On December 9, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data from the ongoing Hemlibra (emicizumab) clinical development programme were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Hoffmann-La Roche, DEC 9, 2017, View Source [SID1234522459]). These data include longer-term results from the pivotal HAVEN 1 and HAVEN 2 studies in people with haemophilia A with inhibitors to factor VIII, showing once-weekly subcutaneous Hemlibra prophylaxis demonstrated superior efficacy compared to prior treatment with bypassing agents (BPAs) as prophylaxis or on-demand. These new data from the largest pivotal studies in people with haemophilia A with inhibitors further support Hemlibra as an important new treatment option for these adults, adolescents and children.

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In updated results from the HAVEN 2 study with six additional months of data and 40 more children (younger than 12 years of age), 94.7% (95% CI: 85.4; 98.9) of children with haemophilia A with inhibitors who received Hemlibra prophylaxis had zero treated bleeds (n=57). The intra-patient analysis comparing the effects of different therapies in the same child (n=13) showed a 99% reduction in treated bleeds with Hemlibra prophylaxis compared to prior treatment with a BPA, either as prophylaxis (n=12) or on-demand (n=1). Substantial improvements in health-related quality of life and aspects of caregiver burden, measured by the haemophilia-specific quality of life short form (Haemo-QoL-SF) and adapted health-related quality of life in haemophilia patients with inhibitors (Inhib-QoL) questionnaires, were also observed with Hemlibra prophylaxis compared to prior BPA prophylaxis. These data were featured today in the official press programme of the ASH (Free ASH Whitepaper) Annual Meeting.

With nearly ten additional months of follow-up, updated results from the HAVEN 1 intra-patient analysis of adults and adolescents showed an 88% (risk rate [RR]=0.12, 95% CI: 0.05; 0.28) reduction in treated bleeds with Hemlibra prophylaxis compared to prior BPA prophylaxis (n=24). The results also showed a 95% (RR=0.05, 95% CI: 0.02; 0.12) reduction in treated bleeds in patients who received Hemlibra prophylaxis compared to prior on-demand BPA treatment (n=24). After more than one year, substantially more patients continued to experience zero bleeds with Hemlibra prophylaxis compared to their prior prophylaxis or on-demand BPA treatment across bleed endpoints, including treated bleeds and all bleeds. The previously reported improvement in health status after 24 weeks, measured by the haemophilia-specific quality of life (Haem-A-QoL) and EuroQol 5-Dimensions 5-level (EQ-5D-5L) questionnaires, was also maintained with longer follow-up.

"These data demonstrate the continued reduction in bleeds over time with Hemlibra prophylaxis and reinforce the potential of this medicine, recently approved by the FDA for haemophilia A with inhibitors, to redefine the standard of care," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are continuing to study Hemlibra in a robust clinical development programme to help advance care for all people with haemophilia A, regardless of age or inhibitor status, and provide even less frequent dosing options."

Data from the run-in cohort of the ongoing phase III HAVEN 4 study showed that Hemlibra prophylaxis dosed once every four weeks in people 12 years of age or older with haemophilia A, with or without inhibitors, resulted in levels of Hemlibra in the blood (pharmacokinetics) that were consistent with predictions. These data supported opening the expansion cohort of the study to further evaluate this dosing regimen. After a median observation time of eight weeks, 85.7% of patients (six out of seven) had zero bleeds while receiving Hemlibra prophylaxis once every four weeks. These data follow the recent announcement that an interim analysis of the phase III HAVEN 4 study showed a clinically meaningful control of bleeding in people 12 years of age or older with haemophilia A who received Hemlibra prophylaxis once every four weeks.

The most common adverse events (AEs) in the HAVEN 1 and HAVEN 2 studies at the time of these follow-up data were consistent with those observed previously in the studies. No unexpected safety findings were observed in the run-in cohort of the HAVEN 4 study. No new cases of thrombotic microangiopathy (TMA) or thrombotic events were observed in HAVEN 1, and no cases occurred in HAVEN 2 or HAVEN 4.

Based on earlier results from the HAVEN 1 and HAVEN 2 studies, Hemlibra was approved by the US Food and Drug Administration (FDA) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with haemophilia A with inhibitors. Data from HAVEN 1 and HAVEN 2 are also being reviewed under accelerated assessment by the European Medicines Agency (EMA) and submissions to health authorities around the world are ongoing. The clinical development programme also includes the ongoing phase III HAVEN 4 study and the phase III HAVEN 3 study, which showed a statistically significant and clinically meaningful reduction in the number of treated bleeds over time in people aged 12 years or older with haemophilia A without inhibitors who received Hemlibra prophylaxis every week or every other week, compared to those receiving no prophylaxis.

