On December 4, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported that 82 percent of patients (9 out of 11) achieved complete remission or complete remission with incomplete or partial hematological recovery in a preliminary analysis of the Phase 1 ZUMA-3 and ZUMA-4 trials of KTE-C19 in adult and pediatric relapsed/refractory acute lymphoblastic leukemia (r/r ALL) (Press release, Kite Pharma, DEC 4, 2016, View Source [SID1234516909]). In these patients, 100 percent of responders tested negative for minimal residual disease (MRD), which has been shown to correlate with risk of disease relapse in ALL. The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

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In the Phase 1 trials, 13 patients were treated with KTE-C19. Eleven patients were evaluable for response and two patients have not reached the evaluation time point at the data cutoff. Patients received a low-dose conditioning chemotherapy regimen based on extensive clinical experience at the National Cancer Institute (NCI).

"We are encouraged by the KTE-C19 safety and efficacy profile in ALL that is suggested by these data," said David Chang M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer of Kite. "In the Phase 1 portion of these studies, we are enrolling patients with high disease burden to rigorously evaluate safety and efficacy of KTE-C19. We look forward to initiating the Phase 2 portions of these studies in 2017."

Five of 13 (38 percent) patients had ≥ grade 3 cytokine release syndrome (CRS) and five of 13 (38 percent) had ≥ grade 3 neurological events. One patient in ZUMA-3 died from KTE-C19 related CRS and one patient in ZUMA-4 died from a disseminated fungal infection unrelated to KTE-C19. No cerebral edema has been observed.

KTE-C19 was successfully manufactured in these 13 patients across a range of absolute lymphocyte and blast counts in a centralized and streamlined process of six to eight days. The KTE-C19 manufacturing process used in the multicenter ZUMA-3 and ZUMA-4 studies will be discussed in an oral presentation on Monday, December 5, 2016, at 6:45 p.m. PST.

Production of Anti-CD19 CAR T Cells for ZUMA-3 and -4: Phase 1/2 Multicenter Studies Evaluating KTE-C19 in Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL)

Abstract #1227 View Source
Presenter: Marianna Sabatino, M.D., Kite Pharma, Director of Product Sciences

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration (FDA) and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On December 5, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that clinical data for lirilumab and IPH4102 were presented in two posters at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) 2016 Annual Meeting (December 3-6, 2016), San Diego, CA, U.S.:

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Poster 1826 entitled "First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results" was presented by Prof. Y. Kim from the Stanford Cancer Institute and investigator of the study(Press release, Innate Pharma, DEC 4, 2016, View Source [SID1234516908]). IPH4102 is Innate Pharma’s wholly-owned first-in-class anti-KIR3DL2 antibody.
This poster presented preliminary results from the first seven dose levels of the dose-escalation part of the Phase I trial of IPH4102 (1). They showed that the drug candidate is well tolerated in patients with relapsed/refractory CTCL (2) and a preliminary global objective response rate (ORR) of 38% in the evaluable population across all dosage levels.

Explorative assessments show that clinical improvement in skin comes along with decreases of malignant cells and normalization of immune parameters in the tumor microenvironment. All responses were ongoing at the time of poster presentation.

Dose level 8 (3 mg/kg) has been completed without dose-limiting toxicity. Two further dose levels (6 and 10 mg/kg) remain to be explored in the dose-escalation part of this study.

Poster 1641 entitled "Phase IB/II Study of Lirilumab in Combination with Azacytidine in Patients with Relapsed Acute Myeloid Leukemia" was presented by Dr N. Daver from the Department of Leukemia at the MD Anderson Cancer Center.
Lirilumab is a first-in-class fully human monoclonal antibody that blocks inhibitory killer-cell immunoglobulin-like receptors (KIRs) expressed predominantly on natural killer (NK) cells to potentiate an anti-tumor immune response mediated by the latter. Lirilumab is licensed to Bristol-Myers Squibb Company by Innate Pharma.

In this Phase Ib/II study testing lirilumab in combination with azacytidine in a heavily pretreated patient population with relapsed AML, full doses of azacytidine and lirilumab (3) were well tolerated. No dose-limiting toxicities were observed. Preliminary efficacy data for 25 evaluable patients showed a response rate of 20% including two patients achieved a CR (4) or a CR with insufficient count recovery and three achieving hematologic improvement.

