On December 1, 2018 ArQule, Inc. (Nasdaq:ARQL) reported that it will present clinical data on the company’s BTK inhibitor, ARQ 531, in a poster presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition to be held from December 1 to 4, 2018 in San Diego (Press release, ArQule, DEC 1, 2018, View Source [SID1234531787]).

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Updated safety, PK, biomarker and anti-tumor activity data from the company’s Phase 1 dose escalation study in patients with relapsed or refractory hematologic malignancies (ARQ 531-101) will be presented.

Presentation Details

Title:

A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies

Abstract #: 3136
Session: CLL: Therapy, excluding Transplantation: Poster II
Date: Sunday, December 2, 2018
Time: 6:00-8:00 p.m. PT
Location: San Diego Convention Center, Hall GH

About BTK and ARQ 531
Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible BTK inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies, ARQ 531 has demonstrated good oral bioavailability as well as favorable pharmacokinetic, pharmacodynamic and metabolic properties.

On December 1, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 allosteric antagonist drugs to improve immune cell trafficking to treat rare diseases and cancer, reported the presentation of additional Phase 2 clinical data demonstrating a positive safety profile and clinical activity of X4P-001 in patients with WHIM syndrome, a rare primary immunodeficiency disease (Press release, X4 Pharmaceuticals, DEC 1, 2018, View Source [SID1234531788]). The clinical results are being presented today in a poster session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place in San Diego.

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"We continue to see encouraging results from this Phase 2 trial, as X4P-001 drug exposure appears to correlate with increases in absolute neutrophil count and absolute lymphocyte count levels. Increases in these biomarkers are an indication of potential improvement in the pathophysiology underlying WHIM syndrome. An example of clinical improvement and impact on symptoms was the continued reduction in a WHIM patient’s human papillomavirus-related warts following X4P-001 therapy," said David C. Dale, MD, Professor of Medicine at the University of Washington School of Medicine, Seattle, WA, and lead investigator of the trial.

The poster presentation at ASH (Free ASH Whitepaper) describes results from the first 8 patients with genetically confirmed WHIM syndrome and demonstrates the dose-dependent biomarker activity used to support dose selection for the Phase 3 trial. Additional updates on safety and clinical activity across all patients who were enrolled as of the August 17, 2018 data-cut off are also presented in the poster.

Information about the clinical trial of X4P-001 in patients with WHIM syndrome can be found on clinicaltrials.gov: View Source

"X4P-001 in WHIM syndrome is X4’s lead product candidate and our team is rapidly advancing toward the Phase 3 trial, with the goal of delivering X4P-001 to the global community of WHIM patients who currently lack any approved treatment specifically for this disease," said Paula Ragan, PhD, president and chief executive officer of X4 Pharmaceuticals. "We are confident in our path forward based on these favorable Phase 2 results, and we look forward to starting the pivotal Phase 3 trial in the first half of 2019."

About WHIM Syndrome
WHIM syndrome is a primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene resulting in susceptibility to certain types of infections. WHIM is an abbreviation for the characteristic clinical symptoms of the syndrome: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. Within the overall category of primary immunodeficiencies, there are between 15,000 and 100,000 patients in the U.S. who are classified with primary immunodeficiency disease of unknown origin – of which WHIM is one.1,2,3 WHIM syndrome is a rare disorder and the precise prevalence or incidence of patients that have the genetic mutation responsible for WHIM syndrome is unknown. Individuals with WHIM syndrome are more susceptible to potentially life-threatening bacterial infections.4 Additionally, WHIM syndrome is associated with significant morbidity beginning in early childhood and continuing throughout life. Current therapy is limited to treatment of acute infections with antibiotics or prevention of infections through the use of intravenous immunoglobulin or G-CSF. There is no approved therapy for the treatment of WHIM syndrome.

On December 1, 2018 Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of bone marrow transplant to more patients, reported that the Company highlighted new preclinical research on its MGTA-145 product candidate for stem cell mobilization in an oral presentation at the 60th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Magenta Therapeutics, DEC 1, 2018, View Source [SID1234531773]). MGTA-145 is being developed as a first-line agent to enable single-day mobilization of high numbers of hematopoietic stem cells for bone marrow transplant.

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"Seventy percent of the bone marrow transplants performed in the US and Europe each year use mobilized peripheral blood as a source of stem cells, but current standards of care require four to six days to mobilize an adequate number of stem cells. This is a notable burden on patients, donors and healthcare resources, and the standard treatment may be contraindicated or not tolerated in some patients who need transplant," said John Davis, M.D., M.P.H, chief medical officer, Magenta Therapeutics. "Data at ASH (Free ASH Whitepaper) this year show that MGTA-145, used in combination with plerixafor, rapidly mobilizes robust numbers of stem cells that successfully engrafted in non-human primates, and the cells mobilized by the combination also blocked GvHD in a preclinical model. Based on the body of preclinical data we have seen with MGTA-145, we will be moving this program into the clinic in the first half of 2019 as a promising investigational first-line therapy for stem cell mobilization."

