On December 1, 2018 ImmunoGen, Inc., (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that new data from the ongoing Phase 1 studies of IMGN632 and IMGN779, next-generation CD123- and CD33-targeting ADCs, respectively, in patients with relapsed or refractory adult acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be presented during an oral session at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, ImmunoGen, DEC 1, 2018, View Source [SID1234531781]). Preclinical data for IMGN632 as a monotherapy in BPDCN patient-derived xenografts, as well as in combination with a PARP inhibitor in AML models, will also be presented at the conference.

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The data presented at ASH (Free ASH Whitepaper) demonstrate the potential of ADCs generated from the company’s IGN platform to overcome the narrow therapeutic window seen with previous generations of DNA-targeted agents and offer new treatment options for AML and other hematological malignancies.

"We designed our IGN payloads to alkylate one strand of DNA to produce potent anti-leukemia activity, while reducing toxicity to normal cells caused by the double-stranded damage associated with earlier DNA-acting approaches," said Anna Berkenblit, MD, Vice President and Chief Medical Officer of ImmunoGen. "IMGN779 and IMGN632 each incorporate an IGN payload and we are pleased to share Phase I clinical results for both programs today at ASH (Free ASH Whitepaper)."

"With IMGN632, we are encouraged by both the tolerability and responses seen thus far, including repeat dosing and complete remissions in AML and BPDCN," said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. "We look forward to continuing to enroll patients at several dose levels to establish a recommended Phase 2 dose and schedule for both indications."

"With IMGN779, I am encouraged to see a significant decrease in blasts in many patients with some achieving CRi," said Jorge Cortes, MD, Deputy Chair and Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center. "The anti-leukemia activity and tolerability seen with both the weekly and the every two week schedule support continued enrollment to identify a dose and schedule to enable further development of IMGN779 as combination therapy in AML."

Phase 1 Data on IMGN632 in AML and BPDCN

Key initial findings from the Phase 1 study of IMGN632 (Abstract #27) include the following:

IMGN632 was administered to 33 patients over dose levels ranging from 0.015 to 0.45 mg/kg intravenously every three weeks. IMGN632 displays a tolerable safety profile and anti-leukemia activity at doses up to 0.3 mg/kg.
Pharmacokinetic (PK) exposures and pharmacodynamic (PD) CD123 saturation increase with dose.
Reported adverse events (AEs) were consistent with underlying disease, with no evidence of cumulative toxicity following multiple doses (up to 6 doses).
Single dose limiting toxicities (DLTs) were seen at the three highest dose levels tested: one prolonged neutropenia and two reversible cases of veno-occlusive disease.
Six of 23 evaluable AML patients (26%) across multiple dose levels achieved an objective response, including two complete remissions (CR) and four CRs with incomplete recovery (CRi) in heavily pretreated patients, including over 60% of patients with primary or relapsed refractory disease.
Two of three evaluable BPDCN patients achieved an objective response after a single dose of IMGN632, 1 CRi and 1 partial remission.
Enrollment in expansion cohorts continues to identify a recommended Phase 2 dose and schedule for both AML and BPDCN.
Phase 1 Data on IMGN779 in AML

Key findings presented from the Phase 1 study of IMGN779 (Abstract #26) include the following:

IMGN779 continues to display a tolerable safety profile with repeat dosing across a wide range of doses explored in 57 patients with relapsed AML. Patients across both schedules (weekly and every two weeks) received a median of four doses of IMGN779 (range, 1-40).
Plasma IMGN779 concentrations indicate consistent and sustained exposure through seven days at doses ≥0.39 mg/kg; the weekly schedule provides more consistent pharmacodynamic CD33 saturation.
Reported AEs were consistent with underlying disease, and with no evidence of cumulative toxicity following multiple doses (up to 40 doses).
One DLT of veno-occlusive disease was observed at the highest dose tested on the weekly schedule, 1.2 mg/kg.
Anti-leukemia activity was seen at doses ≥0.39 mg/kg in both schedules:
41% (12 of 29) of evaluable patients showed a >30% reduction in bone marrow blasts with eight patients (28%) having <8% residual blasts, and two having a CR or CRi.
Enrollment continues to identify the recommended Phase 2 dose and schedule.
Oral Presentation Details

Title: Maturing Clinical Profile of IMGN779, a Next-Generation CD33-Targeting Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Presenter:Jorge Cortes, MD Anderson Cancer Center
Day/Time:Saturday, December 1, 2018, 7:45am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 26
Title: A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies
Presenter: Naval Daver, MD Anderson Cancer Center
Senior Author: Hagop Kantarjian, MD Anderson Cancer Center
Day/Time: Saturday, December 1, 2018, 8:00am PST (Oral session 613)
Location: Manchester Grand Hyatt San Diego, Seaport Ballroom F
Abstract: 27
Preclinical Poster Presentations on IMGN632 in AML and BPDCN

Preclinical data on anti-leukemia activity for IMGN632 in combination with a PARP inhibitor in AML, as well as a monotherapy in BPDCN will also be presented.

