On June 15, 2018 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies*, reported that the company will present updated preliminary results from the ongoing Phase 2 study of its lead proprietary oncology drug MP0250 at the 23th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Stockholm (Press release, Molecular Partners, JUN 15, 2018, View Source [SID1234527337]).

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The ongoing, open label Phase 2 clinical study[1] is examining the safety and efficacy of MP0250 in combination with bortezomib (Velcade) and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) who have failed at least two lines of standard therapies, including bortezomib and an IMiD. The study is being performed at nine centers in Germany, Poland and Italy.

In the first of two cohorts, patients received MP0250 at 8mg/kg every 3 weeks (corresponding to 66% of the recommended dose) in combination with standard doses of bortezomib and dexamethasone.

All patients had been pretreated with at least two lines of therapy, including an IMiD and bortezomib. 50% of those patients were considered proteasome refractory. At the data cutoff on May 21, 2018, five of eight evaluable patients achieved an objective response (4 patients with PR/partial response; 1 patient with VGPR/very good partial response). Responses were durable, with median time on treatment for responding patients of 22.5 weeks and the longest response still ongoing at 41 weeks.

Main adverse events were consistent with the known side effect profile of VEGF-targeting agents and of Velcade, respectively: thrombocytopenia (4 out of 8 patients), hypertension (3 out of 8 patients) and upper respiratory infection (3 out of 8 patients).

"We are very encouraged by the initial activity and the safety profile of MP0250 in combination with bortezomib and dexamethasone, even at the low dose of MP0250. We have started the treatment of the first two patients with the higher dose of 12 mg/kg which may be even more effective," said Andreas Harstrick, Chief Medical Officer of Molecular Partners.

Patrick Amstutz, CEO of Molecular Partners added: "These results further substantiate our development plans in multiple myeloma as well as the launch of our additional phase 1b/2 study of MP0250 in combination with osimertinib in EGFR-mutated NSCLC."

The ongoing Phase study of MP0250 in multiple myeloma is currently recruiting patients at the higher dose of 12mg/kg q3weeks. Overall, a total of at least 40 patients are planned to be treated. Additional safety and efficacy data are expected by the end of 2018.

An additional phase 1b/2 study will evaluate MP0250 in combination with osimertinib in patients with EGFR-mutated NSCLC pretreated with osimertinib (Tagrisso). The study is conducted in the US and is open for patient enrollment[2].

Full details on the Molecular Partners’ poster presentation today, from 5.30 to 7.00pm CET, at EHA (Free EHA Whitepaper) Stockholm can be found on the conference website. Following its presentation at EHA (Free EHA Whitepaper), the poster will also be available one the Molecular Partners website.

[1] ClinicalTrials.gov identifier NCT03136653

[2] ClinicalTrials.gov identifier NCT03418532

*DARPin is a registered trademark owned by Molecular Partners AG.

Financial Calendar
August 30, 2018 – Publication of 2018 Half-year Results
November 01, 2018 – Q3 2018 Management Statement
View Source

About MP0250
MP0250 is a multi-DARPin candidate targeting simultaneously VEGF and HGF, two prominent escape pathways, and has the potential to reverse resistance that has built to standard of care cancer therapies. Increases in VEGF and HGF are associated with disease progression in multiple myeloma and have been linked to poor prognosis. They are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow.

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.
With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.
Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and in Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

On June 15, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that three posters highlighting clinical data from the ongoing Phase 1b/2 STOMP study in patients with multiple myeloma (MM) will be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2018 Annual Meeting taking place June 14-17, 2018 in Stockholm, Sweden (Press release, Karyopharm, JUN 15, 2018, View Source [SID1234527336]). These three poster presentations will feature updated data from the STOMP arms evaluating selinexor, the Company’s lead, novel, oral SINE compound, and dexamethasone in combination with standard approved therapies, Velcade (bortezomib), Pomalyst (pomalidomide) or Darzalex (daratumumab), in patients with previously treated MM.

