On December 5, 2020 GlycoMimetics’ (Nasdaq: GLYC) product candidate uproleselan — when added to a combination therapy of venetoclax and a hypomethylating agent (HMA) — was shown today in an oral presentation to break chemoresistance by dramatically and significantly reducing tumor burden as detected by circulating human AML cells after three weeks of treatment, and by significantly increasing survival (p = 0.0009) in an animal model engrafted with AML from a patient with acquired resistance to venetoclax/HMA combination therapy (Press release, GlycoMimetics, DEC 5, 2020, View Source [SID1234572223]). The oral presentation made by Dr. Kyung Hee Chang, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, at the 62nd ASH (Free ASH Whitepaper) Annual Meeting and Exposition supports the need for further clinical investigation to potentially extend the use of uproleselan, an investigational, first-in-class, targeted E-selectin antagonist, to other drug combinations and, in particular, to venetoclax/HMA.

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"As in previously reported models, uproleselan has shown benefit when added to multiple chemotherapy regimens. These data, showing the potential benefit of adding uproleselan to a combination therapy of venetoclax and HMA, are important given the rapid changes in the landscape of approved AML therapies as well as those in development. The data strongly support conducting a clinical trial with this combination therapy," said Rachel King, GlycoMimetics’ Chief Executive Officer.

"Given investigator interest in this data, we’re actively exploring opportunities for investigator-sponsored clinical trials to study the implications in humans. If successful, these studies would further reinforce our goal of demonstrating the value of uproleselan across the spectrum of AML patients and with a variety of therapeutic combination regimens," she added.

GlycoMimetics previously presented preclinical data showing that hypomethylating agents up-regulate the expression of E-selectin ligand on AML cells. The Company believes E-selectin upregulation increases the binding affinity of the blasts to the vascular endothelium, where E-selectin is expressed, and as a result, contributes to increased chemoresistance. By antagonizing E-selectin’s role in this cascade, GlycoMimetics believes uproleselan may be able to play a key role in deepening patient responses to or enhancing the duration of efficacy of venetoclax/HMA combinations.

Details on this presentation are as follows:

Title: Targeting E-selectin with GMI-1271 Overcomes Microenvironment-mediated Resistance to Venetoclax/HMA Therapy.
Presenters: Kyung Hee Chang, Muharrem Muftuoglu, Weiguo Zhang, Mahesh Basyal, Lauren Ostermann, William E. Fogler, John L. Magnani and Michael Andreeff.
Session: 604 Molecular Pharmacology and Drug Resistance in Myeloid Diseases.
Date and Time: Saturday, December 5, 2020. 5:00 – 8:30 p.m. ET
Presentation Time: 6:15 p.m. ET

About Uproleselan (GMI-1271)

Discovered and developed by GlycoMimetics, uproleselan is an investigational, first-in-class, targeted E-selectin antagonist. Uproleselan (yoo’ pro le’ sel an), currently in a comprehensive Phase 3 development program in AML, has received Breakthrough Therapy designation from the U.S. FDA for the treatment of adult AML patients with relapsed or refractory disease. Uproleselan is designed to block E-selectin (an adhesion molecule on cells in the bone marrow) from binding with blood cancer cells as a targeted approach to disrupting well-established mechanisms of leukemic cell resistance within the bone marrow microenvironment. In a Phase 1/2 clinical trial, uproleselan was evaluated in both newly diagnosed elderly and relapsed or refractory patients with AML. In both populations, patients treated with uproleselan together with standard chemotherapy achieved better-than-expected remission rates and overall survival compared to historical controls, which have been derived from results from third-party clinical trials evaluating standard chemotherapy, as well as lower-than-expected induction-related mortality rates. Treatment in these patient populations was generally well-tolerated, with fewer than expected adverse effects.

On December 5, 2020 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data from the pivotal phase III MURANO and CLL14 studies support the efficacy of fixed-duration, chemotherapy-free Venclexta/Venclyxto (venetoclax)-based combinations in certain people with chronic lymphocytic leukaemia (CLL) and provide more evidence on the potential value of minimal residual disease (MRD) (Press release, Hoffmann-La Roche, DEC 5, 2020, View Source [SID1234572221]). Data were presented at the all-virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Saturday 5 December 2020.

