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Geron Reports Imetelstat Presentations at American Society of Hematology Annual Meeting

On December 12, 2017 Geron Corporation (Nasdaq:GERN) reported four presentations related to imetelstat at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held in Atlanta, Georgia from December 9-12, 2017 (Press release, Geron, DEC 12, 2017, View Source;p=RssLanding&cat=news&id=2322273 [SID1234522575]). Imetelstat is a telomerase inhibitor initially developed by Geron and exclusively licensed to Janssen Biotech, Inc. (Janssen) on a worldwide basis. The presentations are available on Geron’s website at www.geron.com/presentations.

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"We and our partner are pleased to have this first presentation of data from IMerge displaying an 8-week transfusion independence rate of 54% among the subset of patients who were naïve to lenalidomide and HMAs and who lacked del(5q), which suggests that imetelstat could offer lower risk MDS patients a much-needed treatment option," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "In addition, the non-clinical data presentations continue to support the potential use of imetelstat in multiple hematologic malignancies. We continue to be encouraged by the consistent interest in imetelstat by collaborators around the world."

Clinical Data Presentation

Title: Efficacy and Safety of Imetelstat in RBC Transfusion-Dependent (TD) IPSS Low/Int-1 MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agents (ESA) (IMerge) (Abstract #4256)

This poster presentation described data from the first 32 patients enrolled in Part 1 of IMerge, the ongoing Phase 2/3 clinical trial of imetelstat in red blood cell (RBC) transfusion-dependent (TD) patients with lower risk MDS. TD is defined as an RBC transfusion requirement of ≥4 units over 8 weeks prior to entry into the trial. The primary efficacy endpoint is the rate of RBC transfusion-independence (TI) lasting at least 8 weeks, defined as the proportion of patients without any RBC transfusion during any consecutive 8 weeks since entry to the trial. Key secondary endpoints are the rate of 24-week TI and the rate of hematologic improvement-erythroid (HI-E), defined as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least 8 weeks or a reduction of at least 4 units of RBC transfusions over 8 weeks compared with the prior RBC transfusion burden. IMerge is designed in two parts: Part 1 is a Phase 2, open-label, single-arm trial of imetelstat administered as a single agent by intravenous infusion, and Part 2 is designed to be a Phase 3, randomized, controlled trial.

Data as of October 2017 with a median follow-up of 66.1 weeks in Part 1 were presented. Part 2 has not yet begun.

Efficacy in the Overall Trial Population (n=32):

38% (12/32) of patients achieved ≥8-week RBC TI
Mean relative reduction in transfusion burden from baseline was 64%
16% (5/32) of patients achieved ≥24-week RBC TI, with the median TI duration exceeding one year in these patients
63% (20/32) of patients achieved an erythroid hematologic improvement (HI-E)
Efficacy in the Lenalidomide and HMA Naïve and Non-Del(5q) Subset (n=13):

54% (7/13) of patients achieved ≥8-week RBC TI
Mean relative reduction in transfusion burden from baseline was 71%
31% (4/13) of patients achieved ≥24-week RBC TI
69% (9/13) of patients achieved an HI-E
Safety Summary:

Cytopenias, particularly neutropenia and thrombocytopenia, were the most frequently reported adverse events which were predictable, manageable and reversible
Link to IMerge poster: Fenaux P, et al. ASH (Free ASH Whitepaper) 2017

Based on these data, Part 1 of IMerge is being expanded to enroll approximately 20 additional patients who are naïve to lenalidomide and HMA treatment and are non-del(5q) to increase the experience and confirm the benefit-risk profile of imetelstat in this refined target patient population. For more information about IMerge, please visit View Source

Non-Clinical Data Presentations

Data were presented from three non-clinical studies by academic scientists in collaboration with Janssen.

