On June 1, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported findings from an interim analysis of the Phase 3 iNNOVATE (PCYC-1127) study evaluating IMBRUVICA (ibrutinib) plus RITUXAN (rituximab) in previously untreated and relapsed/refractory patients with Waldenström’s macroglobulinemia (WM), a rare type of non-Hodgkin’s lymphoma (NHL) (Press release, AbbVie, JUN 1, 2018, View Source [SID1234527031]). At a median follow up of 26.5 months, the study successfully met its primary endpoint, demonstrating a significant improvement in progression-free survival (PFS) with ibrutinib plus rituximab compared to rituximab alone (30 month PFS rates were 82 percent versus 28 percent, respectively). Patients taking ibrutinib plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab (hazard ratio, 0.20; confidence interval: 0.11-0.38, P <0.0001). Additionally, the data found that the combination with ibrutinib provided reductions in infusion reactions associated with rituximab and immunoglobin M (IgM) flare.1

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These data were presented today in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract #8003) and were simultaneously published in The New England Journal of Medicine. The data were also selected for the 2018 Best of ASCO (Free ASCO Whitepaper) Meetings. With the support of these positive findings, a supplemental New Drug Application (sNDA) to expand the use of IMBRUVICA as a combination therapy in WM was submitted to the U.S. Food and Drug Administration (FDA) for review. The Independent Data Monitoring Committee (IDMC) in late 2017 recommended unblinding iNNOVATE based on these positive findings.

"The iNNOVATE study provides further evidence of the potential clinical benefit of IMBRUVICA-based combination therapy in patients with Waldenström’s macroglobulinemia," said Thorsten Graef, M.D., Ph.D., Head of Clinical Development at Pharmacyclics LLC, an AbbVie company. "The data from this chemotherapy-free combination regimen suggests that patients with Waldenström’s macroglobulinemia, including those who are newly diagnosed, could have another beneficial therapeutic option in the future."

WM is a rare and incurable form of NHL with limited treatment options. There are about 2,800 new cases of WM in the U.S. each year.2 In January 2015, IMBRUVICA received FDA approval for all lines of treatment in WM and is the first and only FDA-approved therapy specifically indicated for this disease. IMBRUVICA has been available in the U.S. since 2013 and is FDA-approved for use in five B-cell blood cancers, as well as previously-treated chronic graft-versus-host disease. IMBRUVICA is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

"The iNNOVATE trial broadens our understanding about how to treat patients with WM, including those with certain subtypes or genomic abnormalities," said Dr. Meletios A. Dimopoulos, Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece and lead investigator of the iNNOVATE study.* "As a clinician, I’m hopeful that the data from iNNOVATE could potentially lead to a new option for treating this rare and incurable disease."

To view all IMBRUVICA company-sponsored or investigator-initiated studies being presented at ASCO (Free ASCO Whitepaper) 2018, please visit: View Source

Abstract #8001: Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenström’s Macroglobulinemia
Oral presentation: Friday, June 1, 3:45pm CDT

In the iNNOVATE study, PFS occurred at a higher rate in patients treated with ibrutinib plus rituximab compared to rituximab alone, with PFS rates of 82% versus 28% at 30 months, respectively. Notably, ibrutinib plus rituximab exhibited longer duration of PFS in all relevant patient subgroups, including treatment-naïve, relapsed, and in patients with MYD88L265P and CXCR4WHIM mutations, versus rituximab. Patients taking ibrutinib plus rituximab also experienced an 80 percent reduction in relative risk of disease progression or death than those only treated with rituximab (median PFS, not reached [NR] vs 20.3 months; HR, 0.20; CI: 0.11-0.38, P <0.0001).

iNNOVATE is a Pharmacyclics-sponsored, placebo-controlled, double-blind, Phase 3 study, which evaluated relapsed/refractory and treatment-naïve WM patients (n=150) who were randomized to receive intravenous rituximab 375 mg/m2 once weekly for four consecutive weeks, followed by a second once-weekly for four consecutive weeks rituximab course after a three-month interval. All patients received either ibrutinib 420 mg or placebo once daily continuously until criteria for permanent discontinuation were met. The IRC-determined primary endpoint was PFS, with secondary objectives including overall response rate, hematological improvement measured by hemoglobin, time-to-next treatment (TTnT), overall survival (OS), and number of participants with adverse events (AEs) as a measure of safety and tolerability within each treatment arm.

