On December 11, 2017 Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients -Italfarmaco Group, a specialty pharmaceutical company, reported the positive results from two clinical trials evaluating its proprietary histone deacetylase (HDAC) inhibitor givinostat in Polycythemia Vera patients. The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.

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"Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."
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In the oral presentation at ASH (Free ASH Whitepaper), the principal investigator described the multi-center, open label Phase Ib/II givinostat study, which included a dose-escalation and an evaluation of preliminary efficacy and tolerability. The data demonstrated that givinostat was well tolerated overall at the defined dose of 100 mg twice daily and the majority of adverse events were mild to moderate in severity. The overall response rate was more than 80% according to European Leukemia Net standard response criteria, which measure a range of parameters including reduction of the size of spleen and liver, peripheral blood count, absence of hemorrhagic and thrombotic events and bone marrow analysis.

In the larger study investigating long-term safety and efficacy, Italfarmaco researchers and collaborators presented data supporting the potential of givinostat as a durable treatment option that reduces the symptoms and underlying risks of the disease while remaining well-tolerated. Overall, 80% of patients maintained at least a partial response for more than four years. After four years of treatment no patient reported microvascular symptoms or headaches. Pruritus (itchiness), one of the typical symptoms of Polycythemia Vera, was absent in 67% of the patients. Furthermore, the overall incidence of thrombosis (1.13% patients per year) was reduced in comparison to the expected incidence rate in this patient population (3% patients/year). Givinostat treatment additionally reduced the levels of mutated Janus Kinase 2 (JAK2), a key underlying cause of the disease, by 25% in over 40% of the patients.

"The givinostat Phase II proof-of-concept and long-term data are very encouraging and demonstrate the potential of this compound to address the underlying mechanism of the disease while remaining well-tolerated," said Dr. Paolo Bettica, Vice President Research and Development. "Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."

"Italfarmaco is particularly gratified that these results were selected for presentation at ASH (Free ASH Whitepaper) because they underscore the value of our internal research and development efforts," added Dr. Francesco De Santis, President of Italfarmaco.

About Polycythemia Vera

Polycythemia Vera is a rare blood disease characterized by an overproduction of red blood cells, white blood cells and platelets, which thickens the blood and increases the risk of blood clots, a major underlying cause of life-threatening conditions such as thrombosis, embolisms, heart attack or stroke. The disease is associated with mutations in the Janus Kinase 2 (JAK2) gene and disease-related symptoms include headaches, itching and microvascular symptoms. The current standard of care ranges from phlebotomy alone or in combination with low-dose aspirin, to drugs such as the cytoreductive hydroxycarbamide or the JAK inhibitor ruxolitinib. These reduce symptoms, but no treatments targeting the underlying disease mechanism are available.

About Givinostat

Givinostat is a potent, orally-available, class I and II histone deacetylase (HDAC) inhibitor and an investigational product discovered through Italfarmaco’s internal research and development efforts. Through the pharmacological modulation of cell growth, differentiation and apoptosis and the additional specific inhibition of the proliferation of cells bearing the JAK2V617F mutation, givinostat may represent a novel disease modifier in Polycythemia Vera. Besides these properties, givinostat has shown immuno-modulatory activity that may specifically target other diseases, making it a very promising candidate for Duchenne Muscular Dystrophy (Phase III) and Becker Muscular Dystrophy (Phase II). The data were presented in an oral and a poster presentation on Saturday December 9th, 2017 at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting & Exposition held in Atlanta, Georgia. In the oral presentation, the company discussed positive safety and efficacy data from a two-part study of givinostat in which over 80% of patients responded to the treatment. These results were further supported by a poster presentation of a long-term evaluation of givinostat’s effect in patients over four years. Combined, the data provide a basis for the company’s decision to proceed with a pivotal Phase III trial in this indication. Polycythemia Vera is a rare blood disease characterized by an increased number of red blood cells, white blood cells and platelets, which significantly raises the risk for thromboembolic and hemorrhagic complications.

"Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."
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In the oral presentation at ASH (Free ASH Whitepaper), the principal investigator described the multi-center, open label Phase Ib/II givinostat study, which included a dose-escalation and an evaluation of preliminary efficacy and tolerability. The data demonstrated that givinostat was well tolerated overall at the defined dose of 100 mg twice daily and the majority of adverse events were mild to moderate in severity. The overall response rate was more than 80% according to European Leukemia Net standard response criteria, which measure a range of parameters including reduction of the size of spleen and liver, peripheral blood count, absence of hemorrhagic and thrombotic events and bone marrow analysis.