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"The Phase 1b/2 STOMP study continues to generate important efficacy and safety data from the multiple ongoing arms evaluating selinexor and dexamethasone (dex) in combination with the standard approved therapies Velcade, Pomalyst and Darzalex in patients with multiple myeloma following at least one prior therapy," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Based on the positive STOMP results reported to date, we have initiated a new all-oral STOMP arm to investigate selinexor plus Revlimid and dex in the front-line setting. Given the observed synergistic activity of selinexor with standard approved myeloma therapies, we believe oral selinexor has the potential to be a future backbone therapy in myeloma, and we look forward to elucidating its activity as part of a front-line treatment regimen."

Selinexor in Combination with Velcade and Low-dose Dexamethasone (SVd)

In the poster presentation titled, "Selinexor combined with low dose bortezomib and dexamethasone (SVd) induces a high response rate in patients with relapsed or refractory multiple myeloma (MM)," (Abstract code PS1322) Nizar Bahlis, MD, Southern Alberta Cancer Research Institute, will present updated clinical data from the SVd arm of the STOMP study. This study includes patients whose disease was proteasome inhibitor (PI) naïve, exposed or refractory, provided their disease was not refractory to Velcade as a last therapy. In this study arm, oral selinexor was dose-escalated in once-weekly (80 or 100mg) or twice-weekly (60 or 80mg) regimens. Velcade (1.3mg/m2 subcutaneously) was administered once-weekly or twice-weekly. Dex was administered orally either 40mg once-weekly or 20mg twice-weekly. The following table is a summary of the efficacy results:

Key: ORR=Overall Response Rate (sCR+CR+VGPR+PR), sCR=Stringent Complete Response, CR=Complete Response, VGPR=Very Good Partial Response, PR=Partial Response
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Two patients not evaluable for response: one death unrelated to myeloma and one withdrawal of consent before disease follow up
4One unconfirmed PR
5Patient population eligible for the ongoing Phase 3, randomized BOSTON study evaluating SVd versus Vd. This a subset of the PI Relapsed/Naïve, ≤3 Prior Treatments

In the PI Relapsed/Naïve population (N=19), the ORR was 84% and the median PFS was 17.8 months with similar results in the "BOSTON" population (N=18). Nearly all patients (38 of 40) had reductions in M-protein, including 33% with a ≥90% reduction. This indication of efficacy in the SVd combination, with weekly Velcade and selinexor, warranted the further evaluation of SVd versus Vd in the BOSTON study given the previously reported ORR of 60-65% and PFS of 7-9 months in the Vd regimen among similar patient populations.

Among the 42 patients evaluable for safety, adverse events were consistent with those reported previously from the SVd arm of the STOMP study, with nausea (60%), anorexia (57%), fatigue (45%), diarrhea (40%), vomiting (29% and weight loss (24%) the most commonly reported Grade 1/2 events. Importantly, the reported peripheral neuropathy across all patients was Grade 1/2 and limited to six patients (14%), of which five had prior Velcade exposure. Grade 3/4 adverse events were also consistent with those reported previously with thrombocytopenia (45%), neutropenia (26%), fatigue (14%) and anemia (12%) being the most common. Based on the activity and tolerability observed in this study arm, the recommended Phase 2 dose (RP2D) regimen for SVd is oral selinexor (100mg once weekly), Velcade (1.3mg/m2 once-weekly subcutaneously) and oral dex (40mg weekly), which represents 40% less Velcade and 25% less dex compared to the approved standard Velcade + dex (Vd) regimen. This once weekly regimen is being evaluated in BOSTON.

Dr. Bahlis commented, "These updated data from the SVd arm of the STOMP study continue to show rapid time to response, high response rates, including an 83% ORR and the emergence of complete responses, along with a 17.8-month median PFS, in patients with relapsed or refractory myeloma. The combination also continues to be well tolerated with low rates of peripheral neuropathy. Importantly, these results are being achieved with 40% less Velcade and 25% less dex than the standard approved regimen, with no overt major organ toxicities."