Title: Imetelstat, a Telomerase Inhibitor, Is Capable of Depleting Myelofibrosis Hematopoietic Stem Cells and Progenitor Cells (Abstract #1654)

This poster presentation described the effects of imetelstat on normal and myelofibrosis (MF) stem and progenitor cells in non-clinical models. The data showed that imetelstat inhibited the proliferation and differentiation of MF progenitor and stem cells in hematopoietic colony assays and xenograft models, but had minimal effects on normal hematopoietic stem and progenitor cells in such experiments. Imetelstat treatment of MF stem and progenitor cells reduced telomerase activity and induced apoptosis. These data provide further support that imetelstat may selectively inhibit the proliferation of and promote apoptosis in MF progenitor and stem cells, suppressing the malignant clones that drive the disease in patients.

Title: Telomerase Inhibition Impairs Self-Renewal of b-Catenin Activated Myeloproliferative Neoplasm Progenitors (Abstract #2860)

This poster presentation described the potential impact of imetelstat on leukemia stem cells in non-clinical models of chronic myeloid leukemia (CML) in blast crisis. The data suggest that imetelstat plus dasatinib, a standard treatment for CML, may inhibit self-renewal of blast crisis cells in vitro compared with normal bone marrow progenitors. In mouse xenograft models of blast crisis CML, imetelstat treatment reduced the number of leukemia progenitor cells detected in bone marrow and spleen, decreased spleen size, inhibited the self-renewal capacity and prolonged survival compared to controls. These data suggest that imetelstat may inhibit proliferation of malignant progenitors in CML.

Title: Integrated Molecular Analysis Identifies Replicative Stress as Sensitizer to Imetelstat Therapy in AML (Abstract #798)

This oral presentation described imetelstat’s activity in human acute myeloid leukemia (AML) patient-derived xenograft models. The preclinical data demonstrated that imetelstat prolonged overall survival of AML xenografts derived from 17 out of 30 individual patient samples compared to saline-treated controls. Molecular analysis showed that sustained responders were associated with gene signatures of replicative stress at baseline. The data also suggest that inducing replicative stress with standard induction chemotherapy may sensitize poorly responding samples to imetelstat. These data build on previously published preclinical work and further support potential application of imetelstat in the treatment of AML.

Webcast Investor Event

Management will be hosting a live webcast of an analyst and investor meeting on December 19, 2017 at 8:30 a.m. ET to discuss the imetelstat clinical data in MDS presented at ASH (Free ASH Whitepaper). The audio and slide presentation webcast will be accessible at www.geron.com on the Investor Relations pages, under Events. Following the live presentation, the webcast will be archived and available for replay at the same address for a period of 30 days.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat might have disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc., to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. All regulatory, development, manufacturing and promotional activities related to imetelstat are being managed through a joint governance structure, with Janssen responsible for these activities.

Roche announces phase III data showing Venclexta/Venclyxto plus MabThera/Rituxan reduced the risk of disease progression or death by 83% compared to a standard of care regimen in previously treated chronic lymphocytic leukaemia

On December 12, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the first results from the pivotal phase III MURANO study evaluating Venclexta/Venclyxto (venetoclax) plus MabThera/Rituxan (rituximab) compared to bendamustine plus MabThera/Rituxan (BR) for the treatment of people with relapsed or refractory chronic lymphocytic leukaemia (CLL) (Press release, Hoffmann-La Roche, DEC 12, 2017, View Source [SID1234522580]). The results showed that a fixed duration of treatment with Venclexta/Venclyxto plus MabThera/Rituxan significantly reduced the risk of disease progression or death (progression-free survival; PFS, as assessed by investigator) by 83% compared with BR (HR=0.17; 95% CI 0.11-0.25; p<0.0001). No new safety signals were observed. 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 United States and commercialised by AbbVie outside of the United States.

"The MURANO study results indicate that Venclexta/Venclyxto plus MabThera/Rituxan has the potential to provide an important new chemotherapy-free option for people with previously treated chronic lymphocytic leukaemia," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are particularly encouraged by the magnitude of benefit observed across key efficacy measures compared to a current standard of care, and we look forward to discussing these results with health authorities."

Results from the study were featured in the official press programme of the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta on Monday, 11 December, and will be presented during the Late-Breaking Abstracts Session on Tuesday, 12 December, at 7.45am EST by John F. Seymour, MD, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia (Abstract #LBA-2).