In the larger study investigating long-term safety and efficacy, Italfarmaco researchers and collaborators presented data supporting the potential of givinostat as a durable treatment option that reduces the symptoms and underlying risks of the disease while remaining well-tolerated. Overall, 80% of patients maintained at least a partial response for more than four years. After four years of treatment no patient reported microvascular symptoms or headaches. Pruritus (itchiness), one of the typical symptoms of Polycythemia Vera, was absent in 67% of the patients. Furthermore, the overall incidence of thrombosis (1.13% patients per year) was reduced in comparison to the expected incidence rate in this patient population (3% patients/year). Givinostat treatment additionally reduced the levels of mutated Janus Kinase 2 (JAK2), a key underlying cause of the disease, by 25% in over 40% of the patients.

"The givinostat Phase II proof-of-concept and long-term data are very encouraging and demonstrate the potential of this compound to address the underlying mechanism of the disease while remaining well-tolerated," said Dr. Paolo Bettica, Vice President Research and Development. "Polycythemia Vera patients have limited treatment options that currently only ameliorate the symptoms of the disease. We look forward to initiating the planned pivotal study in this indication."

"Italfarmaco is particularly gratified that these results were selected for presentation at ASH (Free ASH Whitepaper) because they underscore the value of our internal research and development efforts," added Dr. Francesco De Santis, President of Italfarmaco.

About Polycythemia Vera

Polycythemia Vera is a rare blood disease characterized by an overproduction of red blood cells, white blood cells and platelets, which thickens the blood and increases the risk of blood clots, a major underlying cause of life-threatening conditions such as thrombosis, embolisms, heart attack or stroke. The disease is associated with mutations in the Janus Kinase 2 (JAK2) gene and disease-related symptoms include headaches, itching and microvascular symptoms. The current standard of care ranges from phlebotomy alone or in combination with low-dose aspirin, to drugs such as the cytoreductive hydroxycarbamide or the JAK inhibitor ruxolitinib. These reduce symptoms, but no treatments targeting the underlying disease mechanism are available.

About Givinostat

Givinostat is a potent, orally-available, class I and II histone deacetylase (HDAC) inhibitor and an investigational product discovered through Italfarmaco’s internal research and development efforts. Through the pharmacological modulation of cell growth, differentiation and apoptosis and the additional specific inhibition of the proliferation of cells bearing the JAK2V617F mutation, givinostat may represent a novel disease modifier in Polycythemia Vera. Besides these properties, givinostat has shown immuno-modulatory activity that may specifically target other diseases, making it a very promising candidate for Duchenne Muscular Dystrophy (Phase III) and Becker Muscular Dystrophy (Phase II).

On December 11, 2017 Syntimmune presented Poster Presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting, Atlanta, Georgia (Press release, Syntimmune, DEC 11, 2017, View Source [SID1234522534]).

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On December 11, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported the presentation of six posters highlighting preclinical and clinical data sets for TGR-1202 (umbralisib), the Company’s once-daily PI3K delta inhibitor, and TG-1101 (ublituximab), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting, currently being held at the Georgia World Congress Center in Atlanta, Georgia (Press release, TG Therapeutics, DEC 11, 2017, View Source [SID1234522557]).

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Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are very pleased by the data presented yesterday and today during the ASH (Free ASH Whitepaper) annual meeting. The preclinical data help us to better understand the difference between TGR-1202 and other agents in the class and offers a more complete rationale for the differentiated safety profile seen in the clinic. With the updated and expanded integrated safety analysis of TGR-1202 alone and in combination with other agents, we believe we have provided the long-term follow-up sufficient to allay any lingering safety concerns related to TGR-1202 caused by the toxicity profile of first generation PI3K delta inhibitors." Mr. Weiss continued, "In 2018, with registration-directed data expected in CLL and NHL, our focus will turn to showcasing the efficacy of TGR-1202 and our proprietary combination of TG-1101 plus TGR-1202, our U2 combination, ideally leading to NDA/BLA filings in CLL and NHL."

The following summarizes the highlights from each poster presented at the ASH (Free ASH Whitepaper) 2017 meeting.