Overall response rates and major response rates were significantly higher for ibrutinib plus rituximab versus rituximab (92% vs 47%; 72% vs 32% [both P <0.0001]). In addition, there was also an improvement in hemoglobin seen in patients treated with the combination versus rituximab (73% vs 41%, P <0.0001).

Of the patients on ibrutinib plus rituximab, 75% continued on treatment. Median TTnT was NR for ibrutinib plus rituximab and 18 months for rituximab (HR, 0.096; P <0.0001). The 30-month OS rates were 94% versus 92% in the two arms.

At the median time on treatment (ibrutinib plus rituximab, 25.8 months; rituximab plus placebo, 15.5 months,), grade 3 or higher treatment-emergent AEs occurred in 60% of patients treated with ibrutinib plus rituximab, versus 61% of patients treated with rituximab. Serious AEs occurred in 43% versus 33% of patients on ibrutinib plus rituximab vs rituximab. No fatal AEs occurred with ibrutinib plus rituximab and 3 with rituximab. Meaningful reductions in any grade IgM flare (8% vs 47%) and grade 3 or higher infusion reactions were observed (1% vs 16%) with ibrutinib plus rituximab.

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that mainly works by blocking a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells as well as other serious, debilitating conditions.3 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.

IMBRUVICA is FDA-approved in six distinct patient populations: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL), previously-treated marginal zone lymphoma (MZL) and previously-treated chronic graft-versus-host disease (cGVHD).4

IMBRUVICA was first approved for adult patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in adult CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for adult CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for adult patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for adult patients with previously treated CLL/SLL.
In January 2017, IMBRUVICA was approved for adult patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
In August 2017, IMBRUVICA was approved for adult patients with cGVHD that failed to respond to one or more lines of systemic therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases.5 IMBRUVICA was one of the first medicines to receive FDA approval via the new Breakthrough Therapy Designation pathway.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with more than 130 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 100,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA.

Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9 % (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, stomatitis (29%), muscle spasms (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or 4 adverse reactions (≥5%) reported in patients with cGVHD were fatigue (12%), diarrhea (10%), neutropenia (10%)*, pneumonia (10%), sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS

CYP3A Inhibitors: Dose adjustment may be recommended.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On June 1, 2018 Ruth Plummer, MD, PhD, FRCP, reported it will present an abstract describing the first-in-human Phase 1 study of 2X-121, an investigational PARP 1/2 and tankyrase 1/2 inhibitor, as monotherapy in patients with advanced solid tumors (Press release, 2X Oncology, JUN 1, 2018, View Source [SID1234527030]).

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Abstract Title: First-in-human phase 1 study of the PARP/tankyrase inhibitor 2X-121 (E7449) as monotherapy in patients with advanced solid tumors and validation of a novel drug response predictor (DRP) mRNA biomarker.

Abstract No.: 2505

Date: June 1, 2018

Time: 4:09pm CDT

Location: S406

On June 1, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported that four posters will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting taking place June 1-5, 2018 in Chicago (Press release, Karyopharm, JUN 1, 2018, View Source [SID1234527027]). Among the poster presentations will be clinical results from the Phase 2 portion of the Company’s Phase 2/3 SEAL study evaluating selinexor, its lead, oral SINE compound, in patients with advanced unresectable dedifferentiated liposarcoma. The remaining posters will highlight data from ongoing investigator-sponsored trials evaluating selinexor in combination with approved anti-cancer agents in hematologic and solid tumor malignancies.

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"In the Phase 2 portion of the SEAL study, patients treated with oral selinexor achieved progression-free survival (PFS) of 5.5 months, compared to 2.7 months for placebo-treated patients, an increase of 2.8 months," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Dedifferentiated liposarcoma is particularly difficult to treat because it is resistant to both standard chemotherapy and radiation and there is a significant unmet need for therapies with a novel mechanism that can help these patients with few effective treatment options. The Phase 3 portion of the SEAL study is currently ongoing and we are anticipating top-line data by the end of 2019. Other selinexor data presented at ASCO (Free ASCO Whitepaper) from ongoing investigator-sponsored research continue to highlight early signs of clinical activity and good tolerability when selinexor is combined with approved agents in soft tissue sarcoma (STS) and acute myeloid leukemia (AML), and additional compelling evidence for selinexor’s potential combinability with checkpoint inhibitors, in this case in AML."