Poster Presentation Details

Title: Synergistic anti-leukemia activity of PARP inhibition combined with IMGN632, an anti-CD123 antibody-drug conjugate in acute myeloid leukemia models
Day/Time: Sunday, December 2, 2018, 6:00-8:00pm PST (Poster session 604)
Senior author: Eunice Wang, Roswell Park Cancer Institute
Abstract: 2647
Title: Pre-clinical efficacy of CD123-targeting antibody-drug conjugate IMGN632 in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) models
Day/Time: Monday, December 3, 2018, 6:00-8:00pm PST (Poster session 605)
Senior author:Marina Konopleva, MD Anderson Cancer Center
Abstract: 3956
Additional information can be found at www.hematology.org, including abstracts.

About IMGN779

IMGN779 is a novel ADC that combines a high-affinity, humanized anti-CD33 antibody, a cleavable disulfide linker, and one of ImmunoGen’s novel indolino-benzodiazepine payloads, called IGNs, which alkylate DNA without crosslinking, resulting in potent preclinical anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.1,2 IMGN779 is in Phase 1 clinical testing for the treatment of AML.

About IMGN632

IMGN632 is a novel, anti-CD123 antibody-drug conjugate that is a potential treatment for AML, BPDCN, and other CD123-positive malignancies. IMGN632 uses a novel humanized anti-CD123 antibody coupled via a peptide linker to a unique DNA-alkylating IGN payload. In preclinical models, IMGN632 has exhibited potent antitumor activity with a wide therapeutic index in AML, BPDCN, and acute lymphoblastic leukemia (ALL). IMGN632 is in Phase 1 clinical testing for the treatment of AML and BPDCN.

About IGNs

Indolino-benzodiazepine cancer-killing agents, or IGNs, are a new class of cancer-killing agent developed by ImmunoGen for use in ADCs. These ultra-potent, DNA-acting IGNs alkylate DNA without crosslinking, which preclinically has resulted in potent anti-leukemia activity with relative sparing of normal hematopoietic progenitor cells.3.4 IMGN779, a CD33-targeting ADC in Phase 1 testing for AML, was the first IGN ADC to enter clinical testing. IMGN632, a CD123-targeting ADC entering Phase 1 testing for AML and BPDCN, deploys a novel IGN payload.

About Acute Myeloid Leukemia (AML)

AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia.

It is estimated that, in the U.S. alone, 21,380 patients will be diagnosed with AML this year and 10,590 patients will die from the disease.5

On December 1, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported positive top-line results from the Phase 2b SADAL (Selinexor Against Diffuse Aggressive Lymphoma) study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue (Press release, Karyopharm, DEC 1, 2018, View Source [SID1234531776]). The data were highlighted in a poster presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting in San Diego. For the SADAL study’s primary endpoint, single-agent selinexor achieved a 29.6% overall response rate (ORR), which included a 9.6% complete response (CR) rate in patients with heavily pretreated relapsed or refractory DLBCL. Key secondary endpoints included a median duration of response (DOR, in the responding patients) of 9.2 months and median overall survival (OS, across the entire study) of 9.1 months.

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Selinexor recently received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Karyopharm plans to submit a New Drug Application (NDA) to the FDA during the first half of 2019, with a request for accelerated approval for oral single-agent selinexor as a new treatment for patients with relapsed or refractory DLBCL.

Top-Line Phase 2b SADAL Results

Based on the modified intention-to-treat analysis from the first 115 of 127 patients (median of 2 prior treatment regimens with a range 1-6), as adjudicated by an independent central radiological committee, 34 patients responded (11 patients with a CR and 23 patients with a PR) for an ORR of 29.6%. An additional 8 patients experienced stable disease (SD) for a disease control rate of 36.5%. The median DOR across responding patients was 9.2 months and responses tended to occur rapidly. Patients with a CR had a median DOR of 23.0 months and patients with a PR had a median DOR of 7.8 months. As of the data cutoff date of November 15, 2018, 7 patients who achieved a CR remained on treatment. In addition, 12 patients remain on treatment, but as of November 15th, had not reached their first response assessment and are not included in the top-line efficacy analyses.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were gastrointestinal and constitutional symptoms, along with cytopenias; most manageable with dose modifications and/or supportive care. The most common non-hematologic AEs were nausea (50.0%), fatigue (35.9%), and anorexia (32.0%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 AEs were thrombocytopenia (35.2%), neutropenia (20.3%), and anemia (10.9%) and were generally not associated with clinical sequelae. No significant major organ toxicities were observed, and bleeding and infection rates were low.

