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Entry into a Material Definitive Agreement.

On November 21, 2019, BioCryst Pharmaceuticals, Inc. (the "Company") reported that completed its offering of pre-funded warrants to purchase up to an aggregate of 11,764,706 shares of the Company’s common stock ("Common Stock") at an offering price of $1.69 per share (the "Pre-Funded Warrants") pursuant to a Securities Purchase Agreement (the "Purchase Agreement") dated as of November 19, 2019 among the Company and 667, L.P. and Baker Brothers Life Sciences, L.P (Filing, 8-K, BioCryst Pharmaceuticals, NOV 21, 2019, View Source [SID1234551568]). The offering has been registered under the Securities Act of 1933 (the "Securities Act") pursuant to a registration statement on Form S-3 (Registration No. 333-221421) of the Company (as amended, the "Registration Statement"), and a prospectus supplement dated November 19, 2019, filed with the Securities and Exchange Commission pursuant to Rule 424(b) of the Securities Act on November 21, 2019. Gross proceeds to the Company, before expenses, were approximately $19.9 million.

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The pre-funded warrants have an exercise price of $0.01 per share, which is subject to adjustment in the event of certain stock dividends and distributions, stock splits, stock combinations, reclassifications or similar events affecting the Company’s common stock and also upon any distributions of assets to the Company’s stockholders. Each pre-funded warrant is exercisable upon issuance. In the event of certain corporate transactions, the holders of the pre-funded warrants will be entitled to receive, upon exercise of the pre-funded warrants, the kind and amount of securities, cash or other property that the holders would have received had they exercised the pre-funded warrants immediately prior to such transaction. The pre-funded warrants do not contain voting rights or any of the other rights or privileges as a holder of the Company’s common stock.

The foregoing summary of the Pre-Funded Warrants does not purport to be complete and is subject to, and qualified in its entirety by, the form of Pre-Funded Warrant attached as Exhibit 4.1 to this Current Report on Form 8-K, which is incorporated herein by reference.

BIO-PATH HOLDINGS ANNOUNCES CLEARANCE OF INVESTIGATIONAL NEW DRUG APPLICATION FOR BP1002

On November 21, 2019 Bio-Path Holdings, Inc., (NASDAQ:BPTH), a biotechnology company leveraging its proprietary DNAbilize antisense RNAi nanoparticle technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that the U.S. Food and Drug Administration (FDA) has reviewed and cleared the Investigational New Drug (IND) application for BP1002 (liposomal Bcl-2), the Company’s second drug candidate (Press release, Bio-Path Holdings, NOV 21, 2019, View Source [SID1234551567]). An initial Phase 1 clinical trial will evaluate the ability of BP1002 to treat refractory/relapsed lymphoma and chronic lymphocytic leukemia patients.

BP1002 targets the protein Bcl-2, which is responsible for driving cell survival in up to 60% of all cancers. High expression of Bcl-2 has been correlated with adverse prognosis for patients diagnosed with relapsed, aggressive non-Hodgkin’s lymphoma. Preclinical studies have shown BP1002 to be a potent inhibitor against the Bcl-2 target, and its benign safety profile should enable BP1002 combination therapy with approved agents.

"With this IND submission now accepted by the FDA, the path is now cleared for us to advance our important first-in-human clinical work for BP1002 in cancers with unmet medical need," said Jorge Cortes, M.D., Director of the Georgia Cancer Center and Chairman of the Bio-Path Scientific Advisory Board. "Importantly, BP1002 activity is based on blocking the Bcl-2 messenger RNA and not the BH3 domain, as is the case with venetoclax. As a result, we believe BP1002 may provide an alternative for relapsed venetoclax patients."

The Phase 1 clinical trial is expected to be conducted at several leading cancer centers, including The University of Texas MD Anderson Cancer Center and the Georgia Cancer Center. Initially, a total of six evaluable patients are scheduled to be treated with BP1002 monotherapy in a standard 3+3 design, with a starting dose of 20 mg/m2. The approved treatment cycle is two doses per week over four weeks, resulting in eight doses administered over twenty-eight days.

William G. Wierda, M.D., Ph.D. will serve as Principal Investigator for the trial. Dr. Wierda is a Professor and Center Medical Director for the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Dr. Wierda also serves as Section Chief – Chronic Lymphocytic Leukemia in the Department of Leukemia at MD Anderson.

"This IND clearance for BP1002 marks an important regulatory milestone for Bio-Path, as we progress our second drug candidate into the clinic. Given the encouraging pre-clinical data and safety profile we have seen to-date, we are eager to begin this first-in-human study," said Peter Nielsen, President and Chief Executive Officer of Bio-Path Holdings.