About HAVEN 1 (NCT02622321)
HAVEN 1 is a randomised, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis compared to no prophylaxis in adults and adolescents with haemophilia A with inhibitors to factor VIII. The study included 113 patients (12 years of age and older) with haemophilia A with inhibitors to factor VIII, who were previously treated with BPAs on-demand or as prophylaxis. Patients previously treated with on-demand BPAs were randomised in a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B). Patients previously treated with BPAs as prophylaxis received Hemlibra prophylaxis (Arm C). Additional patients previously treated with on-demand BPAs were also enrolled in a separate arm (Arm D). On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.
The updated HAVEN 1 intra-patient analysis data presented at ASH (Free ASH Whitepaper) comparing treatment with Hemlibra prophylaxis to prior BPAs as prophylaxis or on-demand showed:

No new AEs resulted in treatment discontinuation. No new cases of TMA or thrombotic events were observed. As previously reported, three people experienced TMA events and two people experienced serious thrombotic events in the HAVEN 1 study when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Hemlibra prophylaxis.

About HAVEN 2 (NCT02795767)
HAVEN 2 is a single-arm, multicentre, open-label, clinical study in children younger than 12 years of age with haemophilia A with inhibitors to factor VIII. The study is evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis.
The updated HAVEN 2 analysis after a median of nine weeks of treatment (range 1.6-41.6 weeks) included 60 children with haemophilia A with inhibitors to factor VIII. The updated data presented at ASH (Free ASH Whitepaper) showed:

The most common AEs related to Hemlibra were injection-site reactions. Six patients experienced serious AEs, including bleeding in the muscles (muscle haemorrhage), eye pain, catheter site infection, device-related infection, bleeding of the mouth or gums (mouth haemorrhage) and appendicitis. No cases of TMA or thrombotic events occurred in the study.

About HAVEN 4 (NCT03020160)
HAVEN 4 is a single-arm, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics (PK) of subcutaneous administration of Hemlibra dosed every four weeks. The study included 48 patients (12 years of age or older) with haemophilia A with or without inhibitors to factor VIII who were previously treated with either factor VIII or bypassing agents, on-demand or as prophylaxis.

The study was conducted in two parts: a PK run-in; and an expansion cohort. All patients in the PK run-in (n=7) were previously treated on-demand, and received subcutaneous Hemlibra at 6 mg/kg to fully characterise the PK profile after a single dose during four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Patients in the expansion cohort (n=41) received subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for four weeks, followed by 6 mg/kg every four weeks for at least 24 weeks. Episodic treatment of breakthrough bleeds with factor VIII therapy or bypassing agents, depending on a patient’s inhibitor status, was allowed per study protocol.

About Hemlibra (emicizumab)
Hemlibra is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for haemophilia A patients. Hemlibra is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously). The clinical development programme is assessing the safety and efficacy of Hemlibra and its potential to help overcome current clinical challenges: the short-lasting effects of existing treatments, the development of factor VIII inhibitors and the need for frequent venous access. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche and Genentech. It is marketed in the United States as Hemlibra (emicizumab-kxwh) for patients with factor VIII inhibitors, with kxwh as the suffix designated in compliance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the US Food and Drug Administration.

About haemophilia A
Haemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Haemophilia A affects around 320,000 people worldwide,1,2 approximately 50-60% of whom have a severe form of the disorder.3 People with haemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with haemophilia A can bleed frequently, especially into their joints or muscles.1 These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility, and long-term joint damage.4 In addition to impacting a person’s quality of life,5 these bleeds can be life threatening if they go into vital organs, such as the brain.6,7 A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies.8 Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII,9 making it difficult, if not impossible to obtain a level of factor VIII sufficient to control bleeding.

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.

On December 9, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported preliminary clinical data from an ongoing Phase 1b trial of its investigational Bruton’s Tyrosine Kinase (BTK) inhibitor zanubrutinib (BGB-3111) in combination with the anti-CD20 antibody GAZYVA (obinutuzumab) in patients with chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma (FL) at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, GA(Press release, BeiGene, DEC 9, 2017, View Source;p=RssLanding&cat=news&id=2321934 [SID1234522456]) . The updated preliminary Phase 1b data demonstrated that the combination was generally well tolerated and was highly active in patients with FL and treatment-naïve (TN) or relapsed or refractory (R/R) CLL/SLL.