The median OS was 9.1 months for all patients in the study. As of the data cutoff date, median survival for the patients with a CR or PR was 29.7 months. The median survival for patients with best response of progressive disease or who were not evaluable for response was 3.2 months.

Selinexor showed robust, single-agent activity in patients with either GCB or non-GCB subtypes of DLBCL: of the 53 patients with the GCB-subtype, 18 responded (5 patients with a CR and 13 patients with a PR) for an ORR of 34.0%. Of the 57 patients with the non-GCB subtype, 12 responded (6 patients with a CR and 6 patients with a PR) for an ORR of 21.1%. In addition, there were 5 patients enrolled whose subtype was unclassified and 4 of these patients achieved a PR.

"The SADAL data presented at ASH (Free ASH Whitepaper) this year demonstrate that oral selinexor, when administered as a single-agent, is clinically active and capable of producing durable responses associated with prolonged overall survival," said Marie Maerevoet, MD, Institute Jules Bordet, "The 60mg twice weekly oral dose continues to be well tolerated with a low incidence of Grade 3 or greater adverse events, which were often manageable with dose modifications and supportive care. We are highly encouraged by the results of this single agent study in patients with heavily pretreated DLBCL who have limited available treatment options."

Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm, said, "In addition to the compelling efficacy and safety data observed with single agent oral selinexor, we were especially pleased to see strong response rates in patients with both the GCB and non-GCB subtypes. This is especially important because the prognosis in patients with refractory disease and the GCB-subtype is particularly poor. We believe that if selinexor is ultimately approved for use in patients with DLBCL, it will provide a meaningful therapeutic option for patients battling refractory disease regardless of DLBCL subtype. We look forward to submitting these data to the FDA during the first half of 2019 as part of a New Drug Application, with a request for accelerated approval."

Details for the Poster Presentation at ASH (Free ASH Whitepaper) 2018:

Title: Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b SADAL Study
Presenter: Marie Maerevoet, Institute Jules Bordet, Brussels, Belgium
Abstract Number/Publication ID: 1677
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster I
Date and Time:Saturday, December 1, 2018; 6:15-8:15 PM PT
Location: San Diego Convention Center, Hall GH

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,800 patients have been treated with selinexor. In April and September 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

On December 1, 2018 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported a presentation of the first interim data with melflufen (Ygalo) from the ongoing phase I/II study ANCHOR at the 60th ASH (Free ASH Whitepaper) meeting in San Diego, California, USA (Press release, Oncopeptides, DEC 1, 2018, View Source [SID1234531775]).

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Overall conclusions

The combinations of melflufen and dexamethasone (dex) with either bortezomib or daratumumab in relapsed-refractory multiple myeloma (RRMM) patients are well tolerated
No dose limiting toxicity has been observed at the melflufen 30 and 40 mg dose levels in either regimens. The 40 mg dose level is still recruiting patients
An Overall Response Rate (ORR) of 86% was observed with melflufen and dexamethasone in combination with daratumumab (CD38-directed monoclonal antibody)
An Overall Response Rate (ORR) of 100% was observed with melflufen and dexamethasone in combination with bortezomib (proteasome inhibitor)
The data are presented in a poster that can be found at: www.oncopeptides.com / presentations / 60th ASH (Free ASH Whitepaper)

CEO comments

"Although, these are early data and small patient samples, it is encouraging to see that melflufen is well tolerated and has a very high level of activity with no cross resistant pattern in combination regimens. These patients have undergone 2-3 prior lines of therapy and have developed resistant disease. The interim data show a very good efficacy profile for melflufen in combination with either bortezomib or daratumumab. In a cross-study comparison in RRMM patients treated with combination regimens our interim data with an ORR in the range 86-100% stand out positively. The treatment landscape changes over time and there is a high need of new treatment options with a novel mechanism of action like melflufen" said Jakob Lindberg, CEO of Oncopeptides.

About the ANCHOR study

The study recruitment is ongoing. ANCHOR is a phase I/II study where melflufen and dexamethasone (dex) is dosed in combination with either bortezomib or daratumumab. All patients must have 1-4 prior lines of therapy and be refractory (or intolerant) to an immunomodulary agent (IMiD) or a proteasome inhibitor (PI) or both.