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"These results reinforce the long-term value of fixed-duration, chemotherapy-free Venclexta/Venclyxto-based combinations in CLL, potentially offering patients a significant period of time without treatment following initial therapy," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "These data also reflect our ongoing commitment to accelerating clinical advancements for patients by exploring the novel endpoint minimal residual disease as a potential predictor of patient outcomes."

Five-year data from the pivotal phase III MURANO trial continue to show sustained investigator-assessed progression-free survival (PFS) with Venclexta/Venclyxto plus MabThera/Rituxan (rituximab). Data, presented in an oral session, showed:

Venclexta/Venclyxto plus MabThera/Rituxan reduced the risk of disease progression or death by 81% (HR= 0.19; 95% CI: 0.15, 0.26; p<0.0001) compared to bendamustine plus MabThera/Rituxan (BR) in people with relapsed or refractory (R/R) CLL.
At the time of analysis, median overall survival (OS) had not been reached in either arm, however, five-year OS was 82.1% in the Venclexta/Venclyxto plus MabThera/Rituxan arm, compared to 62.2% in the BR arm (HR=0.40; 95% CI: 0.26, 0.62).
In the Venclexta/Venclyxto arm, among the 130 patients who completed two years of treatment without progressive disease, 63.8% (n=83/130) had undetectable MRD (uMRD) levels at the end of treatment. In an analysis of this patient subgroup, uMRD was associated with improved progression-free survival. 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.
No new safety events were reported in the study.1

Data from the phase III CLL14 study contributes to growing evidence regarding the potential of MRD measurements to predict future outcomes for certain people with previously untreated CLL who were treated with fixed-duration Venclexta/Venclyxto plus Gazyva/Gazyvaro (obinutuzumab):

Patients with uMRD and a partial response (PR) had longer PFS than patients with detectable MRD and a complete response (CR).2
In collaboration with Adaptive Biotechnologies, clonal growth rate, a measure for how quickly cancer cells grow, was analysed using the next-generation sequencing Adaptive clonoSEQ Assay and insights were used to better understand the potential role of MRD in predicting outcomes. In this analysis, after treatment with fixed-duration Venclexta/Venclyxto plus Gazyva/Gazyvaro, the estimated clonal growth rate was slower and lower, suggesting more effective MRD eradication in these patients compared to those treated with Gazyva/Gazyvaro plus chlorambucil. Early data suggest a correlation between MRD responses and PFS, which will be further evaluated by the study authors.3

Exploring novel endpoints, such as MRD, is an important area of development for Roche, which continues to investigate Venclexta/Venclyxto in a robust clinical development programme. This includes 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/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, under the brand name Venclexta, and commercialised by AbbVie outside of the US.

*Minimal residual disease (MRD) is a measure of the number of remaining cancer cells. Undetectable MRD (uMRD), 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.

About the MURANO study 4
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. Patients on the BR arm received six cycles of BR. The study included 389 patients with chronic lymphocytic leukaemia, with or without 17p deletion, who had been previously treated with at least one line of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan or BR. 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 CLL14 study 5
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. 432 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 include PFS assessed by independent review committee, minimal residual disease (MRD) status, overall response rate, complete response rate (with or without complete blood count recovery), overall survival, duration of response, event-free survival, time to next CLL treatment, and safety. MRD-negativity, or undetectable MRD, means no cancer can be detected using a specific and highly sensitive test, and was defined as less than one cancer cell in 10,000 leukocytes. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, MD, University of Cologne.

About Venclexta/Venclyxto (venetoclax)
Venclexta/Venclyxto 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 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, under the brand name Venclyxto 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 and other cancers.

In the US, Venclexta has been granted five Breakthrough Therapy Designations by the US 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 Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B-cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil for people with previously untreated chronic lymphocytic leukaemia, in more than 80 countries in combination with bendamustine for people with certain types of previously treated follicular lymphoma and in more than 70 countries in combination with chemotherapy for previously untreated follicular lymphoma.

Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world. 6 CLL mainly affects men and the median age at diagnosis is about 70 years.7 Worldwide, the incidence of all leukaemias is estimated to be over 400,000, with an incidence of over 100,000 in Europe.[8] CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.6

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.

