Uncategorized – Page 15681 – 1stOncology™: Cancer Intelligence Service

ImmunoCellular Therapeutics Achieves Key Milestone in Stem-to-T-Cell Research Immuno-Oncology Program

On December 13, 2017 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular" or the Company) (NYSE American: IMUC) reported that it has achieved a key milestone in its research-stage Stem-to-T-Cell immuno-oncology program (Press release, ImmunoCellular Therapeutics, DEC 13, 2017, View Source [SID1234522639]). The milestone represents an important step toward stimulating the patient’s immune system to produce an unlimited supply of killer T cells that specifically target and destroy tumor cells with minimal side effects. This approach could be effective in treating many types of cancers.

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The research team at ImmunoCellular successfully packaged a T cell receptor (TCR) DNA sequence into a lentiviral vector, which was then used to transfect human hematopoietic stem cells. The Company has been able to verify successful transfer of genetic material into the stem cells, and plans to continue to work toward optimizing the transfection process. The Company believes that this completed phase of the Stem-to-T-Cell development is an important component of the proof-of-concept work for this technology, and represents a critical step in advancing toward preclinical testing.

"We are excited to have achieved this critical initial milestone in our Stem-to-T-Cell program, and to have generated a body of scientific evidence of successful transfection and proof that the transfected human hematopoietic stem cells bearing the TCR were able to grow robustly for several generations," said Steven J. Swanson, PhD, Senior Vice President, Research. "We and our collaborators are on schedule to undertake next anticipated steps designed to enhance the transfection process and advance toward preclinical testing. We remain committed to our vision to develop solutions for intractable cancers, extending the lives of cancer patients, and providing hope for a potential cure. We believe that our Stem-to-T-Cell program is potentially a game-changing treatment for cancer."

Anthony J. Gringeri, PhD, President and Chief Executive Officer commented: "We are proud of the achievements of our research team and the important scientific validation of our Stem-to-T-Cell program generated to date. We believe that our stem cell technology represents a major step forward in immuno-oncology, and has the potential for meaningful advantages over other novel immuno-oncology technologies, including use in combination approaches. With our strengthened financial condition and cash reserves, we intend to continue to focus our resources on achieving additional research milestones over the next 18 months. We are also continuing to explore potential collaborations for our clinical programs and other strategic alternatives for our Company."

About ImmunoCellular’s Stem-to-T-Cell Program

Based on the technology in-licensed from The California Institute of Technology in 2014 ImmunoCellular’s Stem-to-T-Cell program is designed to harness the power of the immune system in highly directed and specific ways to engineer highly antigen-specific tumor killing. At the core of the Stem-to-T-Cell technology is harvesting stem cells from cancer patients and then cloning into them T cell receptors that are specific for cancer cells. These engineered stem cells can then be reintroduced into the patient and are pre-programed to produce daughter cells that are antigen specific killer T cells that are capable of identifying, binding to, and killing cancer cells. Because stem cells are immortal, these reengineered stem cells could provide a natural and perpetual source of T cells that can target and destroy cancer cells in the patient.

The Stem-to-T-Cell platform has the potential to address many types of cancer, including both solid and hematological tumors and has the potential to result in a potentially curative therapy for many different types of cancers. The stem cell platform represents a novel and more direct approach to generating killer T cells by using the patient’s stem cells as starting material. Thus, ImmunoCellular’s Stem-to-T-Cell technology shares some similarities with other immuno-oncology technologies, such as CAR-T, and could potentially be used in combination approaches. Unlike CAR-T therapies which deliver a large bolus of active T cells into the patient’s circulation and have been associated with toxicity in some patients, ImmunoCellular’s approach enables a more gradual and measured release of killer T cells and has the potential for lower toxicity while also yielding a more sustained response.

Sanofi presents R&D strategy and innovative pipeline 

On December 13, 2017 Sanofi reported that it will host an analyst meeting in Paris today to discuss the company’s Research and Development strategy, development pipeline and milestones for 2018 (Press release, Sanofi, DEC 13, 2017, View Source [SID1234522611]). The company will highlight the progress it has made against "Sustaining Innovation", a key pillar of its 2020 strategic roadmap, and advancing a differentiated portfolio addressing unmet needs.

