shortness of breath; bleeding; low red blood cell count; rash; stomach (abdominal) pain; infection in your blood; muscle and joint pain; dizziness; cough; sore throat; and low blood pressure.

Venclexta may cause fertility problems in males. This may affect the ability to father a child. Patients should talk to their doctor if they have concerns about fertility.

These are not all the possible side effects of Venclexta. Patients should call their doctor for medical advice about side effects.

Report side effects to the FDA at 1-800-FDA-1088 or
View Source">View Source. Report side effects to Genentech at 1-888-835-2555.

Please see the Venclexta full
View Source">
Prescribing Information, including the
View Source">
Medication Guide, for additional Important Safety Information.

About Genentech in Hematology

For more than 20 years, Genentech has been developing medicines with the goal to redefine treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. For more information visit View Sourcehematology" target="_blank" title="View Sourcehematology" rel="nofollow">View Source">View Source/hematology" target="_blank" title="View Source/hematology" rel="nofollow">View Source.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit View Source">View Source.

On June 10, 2021 Xspray Pharma reported that a bioequivalence study with the improved version of dasatinib has commenced (Press release, Xspray, JUN 10, 2021, View Source [SID1234650110]). The objective of the study is to demonstrate that a lower dose strength of Xspray Pharma’s improved version of dasatinib is bioequivalent to a higher dose strength of the original drug Sprycel. The study is being conducted with a previously used formulation of Xspray Pharma’s amorphous version of dasatinib. The findings will form the basis of an application for market approval in the US under the 505(b)(2) regulatory pathway. The preliminary findings from this study are expected in the third quarter of 2021.

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"I am pleased that we are initiating this bioequivalence study as planned. This product candidate that has the potential to improve the therapy for a cohort of cancer patients in a high-value field where no new or improved drugs have been registered for many years. In addition, we have tested this formulation A in previous studies and can better predict the findings compared to the studies that have been based on completely new untested formulations," says Per Andersson, CEO of Xspray Pharma.

Xspray Pharma’s improved version of dasatinib for the treatment of acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) and is designed to enable therapy with proton-pump inhibitors (PPIs) such as omeprazol which should be avoided with the original product. Xspray Pharma’s product will be administered at a lower dose strength compared with Sprycel but with the same availability.

Bioequivalence studies with Xspray Pharma generic product candidate, formulation C, where the objective is to demonstrate bioequivalence with Sprycel, will be initiated this summer. The findings will form the basis of an application for market approval in the US under the ANDA regulatory pathway.

On June 10, 2021 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics designed to selectively engage and modulate targeted T cells directly within the patient’s body, reported that it has dosed the first patient in the Part B expansion phase of its Phase 1 monotherapy clinical trial of CUE-101 at the recommended Phase 2 dose of 4mg/kg (Press release, Cue Biopharma, JUN 10, 2021, View Source [SID1234608277]).

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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

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The Phase 1b portion of the CUE-101 monotherapy clinical trial in patients with HPV+ second line and beyond (2L+) head and neck squamous cell carcinoma (HNSCC) is expected to enroll up to 20 patients. The data supporting the patient expansion has been encouraging to date, with six patients having confirmed stable disease (SD) and one patient with a confirmed partial response of approximately 50% tumor reduction in the dose escalation Phase 1a portion of the CUE-101 monotherapy trial.

"We are very pleased to have initiated the Part B patient expansion of the CUE-101 monotherapy trial," stated Ken Pienta, M.D., acting chief medical officer of Cue Biopharma. "We believe the data supporting the selection of the cohort 6 dose at 4mg/kg to confirm a recommended Phase 2 dose gives us growing confidence that CUE-101 may provide a potential path forward for a registration-directed clinical trial as a single agent treatment for HPV+ 2L+ HNSCC."

About the CUE-101 Clinical Trial
The trial (NCT03978689) is a multi-center, first-in-human, open-label Phase 1 dose escalation and expansion study evaluating the safety, anti-tumor effect and immunogenicity of CUE-101 as a monotherapy in second-line patients with confirmed HPV16-driven recurrent/metastatic HNSCC and HLA-A*02:01 serotype. Based on translational data from the Phase 1a portion of the trial, a recommended Phase 2 dose has been determined. The company has expanded the study to evaluate CUE-101 in combination with KEYTRUDA (pembrolizumab) as first-line treatment in patients with HPV16-driven recurrent/metastatic HNSCC.

About the CUE-100 Series
The CUE-100 series consists of Fc-fusion biologics that incorporate peptide-MHC (pMHC) molecules along with rationally engineered IL-2 molecules. This singular biologic is anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells directly in the patient. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing the potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.

About Immuno-STAT
The company’s Immuno-STAT (Selective Targeting and Alteration of T cells) biologics are designed for targeted modulation of disease-associated T cells in the areas of immuno-oncology and autoimmune disease. Each of our biologic drugs is designed using our proprietary scaffold comprising: 1) a pMHC to provide selectivity through interaction with the T cell receptor (TCR), and 2) a unique co-stimulatory signaling molecule to modulate the activity of the target T cells.

The simultaneous engagement of co-regulatory molecules and pMHC binding mimics the signals delivered by antigen presenting cells (APCs) to T cells during a natural immune response. This design enables Immuno-STAT biologics to engage with the T cell population of interest, resulting in selective T cell modulation. Because our drug candidates are delivered directly in the patient’s body (in vivo), they are fundamentally different from other T cell therapeutic approaches that require the patients’ T cells to be extracted, modified outside the body (ex vivo), and reinfused.