On December 5, 2020 Bristol Myers Squibb (NYSE: BMY) and bluebird bio, Inc. (Nasdaq: BLUE) reported updated data evaluating the companies’ investigational B-cell maturation antigen (BCMA) directed chimeric antigen receptor (CAR) T cell therapy, idecabtagene vicleucel (ide-cel), were presented at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, bluebird bio, DEC 5, 2020, View Source [SID1234572220]). The data include longer-term updated results from the original Phase 1 CRB-401 study of ide-cel in relapsed and refractory multiple myeloma (RRMM), including the primary endpoint of safety and exploratory endpoints of progression-free survival (PFS) and overall survival (OS). Analyses of the pivotal registrational KarMMa trial will also be presented at the ASH (Free ASH Whitepaper) meeting, including an analysis of health-related quality of life in patients with RRMM treated with ide-cel, and a subgroup analysis of outcomes for patients with high-risk RRMM. A subgroup analysis of elderly patients with RRMM treated with ide-cel in the KarMMa study were presented today. In addition, data from the ongoing Phase 1 CRB-402 study of bb21217, an investigational BCMA-directed CAR T cell therapy, were presented today at the meeting.

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"Building on our experience in multiple myeloma, Bristol Myers Squibb is dedicated to delivering the promise of CAR T cell therapy to patients with relapsed and refractory multiple myeloma," said Kristen Hege, senior vice president, Early Clinical Development, Hematology/Oncology and Cell Therapy, Bristol Myers Squibb. "Ide-cel and bb21217 are part of our broad cell therapy development program intended to bring transformative therapies to patients in need, and these data from different studies, including the longest follow-up for any anti-BCMA CAR T cell therapy from the original CRB-401 study and important analyses from our pivotal KarMMa trial, further underscore the potential of ide-cel to improve patient outcomes with durable responses and clinical benefits for patients with triple-class exposed multiple myeloma."

"The breadth of data presented at ASH (Free ASH Whitepaper) from across our studies underscores our commitment to the continued innovation of cell therapies for patients with multiple myeloma," said David Davidson, M.D., chief medical officer, bluebird bio. "We are encouraged by the longer-term results from the Phase 1 CRB-401 study, showing consistency with the depth and durability of responses observed in the Phase 2 KarMMa study, and reinforcing the role of ide-cel as an important potential therapeutic option for patients with triple-class exposed multiple myeloma. Additionally, we are pleased to see the updated results from the Phase 1 CRB-402 study, which continue to suggest promising response rates and durability. As had been hoped, early data also suggest that enrichment of bb21217 for memory-like T cells may be associated with sustained response. We look forward to presenting additional data from across our ide-cel and bb21217 development programs in the future as we work to transform the treatment landscape for patients living with this devastating disease."

Updated Results from CRB-401 Study of Ide-cel

In the Phase 1 CRB-401 study, 62 patients with heavily pretreated relapsed and refractory multiple myeloma were treated with ide-cel across dose levels of 50, 150, 450, or 800 × 106 CAR positive T cells (Presentation #131). The primary endpoint was safety, and secondary and exploratory endpoints included response rates, PFS, OS, and minimal residual disease (MRD).

Safety remained consistent with previously reported results from CRB-401. The most frequent adverse events (AEs) were neutropenia (92%), cytokine release syndrome (CRS; 76%), anemia (76%), and thrombocytopenia (74%). The most frequent Grade 3/4 AEs were neutropenia (89%), leukopenia (61%), anemia (57%), and thrombocytopenia (57%). Most CRS events were Grade 1 or 2. Four patients (7%) had Grade 3 CRS; there were no Grade 4 or 5 CRS events reported.1

Among 62 patients treated with ide-cel in this study, the overall response rate (ORR) was 76%, including 24 patients (39%) who achieved a complete response (CR). The median duration of response (DoR) was 10.3 months. Median PFS was 8.8 months and median OS was 34.2 months, with a median follow-up of 14.7 months. Full results from the CRB-401 study will be presented today in an oral presentation (Presentation #131).1

"The CRB-401 study continues to demonstrate the potential of ide-cel to provide deep and durable responses for heavily pre-treated relapsed and refractory multiple myeloma patients," said Yin Lin, M.D., Ph.D., presenting author, associate professor of hematology at Mayo Clinic. "This longer-term data is also important as it reflects a meaningful median duration of response for hard-to-treat patients, further highlighting the importance of ide-cel as a potential innovative treatment for patients with significant unmet treatment needs."