Phase 2 Portion of the Phase 2/3 SEAL Study Evaluating Selinexor in Patients with Liposarcoma

In the poster presentation titled, "Phase 2 results of selinexor in advanced dedifferentiated (DDLS) liposarcoma (SEAL) study: A phase 2/3, randomized, double blind, placebo controlled cross-over study," (Abstract #11512) Mrinal Gounder, MD, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College and lead investigator of the SEAL study, presented detailed clinical data from the successful Phase 2 portion of the randomized, double-blind, placebo-controlled Phase 2/3 SEAL study evaluating oral selinexor (60mg twice weekly) in 56 patients with previously treated, advanced unresectable dedifferentiated liposarcoma (median 2 prior regimens (range 1-9)). Patients on placebo with confirmed progressive disease are permitted to cross over to the selinexor treatment arm.

For the primary endpoint of PFS, oral selinexor showed superiority over placebo, achieving a median PFS of 5.5 months, compared to 2.7 months for placebo with a hazard ratio (HR) of 0.67, representing a 33% reduction in the risk of progression or death. PFS was assessed by Independent Central Radiological Review based on RECIST v1.1. Additional efficacy assessments included PFS by World Health Organization (WHO) response criteria. PFS per WHO criteria achieved a HR of 1.02. Oral selinexor demonstrated an expected and manageable safety profile, primarily with nausea, fatigue, anorexia and weight loss, with low levels of Grade 3/4 cytopenias, and no new or unexpected safety signals identified. The majority of treatment-related adverse events (AEs) were low grade and reversible with dose modifications and/or standard supportive care. These data from the Phase 2 portion of the SEAL study, which is now complete, demonstrate that treatment with selinexor improves PFS (RECIST v1.1) and supports the currently ongoing Phase 3 portion of the study using RECIST v1.1 response criteria [only], and for which top-line data are expected by the end of 2019.

Dr. Gounder stated, "Extending PFS in patients with recurrent, unresectable DDLS is an important clinical goal and these data highlight that oral selinexor continues to demonstrate an expected and manageable safety profile, along with the ability to prolong PFS. We are pleased to share these data with the medical community at ASCO (Free ASCO Whitepaper) this year and look forward to further elucidating selinexor’s efficacy and safety in the already ongoing Phase 3 portion of the SEAL study."

Selinexor in Combination with Immunotherapy or Standard of Care Agents in Other Hematologic and Solid Tumor Malignancies

In the poster presentation titled, "Phase 1b study of selinexor, a first in class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS)," (Abstract #11562) Eoghan Ruadh Malone, MB BCh, BAO, BA, MSc, MRCPI, Princess Margaret Cancer Centre, presented results from an investigator-sponsored Phase 1b clinical study evaluating selinexor in combination with doxorubicin in 17 patients with locally advanced or metastatic STS. Disease subtypes included leiomyosarcoma (n=6), undifferentiated pleomorphic sarcoma (n=3), liposarcoma (n=2), malignant peripheral nerve sheath tumor (n=3) and other sarcomas (n=3). Preliminary data from this study show that the combination of selinexor plus doxorubicin has a manageable tolerability profile, along with early signals of anti-tumor activity, including partial responses (n=3). Median time on treatment is 20 weeks. Enrollment in the study is ongoing.