"Preliminary results presented at ASH (Free ASH Whitepaper) 2016 are encouraging, as they further reinforce the favorable safety profile of both lirilumab and IPH4102. The study of IPH4102 conducted in patients with CTCL is progressing very well and we look forward to the completion of the dose-escalation part of the trial to confirm the encouraging efficacy signal seen across dose levels to date," said Pierre Dodion, Chief Medical Officer of Innate Pharma. "The good safety profile of lirilumab in combination with azacytidine in patients with relapsed AML further supports the view that lirilumab is well tolerated in numerous combinations."

Posters Details

IPH4102

Poster title: "First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results"
Date: Saturday, December 3, 2016
Time: 5:30 p.m. – 7:30 p.m. PST
Presenter: Pr Youn Kim, Division of Oncology, Department of Medicine, Stanford Cancer Institute, Palo Alto, CA, U.S
Location: Hall GH, San Diego Convention Center, San Diego, CA, U.S.
The poster #1826 is available on Innate Pharma’s website.

Lirilumab

Poster title: "Phase IB/II Study of Lirilumab in Combination with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML)"
Date: Saturday, December 3, 2016
Time: 5:30 p.m. – 7:30 p.m. PST
Presenter: Dr Naval Daver, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.
Location: Hall GH, San Diego Convention Center, San Diego, CA, U.S.
The poster #1641 will be soon available on Innate Pharma’s website.

On December 4, 2016 Incyte Corporation (Nasdaq:INCY) reported an exploratory pooled analysis of data from the five-year follow-up of the Phase 3 COMFORT-I and COMFORT-II trials which further supports previously published overall survival findings and suggests that earlier treatment with Jakafi (ruxolitinib) may result in an improved survival advantage for patients with intermediate-2 or high-risk myelofibrosis (MF) than best available therapy (BAT) or placebo (Press release, Incyte, DEC 4, 2016, View Source;p=RssLanding&cat=news&id=2227338 [SID1234516907]). These data also reinforce previous long-term results observed with ruxolitinib compared with controls (BAT or placebo).

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"Understanding how earlier treatment with Jakafi may impact overall survival for appropriate patients with myelofibrosis is critical as physicians look to identify the most effective treatment approach for patients with this rare and debilitating disease," said Peg Squier, M.D., Ph.D., Incyte’s Head of U.S. Medical Affairs.

The 5-year, intent-to-treat analysis of pooled data from two Phase 3 studies showed prolonged survival for patients with intermediate-2 or high-risk MF randomized to ruxolitinib, with the risk of death reduced by 30 percent for patients who received ruxolitinib compared with the control groups. Ruxolitinib also exhibited an overall survival (OS) advantage in various patient subgroup analyses including age, sex, disease type, risk status, JAK2V617F mutation status, baseline spleen length, anemia, white blood cell count, and platelet count. Additionally, using data-modeling techniques aimed at correcting for crossover delay, overall survival advantage was more pronounced for patients who were randomized to receive ruxolitinib at the start of the trial compared with patients who crossed over from control to ruxolitinib.

These data are scheduled for presentation today at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2016 taking place in San Diego, California.

Results from the COMFORT-I & COMFORT-II Pooled Analysis
The double-blind COMFORT-I trial and the open-label COMFORT-II trial were both randomized Phase 3 studies that evaluated the safety and efficacy of ruxolitinib in 528 patients with intermediate-2 or high-risk primary MF, post–polycythemia vera MF, or post–essential thrombocythemia MF. Across the pooled analysis, there were a total of 301 patients randomized to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146), 227 to placebo in COMFORT-I (n=154) or to BAT in COMFORT-II (n=73).

In both COMFORT-I and COMFORT-II, patients were permitted to cross over to ruxolitinib from control treatment if they had progressive splenomegaly or a protocol-defined progression event. Crossover was mandatory following treatment unblinding in COMFORT 1. All continuing patients in the control arm in COMFORT II crossed over to ruxolitinib by the 3 year follow-up.

At the five-year intent-to-treat analysis, 42.5 percent (n=128) of the patients randomized to the ruxolitinib group died compared with 51.5 percent (n=117) of the patients randomized to the control group. Key findings include the following results:
Median overall survival for ruxolitinib was 5.3 years compared with 3.8 years for the control group.