Selinexor in Combination with Darzalex and Low-dose Dexamethasone (SDd)

In the poster presentation titled, "A Phase 1b study using the combination of selinexor, daratumumab, and dexamethasone in multiple myeloma patients previously exposed to proteasome inhibitors and immunomodulatory drugs," (Abstract code PS1329) Cristina Gasparetto, MD, Duke University Cancer Center, will present new clinical data from the SDd arm of the STOMP study evaluating myeloma patients who received at least three prior lines of therapy, including a PI and an immunomodulatory drug (IMiD), or patients with myeloma refractory to both a PI and an IMiD. In this study arm, oral selinexor was dose escalated using either 100mg once weekly or 60mg twice weekly, with Darzalex (16mg/kg intravenously once weekly) and dex (orally, 40mg once weekly or 20mg twice weekly).

Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3One patient not evaluable for response withdrew consent prior to disease follow up, one patient pending response
4 Three unconfirmed PR

Despite the heavily pretreated nature of the patients in the study, with 100% of the patients having dual- (PI and IMID-) refractory disease, responses occurred rapidly, with a median of one month to onset; 12 of the 19 patients remain on treatment. Based on published data the expected ORR for Darzalex therapy without selinexor in the Darzalex-naïve population is ~30%. Thus, the ORR of 82% provides a basis for further evaluation of the weekly SDd combination.

Among the 21 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (48%), fatigue (38%), diarrhea (24%), constipation (24%), and anorexia (24%). The most common Grade 3/4 adverse events were thrombocytopenia (48%), leukopenia (43%), anemia (33%), neutropenia (33%) and decreased lymphocyte count (24%). Gastrointestinal adverse events were generally manageable with supportive care. The maximum tolerated dose was not reached. Two DLTs (Grade 3 thrombocytopenia and Grade 2 fatigue) were observed in patients receiving selinexor 60mg twice weekly; both patients showed responses. Based on the preliminary tolerability and efficacy data, the RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dex (40mg orally, weekly).

Dr. Gasparetto commented, "These preliminary results from the SDd arm of the STOMP study show high response rates, including an 82% ORR in Darzalex-naïve patients with refractory myeloma. This combination regimen appears to be well tolerated with responses observed rapidly occurring within a median one cycle of treatment. We look forward to continuing enrollment in this treatment arm."

Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In the poster presentation titled, "Selinexor combined with pomalidomide and low dose dexamethasone (SPd) in a relapsed/refractory multiple myeloma patient population," (Abstract code PF586) Christine Chen, MD, FRCP, University of Toronto, Princess Margaret Cancer Center, will present updated clinical data from the SPd arm of the STOMP study which includes patients with multiple myeloma who previously received Revlimid and a PI. In this study arm, selinexor was dosed orally either once weekly (80 or 100mg) or twice weekly (60 or 80mg) with Pomalyst (3 or 4mg orally, once daily) and dexamethasone (dex; orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Four patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, two withdrawal of consent before disease follow up
4One unconfirmed PR

Responses tended to occur rapidly with a median of one month to onset. Median PFS among all evaluable patients was 10.3 months, with a follow up of 9.4 months. The efficacy of the SPd combination warrants further clinical evaluation.

Among the 34 patients evaluable for safety, the most common Grade 1/2 adverse events were anorexia (56%), nausea (47%), fatigue (41%), weight loss (38%), diarrhea (26%) and thrombocytopenia (26%). The most common Grade ≥3 adverse events were neutropenia (56%), thrombocytopenia (32%) and anemia (29%). Gastrointestinal adverse events were generally manageable with supportive care. There were two Grade 5 treatment-related events (febrile neutropenia and intracranial hemorrhage). Six DLTs (Grade 3 fatigue, febrile neutropenia, hyponatremia, neutropenia and thrombocytopenia) were observed in patients receiving selinexor 60mg twice weekly, 80mg twice weekly and 80mg once weekly. Based on the activity and tolerability observed in this study arm, doses of oral selinexor 60-80mg once weekly are being evaluated in combination with Pomalyst (3mg orally, once daily) and low dose dex to determine the RP2D for this combination regimen.