In combination with bortezomib (Regimen A) patients cannot be refractory to a PI and in combination with daratumumab (Regimen B) patients cannot be previously exposed to any anti-CD38. Patients will be treated until documented disease progression or unacceptable toxicity. The primary objective of the phase I part of the study is to determine the optimal dose of melflufen and dex, up to a maximum of 40 mg, in combination with bortezomib or daratumumab. An additional 20 patients per regimen will be recruited in the phase II part of the study where the primary objective is ORR.

Summary of the ANCHOR interim data

Melflufen in combination with bortezomib – Regimen A

At the time of the data cut-off November 12, 2018, 3 patients had been treated with 30 mg melflufen and dex in combination with bortezomib. Median age was 81 years with a median of 3 prior lines of therapy. All patients were relapsed-refractory and 2 out of 3 patients were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off with a median treatment duration of 5.8 months.

The patients received a total of 17 cycles of treatment with a median of 7. All 3 patients achieved partial response (PR). No dose limiting toxicities were observed at the 30 mg melflufen dose level and the melflufen 40 mg has been opened for enrollment. The regimen was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

Melflufen in combination with daratumumab – Regimen B

At the time of the data cut-off, November 12, 2018, 9 patients had been treated with melflufen in combination with daratumumab and dex. Median age was 63 years with a median of 2 prior lines of therapy. No patient had achieved CR in any previous line of therapy, 67% were IMiD refractory and 56% were last line refractory (disease progression while on therapy). All patients were ongoing at the time of the data cut-off.

All 9 patients were still ongoing with a median treatment duration of 3.9 months. They received a total of 39 cycles of treatment with a median of 4.

Overall response rate N/A*
ORR CR VGPR PR MR SD PD
total, N=9 86% 0 4 2 0 1 0 2
*2 of the 9 patients were still in their first cycle of treatment and were therefore not evaluable for response as described at time for data cut.

4 patients were treated with 30 mg melflufen and 5 patients were treated with 40 mg melflufen with no dose limiting toxicity observed. The combination of melflufen, dexamethasone and daratumumab was well tolerated with clinically manageable G3/4 hematological AEs and the low number of non-hematological AEs was noteworthy.

About Melflufen

Melflufen (Ygalo), a peptide conjugated alkylator belonging to a novel class of peptidase-enhanced compounds, targets multiple myeloma (MM) cells with a unique mechanism of action. Aminopeptidases are enzymes found in all cells but are over-expressed in several cancers including MM. Ygalo selectively targets MM cells through aminopeptidase-driven accumulation. In vitro experiments show a 50-fold enrichment of the active substance in MM cells compared with administration of equal amount of an alkylator not enriched by aminopeptidases. The enrichment results in selective cytotoxicity (increased on-target potency and decreased off-target toxicity), and that resistance pathways of existing myeloma treatments (including alkylators) is overcome. Melflufen also demonstrates strong anti-angiogenic properties.

Melflufen in clinical development

Melflufen (Ygalo) has been used to treat late-stage RRMM patients in both phase I and phase II clinical studies (O-12-M1) with favorable results. Currently, melflufen is being studied in four clinical trials for the treatment of multiple myeloma. The current studies are OCEAN, HORIZON, ANCHOR and BRIDGE.

The current clinical study program is intended to demonstrate better results from treatment with melflufen compared to established alternative drugs for patients with multiple myeloma. Melflufen could potentially provide physicians with a new treatment option for patients suffering from this serious disease.

Melflufen has been investigated in the treatment of late-stage relapsed refractory multiple myeloma (RRMM) patients. This was done in the clinical study O-12-M1 where strong final results were reported in December 2017. Currently, four clinical studies are ongoing with melflufen.

OCEAN is Oncopeptides pivotal Phase III study where melflufen is compared directly with current standard of care, pomalidomide, in late-stage RRMM patients.

HORIZON is a Phase II study that studies the effect of melflufen in late-stage RRMM patients with few or no remaining established treatment options. Updated interim data from this study will be presented at ASH (Free ASH Whitepaper) in December 2018.

ANCHOR is a phase I/II study where melflufen is administered in combination with either bortezomib or daratumumab in RRMM patients. The results of this study aim to create understanding and knowledge among treating physicians for how melflufen can be used in combination with these drugs. In addition, the results could open up for the use of melflufen in earlier lines of treatment.

BRIDGE is a phase II study, where melflufen is used in RRMM patients with impaired renal function. This is a positioning study to show melflufen’s treatment profile in these patients.

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.

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.