MGTA-145 in Combination with Plerixafor Rapidly Mobilizes High Numbers of Hematopoietic Stem Cells and Graft-Versus-Host Disease-Inhibiting Myeloid-Derived Suppressor Cells in Non-Human Primates, Abstract #116

Key results, presented by Patrick Falahee, Ph.D., Magenta Therapeutics:

MGTA-145 works synergistically with plerixafor, another agent for stem cell mobilization, to rapidly mobilize large numbers of stem cells.
A single injection of MGTA-145 plus plerixafor mobilized sufficient stem cells for transplant within five hours in non-human primates.
A single injection of MGTA-145 plus plerixafor mobilized 2 to 3 times the number of stem cells in four hours compared to the number mobilized over five days with standard of care agent G-CSF in non-human primates.
When the cells mobilized with MGTA-145 plus plerixafor were transplanted into a non-human primate model, they rapidly engrafted.
MGTA-145 plus plerixafor led to a 3-fold increase in immunosuppressive monocytes mobilized over G-CSF – and the mobilized cells blocked GvHD, a significant challenge in allogeneic bone marrow transplant.

On December 1, 2018 Oxford BioMedica plc ("Oxford BioMedica" or "the Group") (LSE:OXB), a leading gene and cell therapy group, reported by Novartis on the longer-term analyses of both the ELIANA and JULIET pivotal trials in children and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukaemia (ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL), respectively. Kymriah (tisagenlecleucel) continued to demonstrate strong efficacy with durable responses and maintained a consistent and well-characterised safety profile (Press release, Oxford BioMedica, DEC 1, 2018, View Source [SID1234531789]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. Additionally, today, the New England Journal of Medicine published online the 14-month results from JULIET, the study led by the Abramson Cancer Center at the University of Pennsylvania 1.

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In the 24-month follow-up analysis of the ELIANA study in children and young adults with r/r B-cell ALL, Kymriah demonstrated deep and durable responses without subsequent therapy in a significant portion of patients in this population. Among 79 evaluable patients, who were followed for at least three months or discontinued earlier, 82% (95% confidence interval [CI], 72% – 90%) achieved complete response (CR) or CR with incomplete blood count recovery (CRi) within three months of infusion; and among these responding patients, 98% had negative minimal residual disease (MRD). The relapse-free survival rate was 62% at 24 months; and the median duration of remission (mDOR) and median overall survival (mOS) remained unreached, signifying responses are deep and sustained, and further reinforcing the potential for Kymriah to be a definitive therapy for many patients. The probability of OS was 76% (95% CI, 65% – 85%) at 12 months and 66% (95% CI, 58% – 79%) at 24 months. The safety profile observed in this updated analysis was consistent with previously reported results, with no emergence of new safety signals. Grade 3/4 cytokine release syndrome (CRS) – as defined by the rigorous Penn Grading Scale – occurred in 49% of patients. Within eight weeks of infusion, 13% of patients experienced grade 3 neurological events, with no grade 4 events or cerebral oedema2. These updated data will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract # 895; Monday, December 3, 4:30PM PST).

Results from the 19-month analysis from the JULIET study of Kymriah in adult patients with r/r DLBCL (n=99) indicated prolonged durability of response in patients who had previously been through multiple rounds of chemotherapy and unsuccessful stem cell transplants (Abstract # 1684). The overall response rate (ORR) after a median of 19 months of follow-up was 54% (95% CI, 43% – 64%; CR, 40%; partial response [PR], 13%) among patients who were followed for at least 3 months or discontinued earlier. The mDOR was not reached at the time of analysis indicating most responders were still experiencing a response at the time of analysis; and the relapse-free probability, which was 66% (95% CI, 51%-78%) at 6 months, remained consistent at 64% (95% CI, 48%-76%) between 12-month and 18-month analyses. Further, 54% (15/28) of patients who had achieved a PR converted to CR. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). Analyses of ORR, DOR and OS data showed consistent results across all patient subgroups, regardless of relapsed/refractory status, age and high-risk cytogenetics.

The safety profile observed in the 19-month follow-up from JULIET continued to be consistent with previous reports and no deaths occurred due to causes other than disease progression in this longer-term follow up analysis. Within eight weeks of infusion with Kymriah, Grade 3/4 CRS, as defined by the Penn Grading Scale, was reported in 23% of patients. CRS management was conducted per the Penn CRS management algorithm, which is specific to Kymriah. Tocilizumab and steroids were used in 16% and 11% of patients, respectively, to treat CRS. Eleven percent of patients had Grade 3/4 neurologic adverse events, which were managed with supportive care3.