Dr. Chen stated, "This novel, all oral regimen continues to demonstrate strong response rates, including a 55% ORR, along with an 11.6-month median PFS, in Pomalyst-naïve and Revlimid-relapsed or -refractory patients. In this STOMP arm, once-weekly selinexor has been generally well tolerated and rapidly induced durable responses in patients with PI- and Revlimid-exposed myeloma."

Details for the EHA (Free EHA Whitepaper) 2018 presentations are as follows:

Company-sponsored Trials

Title: Selinexor combined with low dose bortezomib and dexamethasone (SVd) induces a high response rate in patients with relapsed or refractory multiple myeloma (MM)
Lead author: Nizar Bahlis, Southern Alberta Cancer Research Institute
Final Abstract Code: PS1322
Topic/Session Title: Myeloma and other monoclonal gammopathies – Clinical
Date and Time: Saturday, June 16, 2018; 17:30 – 19:00 CEST
Location: Poster area

Title: A Phase 1b study using the combination of selinexor, daratumumab, and dexamethasone in multiple myeloma patients previously exposed to proteasome inhibitors and immunomodulatory drugs
Lead author:Cristina Gasparetto, Duke University
Final Abstract Code: PS1329
Topic/Session Title: Myeloma and other monoclonal gammopathies – Clinical
Date and Time: Saturday, June 16, 2018; 17:30 – 19:00 CEST
Location: Poster area

Title: Selinexor combined with pomalidomide and low dose dexamethasone (SPd) in a relapsed/refractory multiple myeloma patient population
Presenter:Christine Chen, University of Toronto, Princess Margaret Cancer Center
Final Abstract Code: PF586
Topic/Session Title: Myeloma and other monoclonal gammopathies – Clinical
Date and Time:Friday, June 15, 2018; 17:30 – 19:00 CEST
Location: Poster area

Investigator-sponsored Trials

Title: A Phase II study of selinexor (KPT-330) combined with bortezomib and dexamethasone (SVD) for induction and consolidation for patients with progressive or refractory multiple myeloma; the selvedex trial
Lead author: Annemiek Broijl, Erasmus MC Cancer Institute
Final Abstract Code: PS1338
Topic/Session Title: Myeloma and other monoclonal gammopathies – Clinical
Date and Time: Saturday, June 16, 2018; 17:30 – 19:00 CEST
Location: Poster area

About Selinexor

Selinexor (KPT-330) 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 2,400 patients have been treated with selinexor. In April 2018, Karyopharm reported positive top-line 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 by the U.S Food and Drug Administration (FDA) for the patient population evaluated in the STORM study. Karyopharm plans to submit a New Drug Application (NDA) to the FDA during the second half of 2018, with a request for accelerated approval for oral selinexor as a 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) and as a potential backbone therapy in combination with approved therapies (STOMP), and 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 one or more 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 June 15, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the final analysis of the CLL11 study evaluating Gazyva/Gazyvaro (obinutuzumab)-based treatment in previously untreated chronic lymphocytic leukaemia (CLL) which will be presented during the Presidential Symposium at the 23rd European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 14 – 17 June, in Stockholm (Press release, Hoffmann-La Roche, JUN 15, 2018, View Source [SID1234527335]). After a follow-up of nearly five years, final results showed clinically meaningful improvements with Gazyva/Gazyvaro plus chlorambucil across multiple endpoints, including progression-free survival (PFS) and overall survival (OS), when compared head-to-head with MabThera/Rituxan (rituximab) plus chlorambucil. Gazyva/Gazyvaro-based treatment reduced the risk of death by 24% compared to MabThera/Rituxan-based treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245). These new data add to the growing body of evidence for the OS benefit with Gazyva/Gazyvaro in first-line CLL after the previously reported OS benefit with Gazyva/Gazyvaro combined with chlorambucil versus chlorambucil alone.