Analyses of Pivotal KarMMa Study: Subgroup Analyses of Ide-cel Outcomes in High-Risk and Elderly Patients and Health-Related Quality of Life

Ide-cel demonstrated deep and durable responses in the pivotal Phase 2 KarMMa study of patients with triple-class exposed relapsed and refractory multiple myeloma. A subgroup analysis was conducted to assess outcomes of treatment with ide-cel across target dose levels of 150 to 450 × 106 CAR positive T cells in patients with poor prognosis, including those with extramedullary disease, high-risk cytogenetics, and high tumor burden.

In the analysis of 128 patients, ide-cel demonstrated deep and durable responses across the majority of subgroups, including those with the highest risk. The ORR and CR rate were ≥65% and ≥20%, respectively, for the majority of high-risk subgroups. Additionally, in the majority of the high-risk subgroups, the median DoR was >9.2 months and the median PFS was >7.5 months. Results will be presented in a poster presentation on Monday, December 7 (Presentation #3234).2

A separate subgroup analysis was conducted to evaluate the outcomes of treatment with ide-cel in elderly patients (Presentation #1367). Multiple myeloma occurs most commonly among the older population, with a median age of 69 at diagnosis. Advanced age has been shown to negatively affect prognosis and limit treatment options.3

Of the 128 patients treated with ide-cel in the KarMMa study, 45 patients (35%) were aged ≥65 years and 20 patients (16%) were aged ≥70 years. Response rates for both age groups were comparable and consistent with the overall ide-cel treated population, across all target dose levels, with ORRs of 84% to 90% and CR rates of 31% to 35%.3

Likewise, median DoR among responders in both age groups (10.7 months in patients aged ≥65 years and 11.0 months in patients aged ≥70 years) was similar to that of the overall ide-cel treated population. Median PFS was 8.6 months (95% CI, 4.9-12.2) in patients aged ≥65 years and 10.2 months (95% CI, 3.1-12.3) in patients aged ≥70 years. Additionally, no new safety signals were observed.3

In an analysis of the impact of ide-cel treatment on health-related quality of life (HRQoL) measures in patients with relapsed and refractory multiple myeloma from the KarMMa study, ide-cel was associated with clinically meaningful QoL benefits without compromising any HRQoL domains (Presentation #437). Patients demonstrated a clinically meaningful improvement in most functioning and symptom scores from baseline to Month 3 through 15, with statistical significance (p<0.05) reached at various time points for different subscales throughout the follow-up period. Full results from the HRQoL analysis will be presented tomorrow, Sunday, December 6, in an oral presentation (Presentation #437).4

Phase 1 CRB-402 Study of bb21217

Updated safety and efficacy results from the ongoing Phase 1 study (CRB-402) of bb21217, an investigational BCMA-directed CAR T cell therapy being studied in patients with relapsed and refractory multiple myeloma, were also presented today in an oral presentation (Presentation #130). bb21217 uses the ide-cel CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention of increasing the in vivo persistence of CAR T cells.

As of the September 1, 2020 cutoff date, 69 patients were treated with bb21217 and updated results include new data following the introduction of a manufacturing process change. The study has completed enrollment and follow-up is ongoing as data continue to mature and the durability of response at the RP2D is assessed.5

About Ide-cel

Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3-ζ chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

Bristol Myers Squibb and bluebird bio’s broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio.

Ide-cel is not approved for any indication in any geography.

About bb21217

bb21217 is an investigational BCMA-targeted CAR T cell therapy that uses the ide-cel CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention of increasing the in vivo persistence of CAR T cells. bb21217 is being studied for patients with multiple myeloma in partnership between bluebird bio and Bristol Myers Squibb.

The companies’ clinical development program for bb21217 includes the ongoing Phase 1 CRB-402 study. CRB-402 is the first-in-human study of bb21217 in patients with relapsed and refractory multiple myeloma (RRMM), designed to assess safety, pharmacokinetics, efficacy and duration of effect. CRB-402 is a two-part (dose escalation and dose expansion), open-label, multi-site Phase 1 study of bb21217 in adults with RRMM. A total of 69 patients have been treated with bb21217 and the study has completed enrollment. For more information visit: clinicaltrials.gov using identifier NCT03274219.

bb21217 is not approved for any indication in any geography.