Using a rank-preserving structural failure time modeling method, the OS advantage was more pronounced for patients originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS: ruxolitinib, 5.3 y; control, 2.3 y; HR, 0.35; 95% CI, 0.23–0.59), which suggests that the delay in ruxolitinib treatment may be the underlying reason for the difference in survival.

This analysis (Abstract #3110) is being presented as a part of a poster session (#634) on Sunday, December 4, 2016, 6:00-8:00 PM PST, Hall GH.

About Myelofibrosis (MF)
MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs). In MF, a patient’s bone marrow can no longer produce enough normal blood cells, causing the spleen and or liver to enlarge.1 MF is a progressive disease, which leads to bone marrow scarring and significant debilitating disease-related symptoms such as anemia, fatigue, and itching which can result in a poor quality of life.2 Patients with MF have a decreased life expectancy, with an average survival of approximately five to six years.3 The cause of MF is unknown but is linked to genetic mutations—between 50% and 60% of people with MF have a specific mutation of the Janus Kinase 2 gene (JAK2).4

About Jakafi (ruxolitinib)
Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration, for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is also indicated for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

Important Safety Information
Jakafi can cause serious side effects, including:
Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of
Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.
Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in Cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: low platelet count, low red blood cell counts, bruising, dizziness, headache.
These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.
Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

On December 4, 2016 Acceleron Pharma Inc. (NASDAQ:XLRN) and Celgene Corporation (NASDAQ:CELG), reported preliminary Phase 2 results from the ongoing three-month base and long-term extension studies with investigational drug luspatercept in patients with lower risk myelodysplastic syndromes (MDS) at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California (Press release, Acceleron Pharma, DEC 4, 2016, View Source [SID1234516906]). Luspatercept is being developed as part of the global collaboration between Acceleron and Celgene.

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"We are encouraged by the additional luspatercept data from the ongoing Phase 2 studies," said Michael Pehl, President, Hematology and Oncology for Celgene. "These data further support luspatercept’s potential in treating a broader spectrum of MDS patients. We are evaluating opportunities to expand our clinical program to include additional MDS patient populations, as we advance our Phase 3 MEDALIST trial in RS+ patients."

Luspatercept Phase 2 Data in First-line, ESA treatment-naive MDS Patients

In lower-risk MDS patients who have not received prior treatment with an erythropoiesis-stimulating agent (ESA) and have erythropoietin (EPO) levels ≤ 500 IU, luspatercept three-month base study data demonstrated encouraging rates of transfusion independence and International Working Group Hematologic Improvement – Erythroid (IWG HI-E) response criteria.

Transfusion Burden IWG HI-E, n/N (%) RBC-TI, n/N (%)
Base N=64 Extension N=42 Base N=49 Extension N=28
All 12/20 (60%) 13/16 (81%) 9/12 (75%) 8/10 (80%)
Low Transfusion Burden 6/13 (46%) 8/11 (73%) 5/5 (100%) 5/5 (100%)
High Transfusion Burden 6/7 (86%) 5/5 (100%) 4/7 (57%) 3/5 (60%)

Luspatercept Phase 2 Data in Ring Sideroblast Positive (RS+) and Negative (RS-) in MDS Patients

In patients with EPO levels < 200, response rates were similar in both RS+ and RS- patients
In the patients with EPO levels ≥ 200 to ≤ 500, luspatercept response rates remained encouraging in those patients who are RS+

Baseline EPO
(U/L)

RS
Status
IWG HI-E, n/N (%) RBC-TI, n/N (%)

Base
N=64*

Extension
N=42*

Base
N=49*

Extension
N=28*

< 200 RS+ 18/29 (62%) 19/23 (83%) 13/19 (68%) 10/14 (71%)
RS- 2/5 (40%) 3/3 (100%) 1/4 (25%) 1/2 (50%)
≥ 200 to ≤ 500 RS+ 5/11 (46%) 7/8 (88%) 3/9 (33%) 3/5 (60%)
RS- 0/3 (0%) 0/1 (0%) 2/2 (100%) 1/1 (100%)
*Table includes both ESA refractory and ESA naïve patients. Subjects treated at dose levels ≥ 0.75 mg/kg.