Data from the MURANO study will be submitted to global health authorities, including the US Food and Drug Administration (FDA), which has granted Breakthrough Therapy Designation for Venclexta in combination with Rituxan for the treatment of relapsed or refractory CLL based on promising results from the phase Ib M13-365 study.

Venclexta was granted accelerated approval by the FDA in April 2016 for the treatment of people with CLL with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. The MURANO study is part of the company’s commitment in the United States to convert the current accelerated approval of Venclexta to a full approval.

A robust clinical development programme for Venclexta/Venclyxto is ongoing, and additional results across multiple blood cancers including acute myeloid leukaemia (AML) and multiple myeloma (MM) were also presented at the ASH (Free ASH Whitepaper) Annual Meeting.

About the MURANO Study
MURANO (NCT02005471) is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of Venclexta/Venclyxto in combination with MabThera/Rituxan compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration. The study included 389 patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who had been previously treated with at least one, but not more than three, lines of therapy. Patients were randomly assigned in a 1:1 ratio to receive either Venclexta/Venclyxto plus MabThera/Rituxan (Arm A) or BR (Arm B). The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints include PFS assessed by independent review committee (IRC), overall response rate (ORR), complete response rate (with or without complete blood count recovery, CR/CRi), overall survival (OS), minimal residual disease (MRD) status, duration of response, event-free survival and time to next CLL treatment.

The results showed:

Patients in the study who received Venclexta/Venclyxto plus MabThera/Rituxan lived significantly longer without their disease worsening (PFS, as assessed by investigator) compared to those who received BR (HR=0.17; 95% CI, 0.11-0.25; p<0.0001; median PFS: not reached vs. 17.0 months, respectively).
At two years, 84.9% of patients in the Venclexta/Venclyxto plus MabThera/Rituxan arm had not experienced disease progression, compared to 36.3% of patients in the BR arm.
Consistent benefit was observed in all patient subgroups for Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, including high-risk and low-risk groups.
IRC assessment was consistent; as assessed by IRC, Venclexta/Venclyxto plus MabThera/Rituxan reduced the risk of disease progression or death by 81% compared to BR (HR=0.19; 95% CI 0.13, 0.28; p<0.0001).
Clinical benefit observed for Venclexta/Venclyxto plus MabThera/Rituxan compared to BR was consistent across key secondary endpoints, including OS (HR=0.48, 95% CI 0.25-0.90; medians not yet reached), ORR as assessed by investigator (93.3% vs. 67.7%), CR/CRi as assessed by investigator (26.8% vs. 8.2%). These results were not statistically significant. In addition, higher rates of MRD-negativity at any time were observed with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR (83.5% vs. 23.1%). MRD negativity was defined as less than one CLL cell in 10,000 leukocytes.
No new safety signals were observed with the treatment combination of Venclexta/Venclyxto plus MabThera/Rituxan. The most common Grade 3-4 adverse events with Venclexta/Venclyxto plus MabThera/Rituxan compared to BR, respectively, were low white blood cell count (57.7% vs. 38.8%), low red blood cell count (10.8% vs. 13.8%), low platelet count (5.7% vs. 10.1%), low white blood cell count with fever (3.6% vs. 9.6%), pneumonia (5.2% vs. 8.0%) and infusion reactions (1.5% vs. 5.3%).
About Venclexta/Venclyxto
Venclexta/Venclyxto is a small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). Overexpression of the BCL-2 protein in CLL has been associated with resistance to certain therapies. It is believed that blocking BCL-2 may restore the signalling system that tells cells, including cancer cells, to self-destruct. Venclexta/Venclyxto is being developed by Roche and AbbVie. It is jointly commercialised by AbbVie and Genentech, a member of the Roche Group, in the United States and commercialised by AbbVie outside of the United States.