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

Bristol Myers Squibb is inspired by a single vision—transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

On December 5, 2020 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), reported clinical data from the LOXO-305 global Phase 1/2 BRUIN clinical trial in mantle cell lymphoma (MCL) and other non-Hodgkin lymphomas (Press release, Eli Lilly, DEC 5, 2020, View Source [SID1234572219]). LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. These data are being presented in an oral presentation at the 2020 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract 117).

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"MCL patients who have been treated with a covalent BTK inhibitor have very few therapeutic options, and outcomes are extremely poor. LOXO-305 has demonstrated a promising efficacy profile in these patients, a setting where we urgently need new therapies," said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center and presenting author. "I am also excited about the emerging data for LOXO-305 in other B-cell malignancies including Waldenström’s macroglobulinemia."

"We are very excited to share this update on LOXO-305 in MCL with the hematology community and look forward to sharing data on chronic lymphocytic leukemia and small lymphocytic lymphoma patients in the coming days," said David Hyman, M.D., chief medical officer of Loxo Oncology at Lilly. "LOXO-305 was designed to overcome some of the limitations seen with current BTK therapies and we believe the promising efficacy and tolerability data demonstrate its potential to be an important new treatment option for MCL patients. In addition, we look forward to initiating an ambitious Phase 3 study in MCL patients early next year where we aim to demonstrate superiority of LOXO-305 against covalent BTK inhibitors."

Additional data from the BRUIN Phase 1/2 trial in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) will be presented in an oral presentation at ASH (Free ASH Whitepaper) (abstract 542) on Monday, December 7 at 10a.m. ET/7a.m. PT.

Key Data Presented at ASH (Free ASH Whitepaper)

As of September 27, 2020, 323 patients were enrolled in the study, including 170 with CLL/SLL, 61 with MCL, 26 with Waldenström’s macroglobulinemia (WM), and 66 with other B-cell lymphomas. The 61 patients with MCL received a median of three prior lines of therapy, with 93% receiving a prior BTK inhibitor, 98% an anti-CD20 antibody, 92% chemotherapy, 20% lenalidomide, 25% autologous transplant, 5% CAR-T cell therapy, and 5% allogeneic transplant.

Pharmacokinetic analyses during dose escalation demonstrated consistent dose-proportional exposures with low inter-patient variability across the entire dosing range of 25mg to 300mg daily. Doses of 100mg QD and greater exceeded BTK IC90 target coverage for the entirety of the dosing interval. Responses were observed starting at the first dose level.

The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Patients were considered efficacy-evaluable if they had at least one post-baseline response assessment or if they discontinued treatment prior to their first post-baseline response assessment.

In the 56 efficacy-evaluable patients with MCL, 29 responded to treatment including 14 complete responses (CR) and 15 partial responses (PR) resulting in an overall response rate (ORR) of 52% (95% CI: 38-65). Among the 52 patients who had received a prior covalent BTK inhibitor, the ORR was also 52% (95% CI: 38-66). Responses in MCL were observed in patients who received prior cellular therapy, including 64% (9/14) of patients with prior autologous or allogeneic transplant, and 100% (2/2) with prior CAR-T. Responses were also observed in two of four patients with blastoid variant MCL, an aggressive subtype associated with worse prognosis. Median time to first response was 1.8 months, corresponding with the first response assessment. Median follow-up for the 56 efficacy-evaluable MCL patients was six months. Of the 29 responding MCL patients, all except five remain on therapy (four for progressive disease and one who achieved a CR and electively discontinued treatment to undergo allogeneic stem cell transplant). The longest-followed responding patient continues on treatment at 18.3 months.
In 19 efficacy-evaluable Waldenström’s macroglobulinemia patients, 13 responded including 9 PR and 4 minor responses (MR), resulting in an ORR of 68% (95% CI: 44-87). Among the 13 patients who had received a prior covalent BTK inhibitor, the ORR was 69% (95% CI: 39-91, 5 PR, and 4 MR). Ten of 13 WM responders are ongoing on LOXO-305 treatment at a median follow-up of 4.6 months.
Among eight efficacy-evaluable patients with follicular lymphoma, responses were observed in four patients.
Among eight patients with Richter’s transformation identified prior to enrollment, responses were observed in six, resulting in an ORR of 75%.
Of the remaining 39 efficacy evaluable patients, eight responses were observed (6/25 patients with Diffuse large B-cell lymphoma (DLBCL), 2/9 patients with marginal zone lymphoma (MZL)).
Safety data were presented for the entire enrolled BRUIN population. Across all 323 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (20%), diarrhea (17%), and contusion (13%). In addition, rates of two adverse events commonly associated with BTK inhibitors, atrial arrythmias and hemorrhage, were low, experienced by two patients and one patient respectively, and considered by investigators as unrelated to LOXO-305. Dose interruptions, reductions and permanent discontinuations for drug-related adverse events were observed in 8%, 2.2%, and 1.5% of patients, respectively. No dose limiting toxicities were reported and a maximum tolerated dose (MTD) was not reached.

