On December 3, 2018 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today data from the primary analysis of the Phase III HAVEN 2 study evaluating Hemlibra (emicizumab-kxwh) prophylaxis in children younger than 12 years of age with hemophilia A with factor VIII inhibitors, including longer follow-up for once-weekly dosing and new data for less frequent dosing schedules (every two weeks or every four weeks) (Press release, Genentech, DEC 3, 2018, View Source [SID1234531845]). These data from the largest pivotal study in children with hemophilia A with factor VIII inhibitors were presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Children with inhibitors are at increased risk of life-threatening bleeds and may experience frequent, repeated bleeding into joints," said Guy Young, M.D., director of Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, and professor of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California. "These updated data from HAVEN 2 showed that the majority of children with hemophilia A with factor VIII inhibitors treated with emicizumab-kxwh had zero treated bleeds across three different dosing schedules, reinforcing the ability of this medicine to provide sustained, effective bleed control."

In updated results from the HAVEN 2 study with a median of 11 additional months of data, 76.9 percent (95 percent CI: 64.8; 86.5) of children with hemophilia A with factor VIII inhibitors treated with Hemlibra once weekly (n=65) experienced zero treated bleeds. Importantly, once-weekly Hemlibra showed a 99 percent (95 percent CI: 97.7; 99.4) reduction in treated bleeds compared to prior treatment with bypassing agents (BPAs) as prophylaxis (n=15) or on-demand (n=3) in a prospective intra-patient comparison. New data also showed that 90 percent (95 percent CI: 55.5; 99.7) of children with factor VIII inhibitors receiving Hemlibra every two weeks (n=10) and 60 percent (95 percent CI: 26.2; 87.8) of children receiving Hemlibra every four weeks (n=10) experienced zero treated bleeds, demonstrating clinically meaningful bleed control at both dosing schedules. No cases of thrombotic microangiopathy (TMA) or thrombotic events occurred. The most common adverse events (AEs) in the HAVEN 2 study primary analysis were consistent with those previously observed in the interim analyses.

"The updated analysis from the HAVEN 2 study supports the potential of Hemlibra to control bleeds at less frequent subcutaneous dosing, providing parents and their children more flexibility to choose a treatment schedule that is right for them," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Many children with hemophilia A with factor VIII inhibitors have already experienced the benefits of Hemlibra, and with these new positive data, we are confident that this treatment will continue to make a meaningful difference in their lives."

Hemlibra is approved in over 50 countries worldwide, including the U.S., EU member states and Japan, to treat people of all ages with hemophilia A with factor VIII inhibitors based on pivotal data that included interim results from the HAVEN 2 study. In October 2018, the U.S. Food and Drug Administration (FDA) also approved Hemlibra to treat people of all ages with hemophilia A without factor VIII inhibitors. Hemlibra is the only FDA-approved treatment for people with hemophilia A with and without factor VIII inhibitors that can be administered subcutaneously (under the skin) and at multiple dosing options (once weekly, every two weeks or every four weeks). Submissions to other regulatory authorities around the world are ongoing.

Hemlibra has been studied in one of the largest pivotal clinical trial programs in people with hemophilia A with and without factor VIII inhibitors, including four Phase III HAVEN studies (HAVEN 1, HAVEN 2, HAVEN 3 and HAVEN 4).

About HAVEN 2 (NCT02795767)

HAVEN 2 is a multicenter, open-label, clinical study in children younger than 12 years of age with hemophilia A with factor VIII inhibitors. The study is evaluating the efficacy, safety and pharmacokinetics of once-weekly, every two weeks or every four weeks subcutaneous administration of Hemlibra prophylaxis.

The HAVEN 2 primary analysis included 85 children (once-weekly dosing, n=65; every two week dosing, n=10; every four week dosing, n=10) with hemophilia A with factor VIII inhibitors. The median follow-up period for each cohort was 58 (range 17.9–92.6), 21.3 (range 18.6–24.1), and 19.9 (range 8.9–24.1) weeks, respectively. The prospective intra-patient comparison included 18 patients from the once-weekly cohort previously treated with BPAs either as prophylaxis (n=15) or on-demand (n=3) as part of a non-interventional study.

