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."

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On December 11, 2017 ADC Therapeutics (ADCT), an oncology drug discovery and development company that specializes in the development of proprietary Antibody Drug Conjugates (ADCs) targeting major cancers, reported clinical data from two ongoing Phase I clinical trials evaluating ADCT-301 (camidanlumab tesirine or "Cami-T") in important subtypes of lymphoma and leukemia (Press release, ADC Therapeutics, DEC 11, 2017, View Source [SID1234522513]). The data were presented at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, USA.

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1. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell Hodgkin’s or non-Hodgkin’s lymphoma

Dr. Steven M. Horwitz, Medical Oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator, said: "Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77 percent overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44 percent complete response rate. We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33 percent) and B-cell lymphomas (ORR: 19 percent). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II."

Data were presented from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies. Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks.

Key findings presented at the poster presentation included:

For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44 percent) and 9 patients achieving a partial response (33 percent).
For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50 percent).
For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77 percent), 13 of 18 patients previously treated with a checkpoint inhibitor (72 percent), 9 of 14 patients who had previously undergone a stem cell transplantation (64 percent), and 4 of 8 patients who had previously received all three of these treatments (50 percent).
ADCT-301 has been reasonably well tolerated.
The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30 percent), rash (26 percent), elevated gamma-glutamyltransferase (22 percent), and pyrexia (21 percent). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13 percent), reduced platelet count (9 percent), elevated alanine aminotransferase (6 percent), anemia (6 percent), and rash (6 percent). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.
These encouraging preliminary safety and efficacy results support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.
2. Interim results of a Phase I open label, single agent, dose-escalating study of ADCT-301 evaluating tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory B-cell acute myeloid leukemia or acute lymphoblastic leukemia

Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 67 years and they had a median of 3 prior therapies. In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings presented at the poster presentation included:

One patient achieved a complete response with incomplete blood count recovery.
ADCT-301 has shown an acceptable safety profile.
The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30 percent), nausea (24 percent), febrile neutropenia (21 percent), and pneumonia (21 percent). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21 percent), thrombocytopenia (15 percent), fatigue (12 percent), reduced neutrophil count (12 percent), and pneumonia (12 percent).
Dose escalation will continue to investigate weekly dosing.
About ADCT-301

ADCT-301 is an antibody-drug conjugate (ADC) composed of a monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD25-expresing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead. CD25 is an attractive target for an ADC approach as it is expressed in a wide range of hematological malignancies, including certain forms of lymphomas and leukemias, while its expression in healthy organs is restricted. ADCT-301 is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), and in patients with relapsed or refractory CD25-positive acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). (www.adct-301.com)