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"We are very pleased that the majority of patients treated with Gazyva/Gazyvaro are still alive after nearly five years of follow-up in the CLL11 study," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "This meaningful survival benefit compared to MabThera/Rituxan-based therapy reinforces that Gazyva/Gazyvaro-based therapy is an important option for people with previously untreated CLL."

After a median observation time of nearly five years (59.4 months) this final analysis of the CLL11 study demonstrated:

A reduction in the risk of disease progression or death of 51% for patients treated with Gazyva/Gazyvaro plus chlorambucil versus those treated with MabThera/Rituxan plus chlorambucil (median PFS 28.9 vs. 15.7 months, HR= 0.49; 95% CI 0.41-0.58; p<0.0001).
A clinically meaningful improvement in OS for patients receiving Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil. At the time of final analysis the median OS in the Gazyva/Gazyvaro plus chlorambucil arm was not yet reached which means that more than half of these patients were still alive after nearly five years. A 24% reduction in the risk of death was observed with Gazyva/Gazyvaro plus chlorambucil treatment (median OS not reached vs. 73.1 months, HR= 0.76; 95% CI 0.60-0.97; p<0.0245).
A prolonged time to initiation of the next therapy (time to new treatment; TTNT) with Gazyva/Gazyvaro plus chlorambucil (median 56.4 vs. 34.9 months, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil, HR= 0.58; 95% CI 0.46-0.73; p<0.0001).
Patients treated with Gazyva/Gazyvaro plus chlorambucil achieved a higher rate of minimal residual disease (MRD) negativity versus those treated with MabThera/Rituxan plus chlorambucil (24% vs. 2% of patients MRD-negative, Gazyva/Gazyvaro plus chlorambucil vs. MabThera/Rituxan plus chlorambucil). Being MRD negative means no cancer can be detected in the blood and or bone marrow using a sensitive test.
No new or unexpected safety concerns for the combination of Gazyva/Gazyvaro plus chlorambucil.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil, for people with previously untreated CLL, based on previously reported data from the CLL11 study.1

About the CLL11 study
CLL11 is a phase III, multicenter, open-label, randomised three-arm study to investigate the safety and efficacy profile of Gazyva/Gazyvaro plus chlorambucil compared to MabThera/Rituxan plus chlorambucil or chlorambucil alone in nearly 800 people with previously untreated CLL and comorbidities. The primary endpoint of the study is PFS with secondary endpoints including response rate, molecular remission rate, OS, TTNT and safety profile. In terms of analysis, the study was divided into three stages:

Stage 1a compared the addition of Gazyva/Gazyvaro to chlorambucil vs. chlorambucil alone
Stage 1b compared the addition of MabThera/Rituxan to chlorambucil vs. chlorambucil alone
Stage 2 compared Gazyva/Gazyvaro plus chlorambucil to MabThera/Rituxan plus chlorambucil
About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system. Gazyva is marketed as Gazyvaro in the EU and Switzerland.

Gazyva/Gazyvaro is currently approved in more than 90 countries in combination with chlorambucil for people with previously untreated chronic lymphocytic leukaemia (CLL), in more than 80 countries in combination with bendamustine for people with certain types of previously treated follicular lymphoma and in more than 60 countries in combination with chemotherapy for previously untreated, follicular lymphoma.

Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are underway across a range of blood cancers.

About Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the Western world. 2 CLL mainly affects men and the median age at diagnosis is about 70 years.3 Worldwide, the incidence of all leukaemias is estimated to be over 350,000 and CLL is estimated to affect around one-third of all people newly diagnosed with leukaemia.4

About Roche in haematology

On June 15, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that results on its investigational BTK inhibitor zanubrutinib, from two poster presentations at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, BeiGene, JUN 15, 2018, View Source;p=RssLanding&cat=news&id=2354713 [SID1234527334]). The EHA (Free EHA Whitepaper) meeting is taking place in Stockholm, Sweden from June 14-17, 2018.

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"We continue to be encouraged by the quality and durability of response with zanubrutinib in the treatment of patients with Waldenström macroglobulinemia (WM), particularly with the observation that 43 percent of the evaluable patients achieved a very good partial response (VGPR). Additionally, the safety results from the combined experience in four ongoing monotherapy trials demonstrate that zanubrutinib was generally well-tolerated," commented Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "As these results mature, and as we near completion of enrollment in our Phase 3 trial comparing zanubrutinib with ibrutinib in patients with WM, we are hopeful that zanubrutinib, if approved, may represent a valuable treatment option for patients with this disease."

In addition to zanubrutinib data presentations, BeiGene is providing the following updates to its planned development program for zanubrutinib:

BeiGene has received results from the independent review of response data from the 86-patient single-arm pivotal Phase 2 study of zanubrutinib in Chinese patients with relapsed or refractory mantle cell lymphoma (MCL). The overall response rate (ORR) of 84 percent (59% complete response rate) met the pre-specified criteria for a positive trial, and the median duration of response has not been reached with 8.3 months median follow-up. The safety profile was consistent with previously reported clinical data for zanubrutinib. BeiGene plans to submit its first new drug application (NDA) for zanubrutinib in China for the treatment of patients with relapsed or refractory MCL later this year. Full results of the study are planned to be presented at an upcoming major medical conference.

The global Phase 3 study comparing zanubrutinib to ibrutinib in patients with WM has met its enrollment target. The trial has closed new patient screening and is expected to complete enrollment in July. The Company plans to submit its first NDA in the United States for zanubrutinib in patients with WM in 2019.
Zanubrutinib in WM from Phase 1 Trial (EHA #PS1186)

A Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including WM, is being conducted in Australia, New Zealand, the United States, Italy, and South Korea. As of November 3, 2017, 67 patients with WM have been enrolled in the trial and were evaluable for safety. Fifty-one patients were evaluable for efficacy, excluding those with less than 12 weeks of follow-up (n=13) and those with IgM less than 5 g/L at baseline (n=3). Of the 51 patients evaluable for efficacy, 12 were treatment naïve and 39 patients were relapsed or refractory to prior treatment. At the time of the data cutoff, 59 patients remained on study treatment. Results included:

For the 51 patients with WM evaluable for response, the ORR was 92 percent (47/51), and major response rate was 80 percent, with 43 percent of patients achieving a VGPR (defined as a >90% reduction in baseline IgM levels and improvement of extramedullary disease by CT scan).

The 12-month progression-free survival (PFS) was estimated at 91 percent. The median PFS had not yet been reached.

Median time to response (partial response or higher) was 88 days (range, 77-279).

The median IgM decreased from 32.5 g/L (range, 5.3-88.5) at baseline to 4.9 g/L (range, 0.1-57).

Of 22 patients with hemoglobin <10 g/dL at baseline, the median increased from 8.7 g/dL (range, 6.3-9.8) to 13.8 g/dL (range, 7.7-15.8).

While the presence of MYD88L265P appears to be associated with response and depth of response with zanubrutinib treatment, significant activity was also observed in patients with MYD88WT (ORR 83%, major response rate 50%, VGPR rate 17%).