The study met its primary endpoint and key secondary endpoints. Data presented at the 60th ASH (Free ASH Whitepaper) Annual Meeting showed:

HAVEN 2 (NCT02795767)
Hemlibra prophylaxis 1.5 mg/kg QW
(Arm A; n=65)*

Annualized bleeding rate [ABR] †
(95% CI)

Median ABR
(Interquartile range; IQR)

Treated bleeds (primary endpoint)**
0.3
(0.17; 0.50)

0.0
(0.00; 0.00)

All bleeds
3.2
(1.94; 5.22)

0.6
(0.00; 2.92)

Treated spontaneous bleeds
0.0
(0.01; 0.10)

0.0
(0.00; 0.00)

Treated joint bleeds
0.2
(0.08; 0.29)

0.0
(0.00; 0.00)

Treated target joint bleeds
Not estimable

0.0
(0.00; 0.00)

*Efficacy assessment was conducted only in patients aged <12 years who had spent at least 12 weeks on the study. Excludes three patients aged >12 years.

A loading dose of 3 mg/kg Hemlibra was given for four weeks followed by the maintenance dose listed.

† Estimated using negative binomial regression

**In patients receiving Hemlibra once weekly (Arm A), 76.9% (95% CI, 64.8; 86.5) experienced zero treated bleeds and 23.1% experienced 1–3 treated bleeds.

Hemlibra prophylaxis 3 mg/kg
Q2W
(Arm B; n=10)*

Hemlibra prophylaxis 6 mg/kg
Q4W
(Arm C; n=10)*

ABR (95% CI) †

0.2
(0.03; 1.72)

2.2
(0.69; 6.81)

Median ABR (IQR)
0.0
(0.00; 0.00)

0.0
(0.00; 3.26)

% patients with zero treated
bleeds
(95% CI)

90.0%
(55.5; 99.7)

60.0%
(26.2; 87.8)

% patients with 1-3 treated
bleeds
(95% CI)

10.0%
(0.3; 44.5)

40.0%
(12.2; 73.8)

*A loading dose of 3 mg/kg Hemlibra was given for four weeks followed by the maintenance dose listed.

† Estimated using negative binomial regression

The most common adverse reactions occurring in 10 percent or more of children treated with Hemlibra were common cold symptoms (nasopharyngitis; 37.5 percent), injection site reactions (29.5 percent), fever (pyrexia; 23.9 percent), upper respiratory tract infection (23.9 percent), cough (23.9 percent), diarrhea (15.9 percent), vomiting (15.9 percent), headache (14.8 percent), contusion (12.5 percent), fall (12.5 percent) and influenza (10.2 percent). No cases of TMA or thrombotic events occurred. Four patients tested positive for anti-drug antibodies (ADAs) to Hemlibra. Of these patients, two had ADAs with neutralizing potential based on reduced Hemlibra levels. As previously reported, the ADA in one of these patients resulted in reduced efficacy of Hemlibra and led to discontinuation of treatment. The other patient had no bleeds as of the clinical cut-off date of the study.

About Hemlibra

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 hemophilia 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) once weekly, every two weeks or every four weeks. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed globally by Chugai, Roche and Genentech.

Hemlibra U.S. Indication

Hemlibra is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children, ages newborn and older, with hemophilia A with or without factor VIII inhibitors.

Important Safety Information

What is the most important information to know about Hemlibra?

Hemlibra increases the potential for blood to clot. Patients should carefully follow their healthcare provider’s instructions regarding when to use an on-demand bypassing agent or factor VIII, and the dose and schedule to use for breakthrough bleed treatment. Hemlibra may cause the following serious side effects when used with activated prothrombin complex concentrate (aPCC; FEIBA), including:

Thrombotic microangiopathy (TMA). This is a condition involving blood clots and injury to small blood vessels that may cause harm to one’s kidneys, brain, and other organs. Patients should get medical help right away if they have any of the following signs or symptoms during or after treatment with Hemlibra:
confusion
weakness
swelling of arms and legs
yellowing of skin and eyes
stomach (abdomen) or back pain
nausea or vomiting
feeling sick
decreased urination
Blood clots (thrombotic events). Blood clots may form in blood vessels in the arm, leg, lung, or head. Patients should get medical help right away if they have any of these signs or symptoms of blood clots during or after treatment with Hemlibra:
swelling in arms or legs
pain or redness in the arms or legs
shortness of breath
chest pain or tightness
fast heart rate
cough up blood
feel faint
headache
numbness in the face
eye pain or swelling
trouble seeing
If aPCC (FEIBA) is needed, patients should talk to their healthcare provider in case they feel they need more than 100 U/kg of aPCC (FEIBA) total.