Clinical Data Presentations:

An Integrated Safety Analysis of the Next Generation PI3K Delta Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

This presentation includes data that were pooled from 5 completed or ongoing Phase 1 or 2 studies containing TGR-1202, including a total of 347 patients with relapsed or refractory hematologic malignancies. Patients were heavily pretreated, with 50% of patients having seen 3 or more prior lines of therapy.

Highlights from this poster include:

● 347 patients have been treated with TGR-1202 across the 5 studies in this pooled analysis, with median duration of exposure of 6.5 months, and 176 patients on drug for 6+ months, 104 patients for 12+ months, with the longest patients on daily TGR-1202 for 4+ years
● In longer follow-up and in an expanded patient population, TGR-1202 exhibits a differentiated safety profile compared to prior generation PI3K delta inhibitors
● Discontinuations due to adverse events (AEs) were rare at under 10% for all studies
● Grade 3/4 AEs commonly associated with PI3K delta inhibitors have been rare, with pneumonitis (< 0.5%), transaminitis (~2%) and colitis (< 1%), the latter occurring with no apparent association to time on therapy
● Improved tolerability with few discontinuations due to AEs has allowed patients to remain on continuous dosing to achieve and sustain promisingly high rates of response:
o 85% Overall Response Rate (ORR) for single agent TGR-1202 in relapsed/refractory Chronic Lymphocytic Leukemia (CLL)
o 53% ORR for single agent TGR-1202 in relapsed/refractory Follicular Lymphoma (FL)

KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) In Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-delta Inhibitor Therapy (Abstract Number 4314)

This poster presentation includes data from patients with CLL who are intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent TGR-1202. To be eligible for the study patients had to have received prior treatment with a BTK inhibitor (ibrutinib, acalabrutinib) or a PI3K delta inhibitor (idelalisib, duvelisib) and discontinued therapy due to intolerance within 12 months of starting treatment on this study. Thirty-three patients were evaluable for safety (30 patients with ibrutinib intolerance, and 3 patients with idelalisib intolerance) of which 32 were evaluable for efficacy (1 patient had a confirmed Richter’s Transformation (RT) at enrollment which did not meet eligibility criteria). TGR-1202 appears to demonstrate a favorable safety profile in patients intolerant to prior ibrutinib or idelalisib, with only 2 patients (6%) discontinuing due to an adverse event, neither of which was a recurrent AE from prior TKI therapy.

Highlights from this poster include:

● 94% (30 of 32) of patients remain progression-free
● Median time on study at the data cut off was approximately 6 months with the majority of patients continuing on study and follow-up ongoing
● No patient discontinued TGR-1202 due to a recurrent AE which led to discontinuation from their prior kinase inhibitor

Phase I/II Study of Pembrolizumab in Combination with Ublituximab (TG-1101) and Umbralisib (TGR-1202) in Patients with Relapsed/Refractory CLL (Abstract Number 3010)

This presentation includes data from patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Richter’s Transformation (RT) treated with the triple combination of TG-1101, TGR-1202, and pembrolizumab. Eleven patients were evaluable for safety (9 CLL patients and 2 RT patients) and 10 were evaluable for efficacy (9 CLL and 1 RT), with one patient too early to evaluate.

Highlights from this poster include:

● One AE of increased LFTs was observed which met criteria for DLT; patient was re-challenged and remains on study treatment with TGR-1202 maintenance now 15+ months
● 78% (7 of 9) ORR in patients with relapsed/refractory CLL
● 75% (3 of 4) ORR in BTK refractory CLL patients
● Responses have been durable with the first patient progression-free for 24+ months

Preclinical Data Presentations:

Differential Regulation of T Cells By PI3K Delta Inhibitors in a CLL Murine Model (Abstract Number: 3009)

This poster presentation included preclinical data describing the differential regulation of human T cells by TGR-1202 in a preclinical CLL murine model.

Highlights from this poster include:

● TGR-1202 oral treatment induced less incidence of toxicity in CLL mice compared to other PI3K delta inhibitors
● TGR-1202 relatively preserved Treg quantity and function in a dose dependent manner compared to other PI3K delta inhibitors in normal and murine CLL T cells
● Inhibition of casein-kinase 1 epsilon (CK1e) by TGR-1202 may explain the relative preservation of Treg cells in these in-vivo models

Umbralisib/TGR-1202 As a Novel Dual PI3K/CK1 Inhibitor Has a Unique Therapeutic Role in Silencing Oncogenes in Aggressive Lymphomas (Abstract Number 2809)

This poster presentation expanded on existing preclinical data demonstrating that TGR-1202 is synergistic with carfilzomib in certain aggressive lymphoma cell lines.