Together, the companies are committed to further research with Venclexta/Venclyxto, which is currently being evaluated in phase III clinical trials for the treatment of CLL, along with studies in several other types of cancers. In the United States, Venclexta has been granted four breakthrough therapy designations by the FDA: in combination with Rituxan for people with relapsed or refractory CLL, as a monotherapy for people with relapsed or refractory CLL with 17p deletion; in combination with hypomethylating agents (azacitidine or decitabine) for people with untreated acute myeloid leukaemia (AML) ineligible for intensive chemotherapy, and in combination with low-dose cytarabine (LDAC) for people with untreated AML ineligible for intensive chemotherapy.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world.1 CLL mainly affects men and the median age at diagnosis is about 70 years.2 Worldwide, the incidence of all leukaemias is estimated to be over 350,0001 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.3

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera /Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), and Venclexta / Venclyxto (venetoclax) in collaboration with AbbVie, Roche’s pipeline of investigational haematology medicines includes Tecentriq (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche’s dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.

Cyclacel Announces Presentation of Results From Phase 3 Seamless Study at Ash Annual Meeting

On December 12, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) "Cyclacel" or the "Company"), a biopharmaceutical company developing oral therapies that target various phases of cell cycle control for the treatment of cancer and other serious disorders, reported results from the Company’s Phase 3 SEAMLESS study (Press release, Cyclacel, DEC 12, 2017, View Source [SID1234522578]). Cyclacel had previously announced top-line results from its Phase 3 SEAMLESS study in February 2017. The study enrolled elderly patients with newly diagnosed acute myeloid leukemia (AML) and compared alternating cycles of decitabine and sapacitabine versus decitabine. Data were reported at an oral presentation on Monday, December 11, at 6:45 PM EST at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia.

"Although the study did not reach its primary endpoint of superiority in survival, we are encouraged by the higher complete remission rate on the sapacitabine-decitabine arm, especially in the subgroup with low white blood cell count; additional analysis of the data should be pursued," said Hagop Kantarjian, M.D., Professor and Chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center, and chair of the study.

"We are pleased to report detailed results of the SEAMLESS study, which as previously announced, did not reach its primary endpoint," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "We believe that the subgroup results have defined a patient population for whom the decitabine-sapacitabine regimen may represent an improvement over low intensity treatment by decitabine alone. We plan to discuss the data, the statistical robustness of the subgroup results and the optimal baseline peripheral white blood cell (WBC) cutpoint with European and US regulatory authorities and will provide updates as appropriate. We are grateful to the patients, their families and the investigators for their contributions to this large study. In parallel, we are progressing our other clinical programs in transcriptional regulation with CYC065 and DNA damage response with sapacitabine-seliciclib in biomarker-selected patients with solid tumors, such as those with BRCA mutations or resistance to existing cancer therapies."

Study Design & Intent-to-Treat Results

The randomized, open label, Phase 3 SEAMLESS study enrolled 482 patients, aged 70 years or older, with newly diagnosed AML who were not candidates for or refused intensive therapy at 110 US and EU sites. Patients were stratified by WBC, antecedent hematologic disorder (AHD), and marrow blasts, and randomized 1:1 to receive either intravenous decitabine administered in alternating cycles with oral sapacitabine versus intravenous decitabine alone.

The trial did not meet its primary endpoint of demonstrating statistically significant improvement in overall survival. A higher complete remission (CR) rate, a secondary endpoint, was observed on the decitabine-sapacitabine arm (17% versus 11%). Other endpoints and safety were similar between the arms.

Prespecified Subgroup Analysis

Baseline WBC

In the less than 10,000 WBC subgroup (n=319) a trend towards improved overall survival (median 8.0 versus 5.8 months, HR=0.84 [0.66, 1.06], p=0.14) favoring decitabine-sapacitabine and a significantly higher CR rate (21.0% versus 8.6%, p=0.0017) was achieved on decitabine-sapacitabine.

In the 10,000 or more WBC subgroup (n=163) significantly better overall survival (median 3.8 versus 5.5 months, HR=1.57 [1.12, 2.19], p=0.007) was observed on decitabine. A trend in CR rate (8.3% versus 15.2%, p=0.18) favoring decitabine was observed but it did not reach statistical significance.

Prior AHD

In the subgroup with prior AHD (n=136) a significantly higher CR rate (16.7% versus 5.7%, p=0.0398) was achieved on decitabine-sapacitabine. There was a numerical difference in median survival (6.4 versus 5.0 months, HR=0.85 [0.59, 1.24], p=0.41) favoring decitabine-sapacitabine but overall survival did not reach statistical significance.