Before using Hemlibra, patients should tell their healthcare provider about all of their medical conditions, including if they:

are pregnant or plan to become pregnant. It is not known if Hemlibra may harm an unborn baby. Females who are able to become pregnant should use birth control (contraception) during treatment with Hemlibra.
are breastfeeding or plan to breastfeed. It is not known if Hemlibra passes into breast milk.
Patients should tell their healthcare provider about all the medicines they take, including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements. Patients should keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.

How should patients use Hemlibra?

Patients should see the detailed "Instructions for Use" that comes with Hemlibra for information on how to prepare and inject a dose of Hemlibra, and how to properly throw away (dispose of) used needles and syringes.

Stop (discontinue) prophylactic use of bypassing agents the day before starting Hemlibra prophylaxis.
Patients may continue prophylactic use of factor VIII for the first week of Hemlibra prophylaxis.
What should patients know about lab monitoring?

Hemlibra may interfere with laboratory tests that measure how well blood is clotting and may cause a false reading. Patients should talk to their healthcare provider about how this may affect their care.

The most common side effects of Hemlibra include: redness, tenderness, warmth, or itching at the site of injection; headache; and joint pain.

These are not all of the possible side effects of Hemlibra. Patients should speak to their healthcare provider for medical advice about side effects.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Patients should not use Hemlibra for a condition for which it was not prescribed. Patients should not give Hemlibra to other people, even if they have the same symptoms that they have. It may harm them. Patients can ask their pharmacist or healthcare provider for information about Hemlibra that is written for health professionals.

Side effects may be reported to the FDA at (800) FDA-1088 or View Source Side effects may also be reported to Genentech at (888) 835-2555.

Please see the Hemlibra full Prescribing Information and Medication Guide for more important safety information including Serious Side Effects.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Hemophilia affects around 20,000 people in the United States, with hemophilia A being the most common form and approximately 50-60 percent of people living with a severe form of the disorder.

People with hemophilia 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 hemophilia A can bleed frequently, especially into their joints or muscles. 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.

A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible, to obtain a level of factor VIII sufficient to control bleeding.

On December 3, 2018 The National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) reported plans to solicit and oversee research projects that evaluate cyclin dependent kinase (CDK)4 & 6 inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer and underlying mechanisms of resistance (Press release, Eli Lilly, DEC 3, 2018, View Source [SID1234531861]). Research funding will be provided by a $2 million grant from Eli Lilly and Company (NYSE: LLY).

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"This program is part of our ongoing efforts to improve the lives of people with cancer," said Wui-Jin Koh, MD, Chief Medical Officer, NCCN. "The NCCN ORP facilitates clinical investigation into important questions. In this instance, we’re managing research to understand mechanisms of resistance to CDK4 & 6 inhibitor treatment in metastatic breast cancer."

"We are excited to support NCCN to further understand the mechanisms of resistance to CDK4 & 6 inhibitors in advanced breast cancer, which is a central and critically important issue in this treatment landscape," said Maura Dickler, MD, Vice President of Late Phase Development, Lilly Oncology. "This work with NCCN is an example of our ongoing commitment to optimize treatment for people living with metastatic breast cancer."

CDK4 & 6 inhibitors have emerged as a key treatment in many patients with HR+ and HER2- metastatic breast cancer. However, resistance to CDK4 & 6 inhibitors, either intrinsic or acquired, can limit their effectiveness. This project seeks to support preclinical and clinical studies that elucidate mechanisms of resistance to CDK4 & 6 inhibitors and provide insights into how this resistance can be overcome or mitigated, resulting in potentially greater efficacy. Lilly will provide abemaciclib, a CDK4 & 6 inhibitor, for studies when needed. This endeavor by the NCCN ORP will utilize the scientific expertise from investigators across the 28 NCCN Member Institutions, and proposals will be reviewed and awarded by a scientific steering committee made up of experts from these NCCN institutions.

Earlier this year, the NCCN ORP was engaged by Lilly for a separate project, seeking scalable, reproducible interventions to address gaps in clinical care for treating gastric cancer. To learn more about the NCCN ORP, including ongoing clinical trials, recent publications, and shared resources, visit NCCN.org/ORP.