Luspatercept Phase 2 Safety Data

The majority of adverse events (AEs) were grade 1 or 2
There were four grade 3/serious AEs possibly or probably related to study drug as of November 28, 2016: blast cell count increase, myalgia, worsening of general condition, progression to AML
Adverse events at least possibly related to study drug that occurred in at least 2 patients during studies were diarrhea, fatigue, headache, hypertension, arthralgia, bone pain, injection site erythema, myalgia and peripheral edema.
Luspatercept is an investigational product that is not approved for use in any country.

The MEDALIST Trial, a global Phase 3 study in patients with very low, low, or intermediate risk, MDS with ring sideroblasts who require red blood cell transfusions, is currently enrolling.

The poster presentation of the ongoing Phase 2 studies is available on Acceleron’s website (www.acceleronpharma.com) under the Science tab.

On December 4, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it will present initial clinical data from a Phase 1a/1b clinical trial evaluating the safety and preliminary anti-tumor activity of the selective HDAC6 inhibitor citarinostat (ACY-241), in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California (Press release, Acetylon, DEC 4, 2016, View Source [SID1234516901]).

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"Early results of this study with citarinostat closely parallel recently published positive data for the Phase 2 trial of Acetylon’s first selective HDAC6 inhibitor ricolinostat in combination with Pom and Dex in multiple myeloma, and compare favorably to historical controls. In early follow-up data for Celgene’s MM-003 trial of Pom/Dex versus high dose Dex, there was a 17% overall response rate at 4.2 months. At a 4-month median follow up with citarinostat in combination with the same Pom/Dex regimen, we are seeing an impressive overall response rate of 46% as well as substantial improvement in progression free survival standing at 6.5 versus historical 4 months," said Robert Markelewicz, Senior Medical Director at Acetylon. "While these are still interim data, we are seeing that citarinostat combines favorably with Pom and Dex, and we will continue cohort expansion to explore selected biomarkers and confirm the dose and schedule for a planned pivotal trial."

Citarinostat (ACY-241) is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat (ACY-1215), and administered in tablet form. The ACE-MM-200 study is a Phase 1a/1b clinical trial to determine the maximum tolerated dose, safety, and preliminary anti-tumor activity of citarinostat alone and in combination with pomalidomide and dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma. Its sequential monotherapy/combination trial design allows patients access to combination therapy based on an established regimen starting in the second cycle of treatment, while establishing the safety, pharmacokinetics, and pharmacodynamics of citarinostat as both a monotherapy and in combination.

Initial results of the study suggest that citarinostat is well tolerated, with no maximum tolerated dose (MTD) observed at doses up to 480 mg once-a-day as a monotherapy and up to 360 mg once-a-day in combination with Pom/Dex. Tolerability in combination is similar to that reported for Pom/Dex alone. In 56 efficacy evaluable patients with a 4-month median follow-up, the confirmed overall response rate (ORR) was 46%, with a clinical benefit rate (CBR) of 59% and disease control rate (DCR) of 91%. The median duration of response (DOR) was 9.2 months and median progression-free survival (PFS) was 6.5 months. Notably, similar response rates were seen across the refractory subsets, including patients who were previously refractory to pomalidomide and daratumumab. A dose of 360 mg once-a-day was selected as the recommended Phase 2 dose for citarinostat based on similarly low incremental toxicity, higher PK/PD exposure, and similar clinical efficacy when compared to the 180 mg dose.

Details of the presentation are as follows:

Date: Sunday, December 4, 2016

Time: 6:00pm – 8:00pm PST

Location: Hall GH (San Diego Convention Center)

Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II

Abstract Number: 3307

Title: Selective HDAC6 Inhibitor ACY-241, an Oral Tablet, Combined with Pomalidomide and Dexamethasone: Safety and Efficacy of Escalation and Expansion Cohorts in Patients with Relapsed or Relapsed-and-Refractory Multiple Myeloma (ACE-MM-200 Study)

About HDAC6 Selective Inhibition

Citarinostat (ACY-241) and ricolinostat (ACY-1215) selectively inhibit the intracellular enzyme HDAC6, leading to an accumulation of excess protein and disrupting critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. HDAC6 inhibition also enhances immune responses to cancer cells, both singly and in synergistic combination with immunomodulatory drugs (IMiDs), immune checkpoint inhibitor antibodies, and/or cytotoxic antibodies. Currently available HDAC drugs non-selectively affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage, and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is anticipated to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.