The company’s pipeline spans 71 R&D projects, which includes 37 new molecular entities and novel vaccines. At least 10 pivotal phase 3 studies are expected to start over the next 12 months and will evaluate new treatments for:
chronic obstructive pulmonary disease and eosinophilic esophagitis (dupilumab[1]);
autosomal dominant polycystic kidney disease (ADPKD), a rare kidney disease (venglustat);
type 2 diabetes (efpeglenatide, a once-weekly GLP-1 agonist);
obesity (a GLP-1/GCG dual agonist);
primary progressive multiple sclerosis (alemtuzumab), and;
first line NSCLC[2] (cemiplimab).

Regulatory filings expected in the next 12 months include two investigational cancer drugs (cemiplimab and isatuximab), a novel therapy for type 1 diabetes (sotagliflozin) and a potential treatment for uncontrolled, persistent asthma (dupilumab).

"We have seen significant advancement on our ambition to sustain innovation in R&D, with the development of leading technology platforms and proof of concept demonstrated in multiple high-potential projects in late stage trials. We are confident this portfolio will be the foundation for Sanofi’s future long-term growth," said Olivier Brandicourt, MD, Chief Executive Officer at Sanofi.

As a key pillar of the 2020 Roadmap, the new Sanofi R&D model is based on three key strategic shifts:
From small molecules to biologics;
From mono-targeting to multi-targeting compounds; and
From licensing to proprietary assets.

The company has continuously adapted its R&D model in recent years to deliver greater efficiency and excellence in development, resulting in a major uplift in productivity. Since 2016, consistent with the three key strategic shifts outlined above, Sanofi has placed increasing emphasis on developing proprietary technology platforms, including multi-specific antibodies (bi- & tri-specific), siRNA, trigonal peptides, dual and triple agonists, and PRR-Antibody conjugates. It has also leveraged external expertise in targeted platforms such as mRNA mixtures and Nanobodies.

"We aim to advance multi-targeting therapeutic approaches for core disease pathways that have the potential to attack more than one disease at a time or bring improved risk benefit in the treatment of a single disease," said Elias Zerhouni, MD, Global Head of R&D at Sanofi. "2018 will be an important year as we expect multiple milestones for Sanofi’s late-stage pipeline, made possible through the prioritization principles we have consistently applied to our early-stage research programs."

Building a competitive position in Specialty Care

Immunology

Sanofi is strengthening its specialty care portfolio and has executed launches in its fast-growing immunology franchise. Dupilumab, which we are developing in collaboration with Regeneron, has potential across multiple indications. Phase 3 trials for uncontrolled, persistent asthma recently demonstrated a potentially clinically important profile among biologic treatments. Submission in this important indication is expected before the end of 2017. Clinical development is underway in nasal polyposis, eosinophilic esophagitis, food allergies and in pediatric populations in most of these indications. Additionally, phase 3 development for dupilumab is now planned in chronic obstructive pulmonary disease (COPD). Sanofi, in collaboration with Regeneron, also expects to bring SAR440340, an anti-IL-33 antibody, which has the potential for a broader spectrum of immune modulation, into phase 2 in atopic dermatitis, asthma and COPD in 2018, alone or in combination with dupilumab.

Oncology

Sanofi is committed to re-building its position in oncology and has made major progress in the past two years. This strategy is starting to deliver and we anticipate 14 new proof-of-concept studies to be initiated, four potential proof-of-concept readouts, six phase one starts and three BLA/ MAA submissions in 2018. Cemiplimab is an investigational PD-1 checkpoint inhibitor and the backbone of our checkpoint immuno-oncology strategy with our partner Regeneron. It is being studied in cutaneous squamous cell carcinoma (CSCC), for which it was granted "Breakthrough Therapy" designation by the U.S. Food and Drug Administration (FDA), with an expected regulatory submission in Q1 2018. The development program also includes large or untapped opportunities in immuno-oncology, such as basal cell carcinoma, cervical cancer, and first line lung cancer.