The IND review process was performed by the FDA’s Office of Oncologic Diseases, Division of Hematologic Malignancies and involved a comprehensive review of data submitted by the Company covering pre-clinical studies, safety, chemistry, manufacturing and controls, and the protocol for the Phase 1 clinical trial.

Beam Therapeutics to Present New Preclinical Data on Base Editing Programs for Hemoglobinopathies at ASH 2019

On November 21, 2019 Beam Therapeutics, a biotechnology company developing precision genetic medicines through base editing, reported that it will present preclinical data for the company’s programs addressing sickle cell disease and beta thalassemia, two blood disorders that lack effective, disease-modifying treatments, at the 61st Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, being held December 7-10, 2019 in Orlando, Fla (Press release, Beam Therapeutics, NOV 21, 2019, View Source [SID1234551565]).

Details of the new data being presented in a poster at ASH (Free ASH Whitepaper) are as follows:

Title: Complementary base editing approaches for the treatment of sickle cell disease and

Beta-thalassemia

Date & Time: Sunday, December 8, 2019, 6:00-8:00 p.m. ET

Poster Session: 801 – Gene Therapy and Transfer: Poster II

Location: Orange County Convention Center, Hall B

Presenter: Ling Lin, Ph.D., senior scientist II, Beam Therapeutics

Calquence approved in the US for adult patients with chronic lymphocytic leukaemia

On November 21, 2019 AstraZeneca reported that the US Food and Drug Administration (FDA) has approved Calquence (acalabrutinib) for adult patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) (Press release, AstraZeneca, NOV 21, 2019, View Source [SID1234551564]).1 The US approval was granted under the FDA’s Real-Time Oncology Review and newly established Project Orbis programmes.

The approval is based on positive results from the interim analyses of two Phase III clinical trials, ELEVATE-TN in patients with previously untreated CLL and ASCEND in patients with relapsed or refractory CLL. Together, the trials showed that Calquence in combination with obinutuzumab or as a monotherapy significantly reduced the relative risk of disease progression or death versus the comparator arms in both 1st-line and relapsed or refractory CLL. Across both trials, the safety and tolerability of Calquence were consistent with its established profile.1

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: "With over 20,000 new cases anticipated this year in the US alone, today’s approval of Calquence provides new hope for patients with one of the most common types of adult leukaemia, offering outstanding efficacy and a favourable tolerability profile. The chronic lymphocytic leukaemia patient population is known to face multiple comorbidities, and tolerability is a critical factor in their treatment."

Dr Jeff Sharman, Director of Research at Willamette Valley Cancer Institute, Medical Director of Hematology Research for The US Oncology Network, and a lead author of the ELEVATE-TN trial, said: "Tolerability remains an issue in the current treatment landscape of chronic lymphocytic leukaemia, which may require ongoing therapy for many years. In the ELEVATE-TN and ASCEND trials comparing Calquence to commonly used treatment regimens, Calquence demonstrated a clinically meaningful improvement in progression-free survival in patients across multiple settings, while maintaining its favourable tolerability and safety profile."

The results of the interim analysis of the ELEVATE-TN trial will be presented at the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) congress.2

The trial showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for patients treated with either Calquence in combination with obinutuzumab or Calquence monotherapy versus chlorambucil chemotherapy plus obinutuzumab, a current standard-of-care combination used in the control arm.1

In the Calquence combination arm, risk of disease progression or death was reduced by 90% (HR 0.10; 95% CI, 0.06-0.17, p<0.0001) and in the monotherapy arm it was reduced by 80% (HR 0.20; 95% CI, 0.13-0.30, p<0.0001).1

The median time to disease progression for patients treated with Calquence in combination with obinutuzumab or as a monotherapy has not yet been reached versus 22.6 months (95% CI, 20-28) for chlorambucil plus obinutuzumab.1

ELEVATE-TN safety overview (most common ARs, ≥15%):1

†Includes multiple ADR terms.

