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Constellation Pharmaceuticals Provides an Update from the Ongoing MANIFEST Study of Pelabresib

On June 11, 2021 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported that three posters relating to the MANIFEST clinical trial of pelabresib (CPI-0610) in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, JUN 11, 2021, View Source [SID1234583890]). The data in these posters are based on a data cutoff of September 29, 2020 from the MANIFEST Phase 2 clinical trial and reflect an analysis of pelabresib clinical and translational activity.

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"We are particularly enthusiastic about the publication of centrally reviewed translational data, which describe early improvements in bone marrow fibrosis in patients treated with pelabresib, and we believe these results support our thesis of disease-modifying treatment effects that go beyond symptom management," said Patrick Trojer, chief scientific officer of Constellation Pharmaceuticals. "We are currently enrolling patients in the Phase 3 pivotal study of MANIFEST-2 and our goal is to transform the standard of care for the treatment of myelofibrosis."

Data Highlights

Translational data, across all three arms of the Phase 2 MANIFEST study, support the disease-modifying potential of pelabresib

Centrally reviewed bone marrow fibrosis (BMF) pathology conducted in 63 patients showed similar improvements as reported previously for local review of BMF grade. 23 out of 63 patients (37%) achieved at least a 1 grade improvement in BMF. Of these patients, 83% achieved improvements in BMF by 24 weeks.
17% of the patients with BMF improvement (4 out of 23), improved by at least 2 grades.
31 out of 63 patients (49%) were stabilized or had no change, and only 4 out of 63 patients (6%) worsened.
An increase in BM erythroid progenitor cells and reduction of the number and cluster formation of megakaryocytes in the BM was observed in 59% and 65%, respectively, of 37 samples from patients treated with pelabresib either as a monotherapy or in combination with ruxolitinib.
Pelabresib durably reduced inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin 18 (IL18) as early as 2 weeks and maintained through 24 weeks of treatment, based on an analysis of patient samples.
Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients

As previously reported at ASH (Free ASH Whitepaper) 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks.
Strong response was observed with pelabresib, irrespective of baseline risk status or demographic and disease characteristics.
Central pathology review of 27 1L patient bone marrow samples showed at least a one-grade improvement in bone marrow fibrosis in 9 out of 27 patients (33%); in all of these patients, improvement was observed within 6 months of starting treatment. 16 out of 27 patients (59%) showed stabilization of bone marrow fibrosis, while only 1 out of 27 patients (4%) showed worsening.
Arm 1 and 2 (2L) – Interim analysis demonstrating that pelabresib monotherapy in JAK-inhibitor-experienced or -ineligible patients, and with pelabresib + ruxolitinib in ruxolitinib-experienced patients, resulted in improvements in anemia

As previously reported at ASH (Free ASH Whitepaper) 2020, 3 of 14 evaluable Transfusion Dependent (TD) patients (21%) in Arm 1A achieved transfusion independence (the primary endpoint for arms 1A and 2A) and 13 of 36 evaluable TD patients (36%) in Arm 2A achieved transfusion independence.
9 out of 15 evaluable TD patients (60%) in Arm 1A, and 25 out of 47 of evaluable TD patients (53%) in Arm 2A achieved a ≥50% reduction in red blood cell transfusions.
Safety

As of the September 29, 2020 data cutoff, pelabresib was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and weight decrease (2%). Amongst the most common TEAEs, there were no Grade 4. Other Grade 3/4 TEAEs (≥5%) include hyperuricemia (9%), hyperkalemia (7%) and dyspnea (7%). Nine patients discontinued treatment because of TEAEs. No Grade 5 events were observed.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Amongst the most common TEAEs, Grade 4 events included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Amongst the most common TEAEs, Grade 4 events included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.

