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Pooled Analysis of Five-Year Data from Two Phase 3 Studies Further Supports Overall Survival Advantage Observed in Patients with Myelofibrosis Treated With Jakafi® (ruxolitinib)

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.

Acceleron and Celgene Announce Updated Results from Ongoing Phase 2 Studies of Luspatercept in Myelodysplastic Syndromes at the 58th Annual Meeting of the American Society of Hematology

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.

"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.

Acetylon Presents Early Phase 1a/1b Results for Citarinostat (ACY-241) in Combination with Pomalyst® and Dexamethasone Showing Promising Treatment Responses in Relapsed or Relapsed-and-Refractory Multiple Myeloma

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]).

"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.

Nordic Nanovector: Single-dose Betalutin® shows promising efficacy, improved duration of response and favourable safety in relapsed NHL patients

On December 4, 2016 Nordic Nanovector ASA (OSE: NANO) reported the updated results from its ongoing Lymrit 37-01 Phase 1/2 clinical trial of Betalutin (177Lu-satetraxetan-lilotomab) in subjects with relapsed non-Hodgkin lymphoma (NHL) at the 58th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) meeting (San Diego, CA, USA) (Press release, Nordic Nanovector, DEC 4, 2016, View Source [SID1234516900]).

The updated data confirm Betalutin’s promising efficacy and favourable safety profile as a single agent in 38 relapsed NHL patients, having failed multiple prior regimens and being eligible for assessments. The results, based on the data cut-off date of 31 October 2016, were presented by the study’s Principal Investigator Dr. Arne Kolstad from the Department of Oncology at the Oslo University Hospital, Radiumhospitalet.

Key conclusions:

• In the 35 patients evaluable for efficacy, the Overall Response Rate (ORR) was 63%, with 29% Complete Responses (CR)

• The 21 evaluable patients in the study who received Betalutin at the dose of 15 MBq/kg with 40 mg/m2 lilotomab pre-dosing had an ORR of 62% and a CR of 38%; of these, the 16 patients enrolled in the Phase 2 expansion of Arm 1, had an ORR of 69% and a CR of 38%

• Durable responses have been observed with a median duration of response of 20.7 months for all patients in Arm 1

• Betalutin is well tolerated, with a predictable and manageable safety profile: most adverse events are haematological in nature, and all have been transient and reversible

• No dose-limiting toxicity (DLT) was reported in Arm 4 (15 MBq/kg Betalutin plus 100 mg/m2 lilotomab pre-dosing) and this regimen demonstrated lower bone marrow toxicity than Arm 1, 2 and 3. Arm 4 is now enrolling patients to evaluate the higher dosing regimen of 20 MBq/kg Betalutin plus 100 mg/m2 lilotomab.

The Lymrit 37-01 study is a Phase 1/2 open label, dose escalation study investigating the optimal lilotomab pre-dosing and Betalutin regimen in patients with relapsed NHL. Data from 38 patients are presented.

Dr. Arne Kolstad, MD commented: "The results we are presenting today are very encouraging and continue to highlight the potential of Betalutin to provide a new treatment option for NHL patients. These patients, particularly those who fail standard CD20-targeted immunotherapy and/or are too frail to receive chemotherapy, are desperately in need of alternative therapies that work through different and complementary mechanisms and are well tolerated. Betalutin is showing exciting promise in an increasing number of NHL patients and we look forward to the results from future studies that will hopefully confirm its attractive profile."

Dr. Lisa Rojkjaer, MD Nordic Nanovector’s Chief Medical Officer, commented: "These new data confirm the promising results for Betalutin, including durable responses in a number of patients, which were presented earlier this year at the AACR (Free AACR Whitepaper) meeting, and continue to demonstrate an encouraging clinical profile as a single agent for treating patients with relapsed NHL. The results also support escalating to a higher dosing regimen in the final stages of this Phase 1/2 study that will allow us to decide an optimal dosing regimen for the pivotal Phase 2 study, PARADIGME, expected in Q1 2017."