In patients treated with the combination of Calquence plus obinutuzumab, adverse reactions (ARs) led to treatment discontinuation in 11% of patients and a dose reduction of Calquence in 7% of patients. In the monotherapy arm, ARs led to discontinuation in 10% and dose reduction in 4% of patients.1 In the control arm, ARs led to regimen discontinuation in 14% of patients with a dose reduction of chlorambucil in 28% of patients.3 There were no dose reductions for obinutuzumab.1,3

In 1,029 patients with haematologic malignancies who were treated with Calquence 100mg approximately every 12 hours across multiple clinical trials, where 88% received treatment for at least six months and 79% received treatment for at least one year, serious or Grade ≥3 infections occurred in 19%, and Grade 3 atrial fibrillation and flutter occurred in 1.1% of patients. In the same patient population, major haemorrhage occurred in 3.0% (serious or Grade ≥3 bleeding or any central nervous system bleeding), with fatal haemorrhage occurring in 0.1% of patients. Second primary malignancies (all grades) including skin cancers occurred in 12% of patients.1

The US approval is among the first to be granted under Project Orbis, an initiative of the US FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology medicines among international partners. The FDA, the Australian Therapeutic Goods Administration, and Health Canada collaborated on this review. 4

About Calquence

In the US, Calquence (acalabrutinib) is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL). In the US, Canada, Australia, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina, Singapore, Chile, and recently India, Calquence is indicated for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Approved under accelerated review in the US, continued approval for previously treated MCL is contingent upon verification and confirmation of clinical benefit in confirmatory trials.

Calquence is a next-generation selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.1,5,6,7 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.1

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinaemia and follicular lymphoma and other haematologic malignancies. Several Phase III clinical trials in CLL are ongoing, including ASCEND, ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating Calquence versus ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating Calquence in combination with venetoclax and with/without obinutuzumab versus chemoimmunotherapy in patients with previously untreated CLL without 17p deletion or TP53 mutation.

About ELEVATE-TN

ELEVATE-TN (ACE-CL-007) is a randomised, multicentre, open-label Phase III trial evaluating the safety and efficacy of Calquence in combination with obinutuzumab, a CD20 monoclonal antibody, or Calquence alone versus chlorambucil, a chemotherapy, in combination with obinutuzumab in previously untreated patients with CLL. In the trial, 535 patients were randomised (1:1:1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab. Patients in the second arm received Calquence (100mg twice daily until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg twice daily until disease progression or unacceptable toxicity).1,8

The primary endpoint is PFS in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee (IRC), and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm. Other secondary endpoints include objective response rate, time to next treatment and overall survival.1,8

About ASCEND

ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy of Calquence in previously treated patients with CLL. In the trial, 310 patients were randomised (1:1) into two arms. Patients in the first arm received Calquence monotherapy (100mg twice daily until disease progression or unacceptable toxicity). Patients in the second arm received investigator’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3K inhibitor, or rituximab in combination with bendamustine, a chemotherapy.1,9

The primary endpoint is PFS assessed by an IRC, and key secondary endpoints include physician-assessed PFS, IRC- and physician-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.1,9

About CLL

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally each year and 20,720 new cases in the US in 2019, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.10,11,12,13 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.10 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells and platelets.10 This could result in anaemia, infection and bleeding.10 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

About AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AbbVie to Present Latest Clinical Research in the Treatment of Leukemias, Lymphomas and Other Blood Cancers at 2019 ASH Annual Meeting

On November 21, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that more than 40 abstracts, including 18 oral presentations, will be presented during the upcoming American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, December 7-10, in Orlando, FL (Press release, AbbVie, NOV 21, 2019, View Source [SID1234551563]). New data include presentations on Ibrutinib (IMBRUVICA) plus venetoclax (VENCLEXTA/ VENCLYXTO) among others.

"At this year’s ASH (Free ASH Whitepaper) Annual Meeting, AbbVie will showcase the latest scientific progress from our portfolio spanning various hematologic malignancies," said Mohamed Zaki, M.D., Ph.D., Head of Hematology Oncology, AbbVie. "We look forward to sharing the new data from our clinical development programs for ibrutinib and venetoclax, which continue to demonstrate the potential to transform care and improve the lives of people living with various difficult-to-treat blood cancers."

Data from two studies of ibrutinib combination regimens in the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) will be featured in the CLL Therapy Oral Session. A new minimal residual disease (MRD)-guided analysis from the Phase 2 CAPTIVATE study (PCYC-1142) of ibrutinib in combination with venetoclax will be presented (Abstract #35), as well as longer-term outcomes data from the Phase 3 E1912 study of ibrutinib in combination with rituximab, which served as the basis of a recent U.S. Food and Drug Administration (FDA) sNDA submission (Abstract #33). In addition, extended follow-up data of up to 7.5 years in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) supporting the long-term disease control and tolerability with ibrutinib (Abstract #1538) and a four-year updated analysis from the Phase 3 MURANO trial of venetoclax in combination with rituximab will be shared (Abstract #355).