Highlights from this poster include:

● TGR-1202 is highly synergistic with the proteasome inhibitor carfilzomib in cell line models of double hit lymphoma and mantle cell lymphoma
● Based on this preclinical work, a Phase 1 clinical study to evaluate the safety and efficacy of TGR-1202 in combination with carfilzomib is currently enrolling patients

PI3K Delta Inhibitors Induce Primary Monocyte Cytotoxicity but Do Not Alter Monocyte Differentiation (Abstract Number 4284)

This poster presentation included preclinical data exploring the effect of PI3K delta inhibitors on monocyte activity.

Highlights from this poster include:

● The clinical benefit and initial lymphocytosis seen with PI3K delta inhibitors in CLL may be related in part to direct effects on monocyte derived cells
● Idelalisib and TGR-1202 differed in the extent of monocyte cytotoxicity induced and inhibition of pAKT
● The direct effects of PI3K delta inhibitors on monocytes suggests these drugs may have efficacy beyond B-cell malignancies, including in monocytic neoplasms or other malignancies with monocyte derived cells in the tumor microenvironment

The above referenced presentations, are available on the Publications page of the Company’s website at www.tgtherapeutics.com.

On December 11, 2017 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, and Celgene Corporation (NASDAQ: CELG) reported additional data from the TRANSCEND study of JCAR017 (lisocabtagene maraleucel; liso-cel) in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (NHL) in a presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Celgene, DEC 11, 2017, View Source [SID1234522552]).

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"We are highly encouraged by the latest efficacy and tolerability data, particularly at dose level two, as these are patients with a poor prognosis who need better treatment options," said Sunil Agarwal, M.D., Juno’s President of Research and Development. "These data support a potential best-in-class profile and further support the importance of a defined cell product. We continue to enroll our pivotal cohort in DLBCL patients and over the next twelve to eighteen months we intend to explore earlier lines of therapy, additional therapeutic areas, and combinations."

TRANSCEND is an open-label, multicenter Phase 1 study to determine the safety, pharmacokinetics, and antitumor activity of JCAR017 in adult patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B, and mantle cell lymphoma.

The data were based on a cutoff date of October 9, 2017 and presented by Jeremy Abramson, M.D., of Massachusetts General Hospital, who is a Principal Investigator for the TRANSCEND study. They add to those disclosed on November 1, 2017 in ASH (Free ASH Whitepaper) Abstract #581.

As with previous readouts, the TRANSCEND data were presented for both the core and full groups. The core group (N=67) includes 29 patients who received dose level two (DL2 = 100 million cells), 34 patients who received dose level one (DL1 = 50 million cells), and 4 patients who received dose level one twice, approximately 14 days apart.

The core group includes patients with DLBCL (NOS and transformed from follicular lymphoma) who are ECOG Performance Status 0-1. These patients represent a high-risk patient population, with approximately 90% of treated patients having one or more predictors of poor survival, including double or triple hit lymphoma, being chemorefractory to front-line or subsequent therapies, never reaching a complete remission with prior treatments, or never having undergone an autologous transplant. Enrollment of the pivotal cohort is ongoing with the core group at DL2.

The full analysis group represents evaluable r/r patients in the DLBCL cohort (N=91), which includes an additional 24 patients with poor performance status (ECOG Performance Status 2) or with niche subtypes of aggressive NHL. In both analysis groups all efficacy data are based on at least one month of follow-up with a 28-day restaging scan and all safety evaluable data are based on having received JCAR017 (liso-cel) with at least one month of follow-up. Product was available for 98% (126/128) of patients apheresed in the DLBCL cohort.

"The results of this study continue to show the exciting potential of this CAR T therapy," said Jay Backstrom, Chief Medical Officer and Global Head of Regulatory Affairs for Celgene. "Our collaboration with Juno reflects our commitment to delivering transformational treatments to patients with blood cancers such as non-Hodgkin lymphoma."