On December 3, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results from the Phase 3 iLLUMINATE (PCYC-1130) trial, evaluating the chemotherapy-free, anti-CD20 combination of IMBRUVICA (ibrutinib) plus obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Press release, AbbVie, DEC 3, 2018, View Source [SID1234531878]). At a median follow-up of 31 months, study results showed IMBRUVICA plus obinutuzumab significantly prolonged progression-free survival (PFS) (median not reached [NR] vs. 19 months) with a 77 percent reduction in risk of progression or death versus chlorambucil plus obinutuzumab, the current National Comprehensive Cancer Network guidelines Category 1 treatment regimen (hazard ratio [HR] 0.23; 95% confidence interval [CI]: 0.15-0.37; P<0.0001).

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The data were presented today in an oral session at the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (abstract #691) and were simultaneously published in The Lancet Oncology. Based on these data, a supplemental New Drug Application (sNDA) was recently accepted for Priority Review by the U.S. Food and Drug Administration (FDA) to expand the use of IMBRUVICA in combination with obinutuzumab in previously untreated CLL/SLL. IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"iLLUMINATE represents one of three IMBRUVICA Phase 3 studies in chronic lymphocytic leukemia being presented at this year’s ASH (Free ASH Whitepaper). Results from the iLLUMINATE study support the use of IMBRUVICA as a chemotherapy-free, anti-CD20 combination treatment option versus the current National Comprehensive Cancer Network guidelines Category 1 treatment of chlorambucil plus obinutuzumab," said Danelle James, M.D., M.A.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "These latest findings, in addition to seven-year long-term data and a Late-Breaker at this year’s ASH (Free ASH Whitepaper), add to the robust amount of data supporting the use of IMBRUVICA as backbone therapy in CLL and SLL."

CLL is one of the two most common forms of leukemia in adults and is a type of cancer that can develop from cells in the bone marrow that later mature into certain white blood cells (called lymphocytes).1 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. with approximately 20,000 newly diagnosed patients every year.2,3 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.4 Both CLL and SLL are predominately diseases of the elderly, with a median age at diagnosis ranging from 65-70 years.5

"For years, we had to rely on chemotherapy as the only treatment option for patients with previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma," said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and lead study investigator of iLLUMINATE. "We’re pleased to share results from iLLUMINATE that help show that it is possible to provide efficacious treatment for patients with CLL and SLL without the use of chemotherapy."

About Abstract #691: Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab as First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE

Oral presentation: Monday, December 3 at 10:30 a.m. PST

In the Phase 3 iLLUMINATE (PCYC-1130) study, newly diagnosed CLL patients were randomized to receive IMBRUVICA 420 milligrams (mg) once daily continuously in combination with obinutuzumab 1000 mg intravenously over six cycles (n=113); or chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle plus obinutuzumab 1000 mg intravenously over six cycles (n=116). The primary endpoint was PFS, as assessed by an Independent Review Committee (IRC). The study also evaluated: PFS for patients with high-risk features (unmutated IGHV, del11q, del17p or TP53 mutation); rate of undetectable minimal residual disease (MRD); overall response rate (ORR); overall survival (OS); and safety.

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the IRC-assessed PFS compared to chlorambucil plus obinutuzumab, with a 77 percent reduction in risk of progression or death (median NR vs. 19 months; hazard ratio [HR] 0.23; 95% CI: 0.15-0.37; P<0.0001). At 30 months, the IRC-assessed PFS rates were 79 percent and 31 percent with ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab, respectively. The investigator-assessed PFS was also significantly improved with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab (median NR vs. 21.9 months; HR 0.26; 95% CI: 0.16-0.42; P<0.0001).

The PFS in the IMBRUVICA plus obinutuzumab arm in the high-risk population, including those with unmutated IGHV, del11q, del17p, or TP53 mutation was assessed, with an 85 percent reduction in risk of progression or death (median not reached vs. 14.7 months; HR 0.15; 95% CI: 0.09-0.27; P<0.0001). In addition, IRC-assessed ORR was higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (88% vs. 73%); complete response (CR)/complete response with incomplete blood recovery (CRi) rates were also higher with 19 percent versus eight percent, respectively. The investigator-assessed ORR was also higher in the ibrutinib plus obinutuzumab arm versus the chlorambucil plus obinutuzumab arm (91% vs. 81%); CR/CRi rates were also higher with 41 percent versus 16 percent, respectively. Depth of remission as reflected by undetectable MRD in blood and/or bone marrow was greater in patients with ibrutinib plus obinutuzumab, with 35 percent of patients showing undetectable MRD compared to 25 percent of patients with chlorambucil plus obinutuzumab. OS rates at 31 months were 86 percent for the ibrutinib arm compared to 85 percent for the chlorambucil arm.