EHA Poster Presentations

TITLE: Pelabresib (CPI-0610) improved anemia associated with myelofibrosis: interim results from MANIFEST Phase 2 study (Abstract Code: EP1077)

TITLE: Clinical benefit of pelabresib (CPI-0610) in combination with ruxolitinib in JAK-inhibitor treatment naïve myelofibrosis patients: Interim efficacy subgroup analysis from Arm 3 of MANIFEST Phase 2 study (Abstract Code: EP1085)

TITLE: BET inhibitor pelabresib decreases inflammatory cytokines, improves bone marrow fibrosis and function, and demonstrates clinical response irrespective of mutation status in myelofibrosis patients (Abstract Code: EP1080)

Date and Time: June 11, 9:00 AM CEST/ 3:00 AM EDT

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation Pharmaceuticals is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

Aptose Presents Highlights from EHA During Corporate Update Event

On June 11, 2021 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage company developing highly differentiated therapeutics that target the underlying mechanisms of cancer, reported that highlights from a corporate update event being held today, Friday, June 11, 2021, at 8:00 a.m. ET, in concurrence with participation at the EHA (Free EHA Whitepaper)2021 Virtual Congress (EHA) (Free EHA Whitepaper) (Press release, Aptose Biosciences, JUN 11, 2021, View Source [SID1234583888]). The event is focused on the current clinical status of luxeptinib, Aptose’s oral, first-in-class FLT3 and BTK kinase inhibitor currently in two Phase 1 a/b trials, one trial in patients with relapsed or refractory acute myeloid leukemia (AML), and the other trial in patients with relapsed or refractory B cell malignancies. The live and archived webcast of the presentation is available on Aptose’s website here.

"Our recent clinical experience has confirmed that luxeptinib is an active drug in several indications across both myeloid and lymphoid malignancies, which is consistent with our hypotheses from our broad portfolio of preclinical work," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "We are especially encouraged to see this anti-tumor activity — including meaningful blast reductions — emerging even in heavily pretreated and clinically challenging patients, and we now look forward to continuing dosing at higher exposures for longer periods in order to explore fully the potential of this singular drug."

Aptose’s presentation provides a recap on luxeptinib, including the following key highlights:

Luxeptinib clinical program in AML

In the ongoing Phase 1a/b study in patients with relapsed or refractory AML, we completed the first two dose cohorts (450mg and 600mg) and have escalated to the third cohort (750mg). We plan to dose escalate further and have observed no safety trends likely to prevent continued escalation.
We achieved anticipated steady state PK levels and PD inhibition of target kinases, in line with our parallel study in different patient populations.
The first two dose cohorts delivered encouraging anti-leukemic activity in multiple patients, including a durable MRD-negative complete response in a FLT3-ITD AML patient who had relapsed after two allogeneic stem cell transplants, multiple lines of chemotherapy, and prior FLT3 inhibitor therapy.
Based on the totality of our preclinical and clinical observations to date, we expect to select an expansion dose and expansion cohort strategy for AML during 2H21 and aim to explore select disease genotypes under monotherapy and combination therapy programs.
Luxeptinib clinical program in B-cell malignancies

In the ongoing Phase 1a/b study in B-cell malignancies, intermediate dose levels to date have delivered all leading indicators of clinical activity, including target engagement with dose-dependent inhibition of phospho-BTK, treatment-related lymphocytosis in patients presenting with classic CLL, and tumor reductions across different B-cell malignancies (FL, CLL, SLL, WM).
We continue to observe cases of clear reversal of aggressively growing disease upon intra-patient dose-escalation and longer times on drug, suggesting that even aggressive disease may be successfully challenged with higher exposure levels and extended dosing duration of luxeptinib.
We currently are treating patients at 750mg BID, and we plan to continue further escalation to higher dose levels and for extended duration to tackle an increasingly treatment refractory presenting population.
We plan to continue exploring the spectrum of B-cell malignancies in line with the preliminary anti-tumor activity observed in the study to date.
In addition, clinical data for luxeptinib and APTO-253 were presented at EHA (Free EHA Whitepaper) this morning. The APTO-253 poster presentation contained a full update of the clinical status of APTO-253, a first-in-class small molecule MYC inhibitor in a Phase 1a/b trial in patients with relapsed or refractory AML or high-risk myelodysplastic syndrome (MDS). The posters are now available on the presentations page of Aptose’s website here.