The most frequent adverse events (AEs) (>15%, all Grade 1-2 but one) of any attribution were petechia/purpura/contusion (37%), upper respiratory tract infection (34%), constipation (18%) and diarrhea (18%). Grade 3-4 AEs of any attribution reported in two or more patients included anemia (7%), neutropenia (6%), basal cell carcinoma (3%), hypertension (3%), squamous cell carcinoma (3%), pyrexia (3%), pneumonia (3%), major hemorrhage (3%), and actinic keratosis (3%).

Serious AEs (SAEs) were seen in 22 patients (33%), with events in five patients (7%) considered possibly related to zanubrutinib treatment: febrile neutropenia, colitis, atrial fibrillation, hemothorax (spontaneous), and headache.

Atrial fibrillation/flutter was experienced by four patients (6%), all Grade 1-2. Major hemorrhage was seen in two patients (3%).

Four patients (6%) discontinued due to AEs: fatal worsening bronchiectasis, prostate cancer, gastric adenocarcinoma, and acute myeloid leukemia.

Two patients (3%) discontinued study treatment due to disease progression as assessed by investigator and one patient remains on treatment post disease progression.
"Zanubrutinib continues to demonstrate robust activity in patients with WM. Deeper response rates have been maintained with longer follow-up in the Phase 1 trial and we are optimistic that zanubrutinib will demonstrate both high rates of activity and tolerability for patients, based on its potency and high-degree of selectivity," said Judith Trotman, M.D., Director, Clinical Research Unit in Haematology, Concord Hospital, and Professor at the University of Sydney, Australia.

Pooled Analysis of Safety Data from Zanubrutinib Monotherapy Trials (EHA #PF445)

Pooled safety data from patients with various B-cell lymphomas in four ongoing zanubrutinib monotherapy studies, totaling 476 patients with a median exposure of seven months, will be presented at the EHA (Free EHA Whitepaper) meeting. Overall, the data suggest that exposure levels of zanubrutinib resulting in complete and sustained BTK inhibition can be achieved and that zanubrutinib was generally well-tolerated. Results included:

Events of interest with BTK inhibitor therapy, such as atrial fibrillation/flutter (2%), major hemorrhage (2%), and Grade 3 and above diarrhea (1%) have been infrequent.

Treatment discontinuation due to zanubrutinib-related AEs was uncommon (3%).

The majority of patients (94%) experienced one or more AE of any attribution, primarily Grades 1 or 2. The most common Grade 3 or higher AEs of any attribution were neutropenia/neutrophil count decreased/febrile neutropenia (14%), anemia (7%) and thrombocytopenia/platelet count decreased (7%).

SAEs were reported in 116 patients (24%), with 38 patients (8%) assessed by the investigator as related to zanubrutinib. The most common SAEs were pneumonia/lung infection (6%), pleural effusion (1%), and febrile neutropenia (1%). The only treatment-related SAE reported in greater than one percent of patients was pneumonia/lung infection (2%). No cases of pneumocystis jiroveci pneumonia (PJP) or cytomegalovirus (CMV) reactivation were reported.

The most common bleeding events observed included petechiae/purpura/contusion (26%) and hematuria (11%). Major hemorrhage (2%) included gastrointestinal hemorrhage/melena (n=3), intraparenchymal CNS hemorrhage Grade 5, hematuria, purpura, hemorrhagic cystitis, renal hematoma, and hemothorax (1 each). The median time to first major hemorrhage was 1.2 months.

Amongst patients with emergent atrial fibrillation/flutter (n=8), a majority had known risk factors including hypertension (n=2), pre-existing cardiovascular disease (n=2), and concurrent infection (n=1).

The cumulative rates of Grade 3 or higher infections were 14 percent at six months, 19 percent at 12 months and 21 percent at 18 months. The exposure-adjusted incidence rate was 1.82 per 100 person-months.