In the poster presentation titled, "Phase 1 study of selinexor plus mitoxantrone, etoposide, and cytarabine in acute myeloid leukemia," (Abstract #7048) Bhavana Bhatnagar, DO, Ohio State University Comprehensive Cancer Center, presented results from an investigator-sponsored Phase 1 clinical study evaluating selinexor in combination with mitoxantrone, etoposide and cytarabine (MEC) in patients with relapsed or refractory AML. Of the 23 evaluable patients, ten responded for an overall response rate of 44%, including six patients (26%) achieving complete remission (CR), two patients (9%) achieving CR with incomplete count recovery (CRi), and two patients (9%) achieving a morphologic leukemia-free state (MLFS). The tolerability of this combination regimen was similar to cytotoxic chemotherapy alone. The most common Grade ≥3 adverse events were febrile neutropenia (48%), catheter related infection (26%), diarrhea (26%), hyponatremia (22%), sepsis (22%), fatigue (13%), hyperglycemia (13%), and hypotension (13%). The RP2D of selinexor in in this combination regimen was established to be 60mg twice weekly. Six responders proceeded to allogeneic stem cell transplantation without evidence of AML at the time of transplant.

In the poster presentation titled, "Profiling the immune checkpoint pathway in acute myeloid leukemia," (Abstract #7015) Paola Dama, PhD, University of Chicago, presented results from an investigator-sponsored study assessing the expression of immune checkpoint biomarkers in AML patients treated with the combination of selinexor, high-dose cytarabine (HiDAC) and mitoxantrone. Data from this study demonstrated high level expression of Gal9 in CD34- cells at diagnosis in patients who failed induction chemotherapy, compared to those in complete remission. There was no difference in PD-L1 expression between the two patient groups. Increased expression of Tim 3 on CD4 and CD8 T cells and high PD-1 in peripheral CD4+ T cell were observed at disease remission suggesting an exhausted immune status at the time of disease remission on the selinexor + HiDAC + mitoxantrone combination, which the researchers believe could be targeted with the addition of checkpoint inhibitors.

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

Company-sponsored Trials

Title:Phase 2 results of selinexor in advanced de-differentiated (DDLS) liposarcoma (SEAL) study: A phase 2/3, randomized, double blind, placebo controlled cross-over study
Lead author:Mrinal Gounder, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College
Poster Board #: 257
Abstract #: 11512
Poster Discussion Session: Sarcoma
Poster Discussion Presenter:Mark Andrew Dickson
Date and Time:Saturday, June 2, 2018; 8:00 AM – 11:30 AM CT; Discussion from 3:18 – 3:30PM CT
Location: Hall A

Investigator-sponsored Trials

Title:Phase 1 study of selinexor plus mitoxantrone, etoposide, and cytarabine in acute myeloid leukemia
Lead author:Bhavana Bhatnagar, Ohio State University Comprehensive Cancer Center
Poster Board #: 108
Abstract: 7048
Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date and Time:Monday, June 4, 2018; 8:00 AM – 11:30 AM CT
Location: Hall A

Title:Phase 1b study of selinexor, a first in class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS)
Lead author: Eoghan Ruadh Malone, Princess Margaret Cancer Centre
Poster Board #: 307
Abstract: 11562
Poster Session: Sarcoma
Date and Time:Saturday, June 2, 2018; 8:00 AM – 11:30 AM CT
Location: Hall A

Title:Profiling the immune checkpoint pathway in acute myeloid leukemia
Lead author:Paola Dama, University of Chicago
Poster Board #: 75
Abstract: 7015
Poster Discussion Session: Hematologic Malignancies – Leukemia, Myelodysplastic Syndromes, and Allotransplant
Date and Time:Monday, June 4, 2018; 8:00 AM – 11:30 AM CT; Discussion from 11:30 AM – 12:45 PM CT
Location: Hall A

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 for the patient population evaluated in the STORM study. Karyopharm plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (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 1, 2018 Exact Sciences Corp. (Nasdaq: EXAS) reported that company management will be presenting at the following investor conferences during June and invited investors to participate by webcast (Press release, Exact Sciences, JUN 1, 2018, View Source [SID1234527026]).

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Jefferies 2018 Global Healthcare Conference, New York Presentation on Tuesday, June 5, 2018, at 9 a.m. EDT

William Blair 38th Annual Growth Stock Conference, Chicago Presentation on Tuesday, June 12, 2018, at 4:10 p.m. CDT

Goldman Sachs 39th Annual Global Healthcare Conference, Rancho Palos Verdes, Calif. Fireside chat on Wednesday, June 13, 2018, at 8 a.m. PDT

On June 1, 2018 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE:CFBI), a biotechnology company advancing a pipeline of proprietary small-molecule drugs that address cancer, liver disease and inflammatory diseases, reported financial results for the three months ended March 31, 2018 and provided clinical and corporate updates (Press release, Can-Fite BioPharma, JUN 1, 2018, View Source [SID1234527025]).