In the subgroup without prior AHD (n=346) there was a numerical difference in median survival (5.9 versus 6.7 months, HR=1.08 [0.86, 1.35], p=0.52) favoring decitabine and CR rate (16.6% versus 12.9%) favoring decitabine-sapacitabine but neither reached statistical significance.

Cytogenetics

In the subgroup with other than unfavorable cytogenetics (n=288) there was a numerical difference in median survival (8.2 versus 5.7 months, HR=0.89 [0.69, 1.15], p=0.38) and CR rate (19.9% versus 11.6%, p=0.16) favoring decitabine-sapacitabine but neither reached statistical significance.

In the subgroup with unfavorable cytogenetics (n=194) there was a numerical difference in median survival (3.8 months versus 5.7 months, HR=1.27 [0.94, 1.73], p=0.12) favoring decitabine but overall survival did not reach statistical significance. There was a numerical difference in CR rate favoring decitabine-sapacitabine (12.0% versus 9.6%) but it did not reach statistical significance.

In the subgroup of patients with below 50% and with 50% or higher bone marrow blasts there were no statistically significant differences in overall survival between the arms.

Presentation

The presentation (abstract 891), titled "Results of a Phase 3 Study of Elderly Patients with Newly Diagnosed AML Treated with Sapacitabine and Decitabine Administered in Alternating Cycles," is available on the Cyclacel website at www.cyclacel.com.

About Sapacitabine

Sapacitabine (CYC682), an orally-available nucleoside analogue, is currently being studied in an ongoing, extension of a Phase 1 study evaluating a combination regimen of sapacitabine and seliciclib, a first generation CDK inhibitor. Parts 1 and 2 of the study evaluated approximately 90 patients with advanced cancers. Part 3 is ongoing in patients with BRCA positive, breast, ovarian and pancreatic cancer. Over 1,000 patients with hematological malignancies and solid tumors have received sapacitabine.

About AML

AML is a rapidly progressing cancer of the blood characterized by the uncontrolled proliferation of immature blast cells in the bone marrow. The American Cancer Society estimates there will be approximately 21,380 new cases of AML and approximately 10,590 deaths from AML in the U.S. in 2017. AML is generally a disease of older adults and the median age is about 67 years. Newly diagnosed elderly patients with poor prognostic risk factors typically die within one year.

Aduro Biotech Provides Update on CRS-207 Programs

On December 12, 2017 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported an update on its clinical development programs for CRS-207, a first-generation proprietary attenuated strain of Listeria that has been engineered to express the tumor-associated antigen mesothelin (Press release, Aduro Biotech, DEC 12, 2017, View Source;p=RssLanding&cat=news&id=2322291 [SID1234522577]). Based on preliminary results from its mesothelioma and ovarian studies, as well as a business and commercial assessment, the company has determined that it will not continue advancement of CRS-207 and will wind down each of its trials in mesothelioma, ovarian and gastric cancer. Aduro will be working closely with investigators to proceed in a manner that is aligned with the best interests of patients still being treated on these studies.

"We would like to thank the patients, their families, our clinical investigators and staff for their time and commitment to these trials, which will contribute important data to the field of oncology. While we are disappointed with the results for CRS-207, our clinical development program was designed to quickly generate data that could inform timely decision-making and allow us to prioritize our portfolio accordingly," said Stephen Isaacs, chairman and chief executive officer of Aduro Biotech. "We will shift our focus and investment toward our STING agonist program, B-select antibodies and personalized neoantigen approach with pLADD. In our STING program in particular, there are several additional clinical trials under consideration to complement our ongoing Phase 1 dose escalation trial of ADU-S100 as well as our combination study with Novartis’ PD-1 checkpoint inhibitor, PDR-001. As a result of our portfolio decisions, we expect our current cash balance to be sufficient to fund planned activities for the next three years through 2020."

Conference Call with Management Today
Aduro’s management will host a conference call to review its programs and provide a general business update today at 8:30 am Eastern Time. To participate in the conference call, please dial (844) 309-0604 (domestic) or (574) 990-9932 (international) and refer to conference ID 2455008. Live audio of the conference call will be simultaneously webcast and available to members of the news media, investors and the general public under the investor section of the Aduro website at investors.aduro.com.