Key highlights from the APTO-253 poster:

In the ongoing Phase 1a/b study in patients with relapsed or refractory AML and high-risk MDS, APTO-253 has been well-tolerated in the patients treated at 20, 40, 66, 100 and 150 mg/m2 over multiple cycles.
In the peripheral blood of patients, APTO-253 monomer rapidly transforms to and co-exists with the mechanistically active Fe(253)3 conjugate, and the serum levels of APTO-253 and the Fe(253)3 conjugate are dose proportional with significantly higher concentrations of Fe(253)3 conjugate that are sustained for longer periods of time compared to monomer, suggesting that further dose escalations may provide more sustained pressure on the MYC target gene and alter the biology of the tumor cells.
Collectively, the findings from the ongoing Phase 1a/b study support continued dose escalation of APTO-253. The study is current enrolling patients with AML and MDS at the sixth dose level of 210 mg/m2, and subsequent dose escalations are anticipated.

Agios Presents Positive Results from Phase 2 Study of Mitapivat in Non-transfusion-dependent α- and ß-Thalassemia at the European Hematology Association Virtual Congress

On June 11, 2021 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat genetically defined diseases, reported positive results from its Phase 2, open-label, multicenter study of mitapivat in adults with non-transfusion dependent α- or β-thalassemia (Press release, Agios Pharmaceuticals, JUN 11, 2021, View Source [SID1234583887]). Data from the study will be featured in an oral presentation on Tuesday, June 15, at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress.

Consistent with previously announced proof-of-concept data, the study met its primary endpoint, with 16 of the 20 patients (80%) achieving a hemoglobin increase of ≥1.0 g/dL from baseline at one or more assessments during Weeks 4-12. Additionally, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both α- or β-thalassemia patients treated with mitapivat. Mitapivat was well tolerated, and the safety profile was consistent with previous studies. Mitapivat is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase R (PKR) enzymes.

"These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia, a disease for which there have been few medical advancements. In particular, we are excited to see data generated, for the first time, in α-thalassemia, demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup," said Kevin Kuo, M.D., hematologist at University Health Network, University of Toronto, and an investigator in the study. "The impressive results reported today underscore the potential of mitapivat to meaningfully improve hallmarks of this disease, including hemolysis and ineffective erythropoiesis."

Mitapivat Phase 2 Proof-of-concept Study
The open-label Phase 2 study evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of mitapivat treatment in adults with either non-transfusion-dependent α- or β-thalassemia who have a baseline hemoglobin (Hb) concentration of ≤10 g/dL. The trial enrolled 20 patients. All patients were treated with an initial dose of mitapivat 50 mg twice daily followed by a dose-level increase to 100 mg twice daily at the Week 6 visit based on safety evaluations and hemoglobin concentrations. Following the completion of the 24-week core period, patients had the opportunity to enroll in an optional 10-year extension period which will evaluate long-term efficacy and safety of mitapivat in this population.

Of the 20 patients, 5 patients had α-thalassemia, and 15 patients had β-thalassemia.
Median hemoglobin at baseline was 8.43 (range 5.13-9.8) g/dL.
Median age was 44 (range 29-67) years.
Efficacy Data

The primary endpoint, defined as a ≥1.0 g/dL increase in hemoglobin concentration from baseline at one or more assessments between Week 4 and Week 12, was met by 16 of 20 (80%) patients (1-sided p<0.0001), including all 5 (100%) α-thalassemia patients and 11 of 15 (73.3%) β-thalassemia patients. The 1-sided p-value associated with the test of H0: hemoglobin response rate =30% vs H1: hemoglobin response rate >30%, based on the Clopper-Pearson method.
The secondary endpoint of sustained hemoglobin response, defined as a primary endpoint response and a ≥1.0 g/dL increase in hemoglobin concentration from baseline at two or more assessments between Week 12 and Week 24, was met by 13 of 20 (65%) patients, including all 5 (100%) α-thalassemia patients and 8 of 15 (53.3%) patients with β-thalassemia.
During Weeks 12-24, the mean hemoglobin change from baseline was 1.3 g/dL. The mean change was 1.2 g/dL for α-thalassemia patients, and 1.3 g/dL for β-thalassemia patients.
Among hemoglobin responders, mean time to first ≥1.0 g/dL increase in hemoglobin concentration was 4.5 weeks.
Markers of hemolysis and erythropoiesis – including indirect bilirubin, lactate dehydrogenase and erythropoietin – demonstrated improvements that were consistent with the hemoglobin increase in both α- and β-thalassemia patients.
Adenosine triphosphate (ATP) levels showed mean increases of up to 86.7% from baseline.
Safety Data
The majority of adverse events (AEs) observed were consistent with previously published data for mitapivat in healthy volunteers and patients with pyruvate kinase (PK) deficiency.