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"These updated Phase 1b data continue to indicate that zanubrutinib in combination with obinutuzumab is well tolerated and highly active in patients with CLL/SLL and FL. Toxicity-related treatment discontinuation has been rare, and the rate and depth of respone in FL, as well as the rate of complete responses in CLL/SLL, is very encouraging," commented Constantine Tam, MD, Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Centre, Director of Haematology at St. Vincent’s Hospital, Australia, and lead author of the presentation.

"We are excited to see the frequency and depth of responses in patients with CLL/SLL and R/R FL from this Phase 1b trial. We believe that these updated preliminary data continue to support our ongoing global pivotal Phase 2 trial of this combination in R/R FL," commented Jane Huang, MD, Chief Medical Officer, Hematology at BeiGene.

Summary of Results from the Ongoing Phase 1b Trial

The open-label, multi-center, Phase 1b trial of zanubrutinib in combination with obinutuzumab in patients with B-cell malignancies is being conducted in Australia, the United States, and South Korea, and consists of a dose-escalation phase and a dose-expansion phase in disease-specific cohorts, which is designed to include TN or R/R CLL/SLL and R/R FL patients. The dose-escalation component is testing zanubrutinib at 320 mg once a day (QD) or 160 mg twice daily (BID) in 28-day cycles, in combination with obinutuzumab; obinutuzumab was administered in line with standard CLL dosing (three loading doses of 1000 mg weekly followed by 1000 mg on day one of cycles 2–6). The ongoing dose-expansion component is testing doses of zanubrutinib at 160 mg BID with the same obinutuzumab schedule. As of September 15, 2017, the date of the most recent data cutoff, 45 patients with CLL/SLL and 26 patients with FL were enrolled in the trial.

At the time of data cutoff, the most common adverse events (AEs) were grade 1-2. The most common AEs in patients with CLL/SLL (occurring in ≥ 20% of patients) of any attribution were petechiae/purpura/contusion (42%), neutropenia (40%), upper respiratory tract infection (URTI) (36%), fatigue (24%), thrombocytopenia (24%), diarrhea (20%), and pyrexia (20%). The most common AEs in patients with FL (occurring in ≥ 20% of patients) of any attribution were URTI (38%), petechia/purpura/contusion (35%), rash (27%), and thrombocytopenia (23%). Grade 3 or 4 AEs of any attribution reported in ≥ 5% of the CLL/SLL patients included neutropenia (24%) and thrombocytopenia (7%). Grade 3 or 4 AEs of any attribution reported in ≥ 5% of the FL patients included neutropenia (12%). There were no cases of serious hemorrhage (≥ grade 3 hemorrhage or central nervous system hemorrhage of any grade), atrial fibrillation, or grade 3 or above diarrhea. Only one patient with CLL/SLL discontinued treatment due to an AE, a case of squamous cell carcinoma (SCC) in a patient who had a prior history of SCC. This was also the only patient in the study who had a fatal AE.

At the time of data cutoff, 45 patients with CLL/SLL (20 TN and 25 R/R) and 21 patients with R/R FL were evaluable for efficacy. In TN CLL/SLL patients, after a median follow-up of 11.4 months (6.0–17.3 months), the overall response rate (ORR) was 95% with complete responses (CRs) in 35% and partial responses (PRs) in 60% of patients. In R/R CLL/SLL patients, at a median follow-up time of 12.7 months (7.9–19.5 months), the ORR was 92% with CRs in 20% and PRs in 72% of patients. In R/R FL patients, at a median follow-up time of 12.1 months (0.8–19.7 months), the ORR was 76% with CRs in 38% and PRs in 38% of patients. ORR in high-risk CLL/SLL patients with del17p/p53 mutation (n=6), del11q mutation (n=6), and unmutated IGHV (n=19) were 83%, 100%, and 95%, respectively. The majority of patients remained on treatment at the time of data cutoff.

About Zanubrutinib

Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of BTK that has demonstrated higher selectivity against BTK than ibrutinib (a BTK inhibitor currently approved by the U.S. Food and Drug Administration and the European Medicines Agency) based on biochemical assays, higher exposure than ibrutinib based on their respective Phase 1 experience in separate studies, and sustained 24-hour BTK occupancy in both the peripheral blood and lymph node compartments.