Most common Grade 3 or higher adverse events (AEs) in the ibrutinib plus obinutuzumab arm versus chlorambucil plus obinutuzumab arm were neutropenia (43% vs. 63%), thrombocytopenia (35% vs. 25%), diarrhea (34% vs. 10%), cough (27% vs. 12%), infusion-related reactions (25% vs. 58%), arthralgia (22% vs. 10%), pyrexia (19% vs. 26%), anemia (17% vs. 25%), and nausea (12% vs. 30%). Ibrutinib plus obinutuzumab also seemed to decrease the risk of infusion reactions related to the use of obinutuzumab.

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASH (Free ASH Whitepaper) 2018, please visit: View Source

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by inhibiting 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.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 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 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.
In August 2018, IMBRUVICA plus rituximab was approved for adult patients with WM.
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 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, more than 135,000 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 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to IMBRUVICA in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% 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 24% of 1,011 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 1,011 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 has occurred in 12% of 1,011 patients treated with IMBRUVICA in clinical trials with a median time to onset of 5 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 (9%) including non-skin carcinomas (2%) have occurred in 1,011 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%)*, neutropenia (58%)*, diarrhea (42%), anemia (39%)*, rash (31%), musculoskeletal pain (31%), bruising (31%), nausea (28%), fatigue (27%), hemorrhage (23%), 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 (36%)*, thrombocytopenia (15%)*, and pneumonia (10%).

Approximately 6% (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%)*, stomatitis (29%), muscle spasms (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.

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

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustments may be recommended.

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.

On December 2, 2018 NewLink Genetics Corporation (NASDAQ:NLNK) reported that updated Phase 1 data evaluating indoximod plus standard-of-care chemotherapy for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) were presented today by Ashkan Emadi, MD, PhD, Professor of Medicine and Associate Director for Clinical Research, University of Maryland Greenebaum Comprehensive Cancer Center, in an oral session today at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA, from 9:30AM – 11:00AM PT, in Grand Hall B, Manchester Grand Hyatt (Press release, NewLink Genetics, DEC 2, 2018, View Source [SID1234531779]).

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This Phase 1 trial evaluated the initial safety and preliminary evidence of clinical activity of adding indoximod to standard 7+3 induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for adult patients with newly diagnosed AML. The presentation highlighted an initial safety profile indicating that the treatment regimen was well tolerated with adverse events commensurate with chemotherapy alone. Evidence of clinical activity was observed for indoximod plus chemotherapy in newly diagnosed AML as supported by these Phase 1 data showing post-induction minimal residual disease (MRD) negativity rate of 86% and post-HiDAC1 MRD negativity of 100%.

"These data demonstrate the promising potential for indoximod in combination therapy for patients with newly diagnosed AML and the use of MRD status as a study endpoint," said Dr. Ashkan Emadi. "We remain encouraged and look forward to additional data as this study proceeds."

Fifty-seven patients were screened, and 38 patients initiated induction therapy on protocol. Five patients never received indoximod resulting in an intent-to-treat (ITT) population of 33 patients. Twenty-two patients received the pre-specified 80% of indoximod dosing required to be included in the per protocol (PP) analysis, 8 received less than 80% of the scheduled indoximod dosage, and 3 patients remained on induction treatment as of the date of data cut off. Of these 22 PP patients, 16/22 (73%) achieved complete morphological response (CR) and 6 were primary refractory. Of the patients who achieved CR, 14 had results available from MRD testing post-induction. MRD negativity was defined by a flow cytometry assay at a level of < 0.02% (Hematologics, Inc., Seattle, WA). Of those tested, 12/14 (86%) were MRD-negative. Of the 14 patients, 1 patient proceeded to transplant, and 13 began HiDAC consolidation therapy. Post-HiDAC consolidation, all 13 patients were tested for MRD status with all 13/13 (100%) reported to be MRD-negative. When benchmarked against available published studies, these initial data appear encouraging. For a more precise comparison, a contemporaneous multi-institutional dataset is being aggregated to benchmark these data against data generated from patients undergoing the same chemotherapy regimen without the addition of indoximod using the same MRD assay assessed at the same reference laboratory.