Topline data from the presentation as of the October 9, 2017 data cutoff date included:

Responses in core group

At DL2, the data showed a 3 month overall response rate (ORR) of 74% (14/19) and a 3 month complete response (CR) rate of 68% (13/19). Of patients that have reached 6 months of follow-up, 50% (7/14) were in CR. Across doses, 80% (16/20) of patients with CR at 3 months stayed in CR at 6 months, and 92% (11/12) of patients in response at 6 months remain in response as of data cutoff.
Across doses, median duration of response (DOR) was 9.2 months and median durability of CR was not reached.
Tolerability in core group

1% (1/67) experienced severe cytokine release syndrome and 15% (10/67) experienced severe neurotoxicity.
36% (24/67) had any grade CRS and 21% (14/67) had any grade NT.
58% (39/67) had no CRS or NT of any grade.
At dose level 1, 3% (1/34) experienced severe CRS and 21% (7/34) experienced severe NT.
At dose level 2, 0% (0/29) experienced severe CRS and 7% (2/29) experienced severe NT.
13% (9/67) received tocilizumab and 18% (12/67) received corticosteroids.
Tolerability across doses in full group

1% (1/91) experienced severe CRS and 12% (11/91) experienced severe NT.
35% (32/91) had any grade CRS and 19% (17/91) had any grade NT.
60% (55/91) had no CRS or NT of any grade.
The most common treatment-emergent adverse events (TEAEs) other than CRS and NT that occurred at ≥25% included neutropenia (49%), anemia (38%), fatigue (37%), thrombocytopenia (29%), nausea (27%), and diarrhea (25%). The most common TEAEs were similar between core and full groups.
JCAR017 (liso-cel) is a defined composition CD19-directed CAR T cell product candidate using a 4-1BB costimulatory domain. Juno believes JCAR017’s clinical profile could enable outpatient administration. A biologics license application filing is expected to be completed in the second half of 2018, with approval as early as the end of 2018.

ASH Investor and Analyst Event and Webcast

The Juno ASH (Free ASH Whitepaper) Investor and Analyst Event and webcast will be held Monday, December 11, 2017 at 8:30 p.m. Eastern Time. The webcast can be accessed live on the Investor Relations page of Juno’s website, www.JunoTherapeutics.com, and will be available for replay for 30 days following the event.

On December 11, 2017 Reata Pharmaceuticals, Inc. (Nasdaq:RETA) ("Reata" or "the Company"), a clinical-stage biopharmaceutical company, reported the presentation of interim data from the ongoing Phase 1b portion of the REVEAL study of omaveloxolone in combination with approved checkpoint inhibitor (CI) therapies, ipilimumab or nivolumab, for the treatment of Stage III or IV unresectable or metastatic melanoma (Press release, Reata Pharmaceuticals, DEC 11, 2017, View Source;p=RssLanding&cat=news&id=2322028 [SID1234522532]). The data were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno Oncology Congress 2017 in Geneva, Switzerland by lead author Dr. Sapna Patel, Assistant Professor, Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center.

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All enrolled patients were required to have biopsy positive inducible nitric oxide synthase (iNOS), which is an independent predictor of poor survival in melanoma patients. Emerging translational data suggest that iNOS is a key mediator of myeloid-derived suppressor cells (MDSCs), whose presence has been shown to correlate with reduced activity of CIs. Of the 30 patients enrolled in REVEAL with evaluable tumor restaging, 7/30 (23%) of patients were checkpoint inhibitor-naïve, while 23/30 (77%) of patients were refractory to prior checkpoint inhibitor therapy. The overall response rate (confirmed + unconfirmed) observed in all evaluable patients was 8/30 (27%, 6 partial responses (PR) and 2 complete responses (CR)).

In CI-naïve patients, 4/7 (57%) had objective responses including 1 CR. 3/18 (17%) patients treated with omaveloxolone + nivolumab who were refractory to prior checkpoint inhibitor therapies had objective responses, including 1 CR. The majority of responses have been durable and are ongoing. Omaveloxolone treatment was associated with decreases in tumor iNOS, programmed death ligand 1 (PD-L1), and indoleamine 2,3-dioxygenase (IDO-1) expression. No serious AEs considered related to omaveloxolone have been reported to date. Commonly reported treatment-related adverse events included fatigue, nausea, pruritus, transaminase increases, and decreased appetite.

"The ongoing REVEAL trial data suggests that omaveloxolone may have activity in patients who are refractory to checkpoint inhibitors, which is an emerging and large unmet need," said Colin Meyer, M.D., Chief Medical Officer of Reata. "We are continuing with the dose escalation phase of the study to identify the optimal dose, and upon completion, we will determine the next steps in the clinical development program for omaveloxolone in melanoma."