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Clinical Development Program and Corporate Highlights Include:

Piclidenoson (CF101) – Can-Fite continues Phase III trial of Piclidenoson in the treatment of rheumatoid arthritis and signed multi-million dollar distribution agreement with Gebro Holdings for Piclidenoson in three European countries
Rheumatoid Arthritis: In January 2018, Can-Fite signed a distribution agreement with Gebro Holding GmBH to distribute Can-Fite’s lead drug candidate, Piclidenoson (CF101), for the treatment of rheumatoid arthritis and psoriasis, in three European countries (Spain, Switzerland and Austria), upon receipt of regulatory approvals. Under the terms of the distribution agreement, Gebro is required to pay additional milestone payments of up to $7,000,000 upon the achievement of certain regulatory, launch and sales milestones plus double-digit percentage royalty payments on net sales.

Rheumatoid arthritis is a treatment market forecast to reach $34.6 billion by 2020.

Psoriasis: In April 2018, Can-Fite published a paper titled "Inhibition of IL-17 and IL-23 in Human Keratinocytes by the A3 Adenosine Receptor Agonist Piclidenoson" (View Source) in the Journal of Immunology Research. The Company has completed the preparatory work for its COMFORT Phase III Psoriasis study, designed to evaluate the efficacy and safety of daily Piclidenoson, administered orally compared to Apremilast (Otezla) and placebo in around 400 patients with moderate-to-severe plaque psoriasis. The study will be conducted in 5 countries in Europe, Israel and Canada. The study protocol has been already submitted and approved by the IRB in Israel, which will be the first country to initiate enrollment.

The psoriasis therapeutic market is estimated to reach $11.4B in 2020 according to Visiongain.

Namodenoson (CF102) – Can-Fite global Phase II advanced liver cancer study is fully enrolled; Potentially favorable drug safety profile has been reported; The Company continues to follow up on patients’ overall survival
Advanced Liver Cancer: During the fourth quarter of 2017, Can-Fite reported on the progress of its Phase II liver cancer study with Namodenoson (CF102) in the treatment of advanced hepatocellular carcinoma (HCC) indicating a potentially favorable drug safety profile. The global Phase II study is being conducted in the U.S., Europe and Israel. Patients with advanced HCC, Child-Pugh Class B, who failed Nexavar (sorafenib) as a first-line treatment are treated twice daily with 25 mg of oral Namodenoson or placebo using a 2:1 randomization. The primary endpoint of the Phase II study is overall survival (OS). Secondary endpoints include progression free survival (PFS), safety, and the relationship between outcomes and A3 adenosine receptor expression. The Company anticipates data release to occur in 2H2018.

According to Datamonitor, the HCC market is expected to generate $1.4 billion in sales in 2019.

NAFLD/NASH:

Phase II clinical study – The Company is currently conducting a Phase II trial with its drug candidate Namodenoson for the treatment of 60 patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). There is currently no U.S. FDA-approved drug for the treatment of NASH, which is an addressable pharmaceutical market estimated to reach $35-40 billion by 2025.

New pre-clinical data – In February 2018, Can-Fite announced new preclinical data supporting a novel anti-NASH mechanism of action for Namodenoson. Preclinical studies were conducted in hepato-stellate cells in vitro and in an experimental NASH CCL4 model, showing that in both systems, the molecular mechanism of action of Namodenoson is conferred by decreased expression levels of the signaling protein phosphoinositol-3-phosphate (PI3K) which confers three downstream signal transduction pathways, the Wnt, NF-kB and α-SMA, altogether, controlling liver inflammation, fibrosis and steatosis. The data were presented at the European Association for the Study of the Liver (EASL) annual conference.