LOXO-305 Development Program Update

Loxo Oncology at Lilly is preparing to initiate a global, randomized, superiority Phase 3 clinical trial to study LOXO-305 versus currently available covalent BTK inhibitors in BTK treatment naïve patients with relapsed-refractory MCL. Participants will be randomized to receive either LOXO-305 monotherapy or investigator’s choice of ibrutinib, acalabrutinib or zanubrutinib. The trial, BRUIN MCL-321, is expected to begin in the first quarter of 2021.

About LOXO-305
LOXO-305 is an investigational, oral, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies can be limited by acquired resistance, most commonly through BTK C481 mutations. In rapidly growing tumors with inherently high rates of BTK turnover, resistance to covalent BTK therapies may be the result of incomplete target inhibition. LOXO-305 was designed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology at Lilly Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates LOXO-305 as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. The dose escalation phase followed a "3+3" design with LOXO-305 dosed orally in 28-day cycles. As dose cohorts were cleared, additional patients could enroll in cleared cohorts and intra-patient dose escalation was permitted. The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose and recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate (ORR) and Duration of Response, as determined by appropriate histology-specific response criteria). In the Phase 2, patients are enrolled across various cohorts, depending on disease type and prior therapy. The primary endpoint for Phase 2 is ORR. Secondary endpoints include duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.

On December 5, 2020 AbbVie (NYSE: ABBV) reported new, updated results from the Phase 3 MURANO and CLL14 clinical trials evaluating VENCLEXTA/VENCLYXTO (venetoclax) fixed duration treatment combinations at the virtual 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (abstracts 125, 127, and 1310, respectively) (Press release, AbbVie, DEC 5, 2020, View Source [SID1234572218]). These findings add to the growing body of data supporting the use of VENCLEXTA/VENCLYXTO in first-line or previously treated chronic lymphocytic leukemia (CLL) patients.

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"MURANO and CLL14 provide a look at the benefits of fixed duration VENCLEXTA combinations in helping many patients to achieve sustained progression-free survival," said John Hayslip, M.D., M.S.C.R., executive medical director, AbbVie. "These responses reinforce that with VENCLEXTA/VENCLYXTO, it is possible for CLL patients to complete treatment and live longer without their disease progressing."

Data from the MURANO and CLL14 trials presented at ASH (Free ASH Whitepaper) reinforce that CLL patients who have relapsed or have not started treatment and receive a VENCLEXTA/VENCLYXTO regimen can experience long-lasting responses, even after stopping treatment, compared to standard of care treatment options.

MURANO Five-Year Analysis1
The results of the final, descriptive analysis of the MURANO trial (median follow-up of 59.2 months with all patients off VENCLEXTA/VENCLYXTO in combination with rituximab [VenR] treatment for at least three years; Abstract 125) demonstrated the following:

Investigator (INV)-assessed progression-free survival (PFS): Patients with relapsed or refractory (R/R) CLL on fixed duration VenR had a median PFS of 53.6 months (95% CI: 48.4-57.0) compared to 17.0 months (95% CI: 15.5-21.7) with bendamustine plus rituximab (BR; HR 0.19, 95% CI: 0.15-0.26).
Overall survival (OS): The OS estimate was 82.1% (95% CI: 76.4-87.8) with VenR compared to 62.2% (95% CI: 54.8-69.6) for BR (HR 0.40, 95% CI: 0.26-0.62), median not reached in either arm.
Minimal residual disease (MRD) status at completion of VenR treatment: Patients who achieved MRD-negativity without disease progression at the end of their treatment course had improved PFS and OS compared to patients with MRD. MRD refers to the small number of cancer cells that remain in the body after treatment. The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods.4
Consistent safety profile: The safety profile of the VenR combination is consistent with the known safety profile of each individual therapy alone. No new, serious safety issues were observed in the five-year MURANO updated analysis.
According to the Leukemia & Lymphoma Society, MRD refers to the small number of cancer cells that remain in the body after treatment.4 The number of remaining cells may be so small that they do not cause any physical signs or symptoms and often cannot even be detected through traditional methods, this is known as undetectable MRD (uMRD). Doctors use MRD/uMRD to measure the effectiveness of treatment and to predict which patients are at risk of relapse.