Dose escalation to 100 mg twice daily was well tolerated.
The most commonly reported AEs were initial insomnia (n=10 [50%]), dizziness (n=6 [30%]) and headache (n=5 [25%]).
One patient (5%) discontinued treatment during the study; the adverse event leading to study drug discontinuation was not treatment-related.
Seventeen patients continued to the extension period of the study, and as of March 27, 2021, 17 patients remain on study drug.
"We are pleased to present data from our Phase 2 trial of mitapivat, which is the first clinical study of a PK activator in thalassemia and the first drug trial in α-thalassemia, and represents a potentially innovative therapeutic approach for these patients who are in need of new treatment options," said Chris Bowden, chief medical officer at Agios. "Our focus now is to advance the development of mitapivat in thalassemia as quickly and efficiently as possible, with the initiation of two Phase 3 studies of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia. Additionally, we look forward to further advancing mitapivat as a potential treatment for other underserved patients with hemolytic anemias, including individuals with pyruvate kinase deficiency, where our U.S. and EU regulatory filing plans are on track, and sickle cell disease, where our pivotal development program is on track to initiate by year-end."

Oral Presentation Information

Title: Results from a Phase 2, open-label, multicenter study of the oral pyruvate kinase activator mitapivat in adults with non-transfusion dependent alpha- or beta-thalassemia
Live Q&A Session Date and Time: Tuesday, June 15, 2021, at 8:45 p.m. CEST / 2:45 p.m. ET
Oral Abstract Session: Changing the scene on thalassemias
Abstract: S267
Presenter: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada

Mitapivat Clinical Development
In addition to the Phase 2 extension study of mitapivat in adults with non-transfusion-dependent α- and β-thalassemia, Agios is initiating two Phase 3 studies of mitapivat in adults with thalassemia in the second half of 2021. They are:

ENERGIZE: A placebo-controlled trial with a 2:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the trial is hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 12 through Week 24 compared with baseline.
ENERGIZE-T: A placebo-controlled trial with a 2:1 randomization evaluating patients who receive regular transfusions. The primary endpoint of the trial is transfusion reduction response, defined as a ≥50% reduction in transfused red blood cell units with a reduction of ≥2 units of transfused red blood cells in any consecutive 12-week period through Week 48 compared with baseline.
In addition to its Phase 2 study of mitapivat in adults with non-transfusion-dependent α- or β-thalassemia, Agios has completed two global, pivotal trials in adults with pyruvate kinase (PK) deficiency. Final data from these studies will be presented in an oral session at the EHA (Free EHA Whitepaper) Virtual Congress. They are:

ACTIVATE: A placebo-controlled trial with a 1:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the study was hemoglobin response, defined as a ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at Weeks 16, 20 and 24 during the fixed dose period.
ACTIVATE-T: A single arm trial of regularly transfused patients with a primary endpoint of reduction in transfusion burden, a reduction of ≥33 percent in the number of red blood cell units transfused during the 24-week fixed dose period compared with the historical transfusion burden standardized to 24 weeks.
ACTIVATE and ACTIVATE-T are intended to support global regulatory filings for mitapivat in adults with PK deficiency in the U.S. in the second quarter of 2021 and in the EU in mid-2021. Agios also is conducting an extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T, which is designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat.

In addition, mitapivat is being evaluated as a potential treatment for sickle cell disease under a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institutes of Health. Mitapivat has been shown to decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine triphosphate (ATP), and through this mechanism, it may reduce hemoglobin S polymerization and red blood cell sickling. Preliminary clinical data establishing proof-of-concept for mitapivat in sickle cell disease were disclosed in June 2020, and updated data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. Agios is initiating its pivotal Phase 2/3 study in sickle cell disease by year-end 2021.

Mitapivat has been granted orphan drug designation for the treatment of PK deficiency by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

Mitapivat is not approved for use by any regulatory authority.