The poster (abstract 1780) is available at: View Source

TRILLIUM PRESENTS INITIAL DATA FROM ONGOING STUDY OF TTI-621 IN PATIENTS WITH ADVANCED HEMATOLOGIC MALIGNANCIES AT THE AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING

On December 3, 2016 Trillium Therapeutics Inc. (NASDAQ: TRIL; TSX: TR), a clinical-stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported data from an ongoing study with its lead drug candidate, TTI-621, in patients with relapsed or refractory hematologic malignancies, at the American Society of Hematology (ASH) (Free ASH Whitepaper) 58th Annual Meeting in San Diego (Press release, Trillium Therapeutics, DEC 3, 2016, View Source [SID1234516895]).

"We are encouraged by the initial results from the study of TTI-621 in advanced hematologic malignancies, as we have seen decreased tumor volume and/or reduced metabolic activity over extended intervals of continued dosing in several patients," commented Niclas Stiernholm, Ph.D., president and chief executive officer of Trillium Therapeutics. "We believe that data from this study provide preliminary evidence that TTI-621 monotherapy is both active and well tolerated, supporting our hypothesis that neutralization of the inhibitory CD47 signal enables macrophage anti-tumor activity. We have determined an optimal dose level, which we are taking forward into the Phase 1b cohort expansion phase of the trial, as we seek to further define the benefit of TTI-621 in patients with multiple types of blood cancers."

TTI-621 Dose-Escalation Phase 1a

CD47 is an immune checkpoint that binds to SIRPa and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells often overexpress CD47 and exploit this pathway to avoid macrophage-mediated destruction. TTI-621 (SIRPaFc) is a novel immune checkpoint inhibitor designed to bind human CD47 and block the "do not eat" signal, promoting both innate and adaptive immunity. The lgG1 region of TTI-621 can engage Fc-gamma receptors on macrophages, enhancing phagocytosis and anti-tumor activity.

A first-in-human, Phase 1a/b, open label, multicenter study (NCT02663518) began in February 2016. During the Phase 1a portion of the study, 18 patients with relapsed/refractory lymphomas were enrolled in sequential dose cohorts (3 + 3 design) and received weekly IV infusions of TTI-621 to characterize safety, tolerability, pharmacokinetics, and to determine the optimal dose for subsequent enrollment in the expansion phase.

The results presented demonstrate that an optimal dose of 0.2 mg/kg/week was well-tolerated and associated with predictable, transient thrombocytopenia – consistent with augmented systemic phagocytosis. Importantly, this dose level obtained both CD47 receptor occupancy in circulating leukocytes and elevations in macrophage-associated cytokines that are both associated with high phagocytosis of tumor targets in vitro. Finally, decreasing volume and/or reduced metabolic activity over extended intervals of continued dosing were observed in several patients and one patient achieved a partial response.

The TTI-621 Phase 1a study poster presented at ASH (Free ASH Whitepaper) can be found on the company’s website at www.trilliumtherapeutics.com. Additional information about this clinical trial of TTI-621 is available at www.clinicaltrials.gov using identifier: NCT02663518.

TTI-621 Cohort Expansion Phase 1b

With the dose-escalation phase of TTI-621 in patients with lymphoma completed, patient enrollment across a broad spectrum of hematologic malignancies commenced in November in the Phase 1b multi-cohort expansion portion of the trial. The trial’s objectives are to further characterize the safety of TTI-621 and gain preliminary evidence of anti-tumor activity in patients with a variety of hematologic malignancies.

In addition to the eight original expansion cohorts, indolent B cell lymphoma, aggressive B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome, the Phase 1b expansion will also include patients with myeloproliferative neoplasms.

In a separate expansion cohort, patients with CD20-positive lymphomas will be treated with TTI-621 in combination with rituximab.