On December 9, 2017 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing treatments for autoimmune/inflammatory diseases and cancer, reported results from a preclinical study of the company’s ALPN-101 program in a humanized model of graft vs. host disease (GvHD) (Press release, Alpine Immune Sciences, DEC 9, 2017, View Source [SID1234522455]). Results showed Alpine’s ICOSL vIgD-Fc fusion proteins demonstrated therapeutic efficacy, including suppressing an allogeneic immune response in vitro, improving survival, and reducing GvHD disease activity. The data were presented in a poster session, titled "Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster I" (poster #1892) during the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta.

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"These preclinical data showing activity with novel ICOS/CD28 dual antagonists from our vIgD platform in a humanized model of GvHD are encouraging because of the ongoing unmet medical need in GvHD," said Stanford Peng, M.D., Ph.D., Executive Vice President of Research and Development and Chief Medical Officer of Alpine. "These preclinical findings suggest our platform can generate novel immuno-oncology molecules with potential broad clinical therapeutic utility."

GvHD, a complication that can occur after stem cell or bone marrow transplants, has a major impact on survival following transplantation. Transplant-related mortality is as high as 92 percent in grade IV acute GvHD. Approximately 30 to 50 percent of bone marrow transplant patients will develop clinically significant GvHD – or 2,500 to 4,200 patients per year in the United States.

Background on Alpine’s ICOSL vIgD-Fc Fusion Proteins

The immunoglobulin superfamily (IgSF) is a large, diverse family of proteins expressed on immune cells collectively playing a critical role in immune regulation. Well-known IgSF proteins include PD-1, PD-L1, CTLA-4, CD28, CD80/CD86 (B7-1/2), inducible T cell costimulator (ICOS), and TIGIT. Most therapeutic strategies targeting this family of proteins for the treatment of cancers and autoimmune/inflammatory diseases have employed monoclonal antibodies binding to a single target.

Alpine’s vIgD platform, in contrast, transforms natural IgSF proteins into multifunctional protein domains. CD28 and ICOS are expressed on T cells, interacting with CD80/CD86 and ICOS ligand (ICOSL), respectively, and play critical roles in T cell activation. Alpine’s ICOSL vIgD-Fc bind and inhibit both ICOS and CD28 co-stimulatory pathways.

Preclinical Study Design and Results

The preclinical study presented at ASH (Free ASH Whitepaper) 2017 evaluated the function of Alpine’s ICOSL vIgD-Fcs both in vitro and in a humanized mouse model of GvHD. Belatacept, an immunosuppressive T cell co-stimulation blocker approved by the U.S. Food and Drug Administration (FDA) to prevent kidney transplant rejection, was used as a comparator.

Results showed Alpine’s ICOSL-vIgD-Fc:

Demonstrated superior efficacy to belatacept in vitro in inhibiting T cell proliferation (CD4 and CD8 T cells) and cytokine production, including interferon gamma and tumor necrosis factor alpha, two key cytokines induced in a GvHD response
Significantly protected against GvHD at levels comparable to or better than belatacept in the humanized model
Significantly prolonged survival and greatly reduced GvHD disease activity in the humanized model as assessed by a disease activity score and weight loss compared with saline and wild-type ICOSL-Fc

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported pooled analysis results of the longest follow-up data to date in Bruton’s tyrosine kinase (BTK) inhibition for relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients treated with IMBRUVICA (ibrutinib) (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522454]). The analysis found that, at three years, 45 percent of patients were able to achieve overall survival (OS) and 26 percent had disease progression-free survival (PFS). The pooled analysis also found that patients who were treated with ibrutinib earlier, after their first relapse/progression, experienced higher rates of OS and PFS.1 The analysis is comprised of data from a total of 370 patients in three different clinical trials: SPARK, RAY and PCYC-1104, and one ongoing Phase 3b extension study, CAN3001, which is eligible to patients who continue to benefit from ibrutinib therapy upon completing a previous ibrutinib clinical trial.2 MCL is an aggressive B-cell malignancy in which most patients relapse after their first line of therapy and receive a poor prognosis.

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These data will be presented in an oral presentation at the 59th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition on Dec. 9 at 12:00 p.m. ET in Atlanta (abstract #151).1 IMBRUVICA is a first-in-class BTK inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"IMBRUVICA continues to provide a beneficial treatment option for patients with relapsed/refractory mantle cell lymphoma," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "Prior to the discovery and introduction of IMBRUVICA, people diagnosed with MCL had limited treatment options. This long-term data analysis adds to our growing understanding of IMBRUVICA’s potential treatment benefits for previously-treated MCL patients."