The webcast will be archived and available for replay for one month after the event.

AbbVie Announces Phase 3 Study of VENCLEXTA™/ VENCLYXTO™ (venetoclax) in Combination with Rituxan® (rituximab) Meets its Primary Endpoint

On December 12, 2017 AbbVie (NYSE: ABBV), a research and development based global biopharmaceutical company, reported the first presentation of efficacy and safety results from MURANO, an international, multicenter, open-label, randomized Phase 3 study of VENCLEXTA/VENCLYXTO (venetoclax) in combination with Rituxan (rituximab) compared with bendamustine in combination with Rituxan in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) AbbVie (NYSE: ABBV), a research and development based global biopharmaceutical company, reported the first presentation of efficacy and safety results from MURANO, an international, multicenter, open-label, randomized Phase 3 study of VENCLEXTA/VENCLYXTO (venetoclax) in combination with Rituxan (rituximab) compared with bendamustine in combination with Rituxan in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) (Press release, AbbVie, DEC 12, 2017, View Source [SID1234522576]).

Investigator-assessed results showed that patients with R/R CLL achieved significantly prolonged median progression-free survival (PFS) with VENCLEXTA/VENCLYXTO in combination with Rituxan [median PFS, not reached], compared with bendamustine in combination with Rituxan [median PFS, 17.0 months; hazard ratio, 0.17; 95% CI, 0.11–0.25; P<0.0001].1 Twenty-four month PFS estimates were 84.9 percent and 36.3 percent, respectively.1 Independent Review Committee (IRC)-assessed PFS showed similar results.1 Additionally, consistent improvement in PFS was observed across the patient subgroups assessed in the trial, including patients with 17p deletion [hazard ratio 0.14; 95% CI, 0.06–0.33].1 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.

At the time of the interim analysis, safety data were consistent with the known safety profiles of the medicines.1

"The data from the MURANO trial represents the next evolution in a potential treatment option for patients with relapsed/refractory CLL, an indication for which we received Breakthrough Therapy Designation," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "We are proud to present these findings at the ASH (Free ASH Whitepaper) annual meeting and are working closely with regulatory authorities to bring this combination therapy to appropriate patients as soon as possible."

The data also serves as the Phase 3 confirmatory study requested by the U.S. Food and Drug Administration (FDA) when VENCLEXTA was granted accelerated approval on April 11, 2016.2 Health authority regulatory submissions of VENCLEXTA/VENCLYXTO in combination with Rituxan are underway.

"This primary analysis of the MURANO trial showed a significant improvement in PFS with VENCLEXTA/VENCLYXTO and Rituxan versus bendamustine and Rituxan, with consistent results in all patient subsets assessed," said John Seymour, M.D., Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia and lead investigator of the MURANO trial. "Based on the efficacy and safety results of this trial, the VENCLEXTA/VENCLYXTO and Rituxan combination has the potential to offer a new chemotherapy-free regimen for patients with relapsed/refractory CLL. We continue to monitor safety and efficacy in trial patients to gain further data and information."

Design and Results of Phase 3 Study Presented at ASH (Free ASH Whitepaper)
A total of 389 patients with R/R CLL who had received one to three prior therapies were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO study.1 The study was designed to evaluate the efficacy and safety of VENCLEXTA/VENCLYXTO in combination with Rituxan (194 patients; median age, 64.5 years) compared with bendamustine in combination with Rituxan (195 patients; median age, 66.0 years).1

For patients receiving VENCLEXTA/VENCLYXTO in combination with Rituxan, a 4-week or 5-week dose ramp-up of VENCLEXTA/VENCLYXTO from 20 to 400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk.1 Beginning at week 6, intravenous (IV) Rituxan was given monthly for six 28-day cycles (375 mg/m2 first dose, then 500 mg/m2).1 Patients continued with VENCLEXTA/VENCLYXTO 400 mg for a maximum of two years or until disease progression, whichever was first.1 For patients receiving bendamustine in combination with Rituxan, patients were given bendamustine (70 mg/m2 IV) on days 1 and 2 of each of six 28-day cycles in combination with Rituxan using the same dosing schedule.1