These new data will provide insights on the ongoing evaluation of ibrutinib (IMBRUVICA) and venetoclax (VENCLEXTA/VENCLYXTO) use among a variety of CLL patients.

Details about presentations are as follows:

Abstract

Presentation Timing

Ibrutinib

Ibrutinib Plus Venetoclax for First-line Treatment of
CLL/SLL: Results from the MRD Cohort of Phase 2
CAPTIVATE Study (PCYC-1142); Tam et al.;
Abstract #35

Saturday, December 7

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 8:30 a.m. ET

Ibrutinib and Rituximab Compared to FCR in
Younger Patients with CLL: Extended Follow-Up
from the E1912 Trial; Shanafelt et al.; Abstract #33*

Saturday, December 7

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 8:00 a.m. ET

Long-Term Outcomes with Ibrutinib Versus the Prior
Regimen: A Pooled Analysis in Relapsed/Refractory
MCL with up to 7.5 Years of Extended Follow-up
(MCL2001, MCL3001, CAN3001, PCYC-1104); Rule
et al.; Abstract #1538

Saturday, December 7

Poster Session: 5:30 p.m. – 7:30 p.m. ET

Planned Analysis of the Phase 1/2 CIRLL Trial for
CLL and MCL of Cirmtuzumab in Combination with
Ibrutinib; Choi et al.; Abstract #1755

Saturday, December 7

Poster Session: 5:30 p.m. – 7:30 p.m. ET

Clinical Impact of Ibrutinib with R-CHOP in Untreated
Non-GCB DLBCL Co-Expressing BCL2 and MYC
Genes in the Phase 3 PHOENIX Trial; Johnson et al.;
Abstract #354**

Sunday, December 8

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 8:45 a.m. ET

Using Ibrutinib in Earlier Lines of Treatment in
CLL/SLL (RESONATE/RESONATE-2); Barr et al.;
Abstract #3054

Sunday, December 8

Poster Session: 6:00 p.m. – 8:00 p.m. ET

Phase 2 Results of the iR2 Regimen (Ibrutinib,
Lenalidomide, and Rituximab) in Patients with
Relapsed/Refractory Non-germinal Center B Cell–
Like (Non-GCB) Diffuse Large B-Cell Lymphoma
(DLBCL) (PCYC-1123); Ramchandren et al.;
Abstract #761

Monday, December 9

Oral Session: 2:45 p.m. – 4:15 p.m. ET

Oral Presentation: 3:45 p.m. ET

Venetoclax

Ibrutinib (Ibr) Plus Venetoclax (Ven) for First-Line
Treatment of Chronic Lymphocytic Leukemia
(CLL)/Small Lymphocytic Lymphoma (SLL): Results
from the MRD Cohort of the Phase 2 CAPTIVATE
Study

Saturday, December 7

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 8:30 a.m. ET

Quantitative Analysis of Minimal Residual Disease
(MRD) Shows High Rates of Undetectable MRD
After Fixed-Duration Chemotherapy-Free Treatment
and Serves as Surrogate Marker for Progression-
Free Survival: A Prospective Analysis of the
Randomized CLL14 trial

Saturday, December 7

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 8:45 a.m. ET

T(11;14) and High BCL2 Expression are Predictive
Biomarkers of Response to Venetoclax in
Combination with Bortezomib and Dexamethasone
in Patients with Relapsed/Refractory Multiple
Myeloma: Biomarker Analyses from the Phase 3
BELLINI Study

Saturday, December 7

Oral Session: 9:30 a.m. – 11:00 a.m. ET

Oral Presentation: 10:15 a.m. ET

Identification of Recurrent Genomic Alterations in the
Apoptotic Machinery in CLL Patients Treated with
Venetoclax Monotherapy

Saturday, December 7

Oral Session: 12:00 p.m. – 1:30 p.m. ET

Oral Presentation: 12:45 p.m. ET

Updated Results from the Venetoclax (Ven) in
Combination with Idasanutlin (Idasa) Arm of a Phase
1b Trial in Elderly Patients (Pts) with Relapsed or
Refractory (R/R) Acute Myeloid Leukemia (AML)
Ineligible for Cytotoxic Chemotherapy

Saturday, December 7

Oral Session: 2:00 p.m. – 3:30 p.m. ET

Oral Presentation: 2:00 p.m. ET

Outcomes After Stem Cell Transplant in Older
Patients with Acute Myeloid Leukemia Treated with
Venetoclax-Based Therapies