"We continue to build positive momentum with our drug candidates. We also secured a significant distribution agreement with Gebro Holding GmBH to distribute Piclidenoson for the treatment of rheumatoid arthritis and psoriasis in three European countries. This quarter we also submitted our annual safety summaries on both Piclidenoson and Namodenoson to regulatory authorities around the world and were pleased to note that both drug candidates continue to demonstrate a favorable safety profile in human clinical trials. We look forward to providing updates on our Phase II study on Namodenoson during the second half of the year," stated Can-Fite CEO Dr. Pnina Fishman.

Financial Results

Change in Functional and Presentation Currency

From the Company’s inception through January 1, 2018, the Company’s functional and presentation currency was the New Israeli Shekel (NIS). Management conducted a review of the functional currency of the Company and decided to change its functional and presentation currency to the U.S. dollar from the NIS effective January 1, 2018. This change was based on an assessment by Company management that the dollar is the primary currency of the economic environment in which the Company operates. Accordingly, the functional and presentation currency of the Company in the financial results presented in this press release is the U.S. dollar.

In determining the appropriate functional currency to be used, the Company followed the guidance in International Accounting Standard (IAS) 21, which states that factors relating to sales, costs and expenses, financing activities and cash flows, as well as other potential factors, should be considered. In this regard, the Company is incurring and expects to continue to incur a majority of its expenses in U.S. dollars as a result of its expanded clinical trials. These changes, as well as the fact that the majority of the Company’s available funds are in U.S. dollars, the Company’s principal source of financing is the U.S. capital market, and all of the Company’s budgeting is conducted solely in U.S. dollars, led to the decision to make the change in functional currency as of January 1, 2018, as indicated above.

For presentation purposes, comparative figures in the financial results have been translated into dollars on the following basis: (i) monetary assets and liabilities of the Company were translated using the current rate method, using the dollar exchange rate as of December 31, 2017, (ii) non-monetary assets and liabilities of the Company and equity were translated using historical exchange rates at the relevant transaction dates, (iii) profit and loss accounts were recorded at the exchange rate at the date of the transaction, and (iv) translation differences resulting from the change in functional currency have been reported as a component of shareholders’ equity.

Revenues for the three months ended March 31, 2018 were U.S. $0.63 million compared to revenues of U.S. $0.07 million during the three months ended March 31, 2017. The increase in revenues for the first quarter of 2018 was mainly due to the recognition of a portion of the U.S. $2.2 million advance payment received in January 2018 under the distribution agreement with Gebro Holding GmbH.

Research and development expenses for the three months ended March 31, 2018 were U.S. $1.31 million compared with U.S. $1.22 million for the same period in 2017. Research and development expenses for the first quarter of 2018 comprised primarily of expenses associated with the Phase II studies for Namodenoson as well as expenses for ongoing studies of Piclidenoson. The increase is primarily due to increased costs associated with the initiation of the Phase III clinical trial of Piclidenoson for the treatment of rheumatoid arthritis. The Company expects that the research and development expenses will increase through 2018 and beyond.

General and administrative expenses were U.S. $0.90 million for the three months ended March 31, 2018 compared to U.S. $0.76 million for the same period in 2017. The increase is primarily due to an increase in investor relations expenses. We expect that the annual general and administrative expenses will remain at the same level as 2017.

Financial expense, net for the three months ended March 31, 2018 aggregated U.S. $0.13 million compared to financial income, net of U.S. $0.17 million for the same period in 2017. The increase in financial expense, net in the first quarter of 2018 was mainly due to an increase in interest expenses related to advance payment recognition and an increase in exchange rate differences on balances of cash and cash equivalents.

Can-Fite’s net loss for the three months ended March 31, 2018 was U.S. $1.72 million compared with a net loss of U.S. $1.74 million for the same period in 2017. The slight difference in net loss for the first quarter of 2018 was primarily attributable to an increase in revenues, which was offset by an increase in general and administrative expenses and in financial expenses, net.

As of March 31, 2018, Can-Fite had cash and cash equivalents of U.S. $8.31 million as compared to U.S. $3.5 million at December 31, 2017. The increase in cash during the three months ended March 31, 2018 is due to U.S. $4.37 million received from the issuance of shares and warrants, net of issuance expenses, and the $2.2 million advance payment received from Gebro.

The Company’s consolidated financial results for the three months ended March 31, 2018 are presented in accordance with International Financial Reporting Standards.