The primary endpoint was investigator-assessed PFS, which was determined using standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.3 Secondary endpoints included Independent Review Committee (IRC)-assessed PFS, as well as PFS in patients with 17p deletion, best overall response (defined as complete response [CR], complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS), event-free survival, duration of response, time to next anti-CLL treatment, and percentage of patients achieving minimal residual disease (MRD)-negativity.3 As of May 8, 2017, median follow-up was 23.8 months (range, 0-37.4 months).1

Study Results:1

Endpoint*

Investigator-Assessed
Independent Review Committee
Progression-Free Survival
VR: 84.9%
VR: 82.8%4
(24-month estimate)
BR: 36.3%
BR: 37.4%4

Median PFS
VR: Not reached
VR: Not reached4

BR: 17.0 months
BR: 18.1 months4

HR (95% CI)
HR=0.17 (0.11–0.25)
HR=0.19 (0.13- 0.28)
P-value
P <0.0001
P <0.0001

Overall Response
VR: 93.3% (181/194)
VR: 92.3% (179/194)
(CR, CRi, PR, nPR)
BR: 67.7% (132/195)
BR: 72.3% (141/195)

Difference (95% CI)
25.6% (17.9-33.3)
20.0% (12.4-27.6)

Complete Response
VR: 26.8% (52/194)
VR: 8.2% (16/194)
(CR/CRi)
BR: 8.2% (16/195)
BR: 3.6% (7/195)

Difference (95% CI)
18.6%
4.7% (-0.3, 9.6)
P-value

P=NS

Partial Response
VR: 66.5% (129/194)
VR: 84.0% (163/194)
(PR/nPR)
BR: 59.5% (116/195)

BR: 68.7% (134/195)
Overall Survival

(OS)

Events
VR 7.7% (15/194)4

BR 13.8% (27/195)4

HR (95% CI)
HR =0.48 (0.25-0.90)4

Peripheral blood Minimal Residual Disease Negativity
VR: 83.5% (162/194)
BR: 23.1% (45/195)
(MRD-)**

Difference (95% CI)
60.4% (52.3–68.6)
*Abbreviations: VR (VENCLYXTO/VENCLEXTA+ Rituxan); BR (bendamustine + Rituxan); NS (not significant)
** Best response at any timepoint; MRD negativity was defined as less than 1 CLL cell in 10,000 leukocytes
In the study, the adverse events (AEs) were consistent with the known safety profile of VENCLEXTA/VENCLYXTO and Rituxan. Grade 3-4 neutropenia was higher in the VENCLEXTA/VENCLYXTO in combination with Rituxan arm of the trial. 1 For patients taking VENCLEXTA/VENCLYXTO in combination with Rituxan and bendamustine in combination with Rituxan, there were 6 (3.1 percent) and 2 (1.1 percent) grade ≥3 TLS AEs reported in each arm, respectively.1 For VENCLEXTA/VENCLYXTO in combination with Rituxan versus bendamustine in combination with Rituxan, respectively, Richter transformation was confirmed in 6 and 5 patients, and AEs leading to death were seen in 10 (5.2 percent) versus 11 (5.9 percent) patients.1

Summary of Adverse Events (AEs):1

Adverse Events*

Venetoclax in combination with
rituximab (N= 194)

Bendamustine in combination with
rituximab (N=195)

Number of AEs
335
255
Grade 3-4 AEs occurring in > 5
percent in either arm, n (%)
Neutropenia
Anemia
Thrombocytopenia
Febrile neutropenia
Pneumonia
Infusion-related reaction

112 (57.7)
21 (10.8)
11 (5.7)
7 (3.6)
10 (5.2)
3 (1.5)

73 (38.8)
26 (13.8)
19 (10.1)
18 (9.6)
15 (8.0)
10 (5.3)
Serious AEs in > 2 patients
in either arm, n (%)

Pneumonia
Influenza
Sepsis
Upper respiratory tract infection
Lung infection
Sinusitis
Appendicitis
Bronchitis
Pharyngitis
Respiratory tract infection