CONFERENCE CALL INFORMATION

Agios will host a virtual investor event today at 7:30 a.m. ET to review the mitapivat clinical data. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

Abbott Declares 390th Consecutive Quarterly Dividend

On June 11, 2021 The board of directors of Abbott (NYSE: ABT) reported a quarterly common dividend of 45 cents per share (Press release, Abbott, JUN 11, 2021, View Source [SID1234583886]).

This marks the 390th consecutive quarterly dividend to be paid by Abbott since 1924. The cash dividend is payable Aug. 16, 2021, to shareholders of record at the close of business on July 15, 2021.

Abbott has increased its dividend payout for 49 consecutive years and is a member of the S&P 500 Dividend Aristocrats Index, which tracks companies that have increased dividends annually for at least 25 consecutive years.

Roche announces data at EHA2021 reinforcing efficacy of Venclexta/Venclyxto combinations in chronic lymphocytic leukaemia and acute myeloid leukaemia

On June 11, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the latest data from three pivotal phase III studies of Venclexta/Venclyxto (venetoclax) – CLL14, MURANO and VIALE-A – to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress, June 9-17 (EHA2021) (Press release, Hoffmann-La Roche, JUN 11, 2021, View Source [SID1234583877]). Long-term follow-up data from the CLL14 and MURANO studies support the primary analysis of Venclexta/Venclyxto in chronic lymphocytic leukaemia (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 leukaemia (AML).

"The data from these Venclexta/Venclyxto 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., Roche’s 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/Venclyxto plus Gazyva/Gazyvaro (obinutuzumab) regimen had an estimated PFS rate of 74.0% vs 35.4% for Gazyva/Gazyvaro plus chlorambucil. Importantly, the time to next treatment (TTNT) was significantly longer among patients treated with the Venclexta/Venclyxto plus Gazyva/Gazyvaro regimen versus the comparator (four-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p<0.0001).1

Furthermore, 30 months after the end of treatment, 26.9% of the Venclexta/Venclyxto-treated patients still had undetectable MRD (uMRD) compared with 3.2% of those treated with the comparator.1 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.4 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/Venclyxto and Gazyva/Gazyvaro at 28 months follow-up were low white blood cell count and infections.5

Substudy from the phase III MURANO study
Results from this substudy suggested that increased prevalence of certain unfavourable genetic risk factors negatively impacted the MRD response of patients who were retreated with Venclexta/Venclyxto plus MabThera/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.2

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/Venclyxto 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.3

Roche is collaborating with regulatory authorities and others in the industry to advance understanding of MRD. The company continues to investigate Venclexta/Venclyxto in a robust clinical development programme, including in the phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.

Venclexta/Venclyxto is approved in the US and EU in combination with MabThera/Rituxan for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva/Gazyvaro 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 US 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 EU, Venclyxto 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 [NCT02242942] is a randomised phase III study evaluating the combination of fixed-duration Venclexta/Venclyxto (venetoclax) plus Gazyva/Gazyvaro (obinutuzumab) compared to Gazyva/Gazyvaro plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and co-existing medical conditions. Four hundred and thirty-two patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta/Venclyxto alongside six-month duration of Gazyva/Gazyvaro (Arm A) or six-month duration of Gazyva/Gazyvaro alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva/Gazyvaro followed by a five-week Venclexta/Venclyxto dose ramp-up to help reduce the risk of tumour 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 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 [NCT02005471] is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of fixed-duration Venclexta/Venclyxto (venetoclax) in combination with MabThera/Rituxan (rituximab) compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta/Venclyxto, patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total. The study included 389 patients with chronic lymphocytic leukaemia (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/Venclyxto plus MabThera/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 [NCT02993523] is a phase III, randomised, double-blind, placebo-controlled multicentre study evaluating the efficacy and safety of Venclexta/Venclyxto (venetoclax) plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy. Two-thirds of patients (n=286) received 400 mg Venclexta/Venclyxto 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/Venclyxto
Venclexta/Venclyxto (venetoclax) 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 tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta/Venclyxto blocks the BCL-2 protein and works to restore the process of apoptosis.

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

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

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes T-cell engaging bispecific antibodies, glofitamab and mosunetuzumab, targeting both CD20 and CD3, and cevostamab, targeting FcRH5 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.