Safety data from this Phase 1 trial indicate that the combination therapy regimen was well tolerated. No RLTs were observed when combining indoximod with standard-of-care chemotherapy. Grade 3 or greater adverse hematologic events included febrile neutropenia, anemia, and thrombocytopenia while non-hematologic events included hypoxia, anemia, and pneumonia. The overall adverse event profile observed in this small sample size is consistent with that of 7+3 induction chemotherapy plus HiDAC consolidation alone.

About AML1,2

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow in which the bone marrow makes abnormal types of white blood cells, red blood cells, or platelets. AML is the most common type of acute leukemia in adults and tends to progress rapidly without treatment. In the US, approximately 19,000 patients per year are diagnosed with AML with only around 25% expected to survive longer than three years. Of those newly diagnosed patients, approximately half are categorized as young and fit for an aggressive chemotherapy treatment regimen.

1National Cancer Institute
2American Society of Clinical Oncology

About Indoximod

Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target, suppressing immune response and allowing for immune escape by degrading tryptophan with the resultant production of kynurenine. Indoximod reverses the immunosuppressive effects of low tryptophan and high kynurenine through mechanisms that include modulation of the AhR-driven transcription of genes that control immune function. This results in increased proliferation of effector T cells, increased differentiation into helper T cells rather than regulatory T cells, and downregulation of IDO expression in dendritic cells. Indoximod is being evaluated in combination with treatment regimens including chemotherapy, radiation, checkpoint blockade and cancer vaccines across multiple indications including recurrent pediatric brain tumors, DIPG, and AML.

On December 2, 2018 Pfizer Inc. (NYSE:PFE) reported at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting that the REFLECTIONS B328-06 study, a comparative safety and efficacy study of PF-05280586 versus Rituxan/MabThera (rituximab-EU)i, met its primary endpoint of overall response rate (ORR) at Week 26 of the 52-week study.1

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"It is encouraging to see new data supporting a potential rituximab Biosimilar. If approved this may help provide a more cost-effective treatment option and expand access for patients and physicians," said Dr. Jeff Sharman, medical director, US Oncology Hematology Research. "The data presented today will help us understand the nuances of the medicine without the confounding influence of additional concurrent treatments."

26-week data from the ongoing 52-week REFLECTIONS B328-06 study (n=394) demonstrated no clinically meaningful differences in efficacy, in terms of ORR at Week 26, between PF-05280586 and MabThera, for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma (LTB-FL).1 ORR at Week 26 was 75.5% (PF-05280586) vs 70.7% (rituximab-EU), and was within the pre-specified equivalence margin. ORR is defined as the percentage of patients achieving complete response (CR) or partial response (PR), based on central review. Additionally, estimated rates of one-year progression-free survival were similar across groups (76.4% vs. 81.2% in the PF-05280586 and MabThera groups, respectively).1 The results also show that PF-05280586 had a similar safety profile to MabThera.1

"With a patient centered approach and over a decade of experience globally,2 Pfizer remains dedicated to developing and delivering high quality biosimilars with similar efficacy and safety profiles to originator medicines that help have a meaningful impact on people living with various conditions including cancer," said Joe McClellan, vice president, Biosimilars Development at Pfizer. "We have also been a committed global partner to the oncology community for almost 20 years, and the continued growth of our oncology and supportive care presence, through both novel therapies and biosimilars, means we are able to provide patients, physicians and healthcare systems with a wider range of treatment options."

PF-05280586 has been accepted for review by the FDA, the BsUFA goal date for a decision by the FDA is in second-quarter 2019. Pfizer is also working towards making PF-05280586 available for patients in Europe. Further results on the safety and efficacy from this ongoing 52-week study in LTB-FL are expected to be presented next year.

About PF-05280586

PF-05280586 is a monoclonal antibody (mAb) that is in development as a potential biosimilar to Rituxan/MabThera. Rituxan/MabThera is indicated for the treatment of patients with certain types of CD20-positive non-Hodgkin lymphoma; CD20-positive chronic lymphocytic leukemia; rheumatoid arthritis; granulomatosis with polyangiitis and microscopic polyangiitis; and other region-specific indications.3, 4

PF-05280586 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities.

About the REFLECTIONS B328-06 Study

REFLECTIONS B328-06 is a randomized, 52-week double-blind clinical trial evaluating the efficacy, safety and immunogenicity, pharmacokinetics and pharmodynamics of PF-05280586 versus MabThera for the first-line treatment of patients with CD20-positive, low tumor burden, follicular lymphoma.

More information about the PF-05280586 REFLECTIONS B32806 study can be found at www.clinicaltrials.gov.