16 (8.2)
3 (1.5)
1 (0.5)
3 (1.5)
3 (1.5)
2 (1.0)
2 (1.0)
0
0
2 (1.0)

15 (8.0)
2 (1.1)
4 (2.1)
2 (1.1)
0
1 (0.5)
0
2 (1.1)
2 (1.1)
0
Fatal AEs, n (%)
10 (5.2)
11 (5.9)
*AE reporting period: up to 90 days after end of bendamustine and rituximab treatment (maximum six months); up to 28 days after end of venetoclax and rituximab treatment (maximum two years).
About VENCLEXTA/VENCLYXTO
VENCLEXTA/VENCLYXTO is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.2,5 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.2,5 VENCLEXTA/VENCLYXTO targets BCL-2 in order to help restore the process of apoptosis.2,5 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.2,5

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 with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.

VENCLEXTA/VENCLYXTO is currently approved in 49 nations, including the U.S., and in the EU. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

About VENCLYXTO (venetoclax) Tablets (EU)
VENCLYXTO (venetoclax) is indicated in the European Union (EU) for the treatment of chronic lymphocytic leukemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.5 It is also being evaluated for the treatment of patients with various blood cancer types. 1,6,7,8,9 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.1 VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.1

Important VENCLYXTO (venetoclax) EU Safety Information
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase. Concomitant use of preparations containing St. John’s wort.

Special Warnings & Precautions for Use
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of VENCLYXTO and at each dose increase. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including IV hydration, frequent monitoring and hospitalization) should be employed as overall risk increases.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period.

Live vaccines should not be administered during treatment or thereafter until B-cell recovery.

Drug Interactions
CYP3A inhibitors may increase VENCLYXTO plasma concentrations. At initiation and dose-titration phase: Strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the SmPC for dose adjustment recommendations.

Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.

CYP3A4 inducers may decrease VENCLYXTO plasma concentrations.

Avoid co-administration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.

Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.

Adverse Reactions
The most commonly occurring adverse reactions (>=20%) of any grade were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS.

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. Advise nursing women to discontinue breastfeeding during treatment.

Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk. Monitor closely for signs of toxicity due to increased risk of TLS.

This is not a complete summary of all safety information. See VENCLYXTO full summary of product characteristics (SmPC) at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About VENCLEXTA (venetoclax) tablets (US)
In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval of VENCLEXTA (venetoclax) tablets for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.2 The FDA approved this indication under accelerated approval based on overall response rate, and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.

VENCLEXTA has been granted four Breakthrough Therapy Designations from the FDA including for the combination treatment of patients with untreated AML not eligible for standard induction chemotherapy. This designation is intended to expedite the development and review of therapies for serious or life-threatening conditions.10 In January 2016, AbbVie announced that the FDA granted priority review for the single agent NDA application for VENCLEXTA.

In November 2017, AbbVie and Genentech received the Prix Galien award for "Best Pharmaceutical Product" for VENCLEXTA.11

What is VENCLEXTA (venetoclax)?
VENCLEXTA (venetoclax) is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior treatment.

VENCLEXTA was approved based on response rate. There is an ongoing study to find out how VENCLEXTA works over a longer period of time.

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

Important VENCLEXTA (venetoclax) US 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 doctor will do tests for TLS. It is important to keep your appointments for blood tests. 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. Tell your doctor 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 when taking 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.

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.

Tell your doctor 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 doctor.
What should I tell my doctor before taking VENCLEXTA?
Before taking VENCLEXTA, tell your doctor 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 doctor tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your 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 your unborn baby. If you are able to become pregnant, your doctor should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with 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 count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your doctor will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your doctor right away if you have a fever or any signs of an infection.
The most common side effects of VENCLEXTA include low white blood cell count, diarrhea, nausea, low red blood cell count, upper respiratory tract infection, low platelet count, and feeling tired.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your doctor if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your doctor if you have any side effect that bothers you or that does not go away.

The full U.S. prescribing information for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

Patient Assistance
For those who qualify, patient assistance options are available for people taking VENCLEXTA in the U.S.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and development efforts, and through collaborations, AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 200 clinical trials and more than 20 different tumor types. For more information, please visit View Source