Oxford BioMedica is the sole manufacturer of the lentiviral vector used in Kymriah. The Group signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate Kymriah and other undisclosed CAR-T products. This collaboration has reached important milestones in 2018 with the US FDA approval of Kymriah to treat adult patients with r/r DLBCL, and the approval of Kymriah in these two distinct indications in the European Union, Canada and Switzerland. These important achievements follow the initial US launch of Kymriah in paediatric and young adult patients with r/r B-cell ALL in 2017. Oxford BioMedica signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate CTL019 and other undisclosed CAR-T products, for which Oxford BioMedica could potentially receive in excess of $100m from Novartis over the next three years.

Notes for editors

About the ELIANA Trial

ELIANA is the first paediatric global CAR-T cell therapy registration trial, examining patients in 25 centres in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain, demonstrating effective distribution of Kymriah across four continents using a global supply chain. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

About the JULIET Trial

JULIET is the first multi-centre global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only global registration study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands.

About Kymriah

In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukaemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

On December 1, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of clinical data from two ongoing trials of its investigational Bruton’s tyrosine kinase (BTK) inhibitor, zanubrutinib, in patients with mantle cell lymphoma (MCL) (Press release, BeiGene, DEC 1, 2018, View Source;p=RssLanding&cat=news&id=2378923 [SID1234531774]). The presentations were made at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), taking place December 1-4, 2018 in San Diego, CA.

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Results from the pivotal Phase 2 trial of zanubrutinib in Chinese patients with relapsed or refractory (R/R) MCL (ClinicalTrials.gov Identifier: NCT03206970) were featured in an oral presentation, while updated results from the global Phase 1 trial of zanubrutinib in patients with multiple subtypes of B-cell malignancies, including treatment naïve (TN) and R/R MCL (ClinicalTrials.gov Identifier: NCT02343120), were featured in a poster presentation.

"Taken together, we believe that these two studies provide encouraging evidence for the use of zanubrutinib as a potential therapy in patients with MCL," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "The results from 86 patients enrolled in our pivotal Phase 2 study in Chinese patients with R/R MCL presented today at ASH (Free ASH Whitepaper), provide a thorough look into the data included in our first new drug application (NDA) in China for zanubrutinib. Additionally, the results from 48 patients with MCL enrolled in our global Phase 1 study illustrated consistent outcomes for patients studied outside of China. We are excited by the prospect that zanubrutinib may be a differentiated BTK inhibitor with deep, durable responses for patients with MCL and potentially for other B-cell malignancies."

Zanubrutinib was discovered by BeiGene scientists, and is being developed globally as a monotherapy and in combination with other therapies to treat various hematologic malignancies. Zanubrutinib is being studied in several clinical trials as part of a broad development program and was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with Waldenström macroglobulinemia (WM). BeiGene plans to submit an initial NDA to the FDA for zanubrutinib in 2019 or early 2020. The NDAs in China for R/R MCL and R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.

"Zanubrutinib was shown to be highly active in Chinese patients with R/R MCL, as evidenced by a high rate of complete responses characterized by PET-based imaging. It was also generally well-tolerated, and we are hopeful of its potential to become a new treatment option for Chinese patients with MCL and potentially other forms of B-cell lymphomas," said Yuqin Song, M.D., Ph.D., Associate Professor of Medical Oncology, Deputy Director of the Lymphoma Department at Peking University Cancer Hospital in China, and presenter of results from the pivotal Phase 2 trial in Chinese patients.

"The outcomes observed in patients treated outside of China are generally consistent with the experiences observed in Chinese patients with R/R MCL. Importantly, the high response rates that were observed appear to extend to patients with both TN and R/R MCL," commented Constantine Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia, and lead author of the poster presentation of results from the global Phase 1 trial.

Summary of Clinical Results From the Pivotal Phase 2 Trial in China
Oral Presentation Data Included in BeiGene’s NDA in China for Zanubrutinib in MCL

This single arm, open-label, multi-center, pivotal Phase 2 trial of zanubrutinib as a monotherapy in Chinese patients with R/R MCL enrolled 86 patients who had received a median of two prior lines of therapy (1-4). Patients were treated with zanubrutinib, dosed at 160 mg orally twice-daily (BID). The primary endpoint of the trial was overall response rate (ORR) assessed by independent review committee (IRC) using PET-based imaging according to the Lugano Classification 2014.