Saturday, December 7

Oral Session: 2:00 p.m. – 3:30 p.m. ET

Oral Presentation: 3:15 p.m. ET

Safety and Efficacy of Venetoclax in Combination
with Navitoclax in Adult and Pediatric
Relapsed/Refractory Acute Lymphoblastic Leukemia
and Lymphoblastic Lymphoma

Saturday, December 7

Oral Session: 4:00 p.m. – 5:30 p.m. ET

Oral Presentation: 4:30 p.m. ET

Four-Year Analysis of MURANO Study Confirms
Sustained Benefit of Time-Limited Venetoclax-
Rituximab (VenR) in Relapsed/Refractory (R/R)
Chronic Lymphocytic Leukemia (CLL)

Sunday, December 8

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 7:30 a.m. ET

Genome and Exome-Wide Studies Reveal Potential
Predictive Efficacy Markers for Venetoclax and
Rituximab (VenR) in Relapsed/Refractory Chronic
Lymphocytic Leukemia (R/R CLL): Subgroup
Analyses of the MURANO Trial

Sunday, December 8

Oral Session: 7:30 a.m. – 9:00 a.m. ET

Oral Presentation: 7:45 a.m. ET

A Phase 1b Study Evaluating the Safety and Efficacy
of Venetoclax as Monotherapy or in Combination
with Azacitidine for the Treatment of
Relapsed/Refractory Myelodysplastic Syndrome

Monday, December 9

Oral Session: 7:00 a.m. – 8:30 a.m. ET

Oral Presentation: 7:00 a.m. ET

A Phase 1b Study Evaluating the Safety and Efficacy
of Venetoclax in Combination with Azacitidine in
Treatment-Naïve Patients with Higher-Risk
Myelodysplastic Syndrome

Monday, December 9

Oral Session: 7:00 a.m. – 8:30 a.m. ET

Oral Presentation: 7:45 a.m. ET

Biomarker Modulation by Mivebresib (ABBV-075) +/–
Venetoclax in Relapsed/Refractory Acute Myeloid
Leukemia

Monday, December 9

Oral Session: 7:00 a.m. – 8:30 a.m. ET

Oral Presentation: 8:00 a.m. ET

Response to Venetoclax in Combination with Low
Intensity Therapy (LDAC or HMA) in Untreated
Patients with Acute Myeloid Leukemia Patients with
IDH, FLT3 and Other Mutations and Correlations
with BCL2 Family Expression

Monday, December 9

Oral Session: 7:00 a.m. – 8:30 a.m. ET

Oral Presentation: 8:15 a.m. ET

First Analysis from a Phase 1/2 Study of Venetoclax
in Combination with Daratumumab and
Dexamethasone, +/- Bortezomib, in Patients with
Relapsed/Refractory Multiple Myeloma

Monday, December 9

Oral Session: 6:15 p.m. – 7:45 p.m. ET

Oral Presentation: 6:15 p.m. ET

Phase 1/2 Study Evaluating the Safety and Efficacy
of Venetoclax in Combination with Dexamethasone
as Targeted Therapy for Patients with t(11;14)
Relapsed/Refractory Multiple Myeloma

Monday, December 9

Oral Session: 6:15 p.m. – 7:45 p.m. ET

Oral Presentation: 6:30 p.m. ET

Navitoclax

Results from a Phase 2 Study of Navitoclax in
Combination with Ruxolitinib in Patients with Primary
or Secondary Myelofibrosis

Monday, December 9

Oral Session: 10:30 a.m. – 12:00 p.m. ET

Oral Presentation: 11:30 a.m. ET

*Abstract was submitted by the National Cancer Institute

**Abstract was submitted by IMBRUVICA co-development partner, Janssen Biotech, Inc.

About Ibrutinib (IMBRUVICA)

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiple and spread.1,2 By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.3

IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. Since its launch in 2013, IMBRUVICA has received 10 FDA approvals across six disease areas: chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.4

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

Please click here for full Prescribing Information.

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. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Uses and Important VENCLEXTA (venetoclax) U.S. Safety Information5

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.

VENCLEXTA was approved based on response rates. Continued approval for this use may depend on the results of 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 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.

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 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 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.
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 low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts; infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

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. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative 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 www.medicineassistancetool.org for assistance.

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

Indication and Important VENCLYXTO (venetoclax) EU Safety Information6

Indication
Venclyxto in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.

Venclyxto monotherapy is indicated for the treatment of 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, or
in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Contraindications
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John’s wort as VENCLYXTO efficacy may be reduced.

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, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

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 coadministration 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 in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab.

Specific Populations
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.

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 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. AbbVie’s oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 clinical trials and more than 20 different tumor types. For more information, please visit View Source