Isatuximab is a Sanofi investigational antiCD38 monoclonal antibody with a first regulatory submission expected in 2018 for relapsed refractory multiple myeloma (RRMM). Beyond multiple myeloma, and building on the emerging evidence that CD38 inhibition may reverse resistance to PD-L1, isatuximab will be studied in combination with cemiplimab or other immuno-oncology agents. Sanofi will also present early research programs for its Selective Estrogen Receptor Degrader (SERD) and TGF-beta program to overcome PD-1 resistance.

Multiple Sclerosis

In multiple sclerosis (MS), Sanofi plans to build on the proven long-term clinical profile of Lemtrada (alemtuzumab) by initiating a Phase 3 study in 2018 for alemtuzumab in patients with primary progressive multiple sclerosis (PPMS). Consistent with Sanofi’s rigorous prioritization methodology, the company will deprioritize GLD-52 in this indication in favor of alemtuzumab. In addition, Sanofi, in collaboration with Principia, will be developing a novel Bruton’s tyrosine kinase (BTK) inhibitor, designed to access the brain and spinal cord by crossing the blood-brain barrier and impact immune cell and brain cell signaling. It is currently being studied in MS with potential applications in other central nervous system diseases[3].

Sustaining leadership in Rare Disease, Diabetes & Cardiovascular and Vaccines
Rare Disease

Sanofi’s Rare Disease pipeline is structured with the goal of sustaining innovation in lysosomal storage disorders, while also expanding strategically into related conditions. Clinical development programs include venglustat, an oral inhibitor of glucosylceramide synthase, in Fabry Disease, Gaucher Disease Type 3, GBA Parkinson’s Disease and autosomal dominant polycystic kidney disease (ADKPD). Late-stage/pivotal programs include olipudase, a first-in-class enzyme replacement therapy (ERT) for the non-neurological manifestations of acid sphingomyelinase deficiency (ASMD), and avalglucosidase alfa, a novel ERT for Pompe disease. Finally, through a strategic collaboration with Alnylam, we are advancing the development of patisiran for hATTR[4] amyloidosis and fitusiran for hemophilia A and B, with and without inhibitors.

Diabetes & Cardiovascular

Sanofi is committed to sustaining a leadership position in diabetes and expanding into adjacent co-morbidities. Its late-stage diabetes pipeline includes sotagliflozin, an investigational SGLT-1/2 inhibitor being developed in collaboration with Lexicon, and efpeglenatide, a once-weekly GLP-1 being developed in collaboration with Hanmi, both of which potentially offer unique patient advantages. Additionally, Sanofi is leveraging its novel peptide incretin platform to develop breakthrough assets for diabetes, obesity and non-alcoholic steatohepatitis (NASH). The lead compound is a dual agonist of GLP-1/GCG which has shown highly competitive weight loss in the clinic and is expected to enter phase 3 in obesity in 2018. A phase 2 study in NASH is also due to start in 2018.
In cardiovascular, Sanofi continues to work in collaboration with Myokardia on therapeutic options for genetic forms of cardiomyopathy. The lead compound is mavacamten, an oral modulator of cardiac myosin, which is in phase 2 for HCM[5] and is expected to start a registrational phase 2b/3 study in 2018.
Vaccines

Sanofi has six key vaccine projects currently in development, and priority disease areas include influenza, meningitis and respiratory syncytial virus (RSV). RSV is the leading cause of infant viral mortality and represents a new potential category for Sanofi. The company is taking a complementary dual approach to RSV with a monoclonal antibody in phase 2, in collaboration with MedImmune, and a vaccine in phase 1.

Webcast details

The event will be webcast live on Sanofi’s website at 8:30 am CET/2:30 am EST. The webcast details and full presentation will be made available on Sanofi’s Investor Relations webpage and an Appendix compiling all Sanofi studies registered on clinicaltrials.gov will also be published.
[1] Partnered products: cemiplimab, dupilumab, anti-IL33 mAb (Regeneron); sotagliflozin (Lexicon); efpeglenatide (Hanmi); fitusiran, patisiran (Alnylam); mavacamten, MYK-491 (Myokardia).
[2] Non-Small Cell Lung Cancer
[3] The Principia transaction remains subject to customary regulatory approvals and has not yet closed.
[4] hATTR = Hereditary Transthyretin-Mediated Amyloidosis
[5] HCM= Hypertrophic cardiomyopathy