As of March 27, 2018, 85 patients with R/R MCL were evaluable for efficacy and 65 patients (75.6%) remained on study treatment. The median follow-up time for patients enrolled in the trial was 35.9 weeks (1.1-55.9). Results included:

The ORR by IRC was 83.5 percent (71/85); the complete response (CR) rate was 58.8 percent (50/85) and the partial response (PR) rate was 24.7 percent (21/85);

The 24-week progression-free survival (PFS) was estimated at 82 percent. The median PFS had not yet been reached;

With 24.1 weeks median follow-up (0.1-41.1), the median duration of response (DOR) had not yet been reached and 90 percent of responders were still in response at 24 weeks;

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequent AEs of any attribution were neutrophil count decreased (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and platelet count decreased (22.1%);

The most frequently reported (in >5 percent of patients) grade 3 or higher AEs were neutrophil count decreased (11.6%) and lung infection (5.8%);

Four patients (4.7%) had treatment emergent adverse events (TEAEs) leading to death (one case each of traffic accident, cerebral hemorrhage, pneumonia, and unknown cause in the setting of infection); and

Among events of special interest for BTK inhibitors, diarrhea was observed in nine patients (10.5%), all grade 1-2. Major hemorrhage was observed in 1 patient (1.2%) with blastoid variant of MCL who had intra-parenchymal CNS bleeding. No cases of atrial fibrillation/flutter were reported in this trial.
Summary of Updated Clinical Results From the Global Phase 1 Trial

This open-label Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including MCL, is being conducted in Australia, New Zealand, the United States, Italy, and South Korea. As of July 24, 2018, 48 patients with TN (n=9) or R/R (n=39) MCL have been enrolled in the trial and the median follow-up time was 12.7 months (0.7-38.0). Forty-five patients including six with TN and 39 with R/R MCL, were evaluable for efficacy in this analysis, per the Lugano 2014 classification. At the time of the data cutoff, 26 patients remained on study treatment. Updated results included:

The ORR by investigator was 88.9 percent (40/45); the CR rate was 26.7 percent (12/45) and the PR rate was 62.2 percent (28/45). The majority of patients were assessed via CT-scan; PET scans were optional per trial protocol;

The median DOR was 16.2 months and the median PFS for R/R patients was 18.0 months (0.7-30.7);

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of AEs were grade 1 or 2 in severity. The most frequent AEs of any attribution were petechia/purpura/contusion (33.3%), diarrhea (33.3%), upper respiratory tract infection (29.2%), fatigue (25.0%), and constipation (18.8%);

Grade 3-5 AEs occurred in 56.3 percent of patients. Grade 3-5 AEs of any attribution reported in > three patients included anemia (8.3%), major hemorrhage (6.3%), cellulitis (6.3%), myalgia (6.3%), neutropenia (6.3%), pneumonia (6.3%); and thrombocytopenia (6.3%);

Discontinuation due to AEs occurred in 18.8 percent of patients with all but one event (peripheral edema) determined to be unrelated to study drug; and

There were four deaths due to AEs, which were all determined by the investigators to be unrelated to zanubrutinib treatment.
Investor Webcast

Date and Time: Monday, December 3, 2018 at 20:00 PST (Tuesday, December 4 at 12:00 China Standard Time)
Webcast: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source
About Mantle Cell Lymphoma
Lymphoma is a diverse group of malignancies that originates from B-, T- or NK- cells. Mantle cell lymphoma (MCL) is typically an aggressive form of non-Hodgkin lymphoma (NHL) that arises from B-cells originating in the "mantle zone." In 2013, the incidence of lymphoma was 4.2 per 100,000 and the mortality was 2.2 per 100,000 in mainland Chinai, making it the eleventh most common cancer and the tenth leading cause of cancer death.ii In the United States, about 70,800 new cases of NHL were expected in 2014, with MCL representing about six percent (about 4,200 cases) of all new cases of NHL in the United Statesiii. Mantle cell lymphoma usually has a poor prognosis, with a median survival of three to four years, although occasionally patients may have an indolent course.iv Frequently, mantle cell lymphoma is diagnosed at a later stage of disease.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

Clinical trials of zanubrutinib include a global Phase 1 trial; a fully-enrolled, global Phase 3 clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib, the currently approved BTK inhibitor for WM; a global Phase 3 clinical trial in patients with previously untreated chronic lymphocytic leukemia (CLL); a pivotal Phase 2 trial in patients with relapsed/refractory (R/R) follicular lymphoma in combination with GAZYVA (obinutuzumab); and a Phase 3 trial comparing zanubrutinib to ibrutinib in patients with R/R CLL/small lymphocytic lymphoma (SLL). In China, BeiGene has completed enrollment in two other pivotal Phase 2 clinical trials of zanubrutinib in patients with CLL/SLL and WM. New drug applications (NDA) for zanubrutinib in patients with R/R MCL and in patients with R/R CLL/SLL have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.