MCL is one of several subtypes of B-cell non-Hodgkin’s lymphoma (NHL) and represents about six percent (about 4,200) of new cases of NHL each year in the U.S. MCL usually begins with lymph node enlargement and can potentially spread to other tissues such as the bone marrow and liver.3 Median overall survival for MCL patients is three to four years.4

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

Abstract #151: Median 3.5-year Follow-Up of Ibrutinib Treatment in Patients with Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis
Oral presentation: Saturday, December 9, 2017, 12:00 PM ET

The pooled analysis includes results from a total of 370 patients from two Phase 2, open-label studies (SPARK and PCYC-1104), one Phase 3, open-label study (RAY), and an additional follow-up of 87 patients across these studies who enrolled in a long-term open-label extension study (CAN3001). Patients enrolled in SPARK, RAY and PCYC-1104 received ibrutinib 560mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar across SPARK, PCYC-1104 and RAY, requiring patients to have received at least one prior therapy for MCL and be chemotherapy-free for at least 3 weeks. However, patients in SPARK were required to have already received rituximab and bortezomib, and patients in RAY were required to have already received rituximab. Patients who continued to benefit from ibrutinib therapy at the end of the studies were eligible to enroll in CAN3001, a Phase 3b open-label study, which provides continued access to ibrutinib for patients who have completed an ibrutinib clinical study. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation.

With 3.5 years (41 months) of follow-up, the proportion of patients achieving complete response (CR) increased to 26.5%. In addition, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients treated with ibrutinib were progression free at 2 and 3 years, respectively, and the median PFS was 13 months. The median PFS in patients with one prior line of therapy was 33.6 (range, 19.4-42.1) months. The median period for patients achieving CR was 46.2 (range, 42.1-not estimable) months. Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib for more than 3 years. Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively, and the median OS was 26.7 months.

In the pooled analysis, the median duration of follow-up was 41.1 months (95% CI, 37.3-42.5) and median exposure to ibrutinib was 11.1 months (range: 0.03-72.1). Eighty-three patients were treated with ibrutinib for 3 or more years, and 40 patients were treated with ibrutinib for 4 or more years. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior lines of therapy before receiving ibrutinib.

Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 79.7% of patients, with the new onset events decreasing after the first year. Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after the first year. The most common grade 3 or higher TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%) and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 61.9% patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively). The data from this pooled analysis have not been reviewed by the U.S. Food and Drug Administration and they are not in the approved label for IMBRUVICA.

About the U.S. Food and Drug Administration (FDA) Approval of IMBRUVICA to Treat R/R MCL
The FDA approved IMBRUVICA (ibrutinib) as a single agent for the treatment of adult patients with MCL who have received at least one prior therapy based on the overall response rate (ORR) seen in the Phase 2 study, PCYC-1104, an open-label, multi-center, single-arm trial of 111 previously-treated MCL patients. IMBRUVICA was administered orally at 560-mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin’s lymphoma (NHL) criteria.5 The efficacy results, which were published in the New England Journal of Medicine in 2013, demonstrated a 68% overall response rate with 47% of patients having a partial response and 21% having a complete response. The median duration of response was 17.5 months.5

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.6 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host-disease (cGVHD).7

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
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.

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.8 IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 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. To date, 90,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

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 (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] 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 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

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

On December 9, 2017 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported new three-year follow-up data from the RESONATE-2 study (PCYC-1115/1116), which found that previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients reported sustained improvements in measures of well-being with IMBRUVICA (ibrutinib) versus chemotherapy with chlorambucil (Press release, AbbVie, DEC 9, 2017, View Source [SID1234522453]). These new data provide the longest quality of life follow up for ibrutinib to date using patient-reported outcomes (PRO). Patients reported their quality of life outcomes for fatigue, mobility, self-care, usual activities, pain/discomfort and anxiety/depression. At 30 months, ibrutinib was also associated with a greater progression-free survival (PFS) rate of 85 percent versus chlorambucil, which had a PFS rate of 28 percent.

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The new RESONATE-2 data will be presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Dec. 9 in Atlanta (abstract #1746). IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"In the RESONATE-2 study, patients who were treated with ibrutinib reported greater and sustained improvements in overall health and well-being and experienced decreased disease-related symptoms," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "For patients with chronic lymphocytic leukemia, a disease that affects primarily older patients, quality of life is an important consideration that should be factored into treatment choices initially and throughout long-term use."