PRINCIPIA BIOPHARMA INITIATES CLINICAL TRIAL FOR PRN1008 IN PATIENTS WITH IMMUNE THROMBOCYTOPENIA PURPURA

On December 13, 2017 Principia Biopharma, a private, clinical-stage biopharmaceutical company, reported that it has initiated a clinical trial for PRN1008, a reversible covalent Bruton’s Tyrosine Kinase (BTK) inhibitor, in patients with Immune Thrombocytopenia Purpura (ITP) in the US. ITP, an autoimmune disorder characterized by thrombocytopenia – a decreased number of circulating platelets – is the second indication for which Principia is evaluating PRN1008 (Press release, Principia Biopharma, DEC 13, 2017, View Source [SID1234522663]). Principia also has an on-going clinical program for PRN1008 in patients with pemphigus, another autoimmune disease, where it has seen a promising efficacy and safety profile to date.

Supporting advancement into clinical trials, the company recently presented preclinical data at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta (abstract #1052). The results from the studies showed that PRN1008 did not adversely affect platelet aggregation in blood from both healthy volunteers and ITP patients. Additionally, results in an animal model of ITP showed that animals treated with PRN1008 had significantly higher platelet counts than control animals (p<0.05).

"These preclinical results are encouraging and provide strong evidence that PRN1008, an oral, BTK inhibitor, inhibits antibody-mediated thrombocytopenia, supporting its study in ITP patients," said Steve Gourlay, MBBS, Ph.D., chief medical officer of Principia Biopharma. "New treatments and modalities are needed for patients with relapsed ITP that are effective in the majority of patients, with fewer toxicities and easier administration than current treatments. Based on these promising early findings, we have initiated the first human clinical trial of PRN1008 in patients with ITP."

Preclinical study design and results
The effect of PRN1008 on platelet function was evaluated in-vitro in the blood from both normal healthy volunteers and patients with ITP. Results showed that treatment with PRN1008 at therapeutically relevant concentrations had no effect on platelet aggregation in either healthy volunteers or ITP patients, and did not interfere with responses to all other platelet agonists tested. In contrast, ibrutinib, a United States Food and Drug Administration-approved BTK inhibitor, had a significant effect on platelet aggregation in healthy volunteers, consistent with published literature.

Additionally, the pharmacologic effect of PRN1008 was evaluated in an animal model of ITP. Animals given three different doses of PRN1008 were challenged with platelet-targeting antibodies, and blood platelet counts were measured. PRN1008 demonstrated significant dose-dependent prevention of platelet loss at six hours compared with the control animals (p<0.05).

About PRN1008
PRN1008 is an oral, reversible covalent BTK inhibitor (Bruton’s Tyrosine Kinase – a component of B-cell signaling and inflammatory pathways in most white blood cell types other than T-cells and plasma cells). It was designed using Principia’s proprietary Tailored Covalency technology to optimize its safety and efficacy profile, resulting in a prolonged and reversible action at the target site while being rapidly eliminated from the body. This approach limits systemic exposure of PRN1008 and enables rapid clinical reversibility of effects on the immune system.

About Immune Thrombocytopenia Purpura
ITP is a chronic autoimmune disease characterized by a decreased number of circulating platelets, which play a key role in clot formation. The disorder affects approximately 70,000 adults in the United States and over 200,000 in the European Union. The typical age of onset of chronic ITP is 40 to 60 years. Individuals with ITP have a tendency to bleed and easily bruise due to blood leaking from capillaries into the skin and mucous membranes. They also suffer from fatigue, diminished quality of life and the risk of mortality (including intracranial hemorrhage).

Approved therapies in the United States for ITP include corticosteroids, intravenous immunoglobulin (IVIg) and splenectomy (surgical removal of the spleen) to stop platelet depletion, and TPO receptor agonists to increase platelet production. There is no cure for ITP and most patients relapse.

About BTK inhibition in autoimmune disease
Bruton’s Tyrosine Kinase (BTK) is a protein important to the proper function of the immune system. BTK is a key part of the signaling pathway downstream of the B-cell and Fcγ receptors on most types of white blood cells except T-cells and plasma cells. Inhibition of BTK results in the down-regulation of various cellular activities that are activated in autoimmune and inflammatory diseases.

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