The most common second primary malignancies included basal cell carcinoma (3%) and squamous cell carcinoma of the skin (1%).
"While BTK inhibitor therapy has historically been shown to be highly effective in the treatment of certain chronic B cell malignancies, such as chronic lymphocytic leukemia (CLL), WM, and MCL, specific events such as atrial fibrillation, serious diarrhea, and CNS bleeding, as well as appreciable overall rates of discontinuation of treatment due to tolerability or toxicity, remain concerns. With this pooled safety analysis of zanubrutinib monotherapy, we wanted to further assess whether its selectivity profile would translate into tolerability. We are encouraged that the low rates of BTK inhibitor-associated events, as well as low rates of toxicity-related treatment discontinuation, may allow for continuous disease control. We are hopeful that, if approved, patients with these hematologic malignancies could potentially lessen drug safety concerns, to focus on their lives rather than their disease," said Constantine Tam, M.D., Director of Haematology, St. Vincent’s Hospital and Consultant Haematologist, Peter MacCallum Cancer Center, in Australia.

Today’s Investor Conference Call & Webcast Information

Date and Time: Friday, June 15, 2018, 8:00 am EDT (Friday, June 15, 2018, 8:00 pm China Standard Time)

Dial-In Numbers: 1-844-461-9930 or 1-478-219-0535 (U.S.), 400-682-8609 or 800-870-0169 (China), 852-30114522 (Hong Kong), 65-66221010 (Singapore), 61-282239773 (Australia), 0856619361 (Sweden), or 1-478-219-0535 (International).

Conference ID Number: 7756029

Webcast and Replay: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source The dial-in replay will be available approximately two hours after the conference and will be available for two days following the event. It can be accessed by dialing 1-855-859-2056 (U.S.) or 1-404-537-3406 (International), or 400-683-7185 (China).
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 and in China as a monotherapy and in combination with other therapies to treat various lymphomas.

On June 15, 2018 ArQule, Inc. (Nasdaq:ARQL) today is presenting preliminary results from the Company’s Phase 1 dose escalation study for ARQ 531, an orally bioavailable, potent and reversible inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies at the 23rd Congress of European Hematological Association (EHA) (Free EHA Whitepaper) in Stockholm, Sweden (Press release, ArQule, JUN 15, 2018, View Source [SID1234527333]).

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"Preliminary data from our Phase 1 dose escalation trial highlights the potential of ARQ 531 to become a new therapeutic option for patients with B-cell malignancies," commented ArQule Chief Medical Officer and Head of Research and Development, Brian Schwartz, M.D. "There is a significant unmet need for patients with relapsed or refractory B-cell malignancies, in particular those with C481S-mediated resistance to irreversible BTK inhibitors such as ibrutinib. We are especially encouraged by the early signs of anti-tumor activity observed in the first three cohorts."

The reported data from the ongoing Phase 1, open label, single arm dose escalation 3+3 study are from the first three cohorts at dose levels of 5 (n=3), 10 (n=4) and 15 mg (n=4) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), Waldenstrom’s macroglobinemia and B-cell Non-Hodgkin lymphoma.

ARQ 531 demonstrated preliminary anti-tumor activity at all dose levels, resulting in an observed tumor reduction of 35% at 5mg, 33% at 10mg, and 29% at 15mg doses. The 29% tumor reduction in the 15mg cohort was achieved after 8 weeks of treatment in a patient with the BTK C481S-mutation, after 5 prior systemic regimens including ibrutinib and venetoclax, with treatment still ongoing. Overall treatment duration ranged from 1 to 46 weeks with 4 of 11 patients treated still ongoing.

ARQ 531 was well tolerated at all three dose levels, supporting continued dose escalation. No dose limiting toxicities or ARQ 531-related Grade 3 or greater adverse events were observed, and the maximum tolerated dose has not been reached.

The half-life of ARQ 531 was between 22-27 hours suggesting the potential for sustained target inhibition and supporting a once daily dosing regimen with preliminary pharmacokinetics showing increases in exposure that are approximately dose proportional.

The poster, A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies, is available on ArQule’s website, www.arqule.com, under "Publications and Presentations": View Source

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.