CLL14 Analyses2,3
Data from descriptive analyses of the Phase 3 CLL14 trial was also presented today evaluating the role of MRD measurements in clinical trials.

One analysis showed that patients with previously untreated CLL and co-existing medical conditions who had partial response (PR) after treatment with VENCLEXTA/VENCLYXTO in combination with obinutuzumab (Ven-Obi) had a similar outcome as patients with complete response (CR) when uMRD levels were achieved. These data suggest that patients on the VENCLEXTA/VENCLYXTO combination with uMRD levels and PR had longer PFS than patients with MRD and CR. This is significant because patients with CLL who show a PR to chemoimmunotherapy have a poorer prognosis than patients with CR.2 These results were not tested for statistical significance. (Abstract 1310)

The second analysis looked at clonal growth patterns – or how quickly cancer cells grow and spread – in patients treated within the CLL14 trial. The findings from the analysis shed light on which patient group may be at risk of relapsing despite initial MRD response.3 (Abstract 127)

The four-year, follow-up analysis showed an OS rate of 85.3% with Ven-Obi versus 83.1% with chlorambucil in combination with obinutuzumab (Obi-Clb; HR 0.85, 95% CI [0.54-1.35]; P=0.4929).

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.

About the MURANO Trial5,6,7
A total of 389 patients with R/R CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VenR (n=194) compared with BR (n=195). The median age of patients in the trial was 65 years (range: 22 to 85).

The trial met its primary efficacy endpoint of INV-assessed PFS. At the time of the primary analysis, median PFS with VenR was not reached compared with 17.0 months for BR (HR: 0.17; 95% CI: 0.11- 0.25; p<0.0001). In the primary efficacy analysis, the median follow-up for PFS was 23.8 months (range: 0 to 37.4). Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), OS and rates of MRD-negativity.

In patients with CLL receiving combination therapy with rituximab, the most frequent serious adverse reaction (AR; ≥5%) was pneumonia (9%). The most common ARs (≥20%) of any grade were neutropenia (65%), diarrhea (40%), upper respiratory tract infection (39%), fatigue (22%), and nausea (21%). Fatal ARs that occurred in the absence of disease progression and within 30 days of the last venetoclax treatment and/or 90 days of the last rituximab were reported in 2% (4/194) of patients.

About the CLL14 Trial6,7,8
The prospective, multicenter, open-label, randomized Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of Ven-Obi (n=216) versus Obi-Clb (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for venetoclax in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on PFS as assessed by an IRC.

Key secondary endpoints were MRD-negativity in peripheral blood and bone marrow, overall and complete response rates, MRD-negativity in complete response in peripheral blood and bone marrow, and OS.

In patients with CLL receiving combination therapy with obinutuzumab, serious ARs were most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥20%) of any grade were neutropenia (60%), diarrhea (28%), and fatigue (21%). Fatal ARs that occurred in the absence of disease progression and with onset within 28 days of the last study treatment were reported in 2% (4/212) of patients, most often from infection.

About VENCLEXTA/VENCLYXTO (venetoclax)
VENCLEXTA/VENCLYXTO (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information7

Uses
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 I 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. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you 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.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects. When restarting VENCLEXTA after stopping for 1 week or longer, your healthcare provider may again check for your risk of TLS and change your dose.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.
Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

have kidney or liver problems.
have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
have a history of high uric acid levels in your blood or gout.
are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. 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 your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment and for 1 week after the last dose of VENCLEXTA.
What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your 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. Your healthcare provider will do blood tests to check your 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. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.
Tell your healthcare provider right away if you 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 counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your 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 your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Call your doctor for medical advice about side effects.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact genentech-access.com/patient/brands/venclexta for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here.

See VENCLYXTO full summary of product characteristics (SmPC) at View Source

Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source