CLL is the most common form of leukemia in adults and is a type of cancer that can form from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes). While these cancer cells start in the bone marrow, they then later spread into the blood. The prevalence of CLL is approximately 115,000 patients in the U.S.1 with approximately 19,000 newly diagnosed patients every year.2 SLL is a slow-growing lymphoma, biologically similar to CLL, in which too many immature white blood cells cause lymph nodes to become larger than normal.3 CLL/SLL are predominately diseases of the elderly, with a median age of 71 at diagnosis.

About the Presentation

Abstract #1746: Prolonged Improvement in Patient-Reported Outcomes (PROs) and Well-being in Older Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia Treated With Ibrutinib (Ibr): 3-Year Follow-up of the RESONATE-2 Study
Poster Presentation; Saturday, December 9, 5:30 – 7:30 p.m. ET

At a median follow up of three years, ibrutinib treatment resulted in significantly longer PFS (median, not reached versus 15 months with chlorambucil), with an 87% reduction in risk of progression or death versus chlorambucil (HR 0.130; 95% CI: 0.081, 0.208). The PFS rate for ibrutinib was 85% versus 28% with chlorambucil. Greater and sustained improvements in PROs were observed with ibrutinib, resulting in significantly greater improvements over time versus chlorambucil (via FACIT-F and EQ-5D-5L Visual Analogue Scale by repeated measures).

In chlorambucil patients with progressive disease, PROs improved after crossing over to ibrutinib. Approximately 87% of patients on ibrutinib (versus 52% on chlorambucil) had decreased/normalized lymphadenopathy within 2 months, which was sustained through 36 months, and disease symptoms, including fatigue and night sweats, improved more frequently for patients on ibrutinib. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib versus chlorambucil for hemoglobin (90% versus 45%) and platelets (83% versus 46%).

Patients 65 years and older (median age 73) were randomized to receive 420mg ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Median treatment duration was 34.1 months on ibrutinib versus 7.1 months on chlorambucil. Further data showed the burden of hematologic support medical resource utilization was less with ibrutinib versus chlorambucil in the first year and subsequently continued to decrease.

The most common adverse events (AEs) of any grade with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight Grade 3 or higher AEs had a prevalence of less than 3% in ibrutinib patients and generally decreased or were stable over time. During the first year of treatment, patients on ibrutinib versus chlorambucil experienced less Grade 3 or higher neutropenia (8% and 18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%); other common Grade 3 or higher AEs were pneumonia (5% and 2%), hypertension (4% and 0%), and infections as combined term (17% and 8%). Grade 3 or higher bleeding occurred in 7% of ibrutinib patients over the 3-year follow up. AEs leading to treatment discontinuation occurred in 16% with ibrutinib over 3 years versus 23% for chlorambucil over 7 months of therapy, respectively.

Additional Presentation on RESONATE-2 at ASH (Free ASH Whitepaper) 2017

A separate presentation at ASH (Free ASH Whitepaper) this year will also discuss the RESONATE-2 clinical trial (with a median follow up of 35.7 months) as part of a cross-trial comparison. The data compares ibrutinib as a single-agent therapy and six different chemoimmunotherapy regimens from additional Phase 3 studies in patients with CLL as a first-line therapy, reviewing results in PFS, overall survival (OS) and safety measures. The six chemoimmunotherapy regimens included as part of the cross-trial comparison are fludarabine, cyclophosphamide and rituximab (FCR); bendamustine and rituximab (BR); obinutuzumab and chlorambucil; rituximab and chlorambucil; and ofatumumab and chlorambucil. This data will also be presented at ASH (Free ASH Whitepaper) on Dec. 9 (abstract #1750).

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2017, which includes 12 oral presentations, please click here.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.4 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host-disease (cGVHD).5

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously-treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
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.

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.6 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 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. To date, 90,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs 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 14% to 29% of patients. 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 (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.
Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.
Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

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 (62%), neutropenia (61%), diarrhea (43%), anemia (41%), musculoskeletal pain (30%), rash (30%), bruising (30%), nausea (29%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%), thrombocytopenia (16%), and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] 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 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%), pneumonia (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.

DRUG INTERACTIONS

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

CYP3A Inhibitors: Dose adjustment may be recommended.

SPECIFIC POPULATIONS

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